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Recent Articles in Molecular Cancer

Rousseau E, Palm T, Scaravilli F, Ruchoux MM, Figarella-Branger D, Salmon I, Ellison D, Lacroix C, Chapon F, Mikol J, Vikkula M, Godfraind C
Trisomy 19 ependymoma, a newly recognized genetico-histological association, including clear cell ependymoma.
Mol Cancer. 2007;647.
Ependymal tumors constitute a clinicopathologically heterogeneous group of brain tumors. They vary in regard to their age at first symptom, localization, morphology and prognosis. Genetic data also suggests heterogeneity. We define a newly recognized subset of ependymal tumors, the trisomy 19 ependymoma. Histologically, they are compact lesions characterized by a rich branched capillary network amongst which tumoral cells are regularly distributed. When containing clear cells they are called clear cell ependymoma. Most trisomy 19 ependymomas are supratentorial WHO grade III tumors of the young. Genetically, they are associated with trisomy 19, and frequently with a deletion of 13q21.31-31.2, three copies of 11q13.3-13.4, and/or deletions on chromosome 9. These altered chromosomal regions are indicative of genes and pathways involved in trisomy 19 ependymoma tumorigenesis. Recognition of this genetico-histological entity allows better understanding and dissection of ependymal tumors. [Abstract/Link to Full Text]

Sengupta TK, Leclerc GM, Hsieh-Kinser TT, Leclerc GJ, Singh I, Barredo JC
Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy.
Mol Cancer. 2007;646.
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy affecting children. Despite significant progress and success in the treatment of ALL, a significant number of children continue to relapse and for them, outcome remains poor. Therefore, the search for novel therapeutic approaches is warranted. The aim of this study was to investigate the AMP activated protein kinase (AMPK) as a potential target in childhood acute lymphoblastic leukemia (ALL) subtypes characterized by non-random translocation signature profiles. We evaluated the effects of the AMPK activator AICAR on cell growth, cell cycle regulators and apoptosis of various childhood ALL cells. RESULTS: We found that treatment with AICAR inhibited cell proliferation, induced cell cycle arrest in G1-phase, and apoptosis in CCRF-CEM (T-ALL), NALM6 (Bp-ALL), REH (Bp-ALL, TEL/AML1) and SupB15 (Bp-ALL, BCR/ABL) cells. These effects were abolished by treatment with the adenosine kinase inhibitor 5'-iodotubericidin prior to addition of AICAR indicating that AICAR's cytotoxicity is mediated through AMPK activation. Moreover, we determined that growth inhibition exerted by AICAR was associated with activation of p38-MAPK and increased expression of the cell cycle regulators p27 and p53. We also demonstrated that AICAR mediated apoptosis through the mitochondrial pathway as revealed by the release of cytochrome C and cleavage of caspase 9. Additionally, AICAR treatment resulted in phosphorylation of Akt suggesting that activation of the PI3K/Akt pathway may represent a compensatory survival mechanism in response to apoptosis and/or cell cycle arrest. Combined treatment with AICAR and the mTOR inhibitor rapamycin resulted in additive anti-proliferative activity ALL cells. CONCLUSION: AICAR-mediated AMPK activation was found to be a proficient cytotoxic agent in ALL cells and the mechanism of its anti-proliferative and apoptotic effect appear to be mediated via activation of p38-MAPK pathway, increased expression of cell cycle inhibitory proteins p27 and p53, and downstream effects on the mTOR pathway, hence exhibiting therapeutic potential as a molecular target for the treatment of childhood ALL. Therefore, activation of AMPK by AICAR represents a novel approach to targeted therapy, and suggests a role for AICAR in combination therapy with inhibitors of the PI3K/Akt/mTOR pathways for the treatment of childhood in ALL. [Abstract/Link to Full Text]

Wu Q, Lothe RA, Ahlquist T, Silins I, Trop� CG, Micci F, Nesland JM, Suo Z, Lind GE
DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets.
Mol Cancer. 2007;645.
BACKGROUND: The epigenetics of ovarian carcinogenesis remains poorly described. We have in the present study investigated the promoter methylation status of 13 genes in primary ovarian carcinomas (n = 52) and their in vitro models (n = 4; ES-2, OV-90, OVCAR-3, and SKOV-3) by methylation-specific polymerase chain reaction (MSP). Direct bisulphite sequencing analysis was used to confirm the methylation status of individual genes. The MSP results were compared with clinico- pathological features. RESULTS: Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9, RASSF1A, APC, CDH13, HOXB5, SCGB3A1 (HIN-1), CRABP1, and MLH1 was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas ADAMTS1, MGMT, NR3C1, p14ARF, and p16INK4a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; P = 0.023). Finally, there was a significant difference in HOXA9 methylation frequency among the histological types (P = 0.007). CONCLUSION: DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9, HOXB5, SCGB3A1, and CRABP1 are identified as novel hypermethylated target genes in this tumour type. [Abstract/Link to Full Text]

Paschoalin T, Carmona AK, Rodrigues EG, Oliveira V, Monteiro HP, Juliano MA, Juliano L, Travassos LR
Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth.
Mol Cancer. 2007;644.
BACKGROUND: Angiogenesis is a fundamental process that allows tumor growth by providing nutrients and oxygen to the tumor cells. Beyond the oxygen diffusion limit from a capillary blood vessel, tumor cells become apoptotic. Angiogenesis results from a balance of pro- and anti-angiogenic stimuli. Endogenous inhibitors regulate enzyme activities that promote angiogenesis. Tumor cells may express pro-angiogenic factors and hydrolytic enzymes but also kinin-degrading oligopeptidases which have been investigated. RESULTS: Angiogenesis induced by B16F10-Nex2 melanoma cells was studied in a co-culture with HUVEC on Matrigel. A stimulating effect on angiogenesis was observed in the presence of B16F10-Nex2 lysate and plasma membrane. In contrast, the B16F10-Nex2 culture supernatant inhibited angiogenesis in a dose-dependent manner. This effect was abolished by the endo-oligopeptidase inhibitor, JA-2. Thimet oligopeptidase (TOP) and neurolysin activities were then investigated in B16F10-Nex2 melanoma cells aiming at gene sequencing, enzyme distribution and activity, influence on tumor development, substrate specificity, hydrolytic products and susceptibility to inhibitors. Fluorescence resonance energy transfer (FRET) peptides as well as neurotensin and bradykinin were used as substrates. The hydrolytic activities in B16F10-Nex2 culture supernatant were totally inhibited by o-phenanthrolin, JA-2 and partially by Pro-Ile. Leupeptin, PMSF, E-64, Z-Pro-Prolinal and captopril failed to inhibit these hydrolytic activities. Genes encoding M3A enzymes in melanoma cells were cloned and sequenced being highly similar to mouse genes. A decreased proliferation of B16F10-Nex2 cells was observed in vitro with specific inhibitors of these oligopeptidases. Active rTOP but not the inactive protein inhibited melanoma cell development in vivo increasing significantly the survival of mice challenged with the tumor cells. On Matrigel, rTOP inhibited the bradykinin - induced angiogenesis. A possible regulation of the homologous tumor enzyme in the perivascular microenvironment is suggested based on the observed rTOP inhibition by an S-nitrosothiol NO donor. CONCLUSION: Data show that melanoma cells secrete endo-oligopeptidases which have an important role in tumor proliferation in vitro and in vivo. rTOP inhibited growth of subcutaneously injected B16F10-Nex2 cells in mice. TOP from tumor cells and bradykinin in endothelial cells are two antagonist factors that may control angiogenesis essential for melanoma growth. A regulatory role of NO or S-nitrosothiols is suggested. [Abstract/Link to Full Text]

Mathur S, Schmidt C
An open democracy.
Mol Cancer. 2007;643.
Sovereign power is retained and shared by the citizens of a country. Using electoral tools, governing structures are formed to ensure protection of national interests. As with any institution, proper control of the government guarantees its adherence to the tasks delegated to it by its citizens. In turn, citizens have to be provided with, and are encouraged to access and evaluate, information generated by the government. On the other hand, governments generate sensitive information (e.g., intelligence, internal reports, etc) that are required for self-evaluation and defense against threats to the nation. Governments are granted a privilege to collect, store and use such information to perform necessary tasks. How far does governmental privilege go relative to the intrinsic right of citizens to access and evaluate information? [Abstract/Link to Full Text]

Kumar PS, Shiras A, Das G, Jagtap JC, Prasad V, Shastry P
Differential expression and role of p21cip/waf1 and p27kip1 in TNF-alpha-induced inhibition of proliferation in human glioma cells.
Mol Cancer. 2007;642.
BACKGROUND: The role of TNF-alpha in affecting the fate of tumors is controversial, while some studies have reported apoptotic or necrotic effects of TNF-alpha, others provide evidence that endogenous TNF-alpha promotes growth and development of tumors. Understanding the mechanism(s) of TNF-alpha mediated growth arrest will be important in unraveling the contribution of tissue associated macrophages in tumor resistance. The aim of this study was to investigate the role of Cyclin Dependent Kinase Inhibitors (CDKI)--21cip/waf1 and p27kip1 in TNF-alpha mediated responses in context with p53 and activation of NF-kappaB and Akt pathways. The study was done with human glioma cell lines -LN-18 and LN-229 cells, using monolayer cultures and Multicellular Spheroids (MCS) as in vitro models. RESULTS: TNF-alpha induced inhibition of proliferation and enhanced the expression of p21cip/waf1 and p27kip1 in LN-18 cells. p21 was induced on exposure to TNF-alpha, localized exclusively in the nucleus and functioned as an inhibitor of cell cycle but not as an antiapoptotic protein. In contrast, p27 was constitutively expressed, localized predominantly in the cytoplasm and was not involved in arrest of proliferation. Our data using IkappaBalpha mutant LN-18 cells and PI3K/Akt inhibitor-LY294002 revealed that the expression of p21 is regulated by NF-kappaB. Loss of IkappaBalpha function in LN-229 cells (p53 positive) did not influence TNF-alpha induced accumulation of pp53 (Ser-20 p53) suggesting that p53 was not down stream of NF-kappaB. Spheroidogenesis enhanced p27 expression and p21 induced by TNF-alpha was significantly increased in the MCS compared to monolayers. CONCLUSION: This study demarcates the functional roles for CDKIs-p21cip/waf1 and p27kip1 during TNF-alpha stimulated responses in LN-18 glioma cells. Our findings provide evidence that TNF-alpha-induced p21 might be regulated by NF-kappaB or p53 independently. p21 functions as an inhibitor of cell proliferation and does not have a direct role in rendering the cells resistant to TNF-alpha mediated cytotoxicity. [Abstract/Link to Full Text]

Jin ZH, Josserand V, Foillard S, Boturyn D, Dumy P, Favrot MC, Coll JL
In vivo optical imaging of integrin alphaV-beta3 in mice using multivalent or monovalent cRGD targeting vectors.
Mol Cancer. 2007;641.
BACKGROUND: The cRGD peptide is a promising probe for early non-invasive detection of tumors. This study aimed to demonstrate how RAFT-c(-RGDfK-)4, a molecule allowing a tetrameric presentation of cRGD, improved cRGD-targeting potential using in vivo models of alphaVbeta3-positive or negative tumors. RESULTS: We chose the human embryonic kidney cells HEK293(beta3) (high levels of alphaVbeta3) or HEK293(beta1) (alphaVbeta3-negative but expressing alphaV and beta1) engrafted subcutaneously (s.c.) in mice. Non-invasive in vivo optical imaging demonstrated that as compared to its monomeric cRGD analogue, Cy5-RAFT-c(-RGDfK-)4 injected intravenously had higher uptake, prolonged retention and markedly enhanced contrast in HEK293(beta3) than in the HEK293(beta1) tumors. Blocking studies further demonstrated the targeting specificity and competitive binding ability of the tetramer. CONCLUSION: In conclusion, we demonstrated that Cy5-RAFT-c(-RGDfK-)4 was indeed binding to the alphaVbeta3 receptor and with an improved activity as compared to its monomeric analog, confirming the interest of using multivalent ligands. Intravenous injection of Cy5-RAFT-c(-RGDfK-)4 in this novel pair of HEK293(beta3) and HEK293(beta1) tumors, provided tumor/skin ratio above 15. Such an important contrast plus the opportunity to use the HEK293(beta1) negative control cell line are major assets for the community of researchers working on the design and amelioration of RGD-targeted vectors or on RGD-antagonists. [Abstract/Link to Full Text]

Davila M, Jhala D, Ghosh D, Grizzle WE, Chakrabarti R
Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer.
Mol Cancer. 2007;640.
BACKGROUND: LIM kinase 1 (LIMK1), a LIM domain containing serine/threonine kinase, modulates actin dynamics through inactivation of the actin depolymerizing protein cofilin. Recent studies have indicated an important role of LIMK1 in growth and invasion of prostate and breast cancer cells; however, the molecular mechanism whereby LIMK1 induces tumor progression is unknown. In this study, we investigated the effects of ectopic expression of LIMK1 on cellular morphology, cell cycle progression and expression profile of LIMK1 in prostate tumors. RESULTS: Ectopic expression of LIMK1 in benign prostatic hyperplasia cells (BPH), which naturally express low levels of LIMK1, resulted in appearance of abnormal mitotic spindles, multiple centrosomes and smaller chromosomal masses. Furthermore, a transient G1/S phase arrest and delayed G2/M progression was observed in BPH cells expressing LIMK1. When treated with chemotherapeutic agent Taxol, no metaphase arrest was noted in these cells. We have also noted increased nuclear staining of LIMK1 in tumors with higher Gleason Scores and incidence of metastasis. CONCLUSION: Our results show that increased expression of LIMK1 results in chromosomal abnormalities, aberrant cell cycle progression and alteration of normal cellular response to microtubule stabilizing agent Taxol; and that LIMK1 expression may be associated with cancerous phenotype of the prostate. [Abstract/Link to Full Text]

Jariwala U, Prescott J, Jia L, Barski A, Pregizer S, Cogan JP, Arasheben A, Tilley WD, Scher HI, Gerald WL, Buchanan G, Coetzee GA, Frenkel B
Identification of novel androgen receptor target genes in prostate cancer.
Mol Cancer. 2007;639.
BACKGROUND: The androgen receptor (AR) plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa). However, little is known about AR target genes that mediate the receptor's roles in disease progression. RESULTS: Using Chromatin Immunoprecipitation (ChIP) Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant) and LNCaP (androgen-dependent) PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells--D-dopachrome tautomerase (DDT), Protein kinase C delta (PRKCD), Glutathione S- transferase theta 2 (GSTT2), Transient receptor potential cation channel subfamily V member 3 (TRPV3), and Pyrroline-5-carboxylate reductase 1 (PYCR1)--most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT), was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation. CONCLUSION: AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are repressed. In general, response is stronger in C4-2B compared to LNCaP cells. Some of the genes near AR-occupied regions appear to be regulated by the AR in vivo as evidenced by their expression levels in prostate cancer tumors of various stages. Several AR target genes discovered in the present study, for example PRKCD and PYCR1, may open avenues in PCa research and aid the development of new approaches for disease management. [Abstract/Link to Full Text]

Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie PS
Androgen-regulated genes differentially modulated by the androgen receptor coactivator L-dopa decarboxylase in human prostate cancer cells.
Mol Cancer. 2007;638.
BACKGROUND: The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We previously reported the identification of a novel AR coactivator protein, L-dopa decarboxylase (DDC), which can act at the cytoplasmic level to enhance AR activity. We have also shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In the present study, we generated tetracycline-inducible LNCaP-DDC prostate cancer stable cells to identify DDC downstream target genes by oligonucleotide microarray analysis. RESULTS: Comparison of induced DDC overexpressing cells versus non-induced control cell lines revealed a number of changes in the expression of androgen-regulated transcripts encoding proteins with a variety of molecular functions, including signal transduction, binding and catalytic activities. There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line. In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function. In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time RT-PCR. CONCLUSION: Taken together, our results provide evidence for linking DDC action with AR signaling, which may be important for orchestrating molecular changes responsible for prostate cancer progression. [Abstract/Link to Full Text]

Desouki MM, Geradts J, Milon B, Franklin RB, Costello LC
hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands.
Mol Cancer. 2007;637.
BACKGROUND: The normal human prostate glandular epithelium has the unique function of accumulating high levels of zinc. In prostate cancer this capability is lost as an early event in the development of the malignant cells. The mechanism and factors responsible for the ability of the normal epithelial cells to accumulate zinc and the loss of this capability in the malignant cells need to be identified. We previously reported that Zip1 is an important zinc uptake transporter in prostate cells and is down regulated in the malignant cells in situ along with the depletion of zinc levels. In this report we investigated the expression of two other Zip family zinc transporters, Zip2 and Zip3 in malignant versus nonmalignant (normal and BPH) glands. Zip2 and Zip3 relative protein levels were determined by immunohistochemistry analysis of human prostate tissue sections. RESULTS: Normal and BPH glandular epithelium consistently exhibited the strong presence of both Zip 2 and Zip3; whereas both transporters consistently were essentially non-detectable in the malignant glands. This represents the first report of the expression of Zip3 in human prostate tissue; and more importantly, reveals that ZiP2 and Zip3 are down regulated in malignant cells in situ as we also had demonstrated for Zip1. Zip2 and Zip3 transporter proteins were localized predominantly at the apical cell membrane, which is in contrast to the Zip1 localization at the basolateral membrane. Zip2 and Zip3 seemingly are associated with the re-uptake of zinc from prostatic fluid. CONCLUSION: These results coupled with previous reports implicate Zip2 and Zip3 along with Zip1 as important zinc uptake transporters involved in the unique ability of prostate cells to accumulate high cellular zinc levels. Zip1 is important for the extraction of zinc from circulation as the primary source of cellular zinc. Zip 2 and Zip3 appear to be important for retention of the zinc in the cellular compartment. The down regulation of all three transporters in the malignant cells is consistent with the loss of zinc accumulation in these cells. Since zinc imposes tumor suppressor effects, the silencing of the gene expression for these transporters is a required event for the manifestation of the malignant activities of the neoplastic cells. This now provides new insights into the genetic/molecular events associated with the development of prostate cancer; and supports our concept of Zip1, and now Zip2 and Zip3, as tumor suppressor genes and zinc as a tumor suppressor agent. [Abstract/Link to Full Text]

Sasai K, Akagi T, Aoyanagi E, Tabu K, Kaneko S, Tanaka S
O6-methylguanine-DNA methyltransferase is downregulated in transformed astrocyte cells: implications for anti-glioma therapies.
Mol Cancer. 2007;636.
BACKGROUND: A novel alkylating agent, temozolomide, has proven efficacious in the treatment of malignant gliomas. However, expression of O6-methylguanine-DNA methyltransferase (MGMT) renders glioma cells resistant to the treatment, indicating that identification of mechanisms underlying the gene regulation of MGMT is highly required. Although glioma-derived cell lines have been widely employed to understand such mechanisms, those models harbor numerous unidentified genetic lesions specific for individual cell lines, which complicates the study of specific molecules and pathways. RESULTS: We established glioma models by transforming normal human astrocyte cells via retroviral-mediated gene transfer of defined genetic elements and found that MGMT was downregulated in the transformed cells. Interestingly, inhibitors of DNA methylation and histone deacetylation failed to increase MGMT protein levels in the transformed astrocyte cells as well as cultured glioblastoma cell lines, whereas the treatment partially restored mRNA levels. These observations suggest that downregulation of MGMT may depend largely on cellular factors other than promoter-hypermethylation of MGMT genes, which is being used in the clinic to nominate patients for temozolomide treatment. Furthermore, we discovered that Valproic acid, one of histone deacetylase inhibitors, suppressed growth of the transformed astrocyte cells without increasing MGMT protein, suggesting that such epigenetic compounds may be used to some types of gliomas in combination with alkylating agents. CONCLUSION: Normal human astrocyte cells allow us to generate experimental models of human gliomas by direct manipulation with defined genetic elements, in contrast to tumor-derived cell lines which harbor numerous unknown genetic abnormalities. Thus, we propose that the study using the transformed astrocyte cells would be useful for identifying the mechanisms underlying MGMT regulation in tumor and for the development of rational drug combination in glioma therapies. [Abstract/Link to Full Text]

Liu D, Shimonov J, Primanneni S, Lai Y, Ahmed T, Seiter K
t(8;14;18): a 3-way chromosome translocation in two patients with Burkitt's lymphoma/leukemia.
Mol Cancer. 2007;635.
Burkitt's lymphoma (BL) is a heterogeneous group of highly aggressive mature B-cell malignancies. It is characterized by a high rate of turnover of malignant cells and deregulation of the c-myc gene. It is typically associated with a t(8;14) translocation. Dual translocation of t(8;14) (c-myc) and t(14;18) (bcl-2) was reported to be associated with extremely poor prognosis. This study reports a novel t(8;14;18) triple translocation in two patients with Burkitt's lymphoma. [Abstract/Link to Full Text]

Hasanuzzaman M, Kutner R, Agha-Mohammadi S, Reiser J, Sehgal I
A doxycycline-inducible urokinase receptor (uPAR) upregulates uPAR activities including resistance to anoikis in human prostate cancer cell lines.
Mol Cancer. 2007;634.
BACKGROUND: The urokinase receptor (uPAR) mediates a diverse array of cellular processes including several events involved in prostate cancer metastasis. Many of these activities are initiated or enhanced by uPAR binding to its proteolytic ligand, urokinase (uPA). Our objective in this study was to generate and test an inducible lentiviral system capable of expressing uPAR and DsRed fluorescent protein in human prostate cancer cell lines. RESULTS: A DsRed-uPAR fusion construct was inserted into a lentiviral vector. Transduction of human prostate cancer cell lines with this virus and with a virus containing a reverse-tetracycline transactivator (rt-TA) resulted in a stable transgene which induced both uPAR and DsRed proteins in a dose-responsive fashion upon stimulation with doxycycline. Immunoblots and immunofluorescence studies indicated no detectable uPAR expression in non-induced prostate cancer cell lines. Cells with induced-uPAR demonstrated increased cellular adhesion to the matrix substrate vitronectin and increased net cell proliferation compared to uninduced cells. Finally, induced uPAR-expressing prostate cancer cells were resistant to anoikis over an extended time period when grown in suspension. CONCLUSION: This doxycycline-inducible lentivirus system produces titerable levels of biologically active uPAR in vitro. This tool can be used to dissect cellular events following induction of uPAR in prostate cancer cells. [Abstract/Link to Full Text]

Wergeland L, Sj�holt G, Haaland I, Hovland R, Bruserud �, Gjertsen BT
Pre-apoptotic response to therapeutic DNA damage involves protein modulation of Mcl-1, Hdm2 and Flt3 in acute myeloid leukemia cells.
Mol Cancer. 2007;633.
BACKGROUND: Acute myeloid leukemia (AML) cells are characterized by non-mutated TP53, high levels of Hdm2, and frequent mutation of the Flt3 receptor tyrosine kinase. The juxtamembrane mutation of FLT3 is the strongest independent marker for disease relapse and is associated with elevated Bcl-2 protein and p53 hyper-phosphorylation in AML. DNA damage forms the basic mechanism of cancer cell eradication in current therapy of AML. Hdm2 and pro-apoptotic Bcl-2 members are among the most intensely induced genes immediately after chemotherapy and Hdm2 is proposed a role in receptor tyrosine kinase regulation. Thus we examined the DNA damage related modulation of these proteins in relation to FLT3 mutational status and induction of apoptosis. RESULTS: Within one hour after exposure to ionizing radiation (IR), the AML cells (NB4, MV4-11, HL-60, primary AML cells) showed an increase in Flt3 protein independent of mRNA levels, while the Hdm2 protein decreased. The FLT3 mutant MV4-11 cells were resistant to IR accompanied by presence of both Mcl-1 and Hdm2 protein three hours after IR. In contrast, the FLT3 wild type NB4 cells responded to IR with apoptosis and pre-apoptotic Mcl-1 down regulation. Daunorubicin (DNR) induced continuing down regulation of Hdm2 and Mcl-1 in both cell lines followed by apoptosis. CONCLUSION: Both IR and DNR treatment resulted in concerted protein modulations of Mcl-1, Hdm2 and Flt3. Cell death induction was associated with persistent attenuation of Mcl-1 and Hdm2. These observations suggest that defining the pathway(s) modulating Flt3, Hdm2 and Mcl-1 may propose new strategies to optimize therapy for the relapse prone FLT3 mutated AML patients. [Abstract/Link to Full Text]

Kudo T, Nakagawa H, Takahashi M, Hamaguchi J, Kamiyama N, Yokoo H, Nakanishi K, Nakagawa T, Kamiyama T, Deguchi K, Nishimura S, Todo S
N-glycan alterations are associated with drug resistance in human hepatocellular carcinoma.
Mol Cancer. 2007;632.
BACKGROUND: Correlations of disease phenotypes with glycosylation changes have been analysed intensively in the tumor biology field. Glycoforms potentially associated with carcinogenesis, tumor progression and cancer metastasis have been identified. In cancer therapy, drug resistance is a severe problem, reducing therapeutic effect of drugs and adding to patient suffering. Although multiple mechanisms likely underlie resistance of cancer cells to anticancer drugs, including overexpression of transporters, the relationship of glycans to drug resistance is not well understood. RESULTS: We established epirubicin (EPI)--and mitoxantrone (MIT)--resistant cell lines (HLE-EPI and HLE-MIT) from the human hepatocellular carcinoma cell line (HLE). HLE-EPI and HLE-MIT overexpressed transporters MDR1/ABCB1 and BCRP/ABCG2, respectively. Here we compared the glycomics of HLE-EPI and HLE-MIT cells with the parental HLE line. Core fucosylated triantennary oligosaccharides were increased in the two resistant lines. We investigated mRNA levels of glycosyltransferases synthesizing this oligosaccharide, namely, N-acetylglucosaminyltransferase (GnT)-IVa, GnT-IVb and alpha1,6-fucosyltransferase (alpha1,6-FucT), and found that alpha1,6-FucT was particularly overexpressed in HLE-MIT cells. In HLE-EPI cells, GnT-IVa expression was decreased, while GnT-IVb was increased. Both GnT-IVs were downregulated in HLE-MIT cells. HLE-MIT cells also showed decreases in fucosylated tetraantennary oligosaccharide, the product of GnT-V. GnT-V expression was decreased in both lines, but particularly so in HLE-MIT cells. Thus both N-glycan and glycosyltransferase expression was altered as cells acquired tolerance, suggesting novel mechanisms of drug resistance. CONCLUSION: N-glycan and glycosyltransferase expression in HLE-EPI and HLE-MIT were analysed and presented that glycans altered according with acquired tolerance. These results suggested novel mechanisms of drug resistance. [Abstract/Link to Full Text]

Huang TS, Myklebust LM, Kjarland E, Gjertsen BT, Pendino F, Bruserud �, D�skeland SO, Lillehaug JR
LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro.
Mol Cancer. 2007;631.
BACKGROUND: Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). The present study was undertaken to elucidate the molecular mechanisms of chemoresistance by comparing differential gene expression in blasts from patients with resistant relapsing AML and chemosensitive AML. RESULTS: About 20 genes were identified as preferentially expressed in blasts pooled from patients with resistant disease, as compared to chemosensitive AML blasts, based on differential gene expression screening. Half of these genes encoded proteins related to protein translation, of these a novel protein related to the ribosomal stalk protein P0. Other upregulated mRNAs coded for cytochrome C oxidase III, the transcription factors ERF-2/TIS11d, and the p75 and p52 splice variants of Lens Epithelial Derived Growth Factor (LEDGF). Analysis of blasts from single patients disclosed that LEDGF/p75 was the most consistently upregulated mRNA in resistant AML. Transfection experiments demonstrated that LEDGF/p75 and p52b antagonized daunorubicin-induced and cAMP-induced apoptosis in an AML cell line. Also HEK-293 cells were protected against daunorubicin by LEDGF/p75 and p52b, whereas LEDGF/p52 splice variants lacking exon 6 had proapoptotic effects. Interestingly, full length LEDGF/p75 protected against truncated pro-apoptotic LEDGF/p75. CONCLUSION: Our results provide evidence for an association between the overexpression of genes encoding survival proteins like LEDGF/p75 and chemo-resistance in acute myelogenous leukemia. LEDGF/p75 has previously not been shown to protect against chemotherapy, and is a potential drug target in AML. [Abstract/Link to Full Text]

Trembath DG, Lal A, Kroll DJ, Oberlies NH, Riggins GJ
A novel small molecule that selectively inhibits glioblastoma cells expressing EGFRvIII.
Mol Cancer. 2007;630.
BACKGROUND: Mutations of the epidermal growth factor receptor (EGFR) are a possible molecular target for cancer therapy. EGFR is frequently amplified in glioblastomas and 30 to 40% of glioblastomas also express the deletion mutation EGFRvIII. This frequent oncogenic mutation provides an opportunity for identifying new anti-glioblastoma therapies. In this study, we sought small molecule inhibitors specific for cancer cells expressing EGFRvIII, using isogenic parental cells without EGFRvIII as a control. RESULTS: A screen of the NCI small molecule diversity set identified one compound, NSC-154829, which consistently inhibited growth of different human glioblastoma cells expressing EGFRvIII, but permitted normal growth of matched control cells. NSC-154829 had no previously established medicinal use, but has a purine-like structural component. Further experiments showed this compound increased apoptosis in cells with EGFRvIII, and moderately affected the expression of p21, independent of any changes in p53 levels or in Akt phosphorylation. CONCLUSION: These initial results suggest that NSC-154829 or a closely related structure might be further investigated for its potential as an anti-glioblastoma drug, although its precise molecular mechanism is still undefined. [Abstract/Link to Full Text]

Arias JI, Aller MA, Arias J
Cancer cell: using inflammation to invade the host.
Mol Cancer. 2007;629.
BACKGROUND: Inflammation is increasingly recognized as an important component of tumorigenesis, although the mechanisms involved are not fully characterized. The invasive capacity of cancers is reflected in the classic metastatic cascade: tumor (T), node (N) and metastasis (M). However, this staging system for cancer would also have a tumoral biological significance. PRESENTATION OF THE HYPOTHESIS: To integrate the mechanisms that control the inflammatory response in the actual staging system of cancer. It is considered that in both processes of inflammation and cancer, three successive phenotypes are presented that represent the expression of trophic functional systems of increasing metabolic complexity for using oxygen. TESTING THE HYPOTHESIS: While a malignant tumor develops it express phenotypes that also share the inflammatory response such as: an ischemic phenotype (anoxic-hypoxic), a leukocytic phenotype with anaerobic glycolysis and migration, and an angiogenic phenotype with hyperactivity of glycolytic enzymes, tumor proliferation and metastasis, and cachexia of the host. The increasing metabolic complexity of the tumor cell to use oxygen allows for it to be released, migrate and proliferate, thus creating structures of growing complexity. IMPLICATION OF THE HYPOTHESIS: One aim of cancer gene therapy could be the induction of oxidative phosphorylation, the last metabolic step required by inflammation in order to differentiate the tissue that it produces. [Abstract/Link to Full Text]

Stuber G, Mattsson K, Flaberg E, Kati E, Markasz L, Sheldon JA, Klein G, Schulz TF, Szekely L
HHV-8 encoded LANA-1 alters the higher organization of the cell nucleus.
Mol Cancer. 2007;628.
The latency-associated nuclear antigen (LANA-1) of Human Herpes Virus 8 (HHV-8), alternatively called Kaposi Sarcoma Herpes Virus (KSHV) is constitutively expressed in all HHV-8 infected cells. LANA-1 accumulates in well-defined foci that co-localize with the viral episomes. We have previously shown that these foci are tightly associated with the borders of heterochromatin 1. We have also shown that exogenously expressed LANA-1 causes an extensive re-organization of Hoechst 33248 DNA staining patterns of the nuclei in non-HHV-8 infected cells 2. Here we show that this effect includes the release of the bulk of DNA from heterochromatic areas, in both human and mouse cells, without affecting the overall levels of heterochromatin associated histone H3 lysine 9 tri-methylation (3MK9H3). The release of DNA from the heterochromatic chromocenters in LANA-1 transfected mouse cells co-incides with the dispersion of the chromocenter associated methylcytosin binding protein 2 (MECP2). The localization of 3MK9H3 to the remnants of the chromocenters remains unaltered. Moreover, exogeneously expressed LANA-1 leads to the relocation of the chromocenters to the nuclear periphery, indicating extensive changes in the positioning of the chromosomal domains in the LANA-1 harboring interphase nucleus. Using a series of deletion mutants we have shown that the chromatin rearranging effects of LANA-1 require the presence of a short (57 amino acid) region that is located immediately upstream of the internal acidic repeats. This sequence lies within the previously mapped binding site to histone methyltransferase SUV39H1. We suggest that the highly concentrated LANA-1, anchored to the host genome in the nuclear foci of latently infected cells and replicated through each cell generation, may function as "epigenetic modifier". The induction of histone modification in adjacent host genes may lead to altered gene expression, thereby contributing to the viral oncogenesis. [Abstract/Link to Full Text]

Boominathan L
Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors.
Mol Cancer. 2007;627.
The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway negate its role as a primary tumor suppressor gene. However, accumulating evidence suggest that p73 gene and its target genes are hypermethylated in the cancer of lymphoid origin. Here I discuss some facts and thoughts that support the idea that p73 could still be a tumor suppressor gene. The tumor suppressor network in which p73 appears to be a participant involves E2F1, JunB, INK4a/p16, ARF/p19, p57kip2 and BRCA1. Knock out of each gene in E2F-1-p73-JunB-p16INK4a network of tumor suppressor proteins result in lymphoma/leukemia formation. Further, I tried to explain why lymphomas are not seen in p73 null mice and why p73 gene is not prone to frequent mutation. [Abstract/Link to Full Text]

Vaish M
Mismatch repair deficiencies transforming stem cells into cancer stem cells and therapeutic implications.
Mol Cancer. 2007;626.
For the exceptional self-renewal capacity, regulated cell proliferation and differential potential to a wide variety of cell types, the stem cells must maintain the intact genome. The cells under continuous exogenous and endogenous genotoxic stress accumulate DNA errors, drive proliferative expansion and transform into cancer stem cells with a heterogeneous population of tumor cells. These cells are a common phenomenon for the hematological malignancies and solid tumors. In response to DNA damage, the complex cellular mechanisms including cell cycle arrest, transcription induction and DNA repair are activated. The cells when exposed to cytotoxic agents, the apoptosis lead to cell death. However, the absence of repair machinery makes the cells resistant to tumor sensitizing agents and result in malignant transformation. Mismatch repair gene defects are recently identified in hematopoietic malignancies, leukemia and lymphoma cell lines. This review emphasizes the importance of MMR systems in maintaining the stem cell functioning and its therapeutic implications in the eradication of cancer stem cells and differentiated tumor cells as well. The understanding of the biological functions of mismatch repair in the stem cells and its malignant counterparts could help in developing an effective novel therapies leaving residual non-tumorigenic population of cells resulting in potential cancer cures. [Abstract/Link to Full Text]

Cho WC
Contribution of oncoproteomics to cancer biomarker discovery.
Mol Cancer. 2007;625.
Oncoproteomics is the study of proteins and their interactions in a cancer cell by proteomic technologies. Proteomic research first came to the fore with the introduction of two-dimensional gel electrophoresis. At the turn of the century, proteomics has been increasingly applied to cancer research with the wide-spread introduction of mass spectrometry and proteinchip. There is an intense interest in applying proteomics to foster an improved understanding of cancer pathogenesis, develop new tumor biomarkers for diagnosis, and early detection using proteomic portrait of samples. Oncoproteomics has the potential to revolutionize clinical practice, including cancer diagnosis and screening based on proteomic platforms as a complement to histopathology, individualized selection of therapeutic combinations that target the entire cancer-specific protein network, real-time assessment of therapeutic efficacy and toxicity, and rational modulation of therapy based on changes in the cancer protein network associated with prognosis and drug resistance. Besides, oncoproteomics is also applied to the discovery of new therapeutic targets and to the study of drug effects. In pace with the successful completion of the Human Genome Project, the wave of proteomics has raised the curtain on the postgenome era. The study of oncoproteomics provides mankind with a better understanding of neoplasia. In this article, the discovery of cancer biomarkers in recent years is reviewed. The challenges ahead and perspectives of oncoproteomics for biomarkers development are also addressed. With a wealth of information that can be applied to a broad spectrum of biomarker research projects, this review serves as a reference for biomarker researchers, scientists working in proteomics and bioinformatics, oncologists, pharmaceutical scientists, biochemists, biologists, and chemists. [Abstract/Link to Full Text]

Alao JP
The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention.
Mol Cancer. 2007;624.
Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed. [Abstract/Link to Full Text]

Lin D, Ippolito GC, Zong RT, Bryant J, Koslovsky J, Tucker P
Bright/ARID3A contributes to chromatin accessibility of the immunoglobulin heavy chain enhancer.
Mol Cancer. 2007;623.
Bright/ARID3A is a nuclear matrix-associated transcription factor that stimulates immunoglobulin heavy chain (IgH) expression and Cyclin E1/E2F-dependent cell cycle progression. Bright positively activates IgH transcriptional initiation by binding to ATC-rich P sites within nuclear matrix attachment regions (MARs) flanking the IgH intronic enhancer (Emu). Over-expression of Bright in cultured B cells was shown to correlate with DNase hypersensitivity of Emu. We report here further efforts to analyze Bright-mediated Emu enhancer activation within the physiological constraints of chromatin. A system was established in which VH promoter-driven in vitro transcription on chromatin- reconstituted templates was responsive to Emu. Bright assisted in blocking the general repression caused by nucleosome assembly but was incapable of stimulating transcription from prebound nucleosome arrays. In vitro transcriptional derepression by Bright was enhanced on templates in which Emu is flanked by MARs and was inhibited by competition with high affinity Bright binding (P2) sites. DNase hypersensitivity of chromatin-reconstituted Emu was increased when prepackaged with B cell nuclear extract supplemented with Bright. These results identify Bright as a contributor to accessibility of the IgH enhancer. [Abstract/Link to Full Text]

Hu J, Yuan X, Ko MK, Yin D, Sacapano MR, Wang X, Konda BM, Espinoza A, Prosolovich K, Ong JM, Irvin D, Black KL
Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model.
Mol Cancer. 2007;622.
BACKGROUND: The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. RESULTS: In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. CONCLUSION: These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors. [Abstract/Link to Full Text]

Cahill S, Smyth P, Denning K, Flavin R, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O
Effect of BRAFV600E mutation on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.
Mol Cancer. 2007;621.
BACKGROUND: microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nucleotides in length that have been found to control cell growth, differentiation and apoptosis. They negatively regulate target genes and have recently been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. Recently, a point mutation in the BRAF gene leading to a V600E substitution has been identified as the most common genetic change in papillary thyroid carcinoma (PTC) occurring in 29-69% of cases. This mutation leads to aberrant MAPK activation that is implicated in tumourigenesis. AIM: The aim of this study was to identify the effect that BRAF oncogene has on post-transcriptional regulation in PTC by using microRNA analysis. RESULTS: A unique miRNA expression signature differentiated between PTC cell lines with BRAF mutations and a normal thyroid cell line. 15 miRNAs were found to be upregulated and 23 miRNAs were downregulated. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis. miRNA profiling will assist in the elucidation of disease pathogenesis and identification biomarkers and targets. [Abstract/Link to Full Text]

Kempaiah P, Chand HS, Kisiel W
Identification of a human TFPI-2 splice variant that is upregulated in human tumor tissues.
Mol Cancer. 2007;620.
BACKGROUND: Previous studies have shown that the expression of tissue factor pathway inhibitor-2 (TFPI-2), a matrix-associated Kunitz-type serine proteinase inhibitor, is markedly down-regulated in several tumor cells through hypermethylation of the TFPI-2 gene promoter. In the present study, RT-PCR analysis of total RNA from both human normal and tumor cells revealed a novel 289 nucleotide splice variant of the TFPI-2 transcript designated as aberrantly-spliced TFPI-2 (asTFPI-2). RESULTS: Nucleotide sequence analyses indicated that asTFPI-2 consists of complete exons II and V, fused with several nucleotides derived from exons III and IV, as well as six nucleotides derived from intron C. 5'- and 3'-RACE analyses of total RNA amplified exclusively the wild-type TFPI-2 transcript, indicating that asTFPI-2 lacks either a 5'-untranslated region (UTR) or a 3'-poly (A)+ tail. Quantitative real-time RT-PCR analyses revealed that several human tumor cells contain 4 to 50-fold more copies of asTFPI-2 in comparison to normal cells. In spite of the absence of a 5'-UTR or poly (A)+ tail, the asTFPI-2 variant exhibited a half-life of ~16 h in tumor cells. CONCLUSION: Our studies reveal the existence of a novel, aberrantly-spliced TFPI-2 transcript predominantly expressed in tumor cells and provides suggestive evidence for an additional mechanism for tumor cells to down-regulate TFPI-2 protein expression enhancing their ability to degrade the extracellular matrix. [Abstract/Link to Full Text]

Gipp J, Gu G, Crylen C, Kasper S, Bushman W
Hedgehog pathway activity in the LADY prostate tumor model.
Mol Cancer. 2007;619.
BACKGROUND: Robust Hedgehog (Hh) signaling has been implicated as a common feature of human prostate cancer and an important stimulus of tumor growth. The role of Hh signaling has been studied in several xenograft tumor models, however, the role of Hh in tumor development in a transgenic prostate cancer model has never been examined. RESULTS: We analyzed expression of Hh pathway components and conserved Hh target genes along with progenitor cell markers and selected markers of epithelial differentiation during tumor development in the LADY transgenic mouse model. Tumor development was associated with a selective increase in Ihh expression. In contrast Shh expression was decreased. Expression of the Hh target Patched (Ptc) was significantly decreased while Gli1 expression was not significantly altered. A survey of other relevant genes revealed significant increases in expression of Notch-1 and Nestin together with decreased expression of HNF3a/FoxA1, NPDC-1 and probasin. CONCLUSION: Our study shows no evidence for a generalized increase in Hh signaling during tumor development in the LADY mouse. It does reveal a selective increase in Ihh expression that is associated with increased expression of progenitor cell markers and decreased expression of terminal differentiation markers. These data suggest that Ihh expression may be a feature of a progenitor cell population that is involved in tumor development. [Abstract/Link to Full Text]

Desai B, Rogers MJ, Chellaiah MA
Mechanisms of osteopontin and CD44 as metastatic principles in prostate cancer cells.
Mol Cancer. 2007;618.
BACKGROUND: The expression level of osteopontin correlates with the metastatic potential of several tumors. Osteopontin is a well-characterized ligand for the alphavbeta3 integrin. The present study was undertaken to elucidate the possible role of osteopontin/alphavbeta3 signaling in prostate cancer cell migration. RESULTS: We generated stable prostate cancer cell (PC3) lines that over-express osteopontin (PC3/OPN), mutant OPN in the integrin binding-site (PC3/RGDDeltaRGA), and null for OPN (PC3/SiRNA). The following observations were made in PC3/OPN cells as compared with PC3 cells: 1) an increase in multinucleated giant cells and RANKL expression; 2) an increase in CD44 surface expression, interaction of CD44/MMP-9 on the cell surface, MMP-9 activity in the conditioned medium, and cell migration; 3) western blot analysis of concentrated conditioned medium exhibited equal levels of MMP-9 protein in all PC3 cells. However, zymography analysis demonstrated that the levels of MMP-9 activity in the conditioned media reflect the CD44 surface expression pattern of the PC3 cell lines; 4) although MMP-9 and MMP-2 are secreted by PC3 cells, only the secretion of MMP-9 is regulated by OPN expression. A strong down regulation of the above-mentioned processes was observed in PC3/OPN (RGA) and PC3/SiRNA cells. PC3/OPN cells treated with bisphosphonate (BP) reproduce the down-regulation observed in PC3/OPN (RGA) and PC3/SiRNA cells. CONCLUSION: Rho signaling plays a crucial role in CD44 surface expression. BPs inhibits the mevalonate pathway, which in turn, prevents the prenylation of a number of small GTPases. Attenuation of Rho GTPase activation by BPs may have contributed to the down regulation of cell surface CD44/MMP-9 interaction, MMP-9 activation/secretion, and cell migration. Taken together, these observations suggest that CD44 surface expression is an important event in the activation of MMP-9 and migration of prostate cancer cells. The various steps involved in the above mentioned signaling pathway and/or the molecules regulating the activation of MMP-9 are potential therapeutic target. [Abstract/Link to Full Text]

Recent Articles in Cancer Cell International

Candia BJ, Hines WC, Heaphy CM, Griffith JK, Orlando RA
Protease nexin-1 expression is altered in human breast cancer.
Cancer Cell Int. 2006;616.
BACKGROUND: Urokinase-type Plasminogen Activator (uPA), a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility. In more advanced breast cancers, uPA activity is significantly up regulated and serves as a prognostic indicator of poor patient outcome. Classically, regulation of uPA activity, especially in breast cancers, is thought to be mediated by Type 1 Plasminogen Activator Inhibitor (PAI-1). However, we have recently found that a lesser known natural inhibitor of uPA, Protease Nexin 1 (PN-1), is expressed in normal human mammary tissue. Based on this observation, we investigated if PN-1 is also expressed in human breast cancers where it may contribute to the regulation of uPA and participate in the development of a metastatic phenotype. RESULTS: Using quantitative real-time PCR analysis, we measured PN-1 mRNA expression in tissues obtained from 26 human breast tumor biopsies and compared these values with those obtained from 10 normal breast tissue samples. Since both PAI-1 and uPA expression levels are known to be elevated in metastatic breast cancer, we also measured their levels in our 26 tumor samples for direct comparison with PN-1 expression. We found that PN-1 expression was elevated over that found in normal mammary tissue; an increase of 1.5- to 3.5-fold in 21 of 26 human breast tumors examined. As anticipated, both PAI-1 and uPA mRNA levels were significantly higher in the majority of breast tumors; 19 of 26 tumors for PAI-1 and 22 of 26 tumors for uPA. A quantile box plot of these data demonstrates that the elevated PN-1 expression in breast tumor tissues directly correlates with the increased expression levels found for PAI-1 and uPA. CONCLUSION: The fact that PN-1 expression is elevated in human breast cancer, and that its increased expression is directly correlated with increases measured for PAI-1 and uPA, suggests that PN-1 may contribute to the regulation of uPA-mediate tumor cell motility and metastatic spread. [Abstract/Link to Full Text]

Rao K, Alper O, Opheim KE, Bonnet G, Wolfe K, Bryant E, O'Hara Larivee S, Porter P, McDougall JK
Cytogenetic characterization and H-ras associated transformation of immortalized human mammary epithelial cells.
Cancer Cell Int. 2006;615.
INTRODUCTION: Immortalization is a key step in malignant transformation, but immortalization alone is insufficient for transformation. Human mammary epithelial cell (HMEC) transformation is a complex process that requires additional genetic changes beyond immortalization and can be accomplished in vitro by accumulation of genetic changes and expression of H-ras. METHODS: HMEC were immortalized by serial passaging and transduction with the catalytic subunit of the human telomerase gene (hTERT). The immortalized cells were passaged in vitro and studied by a combination of G-banding and Spectral Karyotyping (SKY). H-ras transduced, hTERT immortalized cells were cloned in soft agar and injected into nude mice. Extensive analysis was performed on the tumors that developed in nude mice, including immunohistochemistry and western blotting. RESULTS: Immortal HMEC alone were not tumorigenic in gamma-irradiated nude mice and could not grow in soft agar. Late passage hTERT immortalized HMEC from a donor transduced with a retroviral vector containing the mutant, autoactive, human H-ras61L gene acquired anchorage independent growth properties and the capacity for tumorigenic growth in vivo. The tumors that developed in the nude mice were poorly differentiated epithelial carcinomas that continued to overexpress ras. These cells were resistant to doxorubicin mediated G1/S phase arrest but were sensitive to treatment with a farnesyltransferase inhibitor. CONCLUSION: Some of the cytogenetic changes are similar to what is observed in premalignant and malignant breast lesions. Despite these changes, late passage immortal HMEC are not tumorigenic and could only be transformed with overexpression of a mutant H-ras oncogene. [Abstract/Link to Full Text]

Kingsley K, Johnson D, O'Malley S
Transfection of oral squamous cell carcinoma with human papillomavirus-16 induces proliferative and morphological changes in vitro.
Cancer Cell Int. 2006;614.
BACKGROUND: Human papillomavirus has been implicated in virtually all cervical cancers and is believed to be the primary etiological factor that transforms cervical epithelia. The presence of HPV in oral cancers suggests that HPV may play a similar role in transforming the oral epithelia. The prevalence of HPV in oral cancers is highly variable, however, presenting problematic issues regarding the etiology of oral cancers, which must be investigated more thoroughly. Past analyses of HPV in cancers of the oral cavity have largely been confined to retrospective studies of cancer patients. The purpose of this study was to examine the potential for HPV16 infection to alter the proliferative phenotype of oral squamous cell carcinoma in vitro. RESULTS: This study found that the oral squamous cell carcinoma cell line, CAL27, transfected with HPV16, exhibited significantly increased proliferation, compared with non-transfected CAL27. The increased proliferation was observed under low density conditions, even in the absence of serum. Moreover, these effects were specific to proliferation, adhesion, and morphology, while cell viability was not affected. CONCLUSION: This study represents one of the first investigations of the effects of HPV16 infection on the proliferation, adhesion, and morphology of an oral squamous cell carcinoma cell line in vitro. The finding that HPV16 has the ability to measurably alter adhesion and proliferative potential is significant, indicating that HPV may have multiple influences on precancerous and cancerous lesions and should be explored as a risk factor and mediator of cancer phenotypes. These measurements and observations will be of benefit to researchers interested in elucidating the mechanisms of oral cancer transformation and the factors governing carcinogenesis and progression. [Abstract/Link to Full Text]

Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A
Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells.
Cancer Cell Int. 2006;613.
BACKGROUND: Long interspersed nuclear elements (LINEs), Alu and endogenous retroviruses (ERVs) make up some 45% of human DNA. LINE-1 also called L1, is the most common family of non-LTR retrotransposons in the human genome and comprises about 17% of the genome. L1 elements require the integration into chromosomal target sites using L1-encoded endonuclease which creates staggering DNA breaks allowing the newly transposed L1 copies to integrate into the genome. L1 expression and retrotransposition in cancer cells might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome instability. There is however little evidence on the mechanism of L1-induced genetic instability and its impact on cancer cell growth and proliferation. RESULTS: We report that L1 has genome-destabilizing effects indicated by an accumulation of gamma-H2AX foci, an early response to DNA strand breaks, in association with an abnormal cell cycle progression through a G2/M accumulation and an induction of apoptosis in breast cancer cells. In addition, we found that adjuvant L1 activation may lead to supra-additive killing when combined with radiation by enhancing the radiation lethality through induction of apoptosis that we have detected through Bax activation. CONCLUSION: L1 retrotransposition is sensed as a DNA damaging event through the creation DNA breaks involving L1-encoded endonuclease. The apparent synergistic interaction between L1 activation and radiation can further be utilized for targeted induction of cancer cell death. Thus, the role of retrotransoposons in general, and of L1 in particular, in DNA damage and repair assumes larger significance both for the understanding of mutagenicity and, potentially, for the control of cell proliferation and apoptosis. [Abstract/Link to Full Text]

Driver GA, Veale RB
Modulation of integrin-linked kinase (ILK) expression in human oesophageal squamous cell carcinoma cell lines by the EGF and TGFbeta1 growth factors.
Cancer Cell Int. 2006;612.
BACKGROUND: Integrin-linked kinase (ILK) is a ubiquitously expressed protein kinase that has emerged as one of the points of convergence between integrin- and growth factor-signalling pathways. RESULTS: In this study we identify the ILK isoform expressed in five human oesophageal squamous cell carcinoma cell lines of South African origin as ILK1, and demonstrate its cellular distribution. ILK expression, although similar in the majority of the cell lines, did show variation. Furthermore, the ILK expressed was shown to be catalytically functional. The effect of growth factors on ILK expression was examined. An increase in ILK expression, following EGF and TGFbeta1 exposure, was a trend across all the five oesophageal carcinoma cell lines tested. CONCLUSION: These results suggest that growth factor modulation of ILK expression relies on the internalisation/recycling of growth factor receptors and stimulation of the PI3K pathway, which may have implications with regards to cell adhesion and tumourigenesis. [Abstract/Link to Full Text]

Ianzini F, Bertoldo A, Kosmacek EA, Phillips SL, Mackey MA
Lack of p53 function promotes radiation-induced mitotic catastrophe in mouse embryonic fibroblast cells.
Cancer Cell Int. 2006;611.
BACKGROUND: We have demonstrated that in some human cancer cells both chronic mild heat and ionizing radiation exposures induce a transient block in S and G2 phases of the cell cycle. During this delay, cyclin B1 protein accumulates to supranormal levels, cyclin B1-dependent kinase is activated, and abrogation of the G2/M checkpoint control occurs resulting in mitotic catastrophe (MC). RESULTS: Using syngenic mouse embryonic fibroblasts (MEF) with wild-type or mutant p53, we now show that, while both cell lines exhibit delays in S/G2 phase post-irradiation, the mutant p53 cells show elevated levels of cyclin B1 followed by MC, while the wild-type p53 cells present both a lower accumulation of cyclin B1 and a lower frequency of MC. CONCLUSION: These results are in line with studies reporting the role of p53 as a post-transcriptional regulator of cyclin B1 protein and confirm that dysregulation of cyclin B1 promote radiation-induced MC. These findings might be exploited to design strategies to augment the yield of MC in tumor cells that are resistant to radiation-induced apoptosis. [Abstract/Link to Full Text]

Huang L, Kirschke CP, Zhang Y
Decreased intracellular zinc in human tumorigenic prostate epithelial cells: a possible role in prostate cancer progression.
Cancer Cell Int. 2006;610.
BACKGROUND: Zinc plays important roles in maintaining normal function of the prostate and in development of prostate malignancy. It has been demonstrated that prostate malignant epithelial cells contain much less cellular zinc than the surrounding normal epithelial cells. However, the pathway(s) which leads to lower zinc accumulation in malignant prostate epithelial cells is poorly understood. In this study, the zinc homeostatic features of two human prostate epithelial cell lines (non-tumorigenic, RWPE1, and tumorigenic, RWPE2) were investigated. Effects of over-expression of ZIP1 in RWPE2 on cell proliferation and apoptosis were also studied. RESULTS: RWPE2 accumulated less intracellular zinc than RWPE1 due to the decreased zinc uptake activity. The mRNA expression of ZIP1 and ZIP3 in RWPE1 and RWPE2 was comparable. However, the protein expression of ZIP1 in RWPE2 was lower than that in RWPE1. ZIP3 was detected in a lysosomal compartment of RWPE2 while no ZIP3 was detected in the same compartment of RWPE1. Over-expression of ZIP1 in RWPE2 resulted in an elevation of intracellular zinc concentration and suppression of cell growth of RWPE2 due to the increased apoptosis. CONCLUSION: These findings suggest that tumorigenic prostate epithelial cells accumulated less intracellular zinc than non-tumorigenic prostate epithelial cells. The reduction in capacity for accumulation of intracellular zinc in tumorigenic prostate epithelial cells may be caused by the decrease in the ZIP1 protein expression and the intracellular redistribution of ZIP3 in RWPE2. RWPE1 and RWPE2 are excellent cellular models to study the association of intracellular zinc levels with prostate cancer progression. [Abstract/Link to Full Text]

Depasquale I, Wheatley DN
Action of Lovastatin (Mevinolin) on an in vitro model of angiogenesis and its co-culture with malignant melanoma cell lines.
Cancer Cell Int. 2006;69.
BACKGROUND: Lovastatin and other statins may reduce the development of melanomas. The effects on melanoma cells and their ability to enhance angiogenesis in a co-culture system presented an opportunity to assess whether Lovastatin act on melanoma cells, HUVEC or both types of cells. RESULTS: Direct effects of co-culturing two different malignant melanoma cells (A375 and G361) on the process of angiogenesis in vitro was studied with our angiogenesis model, based on human dermal fibroblasts and human umbilical vein endothelial cells (HUVEC). Co-cultures were set up using "sland" and "dispersed seeding" techniques. A statistically significant increase in tubule formation in both cases was observed compared to controls. The effects of doses equivalent to therapeutic concentrations of Lovastatin were analysed. The drug inhibited the growth of all cell types, induced apoptosis, and markedly reduced the formation of tubules in the angiogenesis model at low concentrations. Its action was successfully reversed by the introduction of geranylgeranyl pyrophosphate. CONCLUSION: Lovastatin can reduce both tumour (melanoma) cell growth, and the angiogenic activity of these cells in co-cultures using an established 2-dimensional model angiogenesis system beyond that which would be seen by reduced proliferation alone. [Abstract/Link to Full Text]

Vial D, Monaghan-Benson E, McKeown-Longo PJ
Coordinate regulation of fibronectin matrix assembly by the plasminogen activator system and vitronectin in human osteosarcoma cells.
Cancer Cell Int. 2006;68.
BACKGROUND: Plasminogen activators are known to play a key role in the remodeling of bone matrix which occurs during tumor progression, bone metastasis and bone growth. Dysfunctional remodeling of bone matrix gives rise to the osteoblastic and osteolytic lesions seen in association with metastatic cancers. The molecular mechanisms responsible for the development of these lesions are not well understood. Studies were undertaken to address the role of the plasminogen activator system in the regulation of fibronectin matrix assembly in the osteoblast-like cell line, MG-63. RESULTS: Treatment of MG-63 cells with P25, a peptide ligand for uPAR, resulted in an increase in assembly of fibronectin matrix which was associated with an increase in the number of activated beta1 integrins on the cell surface. Overexpression of uPAR in MG-63 cells increased the effect of P25 on fibronectin matrix assembly and beta1 integrin activation. P25 had no effect on uPAR null fibroblasts, confirming a role for uPAR in this process. The addition of plasminogen activator inhibitor Type I (PAI-1) to cells increased the P25-induced fibronectin polymerization, as well as the number of activated integrins. This positive regulation of PAI-1 on fibronectin assembly was independent of PAI-1's anti-proteinase activity, but acted through PAI-1 binding to the somatomedin B domain of vitronectin. CONCLUSION: These results indicate that vitronectin modulates fibronectin matrix assembly in osteosarcoma cells through a novel mechanism involving cross-talk through the plasminogen activator system. [Abstract/Link to Full Text]

Belkaid A, Currie JC, Desgagn�s J, Annabi B
The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression.
Cancer Cell Int. 2006;67.
BACKGROUND: Chlorogenic acid (CHL), the most potent functional inhibitor of the microsomal glucose-6-phosphate translocase (G6PT), is thought to possess cancer chemopreventive properties. It is not known, however, whether any G6PT functions are involved in tumorigenesis. We investigated the effects of CHL and the potential role of G6PT in regulating the invasive phenotype of brain tumor-derived glioma cells. RESULTS: RT-PCR was used to show that, among the adult and pediatric brain tumor-derived cells tested, U-87 glioma cells expressed the highest levels of G6PT mRNA. U-87 cells lacked the microsomal catalytic subunit glucose-6-phosphatase (G6Pase)-alpha but expressed G6Pase-beta which, when coupled to G6PT, allows G6P hydrolysis into glucose to occur in non-glyconeogenic tissues such as brain. CHL inhibited U-87 cell migration and matrix metalloproteinase (MMP)-2 secretion, two prerequisites for tumor cell invasion. Moreover, CHL also inhibited cell migration induced by sphingosine-1-phosphate (S1P), a potent mitogen for glioblastoma multiform cells, as well as the rapid, S1P-induced extracellular signal-regulated protein kinase phosphorylation potentially mediated through intracellular calcium mobilization, suggesting that G6PT may also perform crucial functions in regulating intracellular signalling. Overexpression of the recombinant G6PT protein induced U-87 glioma cell migration that was, in turn, antagonized by CHL. MMP-2 secretion was also inhibited by the adenosine triphosphate (ATP)-depleting agents 2-deoxyglucose and 5-thioglucose, a mechanism that may inhibit ATP-mediated calcium sequestration by G6PT. CONCLUSION: We illustrate a new G6PT function in glioma cells that could regulate the intracellular signalling and invasive phenotype of brain tumor cells, and that can be targeted by the anticancer properties of CHL. [Abstract/Link to Full Text]

Monazzam A, Razifar P, Simonsson M, Qvarnstr�m F, Josephsson R, Blomqvist C, L�ngstr�m B, Bergstr�m M
Multicellular tumour spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring.
Cancer Cell Int. 2006;66.
BACKGROUND: In order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer. METHODS: The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment. RESULTS : The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease). Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 microM.No effect of Imatinib was observed. CONCLUSION: MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response. In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs. [Abstract/Link to Full Text]

Watt HL, Kumar U
Colocalization of somatostatin receptors and epidermal growth factor receptors in breast cancer cells.
Cancer Cell Int. 2006;65.
BACKGROUND: Somatostatin receptor (SSTR) expression is positively correlated with tumor size and inversely correlated with epidermal growth factor receptor (ErbB) levels and tumor differentiation. In the present study, we compared SSTR1-5 and ErbB1-4 mRNA and protein expression in two breast cancer cell lines: MCF-7 (ER+) and MDA-MB-231 (ERalpha-). RESULTS: All five SSTRs and four ErbBs were variably expressed as both cell surface and cytoplasmic proteins. In both cell lines, SSTR4 and SSTR1 were highly expressed, followed by SSTR2 and SSTR5 with SSTR3 being the least expressed subtype, at the protein level. ErbBs were variably expressed with ErbB1 as the predominant subtype in both cell lines. ErbB1 is followed by ErbB3, ErbB2 and ErbB4 in MCF-7 at both the protein and mRNA levels. In MDA-MB-231 cells, ErbB1 is followed by ErbB2, ErbB4 and ErbB3. Our results indicate significant correlations at the level of mRNA and protein expression in a cell and receptor-specific manner. Using indirect immunofluorescence, we found that, in MCF-7 cells, SSTR5 was the most prominent subtype coexpressed with ErbBs followed by SSTR3, SSTR4, SSTR1 and SSTR2, respectively. In MDA-MB-231 cells, SSTR1 colocalized strongly with ErbBs followed by SSTR5, SSTR4, SSTR3 and SSTR2. ErbBs displayed higher levels of colocalization amongst themselves in MCF-7 cells than in MDA-MB-231 cells. CONCLUSION: These findings may explain the poor response to endocrine therapy in ER-cancer. Differential distribution of SSTR subtypes with ErbBs in breast cancer cells in a receptor-specific manner may be considered as a novel diagnosis for breast tumors. [Abstract/Link to Full Text]

Grizzi F, Chiriva-Internati M
Cancer: looking for simplicity and finding complexity.
Cancer Cell Int. 2006 Feb 15;6(1):4.
ABSTRACT: Cancer is one of the most complex dynamic human disease. Despite rapid advances in the fields of molecular and cell biology, it is still widely debated as to how neoplastic cells progress through carcinogenesis and acquire their metastatic ability. The need to find a new way of observing anatomical entities and their underlying processes, and measuring the changes they undergo, prompted us to investigate the Theory of Complexity, and to apply its principles to human cancer. Viewing a neoplasm as a system that is complex in time and space it is likely to reveal more about its behavioral characteristics, and this manner of thinking may help to clarify concepts, interpret experimental data, indicate specific experiments and categorize the rich body of knowledge on the basis of the similarities and/or shared behaviors of very different tumors. [Abstract/Link to Full Text]

Vietri M, Bianchi M, Ludlow JW, Mittnacht S, Villa-Moruzzi E
Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb.
Cancer Cell Int. 2006 Feb 8;6(1):3.
ABSTRACT: BACKGROUND: The product of the retinoblastoma-susceptibility gene (pRb) is a substrate for Protein Phosphatase 1 (PP1). At mitotic exit, all three PP1 isoforms, a, g1 and d, bind to pRb and dephosphorylate its Ser/Thr sites in a sequential and site-specific way. The pRb-C terminal has been reported to be necessary and sufficient for PP1a binding. The present study investigated whether the three PP1 isoforms from mitotic or asynchronous HeLa cells associate differentially with wild-type and pRb mutants, as well as the holoenzyme composition of the pRb-directed PP1. Results. The requirement for the entire pRb molecule to achieve optimal PP1-binding was indicated by the fact that full-length pRb displayed the highest affinity for all three PP1 isoforms. Ser/Thr-to-Ala substitution for up to 14 pRb sites did not affect the ability of pRb to bind the PP1 isoforms derived from mitotic or asynchronous HeLa cells, thus suggesting that the phosphate-accepting residues on pRb do not regulate the interaction with PP1. To probe for the presence of PP1 targeting subunits in the pRb-directed PP1 complex, PP1 from mitotic or asynchronous HeLa cells was isolated by affinity chromatography on GST-Rb (either full-length or its deletion mutants Rb-big pocket or Rb-C-terminal). The PP1 was always obtained as free catalytic subunit, displaying all three isoforms, thus suggesting direct interaction between pRb and PP1. The direct association was confirmed by the ability of pRb to pull-down purified PP1 catalytic subunits and by in vitro reconstitution of a complex between PP1 catalytic subunit and the pRb-C-terminal. Conclusions. The work indicated that the full length of the pRb molecule is required for optimal interaction with the PP1 isoforms and that the association between pRb and PP1 isoforms is direct. [Abstract/Link to Full Text]

Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, Carrasco-Legleu C, Rangel-Lopez E, Segura-Pacheco B, Taja-Chayeb L, Trejo-Becerril C, Gonzalez-Fierro A, Candelaria M, Cabrera G, Duenas-Gonzalez A
Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines.
Cancer Cell Int. 2006;62.
BACKGROUND: Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines. RESULTS: Hydralazine showed no growth inhibitory effect on cervical, colon, breast, sarcoma, glioma, and head & neck cancer cell lines when used alone. On the contrary, valproic acid showed a strong growth inhibitory effect that is potentiated by hydralazine in some cell lines. Individually, hydralazine and valproic acid displayed distinctive effects upon global gene over-expression but the number of genes over-expressed increased when cells were treated with the combination. Treatment of HeLa cells with hydralazine and valproic acid lead to an increase in the cytotoxicity of gemcitabine, cisplatin and adriamycin. A higher antitumor effect of adriamycin was observed in mice xenografted with human fibrosarcoma cells when the animals were co-treated with hydralazine and valproic acid. CONCLUSION: Hydralazine and valproic acid, two widely used drugs for cardiovascular and neurological conditions respectively have promising antineoplastic effects when used concurrently and may increase the antitumor efficacy of current cytotoxic agents. [Abstract/Link to Full Text]

Serfozo P, Schlarman MS, Pierret C, Maria BL, Kirk MD
Selective migration of neuralized embryonic stem cells to stem cell factor and media conditioned by glioma cell lines.
Cancer Cell Int. 2006;61.
BACKGROUND: Pluripotent mouse embryonic stem (ES) cells can be induced in vitro to become neural progenitors. Upon transplantation, neural progenitors migrate toward areas of damage and inflammation in the CNS. We tested whether undifferentiated and neuralized mouse ES cells migrate toward media conditioned by glioma cell lines (C6, U87 & N1321) or Stem Cell Factor (SCF). RESULTS: Cell migration assays revealed selective migration by neuralized ES cells to conditioned media as well as to synthetic SCF. Migration of undifferentiated ES cells was extensive, but not significantly different from that of controls (Unconditioned Medium). RT-PCR analysis revealed that all the three tumor cell lines tested synthesized SCF and that both undifferentiated and neuralized ES cells expressed c-kit, the receptor for SCF. CONCLUSION: Our results demonstrate that undifferentiated ES cells are highly mobile and that neural progenitors derived from ES cells are selectively attracted toward factors produced by gliomas. Given that the glioma cell lines synthesize SCF, SCF may be one of several factors that contribute to the selective migration observed. [Abstract/Link to Full Text]

Sharma H, Singh A, Sharma C, Jain SK, Singh N
Mutations in the mitochondrial DNA D-loop region are frequent in cervical cancer.
Cancer Cell Int. 2005;534.
BACKGROUND: Mitochondrial DNA (mtDNA) is known for high mutation rates caused by lack of protective histones, inefficient DNA repair systems, and continuous exposure to mutagenic effects of oxygen radicals. Alterations in the non-coding displacement (D) loop of mitochondrial DNA are present in many cancers. It has been suggested that the extent of mitochondrial DNA mutations might be useful in the prognosis of cancer outcome and/or the response to certain therapies. In order to investigate whether a high incidence of mutations exist in mitochondrial DNA of cervical cancer patients, we examined the frequency of mutations in the D-loop region in 19 patients of cervical cancer. RESULTS: Mutations, often multiple, were detected in 18 of 19 (95%) patients. The presence of mutations correlated with Human Papilloma Virus (HPV) infection in these patients. Mutations were also detected in normal samples and lymphocytes obtained from cervical cancer patients, but their frequency of occurrence was much lower as compared to the cervical cancer tissues. CONCLUSION: Our findings indicate that D-loop alterations are frequent in cervical cancers and are possibly caused by HPV infection. There was no association of mtDNA D-loop mutations with the histopathological grade and tumor staging. [Abstract/Link to Full Text]

Wheatley DN
Cell biology as the basis of a better understanding of cancer.
Cancer Cell Int. 2005 Nov 30;533.
Clinicians will argue that cancer can only really receive the treatment that is needed through thorough understanding of medicine. However, even empirical approaches to therapy result in experimental analysis of the agencies involved on test cells, usually in culture. From the obverse perspective, cell biologists will argue that until we fully understand cell cycle regulation, tumour management will be too imprecise to make the best advances. A forum is needed whereby the fundamental studies on cells prior to, during and after transformation in vitro can be freely reported (open access) and discussed. The action of anticancer agents and cancer preventative substances can more easily be studied in vitro before the often excessive complexity of making similar studies in experimental and human cancers is tackled. Cancer Cell International is committed to providing such a forum. Ironically within a few months of launching this open access journal, Elsevier had much the same idea, and there one has to pay for the privilege of downloading vital papers in this biomedical field. [Abstract/Link to Full Text]

Monazzam A, Razifar P, Lindhe O, Josephsson R, L�ngstr�m B, Bergstr�m M
A new, fast and semi-automated size determination method (SASDM) for studying multicellular tumor spheroids.
Cancer Cell Int. 2005 Nov 14;532.
BACKGROUND: Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation. RESULTS: SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining. CONCLUSION: The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments. [Abstract/Link to Full Text]

Abdullah AS, Foong C, Murata-Hori M
Specific distribution of overexpressed aurora B kinase during interphase of normal epithelial cells.
Cancer Cell Int. 2005 Nov 9;531.
BACKGROUND: It is known that aurora B, a chromosomal passenger protein responsible for the proper progression of mitosis and cytokinesis, is overexpressed throughout the cell cycle in cancer cells. Overexpression of aurora B produced multinuclearity and induced aggressive metastasis, suggesting that overexpressed aurora B has multiple functions in cancer development. However, the detailed dynamics and functions of overexpressed aurora B are poorly understood. RESULTS: We overexpressed GFP fused aurora B kinase in normal rat kidney epithelial cells. Using spinning disk confocal microscopy, we found that overexpressed aurora B-GFP was predominantly localized in the nucleus and along the cortex as a dot-like or short filamentous structure during interphase. Time-lapse imaging revealed that a cytoplasmic fraction of overexpressed aurora B-GFP was incorporated into the nucleus after cell division. Immunofluorescence showed that the nuclear fraction of overexpressed aurora B did not induce ectopic phosphorylation of histone H3 after cell division. The cytoplasmic fraction of overexpressed aurora B-GFP was mainly associated with cortical actin filaments but not stress fibers. Myosin II regulatory light chain, one of the possible targets for aurora B, did not colocalize with cortical aurora B-GFP, suggesting that overexpressed aurora B did not promote phosphorylation of myosin II regulatory light chain in interphase cells. CONCLUSION: We conclude that overexpressed aurora B has a specific localization pattern in interphase cells. Based on our findings, we propose that overexpressed aurora B targets the nuclear and cortical proteins during interphase, which may contribute to cancer development and tumor metastasis. [Abstract/Link to Full Text]

Choi CH
ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal.
Cancer Cell Int. 2005 Oct 4;530.
One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC) transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein. [Abstract/Link to Full Text]

Richter TM, Tong BD, Scholnick SB
Epigenetic inactivation and aberrant transcription of CSMD1 in squamous cell carcinoma cell lines.
Cancer Cell Int. 2005 Sep 9;529.
BACKGROUND: The p23.2 region of human chromosome 8 is frequently deleted in several types of epithelial cancer and those deletions appear to be associated with poor prognosis. Cub and Sushi Multiple Domains 1 (CSMD1) was positionally cloned as a candidate for the 8p23 suppressor but point mutations in this gene are rare relative to the frequency of allelic loss. In an effort to identify alternative mechanisms of inactivation, we have characterized CSMD1 expression and epigenetic modifications in head and neck squamous cell carcinoma cell lines. RESULTS: Only one of the 20 cell lines examined appears to express a structurally normal CSMD1 transcript. The rest express transcripts which either lack internal exons, terminate abnormally or initiate at cryptic promoters. None of these truncated transcripts is predicted to encode a functional CSMD1 protein. Cell lines that express little or no CSMD1 RNA exhibit DNA methylation of a specific region of the CpG island surrounding CSMD1's first exon. CONCLUSION: Correlating methylation patterns and expression suggests that it is modification of the genomic DNA preceding the first exon that is associated with gene silencing and that methylation of CpG dinucleotides further 3' does not contribute to inactivation of the gene. Taken together, the cell line data suggest that epigenetic silencing and aberrant splicing rather than point mutations may be contributing to the reduction in CSMD1 expression in squamous cancers. These mechanisms can now serve as a focus for further analysis of primary squamous cancers. [Abstract/Link to Full Text]

Zhu H, Smith C, Ansah C, Gooderham NJ
Responses of genes involved in cell cycle control to diverse DNA damaging chemicals in human lung adenocarcinoma A549 cells.
Cancer Cell Int. 2005 Aug 24;528.
BACKGROUND: Many anticancer agents and carcinogens are DNA damaging chemicals and exposure to such chemicals results in the deregulation of cell cycle progression. The molecular mechanisms of DNA damage-induced cell cycle alteration are not well understood. We have studied the effects of etoposide (an anticancer agent), cryptolepine (CLP, a cytotoxic alkaloid), benzo [a]pyrene (BaP, a carcinogenic polycyclic aromatic hydrocarbon) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP, a cooked-meat derived carcinogen) on the expression of cell cycle regulatory genes to understand the molecular mechanisms of the cell cycle disturbance. RESULTS: A549 cells were treated with DMSO or chemicals for up to 72 h and periodically sampled for cell cycle analysis, mRNA and protein expression. DMSO treated cells showed a dominant G1 peak in cell cycle at all times examined. Etoposide and CLP both induced G2/M phase arrest yet the former altered the expression of genes functioning at multiple phases, whilst the latter was more effective in inhibiting the expression of genes in G2-M transition. Both etoposide and CLP induced an accumulation of p53 protein and upregulation of p53 transcriptional target genes. Neither BaP nor PhIP had substantial phase-specific cell cycle effect, however, they induced distinctive changes in gene expression. BaP upregulated the expression of CYP1B1 at 6-24 h and downregulated many cell cycle regulatory genes at 48-72 h. By contrast, PhIP increased the expression of many cell cycle regulatory genes. Changes in the expression of key mRNAs were confirmed at protein level. CONCLUSION: Our experiments show that DNA damaging agents with different mechanisms of action induced distinctive changes in the expression pattern of a panel of cell cycle regulatory genes. We suggest that examining the genomic response to chemical exposure provides an exceptional opportunity to understand the molecular mechanism involved in cellular response to toxicants. [Abstract/Link to Full Text]

Chi TY, Chen GG, Ho LK, Lai PB
Establishment of a doxycycline-regulated cell line with inducible, doubly-stable expression of the wild-type p53 gene from p53-deleted hepatocellular carcinoma cells.
Cancer Cell Int. 2005 Aug 23;527.
p53 is important in the development of hepatocellular carcinoma (HCC) and in therapeutic approaches, but the mechanism whereby it inhibits HCC growth is still unclear. The aim of the present study was to establish a HCC cell system in which p53 levels can be regulated. Full-length wild-type p53 cDNA obtained by PCR was cloned into a retroviral response vector controlled by the tetracycline responsive element (RevTRE-p53). The regulatory vectors RevTet-Off and RevTRE-p53 were transfected into a packaging cell line, PT67. Hep3B cells in which the p53 gene was deleted were infected with RevTet-Off viral particles from the PT67. Three G418-resistant cell clones with high luciferase expression and low background were infected with RevTRE-p53. By screening dozens of RevTRE-p53-infected clones with hygromycin we identified the one with the highest expression of p53 and the lowest background after doxycycline treatment. The results showed that p53 expression in this cell clone could be simply turned on or off by removing or adding doxycycline. Furthermore, it was found that the level of p53 protein was negatively and sensitively related to the doxycycline concentration. In conclusion, we have established a HCC cell line in which p53 expression can be switched on or off and regulated in a dose- and time-dependent manner. [Abstract/Link to Full Text]

Sharma R, Kline RP, Wu EX, Katz JK
Rapid in vivo Taxotere quantitative chemosensitivity response by 4.23 Tesla sodium MRI and histo-immunostaining features in N-Methyl-N-Nitrosourea induced breast tumors in rats.
Cancer Cell Int. 2005 Aug 3;526.
BACKGROUND: Sodium weighted images can indicate sodium signal intensities from different features in the tumor before and 24 hours following administration of Taxotere. AIM: To evaluate the association of in vivo intracellular sodium magnetic resonance image intensities with immuno-biomarkers and histopathological features to monitor the early tumor response to Taxotere chemotherapy in Methyl-Nitroso-Urea induced rat xenograft breast tumors. METHODS AND MATERIALS: Methyl-Nitroso-Urea (MNU) induced rat xenograft breast tumors were imaged for sodium MRI and compared with tumor histology, immunostaining after 24 hours chemotherapy. RESULTS: Sodium MRI signal intensities represented sodium concentrations. Excised tumor histological sections showed different in vitro histological end points i.e. single strand DNA content of cell nuclei during cell cycle (G1/S-G2/M), distinct S or M histograms (Feulgen labeling to nuclear DNA content by CAS 200), mitotic figures and apoptosis at different locations of breast tumors. Necrosis and cystic fluid appeared gray on intracellular (IC) sodium images while apoptosis rich regions appeared brighter on IC sodium images. After 24 hours Taxotere-treated tumors showed lower 'IC/EC ratio' of viable cells (65-76%) with higher mitotic index; apoptotic tumor cells at high risk due to cytotoxicity (>70% with high apoptotic index); reduced proliferation index (270 vs 120 per high power field) associated with enhanced IC sodium in vivo MR image intensities and decreased tumor size (3%; p < 0.001; n = 16) than that of pre-treated tumors. IC-Na MR signal intensities possibly indicated Taxotere chemosensitivity response in vivo associated with apoptosis and different pre-malignant features within 24 hours of exposure of cancer cells to anti-neoplastic Taxotere drug. CONCLUSION: Sodium MRI imaging may be used as in vivo rapid drug monitoring method to evaluate Taxotere chemosensitivity response associated with neoplasia, apoptosis and tumor histology features. [Abstract/Link to Full Text]

Prehn RT
On the nature of cancer and why anticancer vaccines don't work.
Cancer Cell Int. 2005 Aug 1;5(1):25.
In this essay I suggest that the major difficulty in producing effective anti-cancer vaccines lies in the fact that most cancers have little immunogenicity because of a basic paucity of tumor-specific antigenicity. The lack of antigenicity, despite extensive genomic instability, could be explained if most tumor mutations occur in silenced genes. A further problem is that an immune reaction against tumor antigens, especially in moderate or low amount, may be stimulatory rather than inhibitory to tumor growth. [Abstract/Link to Full Text]

Chandar N, Saluja R, Lamar PC, Kolman K, Prozialeck WC
P53 and beta-catenin activity during estrogen treatment of osteoblasts.
Cancer Cell Int. 2005 Jul 29;524.
BACKGROUND: This study was undertaken to examine the relationship between the tumor suppressor gene p53 and the nuclear signaling protein beta-catenin during bone differentiation. Cross talk between p53 and beta-catenin pathways has been demonstrated and is important during tumorigenesis and DNA damage, where deregulation of beta catenin activates p53. In this study, we used estrogen treatment of osteoblasts as a paradigm to study the relationship between the two proteins during osteoblast differentiation. RESULTS: We exposed osteoblast-like ROS17/2.8 cells to 17-beta estradiol (E2), in a short term assay, and studied the cellular distribution and expression of beta-catenin. We found beta-catenin to be up regulated several fold following E2 treatment. Levels of p53 and its functional activity mirrored the quantitative changes seen in beta-catenin. Alkaline phosphatase, an early marker of osteoblast differentiation, was increased in a manner similar to beta-catenin and p53. In order to determine if there was a direct relationship between alkaline phosphatase expression and beta-catenin, we used two different approaches. In the first approach, treatment with LiCl, which is known to activate beta-catenin, caused a several fold increase in alkaline phosphatase activity. In the second approach, transient transfection of wild type beta-catenin into osteoblasts increased alkaline phosphatase activity two fold over basal levels, showing that beta catenin expression can directly affect alkaline phosphatase expression. However increase in beta catenin activity was not associated with an increase in its signaling activity through TCF/LEF mediated transcription. Immunofluorescence analyses of p53 and beta-catenin localization showed that E2 first caused an increase in cytosolic beta-catenin followed by the accumulation of beta-catenin in the nucleus. Nuclear p53 localization was detected in several cells. Expression of p53 was accompanied by distribution of beta-catenin to the cytoplasm and cell borders. A sub population of cells staining strongly for both proteins appeared to be apoptotic. CONCLUSION: These results suggest that interactions between p53 and beta-catenin signaling pathways may play a key role in osteoblast differentiation and maintenance of tissue homeostasis. [Abstract/Link to Full Text]

Cameron IL, Sun LZ, Short N, Hardman WE, Williams CD
Therapeutic Electromagnetic Field (TEMF) and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis.
Cancer Cell Int. 2005 Jul 26;523.
BACKGROUND: The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc.) (TEMF) alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy); IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1alpha (HIF). RESULTS: Most tumors <35 mm3 were white but tumors >35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at >100 microns from the capsule (subcortex). Tumors >35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. CONCLUSION: TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis. [Abstract/Link to Full Text]

Akan I, Akan S, Akca H, Savas B, Ozben T
Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine sulfoximine.
Cancer Cell Int. 2005 Jul 24;5(1):22.
BACKGROUND: Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs. RESULTS: N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC. CONCLUSION: Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells. [Abstract/Link to Full Text]

Lee DG, Hahm KS, Park Y, Kim HY, Lee W, Lim SC, Seo YK, Choi CH
Functional and structural characteristics of anticancer peptide Pep27 analogues.
Cancer Cell Int. 2005 Jul 11;521.
BACKGROUND: A secreted peptide Pep27 initiates the cell death program in S. pneumoniae through signal transduction. This study was undertaken to evaluate the relation between the structure and cytotoxic activity of Pep27 and its analogues on cancer cells. RESULTS: Pep27anal2 characterized substituting (2R-->W), (4E-->W), (11S-->W) and (13Q-->W) in native Pep27, exhibited greater hydrophobicity and anticancer activity than Pep27 and other analogues. The IC50 values of Pep27anal2 were approximately 10 - 30 microM in a number of cell lines (AML-2, HL-60, Jurkat, MCF-7 and SNU-601). Confocal microscopy showed that Pep27anal2-FITC was localized in the plasma membrane, and then moving from the membrane to subcellular compartments with the initiation of membrane blebbing. Flow cytometric analysis using propidium iodide and Annexin V also revealed that Pep27anal2 induced apoptosis with minor membrane damage. Electron microscopy revealed that Pep27 induced apoptosis in Jurkat cells. The anticancer activity of Pep27anal2 was neither abrogated by pan-caspase inhibitor (Z-VAD-fmk) nor related to cytochrome c release from mitochondria. The 3D solution structures of these two Pep27 peptides revealed that both form a random coil conformation in water; however, they adopted stable alpha-helical conformations in solutions. CONCLUSION: The results indicate that Pep27anal2 can penetrate the plasma membrane, and then induce apoptosis in both caspase-and cytochrome c-independent manner. The hydrophobicity of Pep27anal2 appears to play an important role in membrane permeabilization and/or anticancer properties. The structure-functional relationships of these peptides are also discussed. It is proposed that Pep27anal2 is a potential candidate for anticancer therapeutic agents. [Abstract/Link to Full Text]

Recent Articles in Breast Cancer Research

Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D
Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models.
Breast Cancer Res. 2007;9(1):R12.
INTRODUCTION: The experiments reported here address the question of whether a short-term hormone treatment can prevent mammary tumorigenesis in two different genetically engineered mouse models. METHODS: Two mouse models, the p53-null mammary epithelial transplant and the c-neu mouse, were exposed to estrogen and progesterone for 2 and 3 weeks, respectively, and followed for development of mammary tumors. RESULTS: In the p53-null mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%. At 45 weeks after transplantation, analysis of whole mounts of the mammary outgrowths demonstrated the presence of premalignant hyperplasias in both control and hormone-treated glands, indicating that the hormone treatment strongly affects the rate of premalignant progression. One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice. The same short-term exposure administered to mature mice at a time of premalignant development also decreased mammary tumorigenesis by 60%. A role for stroma and/or systemic mediated changes induced by the short-term hormone (estrogen/progesterone) treatment was demonstrated by an experiment in which the p53-null mammary epithelial cells were transplanted into the cleared mammary fat pads of previously treated mice. In such mice, the tumor-producing capabilities of the mammary cells were also decreased by 60% compared with the same cells transplanted into unexposed mice. In the second set of experiments using the activated Her-2/neu transgenic mouse model, short-term estradiol or estradiol plus progesterone treatment decreased mammary tumor incidence by 67% and 63%, and tumor multiplicity by 91% and 88%, respectively. The growth rate of tumors arising in the hormone-treated activated Her-2/neu mice was significantly lower than tumors arising in non-hormone treated mice. CONCLUSION: Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer. [Abstract/Link to Full Text]

Jerry DJ
Roles for estrogen and progesterone in breast cancer prevention.
Breast Cancer Res. 2007;9(2):102.
Prevention has long been the holy grail of breast cancer research. The significant reduction in breast cancer risk afforded by a full-term pregnancy early in life suggests the great potential of preventive strategies. In contrast to the risks associated with prolonged exposures, exogenous estrogen and progesterone for short durations can mimic the protective effects of pregnancy in carcinogen-induced mammary tumor models. Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer. [Abstract/Link to Full Text]

Borgquist S, Wirf�lt E, Jirstr�m K, Anagnostaki L, Gullberg B, Berglund G, Manjer J, Landberg G
Diet and body constitution in relation to subgroups of breast cancer defined by tumour grade, proliferation and key cell cycle regulators.
Breast Cancer Res. 2007;9(1):R11.
BACKGROUND: The general lack of clear associations between diet and breast cancer in epidemiological studies may partly be explained by the fact that breast cancer is a heterogeneous disease that may have disparate genetic associations and different aetiological bases. METHOD: A total of 346 incident breast cancers in a prospective cohort of 17,035 women enrolled in the Malm� Diet and Cancer study (Sweden) were subcategorized according to conventional pathology parameters, proliferation and expression of key cell cycle regulators. Subcategories were compared with prediagnostic diet and body measurements using analysis of variance. RESULTS: A large hip circumference and high body mass index were associated with high grade tumours (P = 0.03 and 0.009, respectively), whereas low energy and unadjusted fat intakes were associated with high proliferation (P = 0.03 and 0.004, respectively). Low intakes of saturated, monounsaturated and polyunsaturated fatty acids were also associated with high proliferation (P = 0.02, 0.004 and 0.003, respectively). Low energy and unadjusted fat intakes were associated with cyclin D1 overexpression (P = 0.02 and 0.007, respectively), whereas cyclin E overexpression was positively correlated with fat intake. Oestrogen receptor status and expression of the tumour suppressor gene p27 were not associated with either diet or body constitution. CONCLUSION: Low energy and low total fat (polyunsaturated fatty acids in particular) intakes, and high body mass index were associated with relatively more malignant breast tumours. Dietary behaviours and body constitution may be associated with specific types of breast cancer defined by conventional pathology parameters and cyclin D1 and cyclin E expression. Further studies including healthy control individuals are needed to confirm our results. [Abstract/Link to Full Text]

Satram-Hoang S, Ziogas A, Anton-Culver H
Risk of second primary cancer in men with breast cancer.
Breast Cancer Res. 2007;9(1):R10.
INTRODUCTION: A retrospective registry-based cohort study was conducted to examine the risk of second primary cancer following the occurrence of breast cancer in males. METHODS: Data obtained from the California Cancer Registry in the period 1988 to 2003 included 1,926 men aged 85 years and younger diagnosed with a first primary breast cancer. Person-year analysis was applied to determine the risk of second primary cancers after the occurrence of a first primary breast cancer. The effects of age, race, and time since the first breast cancer diagnosis were assessed. RESULTS: Of the 1,926 male breast cancer cases, 221 (11.5%) developed a second primary cancer. Men with first incidence of breast cancer have a significantly higher risk of second cancer (standardized incidence ratio (SIR) = 1.16, 95% confidence interval (CI) = 1.01-1.32). The risk of a second site-specific cancer is elevated for breast cancer (SIR = 52.12, 95% CI = 31.83-80.49), cutaneous melanoma (SIR = 2.98, 95% CI = 1.63-5.00) and stomach cancer (SIR = 2.11, 95% CI = 1.01-3.88). There is a general tendency towards higher risks of second malignancies among younger men compared to older men and the risk increased with the passage of time. CONCLUSION: Male breast cancer patients should be monitored carefully for the occurrence of second primary cancers, especially a second primary breast cancer. [Abstract/Link to Full Text]

McCullough ML, Stevens VL, Diver WR, Feigelson HS, Rodriguez C, Bostick RM, Thun MJ, Calle EE
Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.
Breast Cancer Res. 2007;9(1):R9.
INTRODUCTION: Vitamin D receptor (VDR) polymorphisms have been inconsistently associated with breast cancer risk. Whether risk is influenced by polymorphisms in other vitamin D metabolism genes and whether calcium or vitamin D intake modifies risk by genotype have not been evaluated. METHODS: We conducted a nested case-control study within the Cancer Prevention Study II Nutrition Cohort of associations between breast cancer and four VDR single-nucleotide polymorphisms (SNPs), Bsm1,Apa1,Taq1, and Fok1, a poly(A) microsatellite, and associated haplotypes (baTL and BAtS). We also examined one SNP in the 24-hydroxylase gene (CYP24A1) and two in the vitamin D-binding protein (group-specific component [GC]) gene. Participants completed a questionnaire on diet and medical history at baseline in 1992. This study includes 500 postmenopausal breast cancer cases and 500 controls matched by age, race/ethnicity, and date of blood collection. RESULTS: Incident breast cancer was not associated with any genotype examined. However, women with the Bsm1 bb SNP who consumed greater than the median intake of total calcium (> or = 902 mg/day) had lower odds of breast cancer compared to women with the Bb or BB genotype and less than the median calcium intake (odds ratio 0.61, 95% confidence interval 0.38 to 0.96; p(interaction) = 0.01). Similar interactions were observed for Taq1 (T allele) and the poly(A) (LL) repeat. CONCLUSION: We found no overall association between selected vitamin D pathway genes and postmenopausal breast cancer risk. However, certain VDR gene polymorphisms were associated with lower risk in women consuming high levels of calcium, suggesting that dietary factors may modify associations by VDR genotype. [Abstract/Link to Full Text]

G�tte M, Kersting C, Radke I, Kiesel L, W�lfing P
An expression signature of syndecan-1 (CD138), E-cadherin and c-met is associated with factors of angiogenesis and lymphangiogenesis in ductal breast carcinoma in situ.
Breast Cancer Res. 2007;9(1):R8.
INTRODUCTION: Heparan sulphate proteoglycan syndecan-1 modulates cell proliferation, adhesion, migration and angiogenesis. It is a coreceptor for the hepatocyte growth factor receptor c-met, and its coexpression with E-cadherin is synchronously regulated during epithelial-mesenchymal transition. In breast cancer, changes in the expression of syndecan-1, E-cadherin and c-met correlate with poor prognosis. In this study we evaluated whether coexpression of these functionally linked prognostic markers constitutes an expression signature in ductal carcinoma in situ (DCIS) of the breast that may promote cell proliferation and (lymph)angiogenesis. METHODS: Expression of syndecan-1, E-cadherin and c-met was detected immunohistochemically using a tissue microarray in tumour specimens from 200 DCIS patients. Results were correlated with the expression patterns of angiogenic and lymphangiogenic markers. Coexpression of the three prognostic markers was evaluated in human breast cancer cells by confocal immunofluorescence microscopy and RT-PCR. RESULTS: Coexpression and membrane colocalization of the three markers was confirmed in MCF-7 cells. E-cadherin expression decreased, and c-met expression increased progressively in more aggressive cell lines. Tissue microarray analysis revealed strong positive staining of tumour cells for syndecan-1 in 72%, E-cadherin in 67.8% and c-met in 48.6% of DCIS. E-cadherin expression was significantly associated with c-met and syndecan-1. Expression of c-met and syndecan-1 was significantly more frequent in the subgroup of patients with pure DCIS than in those with DCIS and a coexisting invasive carcinoma. Levels of c-met and syndecan-1 expression were associated with HER2 expression. Expression of c-met significantly correlated with expression of endothelin A and B receptors, vascular endothelial growth factor (VEGF)-A and fibroblast growth factor receptor-1, whereas E-cadherin expression correlated significantly with endothelin A receptor, VEGF-A and VEGF-C staining. CONCLUSION: Syndecan-1, E-cadherin and c-met constitute a marker signature associated with angiogenic and lymphangiogenic factors in DCIS. This coexpression may reflect a state of parallel activation of different signal transduction pathways, promoting tumour cell proliferation and angiogenesis. Our findings have implications for future therapeutic approaches in terms of a multiple target approach, which may be useful early in breast cancer progression. [Abstract/Link to Full Text]

Wegman P, Elingarami S, Carstensen J, St�l O, Nordenskj�ld B, Wingren S
Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer.
Breast Cancer Res. 2007;9(1):R7.
INTRODUCTION: Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer. METHODS: In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography. RESULTS: The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15. CONCLUSION: The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy. [Abstract/Link to Full Text]

Dunnwald LK, Rossing MA, Li CI
Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients.
Breast Cancer Res. 2007;9(1):R6.
BACKGROUND: Breast cancer patients with tumors that are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive have lower risks of mortality after their diagnosis compared to women with ER- and/or PR-negative disease. However, few studies have evaluated variations in the risks of breast cancer-specific mortality across ER/PR status by either demographic or clinical characteristics. METHODS: Using data from 11 population-based cancer registries that participate in the SEER (Surveillance, Epidemiology, and End Results) program, 155,175 women at least 30 years old with a primary diagnosis of invasive breast carcinoma from 1990 to 2001 were included in the study. Associations between joint hormone receptor status and breast cancer mortality risk within categories of diagnosis age, diagnosis year, race/ethnicity, histologic tumor type, stage, grade, size, and axillary lymph node status were evaluated using the Cox proportional hazards model. RESULTS: Compared to ER+/PR+ cases, elevations in risk of mortality were observed across all subcategories of age at diagnosis, ranging from 1.2- to 1.5-fold differences for ER+/PR- cases, 1.5- to 2.1-fold differences for ER-/PR+ cases, and 2.1- to 2.6-fold differences for ER-/PR- cases. Greater differences were observed in analyses stratified by grade; among women with low-grade lesions, ER-/PR- patients had a 2.6-fold (95% confidence interval [CI] 1.7 to 3.9) to 3.1-fold (95% CI 2.8 to 3.4) increased risk of mortality compared to ER+/PR+ patients, but among women with high-grade lesions, they had a 2.1-fold (95% CI 1.9 to 2.2) to 2.3-fold (95% CI 1.8 to 2.8) increased risk. CONCLUSION: Compared to women with ER+/PR+ tumors, women with ER+/PR-, ER-/PR+, or ER-/PR- tumors experienced higher risks of mortality, which were largely independent of the various demographic and clinical tumor characteristics assessed in this study. The higher relative mortality risks identified among ER-/PR- patients with small or low-grade tumors raise the question of whether there may be a beneficial role for adjuvant chemotherapy in this population. [Abstract/Link to Full Text]

Chanock SJ, Burdett L, Yeager M, Llaca V, Langer�d A, Presswalla S, Kaaresen R, Strausberg RL, Gerhard DS, Kristensen V, Perou CM, B�rresen-Dale AL
Somatic sequence alterations in twenty-one genes selected by expression profile analysis of breast carcinomas.
Breast Cancer Res. 2007;9(1):R5.
INTRODUCTION: Genomic alterations have been observed in breast carcinomas that affect the capacity of cells to regulate proliferation, signaling, and metastasis. Re-sequence studies have investigated candidate genes based on prior genetic observations (changes in copy number or regions of genetic instability) or other laboratory observations and have defined critical somatic mutations in genes such as TP53 and PIK3CA. METHODS: We have extended the paradigm and analyzed 21 genes primarily identified by expression profiling studies, which are useful for breast cancer subtyping and prognosis. This study conducted a bidirectional re-sequence analysis of all exons and 5', 3', and evolutionarily conserved regions (spanning more than 16 megabases) in 91 breast tumor samples. RESULTS: Eighty-seven unique somatic alterations were identified in 16 genes. Seventy-eight were single base pair alterations, of which 23 were missense mutations; 55 were distributed across conserved intronic regions or the 5' and 3' regions. There were nine insertion/deletions. Because there is no a priori way to predict whether any one of the identified synonymous and noncoding somatic alterations disrupt function, analysis unique to each gene will be required to establish whether it is a tumor suppressor gene or whether there is no effect. In five genes, no somatic alterations were observed. CONCLUSION: The study confirms the value of re-sequence analysis in cancer gene discovery and underscores the importance of characterizing somatic alterations across genes that are related not only by function, or functional pathways, but also based upon expression patterns. [Abstract/Link to Full Text]

Dalgliesh GL, Futreal PA
The continuing search for cancer-causing somatic mutations.
Breast Cancer Res. 2007;9(1):101.
It is known that cancer is caused by an accumulation of mutations in DNA. Many genes have been associated with tumour progression either through germline or somatic mutations, but mutations in these genes by no means account for all instances of the disease. The availability of the completed human genome sequence and reduced costs of sequencing have allowed large-scale screens to uncover genes that are somatically mutated in cancer. In this issue, Chanock and colleagues present a screen of 91 breast cancers for somatic variants in a set of 21 genes. [Abstract/Link to Full Text]

Fulford LG, Reis-Filho JS, Ryder K, Jones C, Gillett CE, Hanby A, Easton D, Lakhani SR
Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival.
Breast Cancer Res. 2007;9(1):R4.
INTRODUCTION: Cytokeratin (CK) 14, one of several markers expressed in normal myoepithelial/basal cells, is also expressed in a proportion of breast carcinomas. Previous studies have suggested that expression of such 'basal' markers predicts different biological behaviour, with more frequent lung and brain metastases and poorer prognosis than other carcinomas. METHODS: We performed CK14 immunohistochemistry on 443 grade III invasive ductal carcinomas with extended clinical follow-up (mean 116 months), and we correlated CK14 immunopositivity (basal-like phenotype) with clinicopathological criteria. RESULTS: Eighty-eight of 443 (20%) tumours showed CK14 expression. CK14-positive tumours were more likely to be oestrogen receptor-negative (p < 0.0001) and axillary node-negative (p = 0.001) than were CK14-negative cases. CK14-positive cases developed less bone and liver metastases (hazard ratio [HR] 0.49, p = 0.01, and HR 0.53, p = 0.035, respectively) but more frequent brain metastases (HR 1.92, p = 0.051). In patients without metastatic disease, disease-free survival in CK14-positive cases was significantly better than in CK14-negative cases (HR 0.65, p = 0.005). In patients with metastatic disease, however, CK14 positivity was associated with a poorer prognosis (HR 1.84, p = 0.001). The overall survival in CK14-positive and -negative patients was similar at 5 years (60% and 59%, respectively), but the long-term survival was better in CK14-positive patients (HR 0.69, p = 0.02). CONCLUSION: These results demonstrate that basal-like tumours differ in their biological behaviour from other tumours, with a distinct pattern of metastatic spread. Compared to other grade III tumours, basal-like tumours appear to have a relatively good long-term survival but survival after metastases is poor. [Abstract/Link to Full Text]

Cox DG, Buring J, Hankinson SE, Hunter DJ
A polymorphism in the 3' untranslated region of the gene encoding prostaglandin endoperoxide synthase 2 is not associated with an increase in breast cancer risk: a nested case-control study.
Breast Cancer Res. 2007;9(1):R3.
INTRODUCTION: Prostaglandins are integral components in the cellular response to inflammation, promoting cellular proliferation and angiogenesis. The enzyme responsible for the conversion of arachidonic acid to prostaglandins in response to inflammation is prostaglandin endoperoxide synthase 2/cyclo-oxygenase 2 (PTGS2/COX2). Polymorphisms in the PTGS2 gene have been associated with various diseases, including inflammatory bowel disease and cancer of the lung, colorectum, and breast. METHODS: We genotyped the five most common polymorphisms (rs20417, rs5277, rs20432, rs5275, and rs4648298) in the Nurses' Health Study (1,270 cases, 1,762 controls) to test the hypothesis that polymorphisms in PTGS2 are associated with breast cancer risk, using logistic regression analyses. The Nurses' Health Study 2 (317 cases, 634 controls) and Harvard Women's Health Study (702 cases, 703 controls) were used to further examine putative associations. RESULTS: The rs5275 polymorphism in the 3' untranslated region of the PTGS2 gene was associated with a decrease in breast cancer risk. We therefore genotyped this single-nucleotide polymorphism in the Nurses' Health Study 2 and Harvard Women's Health Study. Similar results were observed in these subsequent analyses, with no statistically significant heterogeneity in risk estimates between studies. In pooled analyses, women homozygous for the T allele at rs5275 had a 20% lower risk of breast cancer than those homozygous for the C allele (odds ratio 0.80, 95% confidence interval 0.66 to 0.97). CONCLUSION: Although this polymorphism may be associated with a decrease in breast cancer risk among Caucasian women, we provide strong evidence that it is not associated with an increased risk of breast cancer. [Abstract/Link to Full Text]

Ren Z, Shin A, Cai Q, Shu XO, Gao YT, Zheng W
IGFBP3 mRNA expression in benign and malignant breast tumors.
Breast Cancer Res. 2007;9(1):R2.
INTRODUCTION: Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. METHODS: To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time quantitative PCR. RESULTS: Cancer tissues had significantly lower IGFBP3 expression than benign tumor tissues (p < 0.001). IGFBP3 expressions in both tumor and adjacent tissues were higher in patients who had proliferative benign tumors than in those who had non-proliferative benign tumors. Among patients with benign breast disease, IGFBP3 expression in the tumor was significantly higher than that in their adjacent normal tissue. There were no apparent associations of IGFBP3 expression in cancer tissues with either overall survival or disease-free survival in a cohort of 521 patients with breast cancer. CONCLUSION: Our findings suggest that the expression level of IGFBP3 in breast tissues may be involved in breast tumorigenesis. [Abstract/Link to Full Text]

Li H, Rajendran GK, Liu N, Ware C, Rubin BP, Gu Y
SirT1 modulates the estrogen-insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice.
Breast Cancer Res. 2007;9(1):R1.
INTRODUCTION: Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-kappaB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. METHODS: SirT1-deficient (SirT1(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(co/co)) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. RESULTS: Both male and female SirT1(ko/ko) mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko) mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(ko/ko) mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1(ko/ko) mammary tissues, but not that of IkappaB alpha expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFalpha treatment enhanced the level of the newly synthesized IkappaB alpha in SirT1(ko/ko) cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. CONCLUSION: SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells. [Abstract/Link to Full Text]

Frackelton AR, Lu L, Davol PA, Bagdasaryan R, Hafer LJ, Sgroi DC
p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy.
Breast Cancer Res. 2006;8(6):R73.
INTRODUCTION: Shc adapter proteins are secondary messenger proteins involved in various cellular pathways, including those mediating receptor tyrosine kinase signaling and apoptosis in response to stress. We have previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc) and low levels of its inhibitory p66 Shc isoform are strongly prognostic for identifying both early node-negative and more advanced, node-positive, primary breast cancers with high risk for recurrence. Because aberrant activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen--the most widely prescribed drug for treatment of estrogen receptor-positive breast cancer--we hypothesized that Shc isoforms may identify patients at increased risk of relapsing despite tamoxifen treatment. METHODS: Immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast cancer tumors from a population-based cohort (60 patients, 9 relapses) and, for validation, an independent external cohort (31 patients, 13 relapses) in which all patients received tamoxifen as a sole systemic adjuvant prior to relapse. RESULTS: By univariate and multivariate analyses, the Shc proteins were very strong and independent predictors of treatment failure in both the population-based cohort (interquartile hazard ratio = 8.3, 95% confidence interval [CI] 1.8 to 38, P = 0.007) and the validating cohort (interquartile relative risk = 12.1, 95% CI 1.7 to 86, P = 0.013). CONCLUSION: These results suggest that the levels of PY-Shc and p66 Shc proteins in primary tumors identify patients at high risk for relapsing despite treatment with tamoxifen and therefore with further validation may be useful in guiding clinicians to select alternative adjuvant treatment strategies. [Abstract/Link to Full Text]

Antoniou AC, Shenton A, Maher ER, Watson E, Woodward E, Lalloo F, Easton DF, Evans DG
Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers.
Breast Cancer Res. 2006;8(6):R72.
INTRODUCTION: Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk. METHODS: The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach. RESULTS: Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers. CONCLUSION: The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers. [Abstract/Link to Full Text]

Shen J, Gammon MD, Terry MB, Teitelbaum SL, Neugut AI, Santella RM
Genetic polymorphisms in the cyclooxygenase-2 gene, use of nonsteroidal anti-inflammatory drugs, and breast cancer risk.
Breast Cancer Res. 2006;8(6):R71.
INTRODUCTION: The association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer risk remains unclear. Inconsistencies in previously reported findings may be partly due to differences in expression of cyclooxygenase (COX)-2. We hypothesized that genetic polymorphisms (COX-2 .926, COX-2 .5209, and COX-2 .8473) may reduce overall breast cancer risk or risk for subtypes of breast cancer by modulating the inflammatory response and may interact with aspirin or any NSAID use. METHODS: We conducted a population-based, case-control study in which we genotyped 1,067 breast cancer cases and 1,110 control individuals included in the Long Island Breast Cancer Study Project. RESULTS: No major effects of the three COX-2 variant alleles on breast cancer risk were found. A total of eight distinct haplotypes and 18 diplotypes were observed in the population. Overall, no significant associations between COX-2 haplotypes/diplotypes and breast cancer risk were observed. Among women who used aspirin or any NSAID there was little evidence for an interaction with the at-risk COX-2 genotypes, with one exception. Among women with hormone receptor positive breast cancer, the reduced risk for any NSAID use was only evident among those who had at least one variant C allele of COX-2 .8473 (odds ratio = 0.7, 95% confidence interval = 0.5 to 1.0; P for the interaction = 0.02). There was no corresponding interaction for aspirin use, possibly because of limited power. CONCLUSION: These data provide modest evidence that the C allele of COX-2 .8473 may interact with NSAIDs to reduce risk for hormone receptor positive breast cancer. [Abstract/Link to Full Text]

Perkins RS, Sahm K, Marando C, Dickson-Witmer D, Pahnke GR, Mitchell M, Petrelli NJ, Berkowitz IM, Soteropoulos P, Aris VM, Dunn SP, Krueger LJ
Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.
Breast Cancer Res. 2006;8(6):R70.
INTRODUCTION: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. METHODS: Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR. RESULTS: Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood. CONCLUSION: EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer. [Abstract/Link to Full Text]

Basu GD, Liang WS, Stephan DA, Wegener LT, Conley CR, Pockaj BA, Mukherjee P
A novel role for cyclooxygenase-2 in regulating vascular channel formation by human breast cancer cells.
Breast Cancer Res. 2006;8(6):R69.
INTRODUCTION: Cyclo-oxygenase (COX)-2 expression correlates directly with highly aggressive and metastatic breast cancer, but the mechanism underlying this correlation remains obscure. We hypothesized that invasive human breast cancer cells that over-express COX-2 have the unique ability to differentiate into extracellular-matrix-rich vascular channels, also known as vasculogenic mimicry. Vascular channels have been associated with angiogenesis without involvement of endothelial cells, and may serve as another mechanism by which tumor cells obtain nutrients to survive, especially in less vascularized regions of the tumor. METHODS: To determine whether COX-2 regulates vascular channel formation, we assessed whether treatment with celecoxib (a selective COX-2 inhibitor) or silencing COX-2 synthesis by siRNA inhibits vascular channel formation by breast cancer cell lines. Cell lines were selected based on their invasive potential and COX-2 expression. Additionally, gene expression analysis was performed to identify candidate genes involved in COX-2-induced vascular channel formation. Finally, vascular channels were analyzed in surgically resected human breast cancer specimens that expressed varying levels of COX-2. RESULTS: We found that invasive human breast cancer cells that over-express COX-2 develop vascular channels when plated on three-dimensional matigel cultures, whereas non-invasive cell lines that express low levels of COX-2 did not develop such channels. Similarly, we identified vascular channels in high-grade invasive ductal carcinoma of the breast over-expressing COX-2, but not in low-grade breast tumors. Vascular channel formation was significantly suppressed when cells were treated with celecoxib or COX-2 siRNA. Inhibition of channel formation was abrogated by addition of exogenous prostaglandin E2. In vitro results were corroborated in vivo in tumor-bearing mice treated with celecoxib. Using gene expression profiling, we identified several genes in the angiogenic and survival pathways that are engaged in vascular channel formation. CONCLUSION: Antivascular therapies targeting tumor cell vasculogenic mimicry may be an effective approach to the treatment of patients with highly metastatic breast cancer. [Abstract/Link to Full Text]

Paci E, Miccinesi G, Puliti D, Baldazzi P, De Lisi V, Falcini F, Cirilli C, Ferretti S, Mangone L, Finarelli AC, Rosso S, Segnan N, Stracci F, Traina A, Tumino R, Zorzi M
Estimate of overdiagnosis of breast cancer due to mammography after adjustment for lead time. A service screening study in Italy.
Breast Cancer Res. 2006;8(6):R68.
INTRODUCTION: Excess of incidence rates is the expected consequence of service screening. The aim of this paper is to estimate the quota attributable to overdiagnosis in the breast cancer screening programmes in Northern and Central Italy. METHODS: All patients with breast cancer diagnosed between 50 and 74 years who were resident in screening areas in the six years before and five years after the start of the screening programme were included. We calculated a corrected-for-lead-time number of observed cases for each calendar year. The number of observed incident cases was reduced by the number of screen-detected cases in that year and incremented by the estimated number of screen-detected cases that would have arisen clinically in that year. RESULTS: In total we included 13,519 and 13,999 breast cancer cases diagnosed in the pre-screening and screening years, respectively. In total, the excess ratio of observed to predicted in situ and invasive cases was 36.2%. After correction for lead time the excess ratio was 4.6% (95% confidence interval 2 to 7%) and for invasive cases only it was 3.2% (95% confidence interval 1 to 6%). CONCLUSION: The remaining excess of cancers after individual correction for lead time was lower than 5%. [Abstract/Link to Full Text]

Einarsd�ttir K, Rosenberg LU, Humphreys K, Bonnard C, Palmgren J, Li Y, Li Y, Chia KS, Liu ET, Hall P, Liu J, Wedr�n S
Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study.
Breast Cancer Res. 2006;8(6):R67.
BACKGROUND: Mutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. However, whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear. METHODS: We performed a comprehensive haplotype analysis of the ATM, CHEK2 and ERBB2 genes in a Swedish population-based study, which included 1,579 breast cancer cases and 1,516 controls. We followed the cases for 8.5 years, on average, and retrieved information on the date and cause of death during that period from the nationwide Swedish causes of death registry. We selected seven haplotype-tagging SNPs (tagSNPs) in the ATM gene, six tagSNPs in the CHEK2 gene and seven tagSNPs in the ERBB2 gene that predicted both haplotypic and single locus variations in the respective genes with R2 values > or = 0.8. These tagSNPs were genotyped in the complete set of cases and controls. We computed expected haplotype dosages of the tagSNP haplotypes and included the dosages as explanatory variables in Cox proportional hazards or logistic regression models. RESULTS: We found no association between any genetic variation in the ATM, CHEK2 or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics. CONCLUSION: Our results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristic-defined breast cancer. [Abstract/Link to Full Text]

Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, Lara J, Bleiweiss I, Berry D, Ellis M, Hayes DF, Winer EP, Dressler L
Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342.
Breast Cancer Res. 2006;8(6):R66.
INTRODUCTION: The response to paclitaxel varies widely in metastatic breast cancer. We analyzed data from CALGB 9342, which tested three doses of paclitaxel in women with advanced disease, to determine whether response and outcomes differed according to HER2, hormone receptor, and p53 status. METHODS: Among 474 women randomly assigned to paclitaxel at a dose of 175, 210, or 250 mg/m2, adequate primary tumor tissue was available from 175. Immunohistochemistry with two antibodies and fluorescence in situ hybridization were performed to evaluate HER2 status; p53 status was determined by immunohistochemistry and sequencing. Hormone receptor status was obtained from pathology reports. RESULTS: Objective response rate was not associated with HER2 or p53 status. There was a trend toward a shorter median time to treatment failure among women with HER2-positive tumors (2.3 versus 4.2 months; P = 0.067). HER2 status was not related to overall survival (OS). Hormone receptor expression was not associated with differences in response but was associated with longer OS (P = 0.003). In contrast, women with p53 over-expression had significantly shorter OS than those without p53 over-expression (11.5 versus 14.4 months; P = 0.002). In addition, triple negative tumors were more frequent in African-American than in Caucasian patients, and were associated with a significant reduction in OS (8.7 versus 12.9 months; P = 0.008). CONCLUSION: None of the biomarkers was predictive of treatment response in women with metastatic breast cancer; however, survival differed according to hormone receptor and p53 status. Triple negative tumors were more frequent in African-American patients and were associated with a shorter survival. [Abstract/Link to Full Text]

Saito H, Dubsky P, Dantin C, Finn OJ, Banchereau J, Palucka AK
Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8+ T cells by dendritic cells loaded with killed allogeneic breast cancer cells.
Breast Cancer Res. 2006;8(6):R65.
INTRODUCTION: The ability of dendritic cells (DCs) to take up whole tumor cells and process their antigens for presentation to T cells ('cross-priming') is an important mechanism for induction of tumor specific immunity. METHODS: In vitro generated DCs were loaded with killed allogeneic breast cancer cells and offered to autologous na�ve CD8+ T cells in 2-week and/or 3-week cultures. CD8+ T cell differentiation was measured by their capacity to secrete effector cytokines (interferon-gamma) and kill breast cancer cells. Specificity was measured using peptides derived from defined breast cancer antigens. RESULTS: We found that DCs loaded with killed breast cancer cells can prime na�ve CD8+ T cells to differentiate into effector cytotoxic T lymphocytes (CTLs). Importantly, these CTLs primed by DCs loaded with killed HLA-A*0201- breast cancer cells can kill HLA-A*0201+ breast cancer cells. Among the tumor specific CTLs, we found that CTLs specific for HLA-A2 restricted peptides derived from three well known shared breast tumor antigens, namely cyclin B1, MUC-1 and survivin. CONCLUSION: This ability of DCs loaded with killed allogeneic breast cancer cells to elicit multiantigen specific immunity supports their use as vaccines in patients with breast cancer. [Abstract/Link to Full Text]

Breast cancer research: the past and the future. London, UK, 1 November 2006. Abstracts.
Breast Cancer Res. 2006;8 Suppl 2S1-20. [Abstract/Link to Full Text]

Abba MC, Nunez MI, Colussi AG, Croce MV, Segal-Eiras A, Aldaz CM
GATA3 protein as a MUC1 transcriptional regulator in breast cancer cells.
Breast Cancer Res. 2006;8(6):R64.
INTRODUCTION: Recent studies have demonstrated that members of the GATA-binding protein (GATA) family (GATA4 and GATA5) might have pivotal roles in the transcriptional upregulation of mucin genes (MUC2, MUC3 and MUC4) in gastrointestinal epithelium. The zinc-finger GATA3 transcription factor has been reported to be involved in the growth control and differentiation of breast epithelial cells. In SAGE (serial analysis of gene expression) studies we observed an intriguing significant correlation between GATA3 and MUC1 mRNA expression in breast carcinomas. We therefore designed the present study to elucidate whether MUC1 expression is regulated by GATA3 in breast cancer cells. METHODS: Promoter sequence analysis of the MUC1 gene identified six GATA cis consensus elements in the 5' flanking region (GATA1, GATA3 and four GATA-like sequences). Chromatin immunoprecipitation and electrophoretic mobility-shift assays were employed to study the presence of a functional GATA3-binding site. GATA3 and MUC1 expression was analyzed in vitro with a GATA3 knockdown assay. Furthermore, expression of GATA3 and MUC1 genes was analyzed by real-time RT-PCR and immunohistochemistry on breast cancer-specific tissue microarrays. RESULTS: We confirmed the presence of a functional GATA3-binding site on the MUC1 promoter region in the MCF7 cell line. We determined that GATA3 knockdown assays led to a decrease in MUC1 protein expression in MCF7 and T47D cells. In addition, we detected a statistically significant correlation in expression between GATA3 and MUC1 genes at the mRNA and protein levels both in normal breast epithelium and in breast carcinomas (p = 0.01). GATA3 expression was also highly associated with estrogen receptor and progesterone receptor status (p = 0.0001) and tumor grade (p = 0.004) in breast carcinomas. CONCLUSION: Our study provides evidence indicating that GATA3 is probably a mediator for the transcriptional upregulation of MUC1 expression in some breast cancers. [Abstract/Link to Full Text]

Pan Y, Wang L, Dai JL
Suppression of breast cancer cell growth by Na+/H+ exchanger regulatory factor 1 (NHERF1).
Breast Cancer Res. 2006;8(6):R63.
INTRODUCTION: Na+/H+ exchanger regulatory factor 1 (NHERF1, also known as EBP50 or NHERF) is a putative tumour suppressor gene in human breast cancer. Located at 17q25.1, NHERF1 is frequently targeted during breast tumourigenesis. Loss of heterozygosity (LOH) at the NHERF1 locus is found in more than 50% of breast tumours. In addition, NHERF1 is mutated in a subset of primary breast tumours and breast cancer cell lines. LOH at the NHERF1 locus is strongly associated with aggressive features of breast tumours, implicating NHERF1 as a haploinsufficiency tumour suppressor gene. However, the putative NHERF1 tumour suppressor activity has not been functionally verified. METHODS: To confirm the NHERF1 tumour suppressor activity suggested by our genetic analyses, we used retrovirus-transduced short hairpin RNA (shRNA) to knock down NHERF1 expression in breast cancer cell lines MCF7 and T47D. These cells were then assessed for cell growth in vitro and in vivo. The control and NHERF1 knockdown cells were also serum-starved and re-fed to compare their cell cycle progression as measured by fluorescence-activated cell sorting analyses. RESULTS: We found that downregulation of the endogenous NHERF1 in T47D or MCF7 cells resulted in enhanced cell proliferation in both anchorage-dependent and -independent conditions compared with that of the vector control cells. NHERF1 knockdown T47D cells implanted at mammary fat pads of athymic mice formed larger tumours than did control cells. We found that serum-starved NHERF1 knockdown cells had a faster G1-to-S transition after serum re-stimulation than the control cells. Immunoblotting showed that the accelerated cell cycle progression in NHERF1 knockdown cells was accompanied by increased expression of cyclin E and elevated Rb phosphorylation level. CONCLUSION : Our findings suggested that the normal NHERF1 function in mammary epithelial cells involves blockage of cell cycle progression. Our study affirmed the tumour suppressor activity of NHERF1 in breast which may be related to its regulatory effect on cell cycle. It warrants future investigation of this novel tumour suppressor pathway in human breast cancer which may turn up therapeutic opportunities. [Abstract/Link to Full Text]

Nuyten DS, Kreike B, Hart AA, Chi JT, Sneddon JB, Wessels LF, Peterse HJ, Bartelink H, Brown PO, Chang HY, van de Vijver MJ
Predicting a local recurrence after breast-conserving therapy by gene expression profiling.
Breast Cancer Res. 2006;8(5):R62.
INTRODUCTION: To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients. METHODS: By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy. RESULTS: Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence. CONCLUSION: Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy. [Abstract/Link to Full Text]

Hannemann J, Velds A, Halfwerk JB, Kreike B, Peterse JL, van de Vijver MJ
Classification of ductal carcinoma in situ by gene expression profiling.
Breast Cancer Res. 2006;8(5):R61.
INTRODUCTION: Ductal carcinoma in situ (DCIS) is characterised by the intraductal proliferation of malignant epithelial cells. Several histological classification systems have been developed, but assessing the histological type/grade of DCIS lesions is still challenging, making treatment decisions based on these features difficult. To obtain insight in the molecular basis of the development of different types of DCIS and its progression to invasive breast cancer, we have studied differences in gene expression between different types of DCIS and between DCIS and invasive breast carcinomas. METHODS: Gene expression profiling using microarray analysis has been performed on 40 in situ and 40 invasive breast cancer cases. RESULTS: DCIS cases were classified as well- (n = 6), intermediately (n = 18), and poorly (n = 14) differentiated type. Of the 40 invasive breast cancer samples, five samples were grade I, 11 samples were grade II, and 24 samples were grade III. Using two-dimensional hierarchical clustering, the basal-like type, ERB-B2 type, and the luminal-type tumours originally described for invasive breast cancer could also be identified in DCIS. CONCLUSION: Using supervised classification, we identified a gene expression classifier of 35 genes, which differed between DCIS and invasive breast cancer; a classifier of 43 genes could be identified separating between well- and poorly differentiated DCIS samples. [Abstract/Link to Full Text]

Fehm T, Becker S, Becker-Pergola G, Sotlar K, Gebauer G, D�rr-St�rzer S, Neubauer H, Wallwiener D, Solomayer EF
Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer.
Breast Cancer Res. 2006;8(5):R60.
INTRODUCTION: Neoadjuvant systemic therapy (NST) is an established strategy to reduce tumor size in breast cancer patients prior to breast-conserving therapy. The effect of NST on tumor cell dissemination in these patients is not known. The aim of this study was to investigate the incidence of disseminated tumor cells (DTC), including apoptotic DTC, in breast cancer patients after NST, and to investigate the correlation of DTC status with therapy response. METHODS: Bone marrow aspiration was performed in 157 patients after NST. DTC were detected by immunocytochemistry using the A45-B/B3 anticytokeratin antibody. To detect apoptotic DTC the antibody M30 (Roche Diagnostics, Germany) was used, which detects a neo-epitope expressed only after caspase cleavage of cytokeratin 18 during early apoptosis. RESULTS: The incidence of DTC in breast cancer patients was 53% after completion of NST. Tumor dissemination was observed more frequently in patients with no change/progressive disease (69%) than in patients with partial remission or complete remission of the primary tumor (46%) (P < 0.05). Ten out of 24 patients with complete remission, however, were still bone marrow positive. Apoptotic DTC were present in 36 of 157 (23%) breast cancer patients. Apoptotic cells only were detected in 14% of the patients with partial remission or complete remission, but were detected in just 5% of the patients with stable disease. Apoptotic DTC were detectable in none of the patients with tumor progression. CONCLUSION: The pathological therapy response in breast cancer patients is reflected by the presence of apoptotic DTC. Patients with complete remission, however, may still have nonapoptotic DTC. These patients may also benefit from secondary adjuvant therapy. [Abstract/Link to Full Text]

Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R, Badve S, Nakshatri H
CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis.
Breast Cancer Res. 2006;8(5):R59.
INTRODUCTION: A subpopulation (CD44+/CD24-) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis. METHODS: CD44 and CD24 expression was determined by flow cytometry. Northern blotting was used to determine the expression of proinvasive and 'bone and lung metastasis signature' genes. A matrigel invasion assay and intracardiac inoculation into nude mice were used to evaluate invasion, and homing and proliferation at sites of metastasis, respectively. RESULTS: Five among 13 breast cancer cell lines examined (MDA-MB-231, MDA-MB-436, Hs578T, SUM1315, and HBL-100) contained a higher percentage (>30%) of CD44+/CD24- cells. Cell lines with high CD44+/CD24- cell numbers express basal/mesenchymal or myoepithelial but not luminal markers. Expression levels of proinvasive genes (IL-1alpha, IL-6, IL-8, and urokinase plasminogen activator [UPA]) were higher in cell lines with a significant CD44+/CD24- population than in other cell lines. Among the CD44+/CD24(-)-positive cell lines, MDA-MB-231 has the unique property of expressing a broad range of genes that favor bone and lung metastasis. Consistent with previous studies in nude mice, cell lines with CD44+/CD24- subpopulation were more invasive than other cell lines. However, only a subset of CD44+/CD24(-)-positive cell lines was able to home and proliferate in lungs. CONCLUSION: Breast cancer cells with CD44+/CD24- subpopulation express higher levels of proinvasive genes and have highly invasive properties. However, this phenotype is not sufficient to predict capacity for pulmonary metastasis. [Abstract/Link to Full Text]

Finak G, Sadekova S, Pepin F, Hallett M, Meterissian S, Halwani F, Khetani K, Souleimanova M, Zabolotny B, Omeroglu A, Park M
Gene expression signatures of morphologically normal breast tissue identify basal-like tumors.
Breast Cancer Res. 2006;8(5):R58.
INTRODUCTION: The role of the cellular microenvironment in breast tumorigenesis has become an important research area. However, little is known about gene expression in histologically normal tissue adjacent to breast tumor, if this is influenced by the tumor, and how this compares with non-tumor-bearing breast tissue. METHODS: To address this, we have generated gene expression profiles of morphologically normal epithelial and stromal tissue, isolated using laser capture microdissection, from patients with breast cancer or undergoing breast reduction mammoplasty (n = 44). RESULTS: Based on this data, we determined that morphologically normal epithelium and stroma exhibited distinct expression profiles, but molecular signatures that distinguished breast reduction tissue from tumor-adjacent normal tissue were absent. Stroma isolated from morphologically normal ducts adjacent to tumor tissue contained two distinct expression profiles that correlated with stromal cellularity, and shared similarities with soft tissue tumors with favorable outcome. Adjacent normal epithelium and stroma from breast cancer patients showed no significant association between expression profiles and standard clinical characteristics, but did cluster ER/PR/HER2-negative breast cancers with basal-like subtype expression profiles with poor prognosis. CONCLUSION: Our data reveal that morphologically normal tissue adjacent to breast carcinomas has not undergone significant gene expression changes when compared to breast reduction tissue, and provide an important gene expression dataset for comparative studies of tumor expression profiles. [Abstract/Link to Full Text]

Mylona E, Magkou C, Giannopoulou I, Agrogiannis G, Markaki S, Keramopoulos A, Nakopoulou L
Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: relation to tumor phenotype and clinical outcome.
Breast Cancer Res. 2006;8(5):R57.
INTRODUCTION: Our aim was to study the expression pattern of tissue inhibitor of metalloproteinases (TIMP)-3 protein in invasive breast carcinoma, and its clinicopathological and prognostic value as well as its relation to markers indicative of the tumor phenotype. METHODS: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 173 invasive breast carcinomas to detect the proteins TIMP-3, estrogen receptor (ER), progesterone receptor, p53, c-erbB-2, topoisomerase IIalpha and Bcl-2. RESULTS: TIMP-3 protein was immunodetected in the cytoplasm of the malignant cells and the peritumoral stroma, as well as in in situ carcinoma and normal epithelium. Reduced expression of TIMP-3 protein within cancer cells was correlated with carcinomas of high nuclear and histological grade (p = 0.032 and p = 0.015, respectively), and low ER expression (p = 0.053). Moreover, TIMP-3 immunopositivity was inversely correlated with the expression of p53 and topoIIalpha proteins (p = 0.002 and p = 0.008, respectively), whereas it was positively associated with Bcl-2 expression (p = 0.020). Reduced expression of TIMP-3 protein within cancer cells was found to have an unfavorable impact on disease-free survival (p = 0.052) in the entirety of the patient population, as well as in both subgroups of lymph-node-positive and mutant-p53-negative patients (p = 0.007 and p = 0.037, respectively). Stromal localization of TIMP-3 protein was found to have no clinicopathological or prognostic value. CONCLUSION: This is the first immunohistochemical study to show that TIMP-3 protein within cancer cells is associated with tumor phenotype. Reduced expression of TIMP-3 protein within cancer cells was found to correlate with an aggressive tumor phenotype, negatively affecting the disease-free survival of both subgroups of lymph node-positive and mutant-p53-negative patients. [Abstract/Link to Full Text]

Grigoriadis A, Mackay A, Reis-Filho JS, Steele D, Iseli C, Stevenson BJ, Jongeneel CV, Valgeirsson H, Fenwick K, Iravani M, Leao M, Simpson AJ, Strausberg RL, Jat PS, Ashworth A, Neville AM, O'Hare MJ
Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data.
Breast Cancer Res. 2006;8(5):R56.
INTRODUCTION: Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. METHODS: Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing (MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. RESULTS: MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. Microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/basal cells and upregulated in the tumour sample. One of the most highly overexpressed genes in this category, that encoding periostin, was analysed immunohistochemically on breast cancer tissue microarrays and its expression in neoplastic cells correlated with poor outcome in a cohort of poor prognosis estrogen receptor-positive tumours. CONCLUSION: Using highly enriched cell populations in combination with multiplatform gene expression profiling studies, a comprehensive analysis of molecular changes between the normal and malignant breast tissue was established. This study provides a basis for the identification of novel and potentially important targets for diagnosis, prognosis and therapy in breast cancer. [Abstract/Link to Full Text]

Stuedal A, Ursin G, Veier�d MB, Bremnes Y, Reseland JE, Drevon CA, Gram IT
Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study.
Breast Cancer Res. 2006;8(5):R55.
INTRODUCTION: Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk. METHODS: We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Troms�, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area. RESULTS: After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (P(trend) = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (P(trend) = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (P(trend) = 0.003, P for interaction = 0.05). CONCLUSION: We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast. [Abstract/Link to Full Text]

Recent Articles in International Seminars in Surgical Oncology

Siddiqui AA, Fayiga Y, Huerta S
The role of endoscopic ultrasound in the evaluation of rectal cancer.
Int Semin Surg Oncol. 2006;336.
Accurate staging of rectal cancer is essential for selecting patients who can undergo sphincter-preserving surgery. It may also identify patients who could benefit from neoadjuvant therapy. Clinical staging is usually accomplished using a combination of physical examination, CT scanning, MRI and endoscopic ultrasound (EUS). Transrectal EUS is increasingly being used for locoregional staging of rectal cancer. The accuracy of EUS for the T staging of rectal carcinoma ranges from 80-95% compared with CT (65-75%) and MR imaging (75-85%). In comparison to CT, EUS can potentially upstage patients, making them eligible for neoadjuvant treatment. The accuracy to determine metastatic nodal involvement by EUS is approximately 70-75% compared with CT (55-65%) and MR imaging (60-70%). EUS guided FNA may be beneficial in patients who appear to have early T stage disease and suspicious peri-iliac lymphadenopathy to exclude metastatic disease. [Abstract/Link to Full Text]

Mokbel R, Mokbel K
Skin-sparing mastectomy and radiotherapy: an update.
Int Semin Surg Oncol. 2006;335.
Despite the lack of randomised controlled trials and paucity of the published data, the current evidence suggests that the post-mastectomy radiation therapy (PMRT) does not represent a contraindication to skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) in the multidisciplinary setting. Although PMRT is associated with a higher incidence of complications, a satisfactory cosmetic outcome can be achieved in most patients. Radiation has a deleterious effect on autologous flap reconstruction that relies on fat for volume replacement such as the deep inferior epi-gastric perforator (DIEP) flap reconstruction and this method of reconstruction should be delayed until RT is completed. Until better methods of RT delivery are developed to minimise complications, women at high risk of requiring PMRT, can be safely offered SSM and IBR with a sub-pectoral saline-filled tissue expander and this can be replaced with a permanent prosthesis or converted into an autologous flap reconstruction after the completion of RT. Any capsule formation can be surgically treated at this stage. This new concept, known as immediate-delayed reconstruction, can avoid the cosmetic and RT delivery problems that can occur after IBR.Furthermore, prior RT does not represent a contra-indication to SSM and IBR, however it increases the incidence of complications. [Abstract/Link to Full Text]

Cherian J, Rajan S, Thwaini A, Elmasry Y, Shah T, Puri R
Secondary penile tumours revisited.
Int Semin Surg Oncol. 2006;333.
OBJECTIVE: To highlight the salient features of metastatic malignancies involving the penis, with special reference to the primary tumour sites, metastatic mechanisms, clinical features, differential diagnosis, treatment and prognosis. METHODS: A comprehensive search of the literature was performed using MEDLINE and EMBASE, using the keywords 'penis', 'secondary malignancy', 'metastasis' and 'malignant priapism' to identify reviews and case reports of secondary penile malignancy. A case of rare clinical presentation of metastatic penile lesion is presented along with the review of the literature. CONCLUSION: Secondary malignancy of the penis is a rare clinical entity, despite the rich vascularisation of this organ. The majority of metastatic lesions take their origin from the neighbouring genito-urinary organs, mainly prostate and bladder. These lesions are often associated with disseminated malignancy and hence have a poor outcome. Nodular or ulcerative lesions involving the corpora cavernosa or priapism are the main modes of clinical presentation. In most cases, only palliative or supportive therapy is indicated. [Abstract/Link to Full Text]

Carswell KA, Behranwala KA, Nerurkar A A, Gui GP
Breast carcinoma and malignant melanoma metastasis within a single axillary lymph node.
Int Semin Surg Oncol. 2006;332.
A 58 year old lady presented with a right breast cancer and a prior history of malignant melanoma excised from the right chest wall eight years previously. An abnormal axillary lymph node resected contained features of both metastatic breast carcinoma and malignant melanoma. Following oncologic breast cancer management, the patient is well with no evidence of recurrence at three years. [Abstract/Link to Full Text]

Mokbel R, Karat I, Mokbel K
Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update.
Int Semin Surg Oncol. 2006;331.
There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2-3 years followed by exemestane or anastrozole for 2-3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2-3 years of tamoxifen.The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures. [Abstract/Link to Full Text]

Rubello D, Al-Nahhas A, Mariani G, Gross MD, Rampin L, Pelizzo MR
Feasibility and long-term results of focused radioguided parathyroidectomy using a "low" 37 MBq (1 mCi) 99mTc-sestamibi protocol.
Int Semin Surg Oncol. 2006;330.
Aim of the present study was to investigate the feasibility and long-term results of focused radioguided parathyroidectomy using a "low" 37 MBq (1 mCi) 99mTc-sestamibi dose protocol compared to conventional "high 740 MBq (20 mCi) 99mTc-sestamibi dose protocol" in patients with primary hyperparathyroidism (PHPT). The data of focused radioguided surgery obtained in a group of 320 consecutive PHPT patients with high probability of the presence of a solitary parathyroid adenoma (PA) were studied. All patients underwent preoperative imaging work-up of double-tracer 99mTc-pertechnetate/99mTc-sestamibi subtraction parathyroid scintigraphy (Sestamibi scintigraphy) and high resolution neck ultrasound (US). In 301/320 patients (96.6%) focused minimally invasive radioguided surgery was successfully performed by administering a "low" 37 MBq (1 mCi) 99mTc-sestamibi dose in the operating room 10 minutes before operation. No major intraoperative complications were recorded. Focused radioguided surgery required a mean time of 32 min and a mean hospital stay of 1.2 days. Local anesthesia was applied in 75 patients, 66 of whom (88%) were patients older than 65 years with comorbidities contraindicating general anesthesia. No case of persistent or recurrent PHPT was observed during post-surgical follow-up (range = 18-70 months; mean +/- SD = 15.3 +/- 9.1 months). Radiation exposure dose to the operating surgeon was 1.2 microSi/hour with the "low 37 MBq (1 mCi) 99mTc-sestamibi dose", and less than 1.0 microSi/hour for the other operating-room personnel. Focused low dose radioguided parathyroidectomy is a safe and effective means to localize parathyroid adenomas in patients affected by solitary PA thus reducing by 20 fold the radiation exposure dose to the patients and operating room personnel. [Abstract/Link to Full Text]

de Sousa JA, Facina G, da Silva BB, Gebrim LH
Effects of low-dose tamoxifen on breast cancer biomarkers Ki-67, estrogen and progesterone receptors.
Int Semin Surg Oncol. 2006;329.
Breast carcinoma is the most common malignancy among women and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with a standard dose of the drug, and there has been a reduction in healthcare costs and side effects. The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days. A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group--without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions. Patients underwent incisional biopsy before treatment and 14 days later a tumor tissue sample was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and alpha was set at 5%. Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p = 0.627), estrogen receptor (1D5) (p = 0.296) and progesterone receptor positivity (PgR 636) (p = 0.381). In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki-67 (MIB-1) was 24.69% before and 10.43% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.53% before and 25.99% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.34 before and 29.59% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p < 0.001). Tamoxifen significantly reduced monoclonal antibody Ki-67 (MIB-1), estrogen receptor (1D5) and progesterone receptor positivity (PgR 636) in the breast epithelium of carcinoma patients treated with a 10 mg dose of tamoxifen for 14 days. [Abstract/Link to Full Text]

Willis SF, Barton D, Ind TE
Laparoscopic hysterectomy with or without pelvic lymphadenectomy or sampling in a high-risk series of patients with endometrial cancer.
Int Semin Surg Oncol. 2006;328.
BACKGROUND: The purpose of the study was to determine the outcome of all patients with endometrial adenocarcinoma cancer treated by laparoscopic hysterectomy at our institution, many of whom were high-risk for surgery. METHODS: Data was collected by a retrospective search of the case notes and Electronic Patient Records of the thirty eight patients who underwent laparoscopic hysterectomy for endometrial cancer at our institutions. RESULTS: The median body mass index was 30 (range 19-67). Comorbidities were present in 76% (29 patients); 40% (15 patients) had a single comorbid condition, whilst 18% (7 patients) had two, and a further 18% (7 patients) had more than two. Lymphadenectomy was performed in 45% (17 patients), and lymph node sampling in 21% (8 patients). Median operating time was 210 minutes (range 70-360 minutes). Median estimated blood loss was 200 ml (range 50-1000 ml). There were no intraoperative complications. Post-operative complications were seen in 21% (2 major, 6 minor). Blood transfusion was required in 5% (2 patients). The median stay was 4 post-operative nights (range 1-25 nights). In those patients undergoing lymphadenectomy, the mean number of nodes taken was fifteen (range 8-26 nodes). The pathological staging was FIGO stage I 76% (29 patients), stage II 8% (3 patients), stage III 16% (6 patients). The pathological grade was G1 31% (16 patients), G2 45% (17 patients), G3 24% (8 patients). CONCLUSION: Laparoscopic hysterectomy can be safely carried out in patients at high risk for surgery, with no compromise in terms of outcomes, whilst providing all the benefits inherent in minimal access surgery. [Abstract/Link to Full Text]

Porter NA, Anderson HL, Al-Dujaily S
Renal cell carcinoma presenting as a solitary cutaneous facial metastasis: case report and review of the literature.
Int Semin Surg Oncol. 2006;327.
BACKGROUND: Renal cell carcinoma is well known for its frequency to metastasise, particularly to lungs, liver, bones and brain. Metastasis to the skin is much less common. Presentation as a result of the skin lesion is even more unusual, with only 14 previously reported cases in the English literature. The majority of these cases have been reported in patients with recurrent disease or with other metastases. CASE PRESENTATION: We present only the second case of non-recurrent renal cell carcinoma with a solitary cutaneous facial metastasis reported in the English literature. CONCLUSION: Clinicians should conduct a careful inspection of the skin in patients with renal cell carcinoma and also have a high index of suspicion of primary internal organ malignancy in patients presenting with a skin lesion. [Abstract/Link to Full Text]

Tahir M, Hendry P, Baird L, Qureshi NA, Ritchie D, Whitford P
Radiation induced angiosarcoma a sequela of radiotherapy for breast cancer following conservative surgery.
Int Semin Surg Oncol. 2006;326.
Radiation induced angiosarcomas (RIA) can affect breast cancer patients who had radiotherapy following conservative breast surgery. They are very rare tumors and often their diagnosis is delayed due to their benign appearance and difficulty in differentiation from radiation induced skin changes. Therefore it is very important that clinicians are aware of their existence. We report here a case of RIA followed by discussion and review of literature. [Abstract/Link to Full Text]

Sandiford N, Prussia PR, Chiappa A, Zbar AP
Synchronous mucinous adenocarcinoma of the rectosigmoid seeding onto a pre-existing anal fistula.
Int Semin Surg Oncol. 2006;325.
Carcinoma within a long-standing fistula-in-ano is rare and may be defined by specific neoplastic involvement of the fistulous track in the absence of rectal mucosal carcinoma. The presence of a carcinoma of mucinous histology occurring synchronously in the perianal region and the colon is exceptionally rare. We present a case with a review of the literature concerning its aetiopathogenesis and treatment. A 72-year-old man with a 2 months history of dark red rectal bleeding and mucus per rectum with alternating constipation and diarrhoea, was observed. Clinical examination and a barium enema showed a perianal fistula and an annular stenosing lesion of the rectosigmoid. Preoperative CT scan confirmed the colonic lesion. Colonic resection and wide fistula excision were performed. Histology showed an adenocarcinoma with a clear resection margins. The fistula also showed a similar histology. Chemoradiation (5-Fluorouracil (425 mg/m2) and Leucovorin (20 mg/m2) with 4500 cGy external beam radiotherapy was utilized. Subsequent clinical follow-up and CT examination of the patient has not revealed recurrent disease at 14 months. [Abstract/Link to Full Text]

Sali P, Jewell AP
IL-1 does not reverse the anti-proliferative effect of aspirin in breast cancer cells.
Int Semin Surg Oncol. 2006;324.
OBJECTIVES: Interleukin-1 (IL-1) is a multifunctional proinflammatory cytokine. There have been studies suggesting a role in affecting growth and invasiveness of malignant breast cells by either blocking or stimulating growth of cultured MCF-7 breast cancer cells. This effect may be mediated by induction of COX-2. Aspirin is an inhibitor of COX-2 and has been implicated, with other non-steroidal anti-inflammatory drugs (NSAIDS) in prevention and treatment of breast cancer. In this study the in vitro effects of IL-1 and aspirin on growth of MCF-7 human breast cancer cells was examined. METHODS: MCF-7 cells were treated with various concentrations of IL-1 and aspirin alone and in combination. Cell growth was assessed by cell number measurement. RESULTS: Aspirin significantly decreased growth rate in a dose-dependent manner, alone and as a combined treatment with IL-1 with a maximum reduction in growth rate at 300 mg/ml (P < 0.05). Treatment with IL-1 alone showed no significant effect on growth rate of MCF-7 cells (P > 0.05). CONCLUSION: This study confirms that aspirin suppresses the proliferation rate of MCF-7 cells both as a single agent and in combination with IL-1. It also suggests that IL-1 alone does not stimulate or inhibit growth of MCF-7 cells. [Abstract/Link to Full Text]

Wong C, Wright C, Colclough A, Marsh S
Case report: Metaplastic carcinoma presenting as a breast abscess.
Int Semin Surg Oncol. 2006;323.
Metaplastic breast carcinoma (MBC) is a rare neoplasm containing a mixture of epithelial and mesenchymal elements. The epithelial component is usually ductal carcinoma but may include other variants of breast carcinomas including squamous carcinoma and osteogenic sarcoma. There is a relative paucity of data regarding such tumours. Metaplastic carcinoma carries a prognosis not dissimilar to that of comparable ductal carcinoma. This is the case of a 57 year old patient with MBC presenting with a breast abscess. A thorough literature search has not revealed any previous reports of MBC presenting as a breast abscess. [Abstract/Link to Full Text]

Todoroki T, Murata S, Nakagawa Y, Ohkohchi N, Morishita Y
A long-term survivor of repeated inguinal nodes recurrence of papillary serous adenocarcinoma of CUP: case report.
Int Semin Surg Oncol. 2006;322.
BACKGROUND: Tumor spread beyond the peritoneal cavity in cases of papillary serous adenocarcinoma of the unknown primary (CUP) is a rare late event and carries a poor prognosis. CASE PRESENTATION: A 71-year-old female was referred to our hospital because of a large right inguinal tumor with biopsy evidence of carcinoma as well as an elevated serum CA125 (cancer antigen 125). She underwent complete resection of the right inguinal tumor and multiple pelvic tumors, which involved the rectum, ovary and uterus. Pathological examination revealed the tumors to be metastases of a papillary serous adenocarcinoma with a psammoma body of CUP. On the 28th postoperative day, newly developed asymptomatic small left inguinal node metastases in the setting of a normal CA125 level were removed. Four and a half years after the primary resection, the CA125 level increased again and newly developed asymptomatic metastases were found in the right deep inguinal nodes and extirpated at that time. All surgical resections followed the modified FAM (5FU, Adriamycin; ADM, MMC) regimen, including protracted dairy oral administration of UFT or 5'-FDUR, Cimetidine and PSK (protein-bound polysaccharide K) as an immunomodulator or biological response modifier in conjunction with intermittent one-day continuous infusion (ADM+MMC) or intermittent single bolus injection of ADM+MMC. At present, the patient has been living in good health for almost 7 years with no evidence of relapse. CONCLUSION: Aggressive resection surgery followed by effective adjuvant chemotherapy is necessary for surviving long time without relapse of poorly prognostic patients with metastases outside of the abdominal cavity from peritoneal papillary serous adenocarcinomas. [Abstract/Link to Full Text]

Qureshi NA, Tahir M, Carmichael AR
Granular cell tumour of the soft tissues: a case report and literature review.
Int Semin Surg Oncol. 2006;321.
Granular cell tumours (GCT) of the soft tissues are rare benign tumours but some time may be difficult to distinguish from malignant neoplasms. It is important that clinicians are aware of their existence. We present a new case of GCT of the soft tissues followed by a brief review of literature. [Abstract/Link to Full Text]

Hosseini-Asl S, Atri M, Modarressi MH, Salhab M, Mokbel K, Mehdipour P
The expression of hTR and hTERT in human breast cancer: correlation with clinico-pathological parameters.
Int Semin Surg Oncol. 2006;320.
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesizes telomeres after cell division and maintains chromosomal stability leading to cellular immortalization. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any association between telomerase sub-units: hTERT and hTR and the prognostic indicators including tumour's size and grade, nodal status and patient's age. METHODS: Tumour samples from 46 patients with primary invasive breast cancer and 3 patients with benign tumours were collected. RT-PCR analysis was used for the detection of hTR, hTERT, and PGM1 (as a housekeeping) genes expression. RESULTS: The expression of hTR and hTERT was found in 31(67.4%) and 38 (82.6%) samples respectively. We observed a significant association between hTR gene expression and younger age at diagnosis (p = 0.019) when comparing patients < or = 40 years with those who are older than 40 years. None of the benign tumours expressed hTR gene. However, the expression of hTERT gene was revealed in 2 samples. No significant association between hTR and hTERT expression and tumour's grade, stage and nodal status was seen. CONCLUSION: The expression of hTR and hTERT seems to be independent of tumour's stage. hTR expression probably plays a greater role in mammary tumourogenesis in younger women (< or = 40 years) and this may have therapeutic implications in the context of hTR targeting strategies. [Abstract/Link to Full Text]

Castelli P, Caronno R, Piffaretti G, Tozzi M, Lomazzi C, Dionigi G, Boni L, Dionigi R
Surgical treatment of malignant involvement of the inferior vena cava.
Int Semin Surg Oncol. 2006;319.
BACKGROUND: Resection and replacement of the inferior vena cava to remove malignant disease is a formidable procedure. The purpose of this review is to describe our experience with regard to patient selection, operative technique, and early and late outcome. METHODS: The authors retrospectively reviewed a 12-year series of 11 patients; there were 10 males, with a mean age 57 +/- 13 years (range 27-72) who underwent caval thrombectomy and/or resection for primary (n = 9) or recurrent (n = 2) vena cava tumours. Tumour location and type, clinical presentation, the segment of vena cava treated, graft patency, and tumour recurrence and survival data were collected. Late follow-up data were available for all patients. Graft patency was determined before hospital discharge and in follow-up by CT scan or ultrasonography. More than 80% of patients had symptoms from their caval involvement. The most common pathologic diagnosis was renal cell carcinoma (n = 6), and hepatocarcinoma (n = 2). In all but 2 patients, inferior vena cava surgical treatment was associated with multivisceral resection, including extended nephrectomy (n = 5), resection of neoplastic mass (n = 3), major hepatic resection (n = 2), and adrenal gland resection (n = 1). Prosthetic repair was performed in 5 patients (45%). RESULTS: There were no early deaths. Major complications occurred in 1 patient (9%). Mean length of stay was 16 days. Late graft thrombosis or infection did not occur. The mean follow-up was 22.7 months (range 6-60). There have been no other late graft-related complications. All late deaths were caused by the progression of malignant disease and the actuarial survival rate was 100% at 1 year. Mean survival was 31 months (median 15). CONCLUSION: Aggressive surgical management may offer the only chance for cure or palliation for patients with primary or secondary caval tumours. Our experience confirms that vena cava surgery for tumours may be performed safely with low graft-related morbidity and good patency in carefully selected patients. [Abstract/Link to Full Text]

Quadros CA, Vasconcelos A, Andrade R, Ramos RS, Studart E, Nascimento G, Trajano A
Good outcome after neoadjuvant chemotherapy and extended surgical resection for a large radiation-induced high-grade breast sarcoma.
Int Semin Surg Oncol. 2006;318.
This article is a case report of a high grade, radio-induced, breast malignant fibrous histiocytoma (undifferentiated high grade pleomorphic sarcoma), which developed in a 44-year old female, seven years after breast conservative surgery and radiotherapy for a T1N0M0 invasive left breast ductal carcinoma. The sarcoma presented as a fast growing tumour, 9.5 cm in the largest diameter, with skin, left breast, chest wall muscle and rib invasion. Neoadjuvant chemotherapy was performed with epirubicin and ifosfamide. Extended radical surgery according to oncological standards and soft tissue reconstruction were carried out. Despite bad prognostic features of high grade and large invasive sarcoma, the patient is currently, after 44 months of follow up, without local recurrence, or metastases, exceeding the 12.8-month mean recurrence period and mortality rate for these tumours larger than 8.1 cm (+/- 1.2 cm) as described in the literature. [Abstract/Link to Full Text]

Muslimani AA, Ahluwalia MS, Clark CT, Daw HA
Primary adenoid cystic carcinoma of the breast: case report and review of the literature.
Int Semin Surg Oncol. 2006;317.
Adenoid cystic carcinoma (ACC) of the breast is a rare neoplasm accounting for 0.1% of all breast carcinomas, and presenting most commonly as a painful breast mass. In contrast to the aggressive nature of ACC at other sites, ACC of the breast has a favorable prognosis, lymph node involvement or distant metastases seldom occur. Treatment is basically of simple mastectomy. Chemotherapy, radiation and hormonal treatment have been infrequently used and evaluated. We report a case of ACC of the breast managed with mastectomy and review the literature. [Abstract/Link to Full Text]

Al Sarakbi W, Salhab M, Mokbel K
Does mammary ductoscopy have a role in clinical practice?
Int Semin Surg Oncol. 2006;316.
BACKGROUND: Mammary ductoscopy (MD) is a newly developed endoscopic technique that allows direct visualisation of the mammary ductal epithelium using sub-millimetre fiberoptic microendoscopes inserted through the ductal opening onto the nipple surface. These scopes also provide working channels for insufflation, irrigation, ductal lavage, and possible therapeutic intervention. MD can be performed under local anaesthesia in the office setting.The objective of this study is to assess the technical feasibility of mammary ductoscopy, and examine its role in guiding ductal excision surgery and the early diagnosis of malignancy. METHODS: Mammary ductoscopy (MD) was performed using a 1 mm fiberoptic microendoscope (Mastascope TM) in 26 patients (age range: 14-73 years): 13 patients undergoing mastectomy (n = 12) or lumpectomy (n = 1) for ductal carcinoma (including 12 cases of DCIS and one case of infiltrating ductal carcinoma) and 13 patients with pathological nipple discharge (PND) and benign breast imaging and simple discharge cytology. Of the latter group: 10 procedures were performed under local anaesthesia (LA) in the office setting and 3 procedures were carried out under general anaesthesia (GA) to guide duct excision surgery. The ductoscopic appearances in this group were graded between 0 and 5 (D0-D5) according to the degree of suspicion. RESULTS: Intraoperative MD was accomplished in 11 (84.6%) of 13 patients undergoing surgery for DCIS. MD was unsuccessful in 2 cases: one patient (aged 73 years) had sclerosis of the nipple and one patient had preoperative vital blue injection in the subareolar region as part of the sentinel node biopsy thus resulting in inadequate visualisation. Intraductal pathology was visualised in 8 (80%) of the 10 cases undergoing mastectomy but ductoscopic cytology was positive for malignancy in only 2 cases (sensitivity = 16%, specificity = 100%). In the office setting, MD was accomplished in 9 (90%) out of 10 patients with PND and was well tolerated (mean pain score = 3.8 out of 10: range 0-7). Of these 10 patients; MD was inadequate (D0) in one patient due to complete occlusion of lumen by the lesion, showed a papilloma in 3 patients (D3), duct ectasia (D2) in 3 patients, irregular thickening of the lumen suspicious of DCIS (D4) in one patient and non-specific benign findings (D2) in 2 patients. Three women with benign ductoscopy and ductoscopy-assisted cytology were reassured and treated conservatively. The remaining 7 patients had ductoscopy-guided duct excision which revealed DCIS in one, papilloma in 4 and benign breast disease in 2 patients. Adequate cellular yield was obtained in 7 (70%) out of 10 cases (benign cytology). The three patients who had MD under GA during microdochectomy had benign endoscopic appearances and final histology (one papilloma and 2 cases of duct ectasia). CONCLUSION: MD is technically feasible in most patients and has a potential in the early detection of breast cancer. The procedure can be performed safely in the office setting and should be considered in all patients presenting with a single duct PND. MD has the potential to reduce the number of duct excision procedures and minimise the extent of surgical resection. Ductoscopic cytology is not sufficiently sensitive for the diagnosis of malignancy and the development of a biopsy tool that obtains tissue under direct visualisation is required. [Abstract/Link to Full Text]

Qureshi NA, Hallissey MT, Fielding JW, Gourevitch D
Primary intra-abdominal malignant fibrous histiocytoma presenting as pyrexia of unknown origin--report of a case with review of literature.
Int Semin Surg Oncol. 2006;315.
Primary intra-abdominal malignant mesenchymal tumours are very rare and there are not many cases of visceral malignant fibrous histiocytoma in the English literature. We report a new case of abdominal malignant fibrous histiocytoma presenting as abdominal pain and pyrexia of unknown origin in a 54 year old female followed by a brief review of literature. Presentation with pyrexia of unknown origin is extremely rare in this condition. [Abstract/Link to Full Text]

Cunnick GH, Mokbel K
Oncological considerations of skin-sparing mastectomy.
Int Semin Surg Oncol. 2006;314.
AIM: To review evidence concerning the oncological safety of performing skin-sparing mastectomy (SSM) for invasive breast cancer and ductal carcinoma in situ (DCIS). Furthermore, the evidence concerning RT in relation to SSM and the possibility of nipple preservation was considered. METHODS: Literature review facilitated by Medline and PubMed databases. FINDINGS: Despite the lack of randomised controlled trials, SSM has become an accepted procedure in women undergoing mastectomy and immediate reconstruction for early breast cancer. Compared to non-skin-sparing mastectomy (NSSM), SSM seems to be oncologically safe in patients undergoing mastectomy for invasive tumours smaller than 5 cm, multicentric tumours, DCIS or risk-reduction. However, the technique should be avoided in patients with inflammatory breast cancer or in those with extensive tumour involvement of the skin in view of the high risk of local recurrence. SSM with nipple areola complex (NAC) preservation appears to be oncologically safe, provided the tumour is not close to the nipple and a frozen section protocol for the retro-areolar tissue is followed. Although radiotherapy (RT) does not represent a contraindication to SSM, the latter should be used with caution if postoperative RT is likely, since it detracts from the final cosmetic outcome. [Abstract/Link to Full Text]

Papagrigoriadis S
Transanal endoscopic micro-surgery (TEMS) for the management of large or sessile rectal adenomas: a review of the technique and indications.
Int Semin Surg Oncol. 2006;313.
In this review article the surgical technique of Transanal Endoscopic Microsurgery (TEMS) is examined. A number of techniques have been used to treat adenomas of the rectum. The treatment of large adenomas which occupy a large surface of the rectal lumen or adenomas which are flat and grow in a "carpet-like" fashion is particularly challenging. Major rectal surgery carries a risk of morbidity and mortality, particularly in elderly and unfit patients. Although local excision with transanal resection (TAR) and the Kraske sacral operation have been used in the past, during the last twenty years TEMS has become the method of choice for those lesions. TEMS is efficient and minimally invasive. The technique allows the patient to recover rapidly and the incidence of complications is much lower than that of major surgery. In case of recurrence the option of repeat TEMS or major surgery remain available. TEMS has been slow to gain popularity mainly for reasons of cost and steep learning curve but it is now an established procedure and a valuable therapeutic option which is particularly useful for elderly and unfit patients. Gastroenterologists should be aware of the nature and indications of TEMS in order to advise and refer selected patients with rectal adenomas accordingly. [Abstract/Link to Full Text]

Khan AA, Davenport K
A reminder of the association between Clostridium septicum and colonic adenocarcinoma.
Int Semin Surg Oncol. 2006;312.
We present the case of a patient, with previously unknown liver metastases, presenting with a liver abscess and Clostridium septicum septicaemia. C. septicum is known to be associated with both malignancy and immunosuppression and therefore in patients where this organism is isolated, efforts must be made to exclude an occult underlying malignancy or haematological disorder. [Abstract/Link to Full Text]

Lisewski D, Ryan S, Lim EM, Frost F, Nguyen H
Concomitant compostite adrenal phoechromocytoma, multipte gastric stromal tumours and pseudohermaphrodism in a patient with von Recklinghausen's disease.
Int Semin Surg Oncol. 2006;311.
Although pheochromocytoma occurs in 1% of patients with von Recklinghausen's disease, composite tumors in this syndrome are much rarer, with isolated case reports in the literature. Most gastrointestinal stromal tumors (GISTs) are solitary and sporadic. Multiple GISTs however, are associated with clinical syndromes particularly von Recklinghausen's disease. We believe this is the first report of composite adrenal pheochromocytoma and multiple GISTs occurring in an 82 year old woman with neurofibromatosis type 1 (NF1), manifested by clitoral and subcutaneous neurofibromas, epilepsy and Lisch nodules. The extreme clitoromegaly raised concerns of pseudohermaphrodism at presentation. [Abstract/Link to Full Text]

Dionigi G, Dionigi R, Rovera F, Boni L, Carcano G
Reconstruction after esophagectomy in patients with [partial] gastric resection. Case report and review of the literature of the use of remnant stomach.
Int Semin Surg Oncol. 2006;310.
BACKGROUND: Bowel reconstruction after subtotal esophagectomy represents a problem when a previous distal gastrectomy was performed: usually the colon or jejunum is used. METHODS: In a 10 year period 126 patients with primary esophageal cancer underwent esophageal resection in our Department. Surgical procedures were 57% two-phase subtotal oesophagectomy, 23% transhiatal, 9% stripping, 10 three-phase total esophagectomy and 2 endoscopic resections. RESULTS: In 112 patients alimentary tract reconstruction was achieved by means of esophago-gastric anastomosis. Reconstruction was performed using colon in 10 cases and jejunum in 2. We describe the technical aspects of esophagectomy and gastric reconstruction in a patient with previous antrectomy and Billroth II reconstruction. The procedure was performed via a combined laparotomy and thoracotomy with anastomosis at the level of the azygous vein using the remnant stomach. CONCLUSION: Few technical reports have been reported in literature about the use of remnant stomach in reconstruction for subtotal esophagectomy subsequent to distal gastrectomy. Several hypotheses are made to explain the maintenance of the gastric vascular integrity as its intramural network without micro-vascular anastomosis. [Abstract/Link to Full Text]

Sangster P, Ind TE
The use of the 1 mm laparoscope to assist in port insertion in pelvic oncological surgery.
Int Semin Surg Oncol. 2006;39.
BACKGROUND: A 1 mm minilaparoscope (Lifeline Biotechnoligies, Florida, USA) was assessed for aiding port site insertions. METHODS: Ten consecutive patients having laparoscopic procedures in a gynaecological oncology unit were included. Minilaparoscopy was feasible in all cases and was used to insert the umbilical port under direct vision in all patients. In one case, a thick band of abdominal adhesions was identified and a further lateral port site was inserted to aid their dissection. RESULTS: The minilaparoscope correctly identified all 10 patients with peritoneal disease and identified all patients who were suitable for debulking procedures. CONCLUSION: Minilaparoscopy with the 1 mm endoscope appears to be safe and accurate and we feel that it has a place in helping the surgeon identify adhesions and peritoneal disease as well as assisting further port site insertion safely and with minimal complications. [Abstract/Link to Full Text]

Salhab M, Keith LG, Laguens M, Reeves W, Mokbel K
The potential role of dynamic thermal analysis in breast cancer detection.
Int Semin Surg Oncol. 2006;38.
BACKGROUND: It is presently well accepted that the breast exhibits a circadian rhythm reflective of its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian. Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development. The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. The aim of this prospective study was to evaluate the feasibility of dynamic thermal analysis (DTA) as a potential breast cancer screening tool. METHODS: 173 women undergoing mammography as part of clinical assessment of their breast symptoms were recruited prior to having a biopsy. Thermal data from the breast surface were collected every five minutes for a period of 48 hours using eight thermal sensors placed on each breast surface [First Warning System (FWS), Lifeline Biotechnologies, Florida, USA]. Thermal data were recorded by microprocessors during the test period and analysed using specially developed statistical software. Temperature points from each contra-lateral sensor are plotted against each other to form a thermal motion picture of a lesion's physiological activity. DTA interpretations [positive (abnormal thermal signature) and negative (normal thermal signature)] were compared with mammography and final histology findings. RESULTS: 118 (68%) of participating patients, were found to have breast cancer on final histology. Mammography was diagnostic of malignancy (M5) in 55 (47%), indeterminate (M3, M4) in 54 (46%) and normal/benign (M1, M2) in 9 (8%) patients. DTA data was available on 160 (92.5%) participants. Using our initial algorithm, DTA was interpreted as positive in 113 patients and negative in 47 patients. Abnormal thermal signatures were found in 76 (72%) out of 105 breast cancer patients and 37 of the 55 benign cases. Then we developed a new algorithm using multiple-layer perception and SoftMax output artificial neural networks (ANN) on a subgroup (n = 38) of recorded files. The sensitivity improved to 76% (16/21) and false positives decreased to 26% (7/27) CONCLUSION: DTA of the breast is a feasible, non invasive approach that seems to be sensitive for the detection of breast cancer. However, the test has a limited specificity that can be improved further using ANN. Prospective multi-centre trials are required to validate this promising modality as an adjunct to screening mammography especially in young women with dense breasts. [Abstract/Link to Full Text]

Ek ET, Ojaimi J, Kitagawa Y, Choong PF
Outcome of patients with osteosarcoma over 40 years of age: is angiogenesis a marker of survival?
Int Semin Surg Oncol. 2006;37.
BACKGROUND: Osteosarcoma predominantly afflicts young people in their second and third decades of life. When osteosarcoma arises in patients older than 40 years, the prognosis is usually poorer compared to their younger counterparts. Although the clinical, histopathologic features and prognostic indicators are well defined for young patients, much less is known about affected adults. The purpose of this study is to describe our institution's experience with the management of osteosarcoma in patients greater than 40 years and also evaluate, by immunohistochemical analysis, the prognostic significance of microvessel density, as a marker of intratumoural angiogenesis. METHODS: A retrospective clinicopathological analysis was performed on 11 patients over the age of 40 years that were treated at our institution between 1996 and 2004. Archival pre-treatment biopsy tissue was retrieved for immunohistochemical staining against two endothelial cell markers (CD31 and CD34) and also against VEGF. Angiogenesis was assessed by determining the intratumoural microvessel density (MVD) and the degree of VEGF expression in these specimens. This was correlated with patient outcome in terms of local recurrence, metastasis and death. Histological results were also compared to a group of patients less than 40 years of age. RESULTS: Of the 11 patients, 9 were male and 2 were female and the mean age was 58 years (range, 42-85). In 7 patients, osteosarcoma arose secondarily from Paget's disease of the bone. The most common site involved was the humerus (7) followed by the femur (2) then pelvis (1) and ulna (1). At the time of diagnosis, 4 patients had metastatic disease. Preoperative chemotherapy was given to 4 patients, with a good response in 3 patients. Six patients underwent limb-sparing surgery, 4 had amputations and 1 was treated with radiotherapy alone. The mean follow up time was 31.5 months (range, 8-81). At this time, 4 patients (36%) had developed lung metastases and 5 patients (46%) had died. Overall survival was 54.5%. Intratumoural MVD was higher in patients over 40 years, although not statistically significant (p = 0.111, CD31; p = 0.134, CD34). VEGF was uniformly expressed in all sections, however no relationship was found between the degree of expression and patient age. CONCLUSION: The prognosis for older patients with osteosarcoma is generally poor. Initial presentation is commonly associated with metastatic disease and neoadjuvant chemotherapy is often avoided because of its side effects. Increased intratumoural vascularity may contribute to the poorer prognosis in these patients, however further studies are needed. [Abstract/Link to Full Text]

Barbetakis N, Efstathiou A, Xenikakis T, Konstantinidis H, Fessatidis I
An unusual cause of haemoptysis in a young male.
Int Semin Surg Oncol. 2006;36.
Inflammatory myofibroblastic tumours are reported to occur in a variety of sites, including the head and neck, abdominal organs, central nervous system and urinary tract. They only rarely occur in the lung.We report a case of a 25-year-old male admitted with haemoptysis. His chest radiograph showed a peripheral right lung opacity and computed tomography revealed a right lower lobe soft tissue density mass. Bronchoscopy and fine needle aspiration were unhelpful. a diagnosis of pulmonary carcinoma was made, and the patient underwent a right lower lobectomy. On pathology, the tumor was found to be an inflammatory pseudotumor. These lesion are extremely rare, constituting less than 1% of pulmonary malignancies, but are known to occur in young patients. We believe clinicians need to retain an index of suspicion for the presence of this disease in young patients, which can masquerade as more common malignancies. [Abstract/Link to Full Text]

Recent Articles in World Journal of Surgical Oncology

Wang TS, Ocal IT, Salem RR, Elefteriades J, Sosa JA
Leiomyosarcoma of the adrenal vein: a novel approach to surgical resection.
World J Surg Oncol. 2007;5109.
BACKGROUND: Leiomyosarcomas typically originate within smooth muscle cells. Leiomyosarcomas arising from the adrenal vein are rare malignancies associated with delayed diagnosis and poor prognosis. The most common vascular site of origin is the inferior vena cava. CASE PRESENTATION: This is a 64-year old woman who presented with a 13 x 6.5 x 6.6 cm heterogeneous mass arising in the region of the right adrenal gland and extending into the inferior vena cava (IVC) and the right atrium. Biochemical evaluation excluded a functional tumor of the adrenal gland, and multiple tumor markers were negative. We present the novel use of deep hypothermic circulatory arrest (DHCA) in the resection of an adrenal vein leiomyosarcoma extending into the right atrium. The patient remains free of disease ten months after surgery. DHCA afforded a bloodless operative field for optimal resection of disease from within the IVC. CONCLUSION: The diagnosis of leiomyosarcomas of the adrenal vein is one of exclusion and involves preoperative radiological imaging and biochemical evaluation to exclude other functional tumors of the adrenal gland. Aggressive surgical resection is associated with improved survival and may be best achieved via collaboration among different surgical subspecialties. [Abstract/Link to Full Text]

Wasserman LJ, Apffelstaedt JP, Odendaal Jde V
Conservative management of breast cancer in the elderly in a developing country.
World J Surg Oncol. 2007;5108.
BACKGROUND: The cost effective treatment of cancer in developing countries remains challenging. In the elderly with possible limited life expectancy, the health expenditure associated with standard treatment regimes should be carefully considered. We present the results of conservative management of breast cancer in the aged in a resource-limited environment. METHODS: Patients aged 70 or older with early breast cancer were treated with tumour excision or simple mastectomy and adjuvant tamoxifen. The records of patients presenting to the Breast Unit between January 1990 and December 2004 were retrieved and demographic, clinical, pathological and oncological data were reviewed. Survival statistics were calculated using the life table method. RESULTS: A total of 483 patients above 70 years of age were identified. One hundred and eighty eight patients were managed according to the conservative protocol. Forty-one had a simple mastectomy and 147 tumour excision. Their mean age was 77.3 years. The mean follow-up is 62 months. Thirty-one patients (16.4%) were not compliant with tamoxifen use. TNM staging was 0 in 4 patients, I in 42 patients, II in 116 patients and III in 26 patients. There was no 30-day mortality. The cumulative incidence of local recurrence was 3.3% at 5 and 10 years. The cumulative incidence of regional recurrence was 3.3% at 5 years and 4.5% at 10 years. The cumulative incidence of distant recurrence was 6.2% at 5 years and 12.2% at 10 years. The cumulative overall, disease specific and disease free survival at 10 years was 59%, 88% and 81% respectively. CONCLUSION: Limited surgery and tamoxifen provide excellent control of breast cancer in the elderly in a resource restricted environment. Radiotherapy and axillary dissection and can be safely omitted thereby reducing health care resource utilization. [Abstract/Link to Full Text]

Jeyarajah S, King A, Papagrigoriadis S
Faecal incontinence as presentation of an ependymomas of the spinal cord.
World J Surg Oncol. 2007;5107.
ABSTRACT: BACKGROUND: Spinal tumours and ependymomas in particular are rare causes of cauda equina syndrome that present with faecal incontinence. CASE PRESENTATION: We present a case of a 45 year old gentleman who presents to a colorectal clinic with incontinence. We then present a review of ependymomas with particular reference to the symptoms they cause as well a review of the neurophysiology of faecal continence. CONCLUSION: Suspicion for non-colonic causes for faecal incontinence should arise when there is absence of other etiologic factors. Establishment of the diagnosis of spinal tumours is with neurological examination and MRI spine. [Abstract/Link to Full Text]

Selvan DR, Philip J, Manikandan R, Helliwell TR, Lamb GH, Desmond AD
Inflammatory pseudotumor of the Kidney.
World J Surg Oncol. 2007;5106.
ABSTRACT: BACKGROUND: Inflammatory pseudotumor of the kidney or inflammatory myofibroblastic tumor (IMT) is composed of spindle cells admixed with variable amount of proliferating myofibroblasts, fibroblasts, extracellular collagen, lymphocytes and plasma cells. This mainly affects the urinary bladder or prostate. Renal involvement is rare. CASE PRESENTATION: A 56 year-old man was diagnosed with asymptomatic left sided hydronephrosis while being investigated for rheumatoid arthritis. CT scan imaging showed ill defined fascial plains around the kidney and thickening around the renal hilum suggestive of localized inflammatory change. Worsening intermittent left loin pain with increasing hydronephrosis, significant cortical thinning and marked deterioration of renal function necessitated nephrectomy. Macroscopy showed a hydronephrotic fibrotic kidney with microscopy and immunohistochemistry consistent with a histological diagnosis of IMT. CONCLUSION: We report a case of an inflammatory pseudotumor of the kidney. It is unique in that the patient presented with painless hydronephrosis followed two years later with progressive deterioration in renal function and worsening loin pain. [Abstract/Link to Full Text]

Ball E, Morris-Stiff G, Coxon M, Lewis MH
Mucinous adenocarcinoma presenting as an isolated sternal metastasis.
World J Surg Oncol. 2007;5105.
ABSTRACT: BACKGROUND: As a result of improvements in diagnostic accuracy, the primary source of the tumour is identified in more than 99% of cases presenting with a malignancy. Whilst the axial skeleton is a common site of metastases, the sternum is rarely affected, especially by isolated metastases. CASE PRESENTATION: We report a case of a 68 year old male who was referred to the surgical outpatient clinic with a six month history of sternal pain. The patient was known to have essential thrombocythaemia, which had recently transformed into acute myeloid leukaemia but a sternal biospy showed mucinous adenocarcinoma. He had not localising symptoms and full evaluation failed to localise the primary tumour. CONCLUSION: Solitary sternal metastases are rare and when found an underlying neoplasm is usually identified allowing targeted treatment. If however, there is no symptomatic tumour, the metastasis should simply be treated symptomatically. [Abstract/Link to Full Text]

Stanczyk M, Grala B, Zwierowicz T, Maruszynski M
Surgical resection for persistent seroma, following modified radical mastectomy.
World J Surg Oncol. 2007;5104.
BACKGROUND: Seroma formation following modified radical mastectomy with axillary lymph node dissection for breast cancer is a most common wound complication. In our experience seroma occurs in approximately 50% of patients undergoing mastectomy. Postmastectomy seromas usually vanishes within a few weeks after operation. CASE PRESENTATION: In this report we present the case of a 73 year old woman who had undergone mastectomy with axillary lymph node dissection for breast cancer, complicated by lymphorrhea and formation fibrous encapsulated seroma resistant to conservative treatment which required surgical resection. CONCLUSION: We stand in opinion that in some cases of prolonged seromatous effusion with confirmed formation of thick walled reservoir the operation with resection and closure of supplying regional lymph vessels may be the best treatment, if possible preceded by arm lymphoscyntygraphy. [Abstract/Link to Full Text]

Alzaraa A, Udom V, Mousa H, Alzein A, Benhamida A, Dalal N
Combined endocrine and exocrine tumours of the pancreas.
World J Surg Oncol. 2007;5103.
ABSTRACT: BACKGROUND: Cystic neoplasms of the pancreas comprise 10%-15% of pancreatic cystic lesions, with the serous cystadenoms being the commonest. The association of exocrine and endocrine tumours of the pancreas unrelated to Von Hipple Lindau disease is very rare. Very few cases have been reported in the literature. We present another case of both these tumours in one patient. CASE PRESENTATION: A female patient was seen in the surgical clinic for a pain in the right groin. Clinical examination and investigations confirmed a diagnosis of combined endocrine and exocrine tumours of the pancreas. She underwent surgery and is under regular follow-up in the surgical clinic. CONCLUSION: Biphasic differentiation of pancreatic stem cell during embryological development could happen and may result in combined endocrine and exocrine tumours of the pancreas. Imaging studies are excellent in diagnosing theses lesions. Surgery has a central role and could be curative. [Abstract/Link to Full Text]

Chand M, Moore PJ, Clarke AD, Nash GF, Hickisk T
A diagnostic dilemma following risk-reducing surgery for BRCA1 mutation - a case report of primary papillary serous carcinoma presenting as sigmoid cancer.
World J Surg Oncol. 2007;5102.
BACKGROUND: Women that carry germ-line mutations for BRCA1 or BRCA2 genes are at an increased risk of developing breast, ovarian and peritoneal cancer. Primary peritoneal carcinoma is a rare tumour histologically identical to papillary serous ovarian carcinoma. Risk-reducing surgery in the form of mastectomy and oophorectomy in premenopausal women has been recommended to prevent breast and ovarian cancer occurrence and decrease the risk of developing primary peritoneal cancer. CASE PRESENTATION: We present a case report of a woman with a strong family history of breast cancer who underwent risk-reducing surgery in the form of bilateral salpingo-oophorectomy following a mastectomy for a right-sided breast tumour. Following the finding of a BRCA1 mutation, a prophylactic left-sided mastectomy was performed. After remaining well for twenty-seven years, she presented with rectal bleeding and altered bowel habit, and was found to have a secondary cancer of the sigmoid colon. She was finally diagnosed with primary papillary serous carcinoma of the peritoneum (PSCP). CONCLUSION: PSCP can present many years after risk-reducing surgery and be difficult to detect. Surveillance remains the best course of management for patients with known BRCA mutations. [Abstract/Link to Full Text]

Zagouri F, Sergentanis TN, Koulocheri D, Nonni A, Bousiotou A, Domeyer P, Michalopoulos NV, Dardamanis D, Konstadoulakis MM, Zografos GC
Bilateral synchronous breast carcinomas followed by a metastasis to the gallbladder: a case report.
World J Surg Oncol. 2007;5101.
BACKGROUND: Breast cancer is usually associated with metastases to lungs, bones and liver. Breast carcinoma metastasizing to the gallbladder is very rare. CASE PRESENTATION: A 59-year-old woman presented with bilateral synchronous breast lesions. A palpable, retroareolar solid lesion of diameter equal to 5 cm was present in the right breast, and a newly developed, non-palpable lesion with microcalcifications (diameter equal to 0.7 cm) was present in the upper outer quadrant of the left breast. Modified radical mastectomy was performed on the right breast and lumpectomy after hook-wire localization was performed on the left breast, combined with lymph node dissection in both sides. The pathological examination revealed invasive lobular carcinoma grade II in the right breast and invasive ductal carcinoma grade I in the left breast. Chemotherapy, radiation therapy, trastuzumab and letrozole were appropriately administered. At her 18-month follow-up, the patient was free of symptoms; the imaging tests (chest CT, abdominal U/S, bone scan), biochemical tests, blood cell count and tumor markers were also normal. At the 20th month after surgery however, the patient developed symptoms of cholecystitis and underwent cholecystectomy. The histopathological examination revealed metastasis of the lobular carcinoma to the gallbladder. CONCLUSION: This extremely rare case confirms on a single patient the results of large series having demonstrated the preferential metastasis of lobular breast cancer to the gallbladder. Symptoms of cholecystitis should not be neglected in such patients, as they might indicate metastasis to the gallbladder. [Abstract/Link to Full Text]

Leung TH, Lee HH, Chang SC
Perianal eccrine adenocarcinoma.
World J Surg Oncol. 2007;5100.
ABSTRACT: BACKGROUND: Eccrine carcinoma is a quite rare malignant tumor that typically arises from a normal sweat gland and that features a rather high recurrence rate subsequent to simple excision. Given its rather poor response to adjuvant therapy, wide excision of the lesion with tumor-free margins may offer a reasonable chance for long-term control of this neoplasm. CASE PRESENTATION: Herein, we report on an unusual case of perianal eccrine carcinoma, initially presenting as a perianal abscess. CONCLUSION: Even though eccrine carcinomas would appear to be rare, when dealing with recurrent skin tumors or recurrent perianal fistulas, the possibility of eccrine carcinoma should be considered by consulting clinicians. [Abstract/Link to Full Text]

Kumar A, Singh S, Pradhan S, Shukla RC, Ansari MA, Singh TB, Shyam R, Gupta S
Doppler ultrasound scoring to predict chemotherapeutic response in advanced breast cancer.
World J Surg Oncol. 2007;599.
ABSTRACT: BACKGROUND: Doppler ultrasonography (US) is increasingly being utilized as an imaging modality in breast cancer. It is used to study the vascular characteristics of the tumor. Neoadjuvant chemotherapy is the standard modality of treatment in locally advanced breast cancer. Histological examination remains the gold standard to assess the chemotherapy response. However, based on the color Doppler findings, a new scoring system that could predict histological response following chemotherapy is proposed. METHODS: Fifty cases of locally advanced infiltrating duct carcinoma of the breast were studied. The mean age of the patients was 44.5 years. All patients underwent clinical, Doppler and histopathological assessment followed by three cycles of CAF (Cyclophosphamide, Adriamycin and 5-Fluorouracil) chemotherapy, repeat clinical and Doppler examination and surgery. The resected specimens were examined histopathologically and histological response was correlated with Doppler findings. The Doppler characteristics of the tumor were graded as 1-4 for <25%, 25-50%, >50% and complete disappearance of flow signals respectively. A cumulative score was calculated and compared with histopathological response. Results were analyzed using Chi square test, sensitivity, specificity, positive and negative predictive values. RESULTS: The maximum Doppler score according to the proposed scoring system was twelve and minimum three. Higher scores corresponded with a more favorable histopathological response. Twenty four patients had complete response to chemotherapy. Sixteen of these 24 patients (66.7%) had a cumulative Doppler score more than nine. The sensitivity of cumulative score >5 was 91.7% and specificity was 38.5%. The area under the ROC curve of the cumulative score >9 was 0.72. CONCLUSION: Doppler scoring can be accurately used to objectively predict the response to chemotherapy in patients with locally advanced breast cancer and it correlates well with histopathological response. [Abstract/Link to Full Text]

Yamashita Y, Fukuzawa K, Taketomi A, Aishima S, Yoshizumi T, Uchiyama H, Tsujita E, Harimoto N, Harada N, Wakasugi K, Maehara Y
Mucin-hypersecreting bile duct neoplasm characterized by clinicopathological resemblance to intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
World J Surg Oncol. 2007;598.
ABSTRACT: BACKGROUND: Although intraductal papillary mucinous neoplasm (IPMN) of the pancreas is acceptable as a distinct disease entity, the concept of mucin-secreting biliary tumors has not been fully established. CASE PRESENTATION: We describe herein a case of mucin secreting biliary neoplasm. Imaging revealed a cystic lesion 2 cm in diameter at the left lateral segment of the liver. Duodenal endoscopy revealed mucin secretion through an enlarged papilla of Vater. On the cholangiogram, the cystic lesion communicated with bile duct, and large filling defects caused by mucin were observed in the dilated common bile duct. This lesion was diagnosed as a mucin-secreting bile duct tumor. Left and caudate lobectomy of the liver with extrahepatic bile duct resection and reconstruction was performed according to the possibility of the tumor's malignant behavior. Histological examination of the specimen revealed biliary cystic wall was covered by micropapillary neoplastic epithelium with mucin secretion lacking stromal invasion nor ovarian-like stroma. The patient has remained well with no evidence of recurrence for 38 months since her operation. CONCLUSION: It is only recently that the term "intraductal papillary mucinous neoplasm (IPMN)," which is accepted as a distinct disease entity of the pancreas, has begun to be used for mucin-secreting bile duct tumor. This case also seemed to be intraductal papillary neoplasm with prominent cystic dilatation of the bile duct. [Abstract/Link to Full Text]

Gillham CM, Reynolds J, Hollywood D
Predicting the response of localised oesophageal cancer to neo-adjuvant chemoradiation.
World J Surg Oncol. 2007;597.
ABSTRACT: BACKGROUND: A complete pathological response to neo-adjuvant chemo-radiation for oesophageal cancer is associated with favourable survival. However, such a benefit is seen in the minority. If one could identify, at diagnosis, those patients who were unlikely to respond unnecessary toxicity could be avoided and alternative treatment can be considered. The aim of this review was to highlight predictive markers currently assessed and evaluate their clinical utility. METHODS: A systematic search of Pubmed and Google Scholar was performed using the following keywords; "neo-adjuvant", "oesophageal", "trimodality", "chemotherapy", "radiotherapy", "chemoradiation" and "predict". The original manuscripts were sourced for further articles of relevance. RESULTS: Conventional indices including tumour stage and grade seem unable to predict histological response. Immuno-histochemical markers have been extensively studied, but none has made its way into routine clinical practice. Global gene expression from fresh pre-treatment tissue using cDNA microarray has only recently been assessed, but shows considerable promise. Molecular imaging using FDG-PET seems to be able to predict response after neo-adjuvant chemoradiation has finished, but there is a paucity of data when such imaging is performed earlier. CONCLUSION: Currently there are no clinically useful predictors of response based on standard pathological assessment and immunohistochemistry. Genomics, proteomics and molecular imaging may hold promise. [Abstract/Link to Full Text]

Efstathios P, Athanasios P, Papaconstantinou I, Alexandros P, Frangisca S, Sotirios G, Evangelos F, Athanasios G
Coexistence of gastrointestinal stromal tumor (GIST) and colorectal adenocarcinoma: A case report.
World J Surg Oncol. 2007;596.
ABSTRACT: BACKGROUND: Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the digestive tract. Over the last ten years the management of GISTs has dramatically altered but their coexistence with other gasrointesinal tumors of different histogenesis presents a special interest. The coexistence of GISTs with other primaries is usually discovered incidentally during GI surgery for carcinomas. CASE PRESENTATION: We present here, a case of a 66-year-old patient with intestinal GIST and a synchronous colorectal adenocarcinoma discovered incidentally during surgical treatment of the recurrent GIST. Immunohistochemical examination revealed the concurrence of histologically proved GIST (strongly positive staining for c-kit, vimentin, SMA, and focal positive in S-100, while CD-34 was negative) and Dukes Stage C, (T3, N3, M0 according the TNM staging classification of colorectal cancer). CONCLUSION: The coexistence of GIST with either synchronous or metachronous colorectal cancer represents a phenomenon with increasing number of relative reports in the literature the last 5 years. In any case of GIST the surgeon should be alert to recognize a possible coexistent tumor with different histological origin and to perform a thorough preoperative and intraoperative control. The correct diagnosis before and at the time of the surgical procedure is the cornerstone that secures the patients' best prognosis. [Abstract/Link to Full Text]

Suttie SA, Li AG, Quinn M, Park KG
The impact of operative approach on outcome of surgery for gastro-oesophageal tumours.
World J Surg Oncol. 2007;595.
ABSTRACT: BACKGROUND: The choice of operation for tumours at or around the gastro-oesophageal junction remains controversial with little evidence to support one technique over another. This study examines the prevalence of margin involvement and nodal disease and their impact on outcome following three surgical approaches (Ivor Lewis, transhiatal and left thoraco-laparotomy) for these tumours. METHODS: A retrospective analysis was conducted of patients undergoing surgery for distal oesophageal and gastro-oesophageal junction tumours by a single surgeon over ten years. Comparisons were undertaken in terms of tumour clearance, nodal yield, postoperative morbidity, mortality, and median survival. All patients were followed up until death or the end of the data collection (mean follow up 33.2 months). RESULTS: A total of 104 patients were operated on of which 102 underwent resection (98%). Median age was 64.1 yrs (range 32.1-79.4) with 77 males and 25 females. Procedures included 29 Ivor Lewis, 31 transhiatal and 42 left-thoraco-laparotomies. Postoperative mortality was 2.9% and median survival 23 months. Margin involvement was 24.1% (two distal, one proximal and 17 circumferential margins). Operative approach had no significant effect on nodal clearance, margin involvement, postoperative mortality or morbidity and survival. Lymph node positive disease had a significantly worse median survival of 15.8 months compared to 39.7 months for node negative (p = 0.007), irrespective of approach. CONCLUSION: Surgical approach had no effect on postoperative mortality, circumferential tumour, nodal clearance or survival. This suggests that the choice of operative approach for tumours at the gastro-oesophageal junction may be based on the individual patient and tumour location rather than surgical dogma. [Abstract/Link to Full Text]

Pandey M
Helicobacter species are associated with possible increase in risk of biliary lithiasis and benign biliary diseases.
World J Surg Oncol. 2007;594.
ABSTRACT: BACKGROUND: Hepato-biliary tract lithiasis is common and present either as pain or as asymptomatic on abdominal ultrasonography for other causes. Although the DNA of Helicobacter species are identified in the gallbladder bile, tissue or stones analyzed from these cases, still a causal relationship could not be established due to different results from different geographical parts. METHODS: A detailed search of pubmed and pubmedcentral was carried out with key words Helicobacter and gallbladder, gallstones, hepaticolithiasis, cholelithiasis and choledocholithiasis, benign biliary diseases, liver diseases. The data was entered in a data base and meta analysis was carried out. The analysis was carried out using odds ratio and a fixed effect model, 95% confidence intervals for odds ratio was calculated. Chi square test for heterogeneity was employed. The overall effect was calculated using Z test. RESULTS: A total of 12 articles were identified. One study used IgG for diagnosis while others used the PCR for Ure A gene, 16 S RNA or Cag A genes. A couple of studies used culture or histopathology besides the PCR. The cumulative results show a higher association of Helicobacter with chronic liver diseases (30.48%), and stone diseases (42.96%)(OR 1.77 95% CI 1.2-2.58; Z = 2.94, p = 0.003), the effect of each could not be identified as it was difficult to isolate the effect of helicobacter due to mixing of cases in each study. CONCLUSION: The results of present meta analysis shows that there is a slight higher risk of cholelithiasis and benign liver disease (OR 1.77), however due to inherent inability to isolate the effect of stone disease from that of other benign lesions it is not possible to say for sure that Helicobacter has a casual relationship with benign biliary disease or stone disease or both. [Abstract/Link to Full Text]

Sen-Oran E, Ozmen V, Bilir A, Cabioglu N, Muslumanoglu M, Igci A, Guney N, Kecer M
Is the thymidine labeling index a good prognostic marker in breast cancer?
World J Surg Oncol. 2007;593.
ABSTRACT: BACKGROUND: The aim of the present study was to determine the prognostic relevance of thymidine labeling index (TLI) in patients with breast cancer. METHODS: TLI of the primary tumor was measured in 268 patients at the time of the surgical biopsy by an in vitro method. RESULTS: Fifty-four patients had stage I disease, and 138 patients had stage II disease, and 76 patients had stage III disease. One hundred-four patients were found to have low TLI-index (<3%), and 164 patients had high TLI-index (>/=3%). The median follow-up was 71.5 months (range, 6-138 months). The 5-year overall survival (OS) and disease free survival (DFS) rates was 84% and 74%, respectively. Lymph node involvement, tumor size more than 2 cm, high nuclear grade and estrogen receptor negativity were found to be associated with poorer DFS and OS rates. On subgroup analysis, however, the 5-year OS rate was significantly higher in the low TLI-group than in the high TLI-group in patients with stage I disease (100% vs 76%, p = 0.05). CONCLUSION: Our findings suggest that the prognostic significance of TLI appears to be limited to early breast cancer that might help to distinguish patients who need more aggressive adjuvant treatment. [Abstract/Link to Full Text]

Chalidis BE, Dimitriou CG
Carpal tunnel syndrome due to an atypical deep soft tissue leiomyoma: The risk of misdiagnosis and mismanagement.
World J Surg Oncol. 2007;592.
ABSTRACT: BACKGROUND: Leiomyomas of the deep soft tissue are quite uncommon and occur even more rarely in upper extremity. CASE PRESENTATION: A 32-year old manual laborer man presented with a two-year history of numbness, tingling and burning pain in the palmar surface of the left hand and fingers. His medical history was unremarkable and no trauma episode was reported. According to the clinical examination and the result of median nerve conduction study (NCS) the diagnosis of carpal tunnel syndrome was established. Operative release of the transverse carpal ligament was subsequently performed but the patient experienced only temporary relief of his symptoms. MRI examination revealed a deep palmary located mass with well-defined margins and ovoid shape. Intraoperatively, the tumor was in continuity with the flexor digitorum superficialis tendon of the middle finger causing substantial compression to median nerve. Histopathological findings of the resected mass were consistent with leiomyoma. After two years the patient was pain-free without signs of tumor recurrence. CONCLUSION: Despite the fact that reports on deep soft tissue leiomyoma are exceptional, this tumor had to be considered as differential diagnosis in painful non-traumatic hand syndromes especially in young patients. [Abstract/Link to Full Text]

Funahashi K, Koike J, Saito N, Shiokawa H, Shirasaka K, Teramoto T
A rare case of repeated anastomotic recurrence due to tumor implantation after curative surgery for sigmoid colon cancer.
World J Surg Oncol. 2007;591.
ABSTRACT: BACKGROUND: Anastomotic recurrence is often experienced at colocolic or colorectal anastomoses. Tumor cell implantation has been reported as the mechanism of anastomotic recurrence. However, anastomotic recurrence occurring repeatedly after curative surgery is rare. We herein report a rare case of repeated anastomotic recurrence after curative surgery for sigmoid colon cancer. CASE PRESENTATION: A 51-year-old man underwent radical surgery for sigmoid colon cancer. However, anastomotic recurrence developed three times during three years and six months after the initial operation in spite of irrigation with 5% povidone-iodine before anastomosis. The serum carcinoembryonic antigen (CEA) level had been within normal limits after sigmoidectomy. Finally, the patient underwent abdominoperineal resection. The clinico-pathological findings revealed that possible tumor cell implantation caused these anastomotic recurrences. The patients survived without recurrence during the follow-up period of seven years and nine months. CONCLUSION: We experienced a rare case of repeated anastomotic recurrence due to possible tumor implantation after curative surgery for sigmoid colon cancer; however the prognosis was ultimately very good. CEA monitoring was insensitive for detection of anastomotic recurrence in this case. [Abstract/Link to Full Text]

Patel NN, Shah PR, Wilson E, Haray PN
An unexpected supraclavicular swelling.
World J Surg Oncol. 2007;590.
ABSTRACT: BACKGROUND: Colorectal cancer is the third commonest cause of cancer death in UK. It commonly metastasises to the liver but rarely to small bones. CASE PRESENTATION: We describe a case of a patient with adenocarcinoma of the descending colon who presented preoperatively with a right supraclavicular swelling. Subsequent imaging and cytology of the lesion revealed this to be a metastasis to the right clavicle resulting in a pathological fracture. CONCLUSION: This report describes the rare occurrence of a colorectal metastasis to the clavicle. It emphasises that although bone metastases from primary colorectal tumours are rare events, they tend to metastasise to small, non-weight bearing bones. It also discusses the utility of isotope bone scanning and that on certain occasions this imaging method may prove to be equivocal. In such circumstances, biopsy or magnetic resonance imaging is more sensitive for the detection of bone metastases. [Abstract/Link to Full Text]

Fujimaki T, Ishii H, Matsuno A, Arai H, Nakagomi T
Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma.
World J Surg Oncol. 2007;589.
ABSTRACT: BACKGROUND: Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT) in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA) who was treated successfully with a combination of interferon-beta and TMZ. CASE PRESENTATION: A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 x 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR). The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. CONCLUSION: It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy. [Abstract/Link to Full Text]

Sakamoto A, Yoshida T, Matsuura S, Tanaka K, Matsuda S, Oda Y, Hori Y, Yokomizo A, Iwamoto Y
Metastasis to the gluteus maximus muscle from renal cell carcinoma with special emphasis on MRI features.
World J Surg Oncol. 2007;588.
ABSTRACT: BACKGROUND: The skeletal muscle is an unusual site for metastasis from renal cell carcinoma (RCC). Metastatic RCC must be differentiated from benign primary soft-tissue tumors because aggressive surgical resection is necessary. CASE PRESENTATION: We present the case of a 65-year-old man with metastatic RCC in the gluteus maximus muscle (3.8 cm in diameter) found on enhanced computed tomography (CT) 6 years after nephrectomy. Retrospectively, the small mass (1 cm in diameter) was overlooked 5 years earlier on enhanced CT. Because the growth of the lesion was slow, benign tumor was a differential diagnosis. However, magnetic resonance imaging (MRI) showed that the mass had high-signal intensity on T1- and T2-weighted images (WIs) compared to that of skeletal muscle, with mild enhancement by Gadolinium. The MRI features were unusual for most soft-tissue tumors having low-signal intensity on T1-WI and high-signal intensity on T2-WI. Therefore, under a diagnosis of metastatic RCC, the lesion was resected together with the surrounding skeletal muscle. The histology was confirmed to be metastatic RCC. CONCLUSION: MRI features of metastatic RCC may be beneficial in differentiating it from primary soft-tissue tumor. [Abstract/Link to Full Text]

Archontovasilis F, Markogiannakis H, Dikoglou C, Drimousis P, Toutouzas KG, Theodorou D, Katsaragakis S
Paraganglioma of the greater omentum: Case report and review of the literature.
World J Surg Oncol. 2007;587.
ABSTRACT: BACKGROUND: Extra-adrenal, intra-abdominal paraganglioma constitutes a rare neoplasm and, moreover, its location in the greater omentum is extremely infrequent. CASE PRESENTATION: A 46-year-old woman with an unremarkable medical history presented with an asymptomatic greater omentum mass that was discovered incidentally during ultrasonographic evaluation due to menstrual disturbances. Clinical examination revealed a mobile, non-tender, well-circumscribed mass in the right upper and lower abdominal quadrant. Blood tests were normal. Contrast-enhanced abdominal computed tomography (CT) scan confirmed a huge (15 x 15 cm), well-demarcated, solid and cystic, heterogeneously enhanced mass between the right liver lobe and right kidney. Exploratory laparotomy revealed a large mass in the greater omentum. The tumor was completely excised along with the greater omentum. Histopathology offered the diagnosis of benign greater omentum paraganglioma. After an uneventful postoperative course, the patient was discharged on the 4th postoperative day. She remains free of disease for 2 years as appears on repeated CT scans as well as magnetic resonance imaging (MRI) and scintigraphy performed with radiotracer-labeled metaiodobenzyl-guanidine (MIBG) scans. CONCLUSION: This is the second reported case of greater omentum paraganglioma. Clinical and imaging data of patients with extra-adrenal, intra-abdominal paragangliomas are variable while many of them may be asymptomatic even when the lesion is quite large. Thorough histopathologic evaluation is imperative for diagnosis and radical excision is the treatment of choice. Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, prolonged follow-up is necessary. [Abstract/Link to Full Text]

Park YM, Cho JH, Cho JY, Huh JS, Ahn JY
Non-Hodgkin's lymphoma of the sphenoid sinus presenting as isolated oculomotor nerve palsy.
World J Surg Oncol. 2007;586.
BACKGROUND: Solitary involvement of the sphenoid sinus has rarely been reported in non-Hodgkin's lymphoma. Isolated oculomotor nerve palsy is uncommon as an initial presentation of malignant tumors of the sphenoid sinus. CASE PRESENTATION: A 53-year-old woman presented with a three-month history of headache and diplopia. Neurological examination revealed complete left oculomotor nerve palsy. Magnetic Resonance Imaging (MRI) demonstrated a homogenous soft-tissue lesion occupying the left sphenoid sinus and invading the left cavernous sinus. The patient underwent transsphenoidal biopsy and the lesion was histologically diagnosed as non-Hodgkin's lymphoma, diffuse large B-cell type. Tumor cells were positive for CD20 and negative for CD3. Following six cycles of chemotherapy, the left oculomotor nerve palsy that had been previously observed was completely resolved. There was no enhancing lesion noted on follow-up MRI. CONCLUSION: It is important to recognize that non-Hodgkin's lymphoma of the sphenoid sinus can present with isolated oculomotor nerve palsy, although it is extremely rare. The cranial nerve deficits can resolve dramatically after chemotherapy. [Abstract/Link to Full Text]

Tucci G, Muzi MG, Nigro C, Cadeddu F, Amabile D, Servadei F, Farinon AM
Dermoid cyst of the pancreas: presentation and management.
World J Surg Oncol. 2007;585.
BACKGROUND: Dermoid cyst of the pancreas is a benign, well-differentiated, extremely rare germ cell neoplasm. Published data indicate that differential diagnosis of cystic lesions of the pancreas is challenging and although ultrasonography, computed tomography and magnetic resonance may be useful, radiological findings are often inconclusive and the diagnosis is intraoperative. We report a case of a dermoid cyst of the tail of the pancreas intraoperatively diagnosed and successfully treated with left pancreatectomy. Further, characteristics, preoperative detection and differential diagnosis of this rare pathology are also discussed. CASE PRESENTATION: This report documents the findings of a 64-year-old male presenting with a well defined echogenic pancreatic mass on ultrasonography. Computerized Tomography (CT) showed a 5 cm cystic tumor arising from pancreatic tail and Magnetic Resonance Imaging (MRI) suggested a tumor extension to the middle side of the stomach without defined margins. A left pancreatectomy was performed. On surgical specimen, histological evaluation revealed a dermoid cyst of the tail of the pancreas measuring 8.5 x 3.0 cm. CONCLUSION: Given the benign nature of the dermoid cyst, surgical resection most likely represents the definitive treatment and cure. In addition, resection is indicated in consideration of the difficulty in diagnosing dermoid cyst preoperatively. However, endoscopic ultrasound and fine needle aspiration cytology have recently been shown to be effective, safe, reliable and cost-saving preoperative diagnostic tools. Therefore, until more cases of dermoid cyst are identified to further elucidate its natural history and improve the reliability of the preoperative diagnostic tools, surgical resection should be considered the standard therapy in order to exclude malignancy. [Abstract/Link to Full Text]

W�gs�ter D, L�fgren S, Hugander A, Dienus O, Dimberg J
Analysis of single nucleotide polymorphism in the promoter and protein expression of the chemokine eotaxin-1 in colorectal cancer patients.
World J Surg Oncol. 2007;584.
BACKGROUND: Previous studies suggest that chemokines (chemotactic cytokines) promote and regulate neoplastic progression including metastasis and angiogenesis. The chemokine eotaxin-1 is a powerful eosinophil attractant but also exerts chemotaxis of other leukocytes. Eotaxin-1 has been implicated in gastrointestinal disorders and may play an important role in colorectal mucosal immunity. PATIENTS AND METHODS: The objective of this study was to assess the role of eotaxin-1 in colorectal cancer (CRC). Levels of eotaxin-1 protein in CRC tissues (n = 86) and paired normal mucosa were compared after determination by ELISA. Plasma eotaxin-1 levels from CRC patients (n = 67) were also compared with controls (n = 103) using the same method. Moreover, a TaqMan system was used to evaluate the -384A>G eotaxin-1 gene variant in CRC patients (n = 241) and in a control group (n = 253). RESULTS: Eotaxin-1 protein levels in colorectal tumours were significantly (P < 0.0001) higher than in normal tissue. Immunohistochemistry revealed eotaxin-1 expression in stromal cells such as fibroblasts and leukocytes of the CRC tissue. The plasma eotaxin-1 level in CRC patients was lower compared with controls (P < 0.0001). Patients with tumours classified as Dukes' stage B and C had lower levels than patients with tumours in Dukes' stage A. We found no difference in genotype distribution but noted a difference regarding allele distribution (P = 0.036) and a dominance of allele G in rectal cancer patients. CONCLUSION: The up-regulated eotaxin-1 protein expression in cancer tissue may reflect an eotaxin-1 mediated angiogenesis and/or a recruitment of leukocytes with potential antitumourigenic role. We noticed a dominance of the G allele in rectal cancer patients compared with colon cancer patients that was independent of eotaxin-1 expression. [Abstract/Link to Full Text]

Povoski SP, Jimenez RE
A comprehensive evaluation of the 8-gauge vacuum-assisted Mammotome(R) system for ultrasound-guided diagnostic biopsy and selective excision of breast lesions.
World J Surg Oncol. 2007;583.
ABSTRACT: BACKGROUND: Minimally invasive breast biopsy technology is now considered a standard of care for the diagnostic evaluation of suspicious breast lesions. The aim of the current study was to present a comprehensive evaluation of the 8-gauge vacuum-assisted Mammotome(R) system for ultrasound-guided diagnostic biopsy and selective excision of breast lesions. METHODS: A retrospective analysis was conducted of a series of 304 consecutive 8-gauge Mammotome(R) procedures that were performed under ultrasound guidance by a single surgeon from March 2004 to December 2006. Multiple variables, including patient demographics, characteristics of the breast lesion (based on ultrasound and mammography), procedural and histopathology variables, and interval follow-up variables (based on ultrasound and mammography), were evaluated. RESULTS: Among 304 procedures, 235 (77%) were performed with the presumption of complete excision of the ultrasound lesion during Mammotome(R) core acquisition, while 69 (23%) were performed with only partial excision of the ultrasound lesion during Mammotome(R) core acquisition (diagnostic tissue sampling only). 100% of all ultrasound lesions were accurately diagnosed, demonstrating no apparent false-negative results among the 256 patients that were compliant with follow-up at a median interval follow-up duration of 11 months (range 1 to 37). Likewise, 89% of all appropriately selected ultrasound lesions were completely excised, as demonstrated on interval follow-up ultrasound at a median time of 6 months (range, 3 to 16). There were no independent predictors of successful complete excision of any given appropriately selected ultrasound lesion by the ultrasound-guided 8-gauge Mammotome(R) biopsy technique. CONCLUSION: The 8-gauge vacuum-assisted Mammotome(R) system is highly accurate for ultrasound-guided diagnostic biopsy of suspicious breast lesions and is highly successful for complete excision of appropriately selected presumed benign breast lesions. This particular technology should be routinely offered to all appropriately selected patients that are evaluated by physicians involved in breast-specific health care. [Abstract/Link to Full Text]

Abbas SM, Hill AG
Prostatic sarcoma after treatment of rectal cancer.
World J Surg Oncol. 2007;582.
BACKGROUND: The relationship between radiation exposure for treatment of cancer and occurrence of a second primary cancer at the irradiated site is well known. This phenomenon is however rare in prostate. CASE PRESENTATION: A 75-year-old farmer was treated for rectal cancer with preoperative 45 Gy of radiotherapy and abdominoperineal resection. Four years later he developed symptoms of bladder outlet obstruction and acute urinary retention. He underwent a transurethral resection of the prostate. Histological examination of the removed prostate tissue and immunohistochemistry revealed it to be a poorly differentiated sarcoma. CONCLUSION: We believe this to be the first reported case of radiation-induced sarcoma following radiotherapy treatment for rectal cancer. Since radiotherapy plays a pivotal role in the contemporary treatment of rectal adenocarcinoma, it is relevant to be aware of the potential long-term carcinogenic complications of radiotherapy of the pelvis. [Abstract/Link to Full Text]

Heemskerk VH, Lentze F, Hulsew� KW, Hoofwijk TG
Gastric carcinoma: review of the results of treatment in a community teaching hospital.
World J Surg Oncol. 2007;581.
BACKGROUND: The aim of this study is to provide data on long term results of gastric cancer surgery and in particular the D1 gastric resection. METHODS: In the period 1992-2004, 235 male and female patients with a median age of 69 and 70 years respectively, were included with a stage I through IV gastric carcinoma, of which 37% was stage IV disease. Whenever possible a gastric resection was performed. In case of obstructive tumour growth palliation was provided by means of a gastro-enterostomy. RESULTS: Gastrectomy with curative intent was achieved in 50%, palliative resection in 22%, palliative surgery (gastro-enterostomy) in 10% and in 18% irresectability led to surgical exploration only. Patients in the curative intent group demonstrated a 47% survival after 5 years and up to 34% after 10 years. However metastases where seen in 32% of the patients after gastrectomy with curative intent. After palliative resection one year survival was 57%, whereas 19% survived more than 3 years. Overall postoperative morbidity and mortality rates were 40% and 13% respectively. CONCLUSION: Long term survival after surgery for gastric cancer is poor and is improved by early detection and radical resection. However, palliative resection showed improved survival compared to gastro-enterostomy alone or no resection at all which may be an effect of adjuvant therapy. [Abstract/Link to Full Text]

Sarikaya I, Povoski SP, Al-Saif OH, Kocak E, Bloomston M, Marsh S, Cao Z, Murrey DA, Zhang J, Hall NC, Knopp MV, Martin EW
Combined use of preoperative 18F FDG-PET imaging and intraoperative gamma probe detection for accurate assessment of tumor recurrence in patients with colorectal cancer.
World J Surg Oncol. 2007;580.
BACKGROUND: The purpose of this study was to combine intraoperative gamma probe (GP) detection with preoperative fluorine 18-fluoro-2-deoxy-glucose positron emission tomography (18F FDG-PET) imaging in order to improve detection of tumor recurrence in colorectal cancer (CRC) patients. METHODS: Twenty-one patients (12 females, 9 males) with a mean age of 54 years (range 31-78) were enrolled. Patients were suspected to have recurrent CRC by elevated CEA (n = 11), suspicious CT findings (n = 1), and clinically suspicious findings (n = 9). Preoperative FDG-PET scan and intraoperative GP study were performed in all patients. Mean time interval between preoperative FDG-PET scan and surgery was 16 days (range 1-41 days) in 19 patients. For intraoperative GP studies, 19 patients were injected with a dose of 10-15 mCi 18F FDG at approximately 30 minutes before the planned surgery time. In two patients, the intraoperative GP study was performed immediately after preoperative FDG-PET scan. RESULTS: Preoperative FDG-PET and intraoperative GP detected 48 and 45 lesions, respectively. A total of 50 presumed site of recurrent disease from 20 patients were resected. Thirty-seven of 50 presumed sites of recurrent disease were histological-proven tumor positive and 13 of 50 presumed sites of recurrent disease were histological-proven tumor negative. When correlated with final histopathology, the number of true positive lesions and false positive lesions by preoperative FDG-PET and intraoperative GP were 31/9 and 35/8, respectively. Both preoperative FDG-PET and intraoperative GP were true positive in 29 lesions. Intraoperative GP detected additional small lesions in the omentum and pelvis which were not seen on preoperative FDG-PET scan. FDG-PET scan demonstrated additional liver metastases which were not detected by intraoperative GP. Preoperative FDG-PET detected distant metastasis in the lung in one patient. The estimated radiation dose received by a surgeon during a single 18F FDG GP surgery was below the occupational limit. CONCLUSION: The combined use of preoperative FDG-PET and intraoperative GP is potentially helpful to the surgeon as a roadmap for accurately locating and determining the extent of tumor recurrence in patients with CRC. While intraoperative GP appears to be more sensitive in detecting the extent of abdominal and pelvic recurrence, preoperative FDG-PET appears to be more sensitive in detecting liver metastases. FDG-PET is also a valuable method in detecting distant metastases. [Abstract/Link to Full Text]

Recent Articles in Journal of Carcinogenesis

Al Sarakbi W, Chong YM, Williams SL, Sharma AK, Mokbel K
The mRNA expression of IGF-1 and IGF-1R in human breast cancer: association with clinico-pathological parameters.
J Carcinog. 2006;516. [Abstract/Link to Full Text]

Whitsett T, Carpenter M, Lamartiniere CA
Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats.
J Carcinog. 2006;515.
Despite the advent of new and aggressive therapeutics, breast cancer remains a leading killer among women; hence there is a need for the prevention of this disease. Several naturally occurring polyphenols have received much attention for their health benefits, including anti-carcinogenic properties. Two of these are resveratrol, a component of red grapes, and epigallocatechin-3-gallate (EGCG), the major catechin found in green tea. In this study, we tested the hypothesis that these two polyphenols protect against chemically-induced mammary cancer by modulating mammary gland architecture, cell proliferation, and apoptosis. Female Sprague-Dawley CD rats were exposed to either resveratrol (1 g/kg AIN-76A diet), EGCG (0.065% in the drinking water), or control diet (AIN-76A) for the entirety of their life starting at birth. At 50 days postpartum, rats were treated with 60 mg dimethylbenz[a]anthracene (DMBA)/kg body weight to induce mammary cancer. Resveratrol, but not EGCG, suppressed mammary carcinogenesis (fewer tumors per rat and longer tumor latency). Analysis of mammary whole mounts from 50-day-old rats revealed that resveratrol, but not EGCG, treatment resulted in more differentiated lobular structures. Bromodeoxyuridine (BrdU) incorporation studies showed that resveratrol treatment caused a significant reduction in proliferative cells in mammary terminal ductal structures at 50 days postpartum, making them less susceptible to carcinogen insult. The epithelial cells of terminal end buds in the mammary glands of resveratrol-treated rats also showed an increase in apoptotic cells compared to the control or EGCG-treated rats as measured by a DNA fragmentation assay. At the given doses, resveratrol treatment resulted in a serum resveratrol concentration of 2.00 microM, while treatment with EGCG resulted in a serum EGCG concentration of 31.06 nM. 17beta-Estradiol, progesterone, and prolactin concentrations in the serum were not significantly affected by resveratrol or EGCG. Neither polyphenol treatment resulted in toxicity as tested by alterations in body weights, diet and drink consumptions, and day to vaginal opening. We conclude that resveratrol in the diet can reduce susceptibility to mammary cancer, while EGCG in the drinking water at the dose used was not effective. [Abstract/Link to Full Text]

Waris G, Ahsan H
Reactive oxygen species: role in the development of cancer and various chronic conditions.
J Carcinog. 2006;514.
Oxygen derived species such as superoxide radical, hydrogen peroxide, singlet oxygen and hydroxyl radical are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. The changes in DNA such as base modification, rearrangement of DNA sequence, miscoding of DNA lesion, gene duplication and the activation of oncogenes may be involved in the initiation of various cancers. Elevated levels of ROS and down regulation of ROS scavengers and antioxidant enzymes are associated with various human diseases including various cancers. ROS are also implicated in diabetes and neurodegenerative diseases. ROS influences central cellular processes such as proliferation a, apoptosis, senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention. [Abstract/Link to Full Text]

Prayitno A
Cervical cancer with human papilloma virus and Epstein Barr virus positive.
J Carcinog. 2006;513.
The Early-7 (E7) protein of HPV binds to the underphosphorelated form of the tumor suppressor protein--pRb and displaces the E2F transcription factor that is normally bound by pRb. The latent membrane protein-1 (LMP-1) of EBV prevents apoptosis of B cells by up regulating the expression of bcl-2, and it activates growth promoting pathway that are normally triggered by T cell-derivate signal. The aims of this study to know that in cervical cancer stay HPV and EBV. DNA was isolated from nineteen sample cervical cancer tissues frozen section. Diagnose related with HPV and EBV was made by Polymerase Chains Reaction (PCR). The result of this experiment showed that from 19 samples diagnosed as cervical cancer, 17 samples are positive HPV and 13 samples had HPV and EBV positive. The conclusion of this experiment is 89% of cervical cancers are infected with HPV and 68% also infected with HPV and EBV. [Abstract/Link to Full Text]

Okobia MN, Bunker CH, Zmuda JM, Ezeome ER, Anyanwu SN, Uche EE, Ojukwu J, Kuller LH, Ferrell RE
Simple tandem repeat (TTTA)n polymorphism in CYP19 (aromatase) gene and breast cancer risk in Nigerian women.
J Carcinog. 2006;512.
BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer related deaths in women worldwide. The incidence of the disease is increasing globally and this increase is occurring at a faster rate in population groups that hirtherto enjoyed low incidence. This study was designed to evaluate the role of a simple tandem repeat polymorphism (STRP) in the aromatase (CYP19) gene in breast cancer susceptibility in Nigerian women, a population of indigenous sub-Saharan African ancestry. METHODS: A case-control study recruiting 250 women with breast cancer and 250 women without the disease from four University Teaching Hospitals in Southern Nigeria was carried out between September 2002 and April 2004. Participants were recruited from the surgical outpatient clinics and surgical wards of the Nigerian institutions. A polymerase chain reaction (PCR)-based assay was employed for genotyping and product sizes were detected with an ABI 3730 DNA Analyzer. RESULTS: Conditional logistic regression analysis revealed that harboring the putative high risk genotypes conferred a 29% increased risk of breast cancer when all women in the study were considered (Odds ratio [OR] = 1.29, 95% confidence interval [CI] 0.83-2.00), although this association was not statistically significant. Subgroup analysis based on menopausal status showed similar results among premenopausal women (OR = 1.35, 95% CI 0.76-2.41 and postmenopausal women (OR = 1.27, 95% CI 0.64-2.49). The data also demonstrated marked differences in the distribution of (TTTA)n repeats in Nigerian women compared with other populations. CONCLUSION: This study has shown that harboring 10 or more repeats of the microsatellite (TTTA)n repeats of the CYY19 gene is associated with a modest increased risk of breast cancer in Nigerian women. [Abstract/Link to Full Text]

Iddamaldeniya SS, Thabrew MI, Wickramasinghe SM, Ratnatunge N, Thammitiyagodage MG
A long-term investigation of the anti-hepatocarcinogenic potential of an indigenous medicine comprised of Nigella sativa, Hemidesmus indicus and Smilax glabra.
J Carcinog. 2006;511.
BACKGROUND: A decoction comprised of Nigella sativa seeds, Hemidesmus indicus root bark and Smilax glabra rhizome is being recommended for cancer patients by a family of traditional medical practitioners of Sri Lanka. Previous investigations have demonstrated that a short term (10 weeks) treatment with the decoction can significantly inhibit diethylnitrosamine (DEN) mediated expression of Glutathione S-transferase P form (GST-P) in rat liver. The objective of the present investigation was to determine whether long term (16 months) treatment with the decoction would be successful in inhibiting in rat livers, not only DEN- mediated expression of GST-P, but also the carcinogen mediated development of overt tumours (OT) or histopathological changes leading to tumour development (HT). METHODS: Thirty-six male Wistar rats were divided into 3 groups of 12 each. Groups 1 and 2 were injected intraperitoneally (i.p) with DEN (200 mg/kg) while group 3 was injected normal saline (NS). Twenty-four hours later, decoction (DC; 6 g/kg body weight/day) was orally administered to group 1 rats, while groups 2 and 3 (DEN-control and normal control) were given distilled water (DW). Treatment with DC or DW continued for 16 months. At the end of the 9th month and 16th months (study 1 and study 2 respectively), six rats from each group were sacrificed, and livers observed for OT or HT, both visually and by subjecting liver sections to staining with Haemotoxylin and Eosin (H & E), Sweet's Silver stain (for reticulin fibers), Periodic Acid Schiff (PAS) staining (for glycogen), and immunohistochemical staining (for GST-P). RESULTS: At the end of 9 months (study 1) a hepatocellular adenoma (HA) developed in one of the rats in the DEN + DW treated group (group 2). At the end of 16 months (study 2), livers of all rats of group 2 developed OT and HT. Large areas of GST-P positive foci were also observed. No OT, HT or GST-P positive foci were detected in any of the other groups. CONCLUSION: Protection against DEN-mediated carcinogenic changes in rat liver can be achieved by long term treatment with the DC comprised of N. sativa seeds, S. glabra rhizome and H. indicus root bark. [Abstract/Link to Full Text]

Vijayababu MR, Arunkumar A, Kanagaraj P, Arunakaran J
Effects of quercetin on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) secretion and induction of apoptosis in human prostate cancer cells.
J Carcinog. 2006;510.
BACKGROUND: Quercetin, the predominant flavonoid, has been reported to lower the risk of several cancers. This flavonoid found in onion, grapes, green vegetables, etc. has been shown to possess potent antiproliferative effects against various malignant cells. This study was designed to investigate its effects on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) proteins secretion and also apoptosis induction in the human prostate cancer cell line, PC-3. METHODS: We evaluated the secretion of IGF-I, -II and IGFBP-3 in quercetin treated cells by immunoradiometric (IRMA) method. Apoptosis was studied in quercetin treated cells by TUNEL and DNA fragmentation. Protein expressions of Bcl-2, Bcl-xL, Bax and caspase-3 were studied by western blot. RESULTS: At a dose of 100 microM concentration, we observed increased IGFBP-3 accumulation in PC-3 cells conditioned medium with a dose dependent increase with 2 fold over a base line, and significantly reduced the both IGF-I and IGF-II levels. Apoptosis induction was also confirmed by TUNEL assay. Bcl-2 and Bcl-xL protein expressions were significantly decreased and Bax and caspase-3 were increased. CONCLUSION: These results suggest that the decreased level of IGFs could be due to the increased levels of IGFBP-3, because of the high binding affinity towards IGFs, thereby decreasing the cell proliferation. The increased level of IGFBP-3 was associated with increased pro-apoptotic proteins and apoptosis in response to quercetin, suggesting it may be a p53-independent effector of apoptosis in prostate cancer cells. [Abstract/Link to Full Text]

Kelavkar U, Lin Y, Landsittel D, Chandran U, Dhir R
The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate.
J Carcinog. 2006;59.
One of the major components in high-fat diets (Western diet) is the omega (omega, n)-6 polyunsaturated fatty acid (PUFA) called linoleic acid (LA). Linoleic acid is the precursor for arachidonic acid (AA). These fatty acids are metabolized to an array of eicosanoids and prostaglandins depending upon the enzymes in the pathway. Aberrant expression of the catabolic enzymes such as cyclooxygenases (COX-1 and/or -2) or lipoxygenases (5-LO, 12-LO, 15-LO-1, and 15-LO-2) that convert PUFA either AA and/or LA to bioactive lipid metabolites appear to significantly contribute to the development of PCa. However, PUFA and its cellular interactions in PCa are poorly understood. We therefore examined the mRNA levels of key enzymes involved in the LA and AA pathways in 18 human donor (normal) prostates compared to 60 prostate tumors using the Affymetrix U95Av2 chips. This comparative (normal donor versus prostate cancer) study showed that: 1) the level of 15-LO-1 expression (the key enzyme in the LA pathway) is low (P < 0.001), whereas the levels of delta-5 desaturase (P < 0.001, the key enzyme in the AA pathway), delta-6 desaturase (P = 0.001), elongase (P = 0.16) and 15-lipoxygenase-2 (15-LO-2, P = 0.74) are higher in donor (normal) prostates, and 2) Contrary to the observation in the normal tissues, significantly high levels of only 15-LO-1; whereas low levels of delta-6 desaturase, elongase, delta-5 desaturase and 15-LO-2 respectively, were observed in PCa tissues. Although the cyclooxygenase (COX)-1 and COX-2 mRNA levels were high in PCa, no significant differences were observed when compared in donor tissues. Our study underscores the importance of promising dietary intervention agents such as the omega-3 fatty acids as substrate competitors of LA/AA, aimed primarily at high 15-LO-1 and COX-2 as the molecular targets in PCa initiation and/or progression. [Abstract/Link to Full Text]

Jacobs FM
"The case for clean indoor air".
J Carcinog. 2006;58. [Abstract/Link to Full Text]

Orner GA, Roebuck BD, Dashwood RH, Bailey GS
Post-initiation chlorophyllin exposure does not modulate aflatoxin-induced foci in the liver and colon of rats.
J Carcinog. 2006 Feb 6;5(1):6.
ABSTRACT: Chlorophyllin (CHL) is a promising chemopreventive agent believed to block cancer primarily by inhibiting carcinogen uptake through the formation of molecular complexes with the carcinogens. However, recent studies suggest that CHL may have additional biological effects particularly when given after the period of carcinogen treatment. This study examines the post-initiation effects of CHL towards aflatoxin B1 (AFB1)-induced preneoplastic foci of the liver and colon. The single concentration of CHL tested in this study (0.1% in the drinking water) had no significant effects on AFB1-induced foci of the liver and colons of rats. [Abstract/Link to Full Text]

Ryan AE, Lane S, Shanahan F, O'connell J, Houston A
Fas ligand expression in human and mouse cancer cell lines; a caveat on over-reliance on mRNA data.
J Carcinog. 2006 Feb 2;5(1):5.
ABSTRACT: BACKGROUND: During carcinogenesis, tumors develop multiple mechanisms for evading the immune response, including upregulation of Fas ligand (FasL/CD95L) expression. Expression of FasL may help to maintain tumor cells in a state of immune privilege by inducing apoptosis of anti-tumor immune effector cells. Recently this idea has been challenged by studies reporting that tumor cells of varying origin do not express FasL. In the present study, we aimed to comprehensively characterize FasL expression in tumors of both murine and human origin over a 72 hour time period. Methods: RNA and protein was extracted from six human (SW620, HT29, SW480, KM12SM, HCT116, Jurkat) and three mouse (CMT93, CT26, B16F10) cancer cell lines at regular time intervals over a 72 hour time period. FasL expression was detected at the mRNA level by RT-PCR, using intron spanning primers, and at the protein level by Western Blotting and immunofluorescence, using a polyclonal FasL- specific antibody. Results: Expression of FasL mRNA and protein was observed in all cell lines analysed. However, expression of FasL mRNA varied dramatically over time, with cells negative for FasL mRNA at many time points. In contrast, 8 of the 9 cell lines constitutively expressed FasL protein. Thus, cells can abundantly express FasL protein at times when FasL mRNA is absent. Conclusion: These findings demonstrate the importance of complete analysis of FasL expression by tumor cells in order to fully characterize its biological function and may help to resolve the discrepancies present in the literature regarding FasL expression and tumor immune privilege. [Abstract/Link to Full Text]

Rehfeld N, Geddert H, Atamna A, Rohrbeck A, Garcia G, Kliszewski S, Neukirchen J, Bruns I, Steidl U, Fenk R, Gabbert HE, Kronenwett R, Haas R, Rohr UP
The influence of the pituitary tumor transforming gene-1 (PTTG-1) on survival of patients with small cell lung cancer and non-small cell lung cancer.
J Carcinog. 2006;54.
BACKGROUND: PTTG-1 (pituitary tumor transforming gene) is a novel oncogene that is overexpressed in tumors, such as pituitary adenoma, breast and gastrointestinal cancers as well as in leukemia. In this study, we examined the role of PTTG-1 expression in lung cancer with regard to histological subtype, the correlation of PTTG-1 to clinical parameters and relation on patients' survival. METHODS: Expression of PTTG-1 was examined immunohistochemically on formalin-fixed, paraffin-embedded tissue sections of 136 patients with small cell lung cancer (SCLC) and 91 patients with non-small cell lung cancer (NSCLC), retrospectively. The intensity of PTTG-1 expression as well as the proportion of PTTG-1 positive cells within a tumor was used for univariate and multivariate analysis. RESULTS: PTTG-1 expression was observed in 64% of SCLC tumors and in 97.8% of NSCLC tumors. In patients with SCLC, negative or low PTTG-1 expression was associated with a shorter mean survival time compared with patients with strong PTTG-1 expression (265 +/- 18 days vs. 379 +/- 66 days; p = 0.0291). Using the Cox regression model for multivariate analysis, PTTG-1 expression was a significant predictor for survival next to performance status, tumor stage, LDH and hemoglobin.In contrast, in patients with NSCLC an inverse correlation between survival and PTTG-1 expression was seen. Strong PTTG-1 expression was associated with a shorter mean survival of 306 +/- 58 days compared with 463 +/- 55 days for those patients with no or low PTTG-1 intensities (p = 0.0386). Further, PTTG-1 expression was associated with a more aggressive NSCLC phenotype with an advanced pathological stage, extensive lymph node metastases, distant metastases and increased LDH level. Multivariate analysis using Cox regression confirmed the prognostic relevance of PTTG-1 expression next to performance status and tumor stage in patients with NSCLC. CONCLUSION: Lung cancers belong to the group of tumors expressing PTTG-1. Dependent on the histological subtype of lung cancer, PTTG-1 expression was associated with a better outcome in patients with SCLC and a rather unfavourable outcome for patients with NSCLCs. These results may reflect the varying role of PTTG-1 in the pathophysiology of the different histological subtypes of lung cancer. [Abstract/Link to Full Text]

Bradbury BD, Wilk JB, Aschengrau A, Lash TL
Departure from multiplicative interaction for catechol-O-methyltransferase genotype and active/passive exposure to tobacco smoke among women with breast cancer.
J Carcinog. 2006 Jan 17;5(1):3.
ABSTRACT: BACKGROUND: Women with homozygous polymorphic alleles of catechol-O-methyltransferase (COMT-LL) metabolize 2-hydroxylated estradiol, a suspected anticarcinogenic metabolite of estrogen, at a four-fold lower rate than women with no polymorphic alleles (COMT-HH) or heterozygous women (COMT-HL). We hypothesized that COMT-LL women exposed actively or passively to tobacco smoke would have higher exposure to 2-hydroxylated estradiol than never-active/never passive exposed women, and should therefore have a lower risk of breast cancer than women exposed to tobacco smoke or with higher COMT activity. METHODS: We used a case-only design to evaluate departure from multiplicative interaction between COMT genotype and smoking status. We identified 502 cases of invasive incident breast cancer and characterized COMT genotype. Information on tobacco use and other potential breast cancer risk factors were obtained by structured interviews. RESULTS: We observed moderate departure from multiplicative interaction for COMT-HL genotype and history of ever-active smoking (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 0.7, 3.8) and more pronounced departure for women who smoked 40 or more years (aOR = 2.3, 95% CI: 0.8, 7.0). We observed considerable departure from multiplicative interaction for COMT-HL genotype and history of ever-passive smoking (aOR = 2.0, 95% CI: 0.8, 5.2) or for having lived with a smoker after age 20 (aOR = 2.8, 95% CI: 0.8, 10). CONCLUSIONS: With greater control over potential misclassification errors and a large case-only population, we found evidence to support an interaction between COMT genotype and tobacco smoke exposure in breast cancer etiology. [Abstract/Link to Full Text]

Boregowda RK, Appaiah HN, Siddaiah M, Kumarswamy SB, Sunila S, Thimmaiah KN, Mortha K, Toole B, Banerjee S
Expression of hyaluronan in human tumor progression.
J Carcinog. 2006;52.
BACKGROUND: The development and progression of human tumors is accompanied by various cellular, biochemical and genetic alterations. These events include tumor cells interaction with extracellular matrix molecules including hyaluronan (HA). Hyaluronan is a large polysaccharide associated with pericellular matrix of proliferating, migrating cells. Its implication in malignant transformation, tumor progression and with the degree of differentiation in various invasive tumors has well accepted. It has been well known the role HA receptors in tumor growth and metastasis in various cancer tissues. Previously we have observed the unified over expression of Hyaluronic Acid Binding Protein (HABP), H11B2C2 antigen by the tumor cells in various types progressing tumor tissues with different grades. However, the poor understanding of relation between HA and HA-binding protein expression on tumor cells during tumor progression as well as the asymmetric observations of the role of HA expression in tumor progression prompted us to examine the degree of HA expression on tumor cells vs. stroma in various types of human tumors with different grades. METHODS: In the present study clinically diagnosed tumor tissue samples of different grades were used to screen the histopathological expression of hyaluronan by using b-PG (biotinylated proteoglycan) as a probe and we compared the relative HA expression on tumor cells vs. stroma in well differentiated and poorly differentiated tumors. Specificity of the reaction was confirmed either by pre-digesting the tissue sections with hyaluronidase enzyme or by staining the sections with pre-absorbed complex of the probe and HA-oligomers. RESULTS: We show here the down regulation of HA expression in tumor cells is associated with progression of tumor from well differentiated through poorly differentiated stage, despite the constant HA expression in the tumor associated stroma. CONCLUSION: The present finding enlighten the relative roles of HA expression on tumor vs. stroma during the progression of tumors. [Abstract/Link to Full Text]

Kumi-Diaka J, Hassanhi M, Brown J, Merchant K, Garcia C, Jimenez W
CytoregR inhibits growth and proliferation of human adenocarcinoma cells via induction of apoptosis.
J Carcinog. 2006;51.
BACKGROUND: Cancer is one of the devastating neovascular diseases that incapacitate so many people the world over. Recent reports from the National Cancer Institute indicate some significant gain therapy and cancer management as seen in the increase in the 5-year survival rate over the past two decades. Although near-perfect cure rate have been reported in the early-stage disease, these data reveal high recurrence rate and serious side effects including second malignancies and fatalities. Most of the currently used anticancer agents are only effective against proliferating cancer cells. Thus attention has been focused on potential anti-cancer agents capable of killing cancer cells independent of the cell cycle state, to ensure effective elimination of most cancer cells. The objective of this study was to test the chemosensitivity and potential mechanism of action of a novel cancer drug, CytoregR, in a panel of human cancer cells. METHODS: the study was performed using a series of bioassays including Trypan blue exclusion, MTS Growth inhibition, LDH-cytotoxicity, TUNEL-Terminal DNA fragmentation Apoptosis Assay, and the Caspase protease CPP32 activity assays. RESULTS: CytoregR induced significant dose- and time-dependent inhibition of growth in all the cells; with significant differences in chemosensitivity (P < 0.05) between the target cells becoming more apparent at 48 hr exposure. CytoregR showed no significant effect on normal cells relative to the tumor cells. Growth inhibition in all the cells was due to induction of apoptosis at lower concentrations of cytoregR (> 1:300). CytoregR-induced caspase protease-3 (CPP32) activation significantly and positively correlated with apoptosis induction and growth inhibition; thus implicating CPP32 as the principal death pathway in cytoregR-induced apoptosis. CONCLUSION: CytoregR exerted a dose-and time-dependent growth inhibitory effect in all the target cells through induction of apoptosis via the CPP32 death pathway, independent of hormonal sensitivity of the cells. The present data indicate that not only could CPP32 provide a potential target for regulation of cytoregR-induced apoptosis but also that cytoregR could play a significant role in chemotherapeutic regimen in many human malignant tumors. [Abstract/Link to Full Text]

Houben R, Becker JC, Rapp UR
Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma.
J Carcinog. 2005;423.
BACKGROUND: Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK)) is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. METHODS: 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. RESULTS: This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. CONCLUSION: Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor. [Abstract/Link to Full Text]

Kovvali G
New paradigms, new hopes: the need for socially responsible research on carcinogenesis.
J Carcinog. 2005 Nov 21;422. [Abstract/Link to Full Text]

Jain RV, Mills PK, Parikh-Patel A
Cancer incidence in the south Asian population of California, 1988-2000.
J Carcinog. 2005 Nov 10;421.
BACKGROUND: Although South Asians (SA) form a large majority of the Asian population of U.S., very little is known about cancer in this immigrant population. SAs comprise people having origins mainly in India, Pakistan, Bangladesh and Sri Lanka. We calculated age-adjusted incidence and time trends of cancer in the SA population of California (state with the largest concentration of SAs) between 1988-2000 and compared these rates to rates in native Asian Indians as well as to those experienced by the Asian/Pacific Islander (API) and White, non-Hispanic population (NHW) population of California. METHODS: Age adjusted incidence rates observed among the SA population of California during the time period 1988-2000 were calculated. To correctly identify the ethnicity of cancer cases, 'Nam Pehchan' (British developed software) was used to identify numerator cases of SA origin from the population-based cancer registry in California (CCR). Denominators were obtained from the U.S. Census Bureau. Incidence rates in SAs were calculated and a time trend analysis was also performed. Comparison data on the API and the NHW population of California were also obtained from CCR and rates from Globocan 2002 were used to determine rates in India. RESULTS: Between 1988-2000, 5192 cancers were diagnosed in SAs of California.Compared to rates in native Asian Indians, rates of cancer in SAs in California were higher for all sites except oropharyngeal, oesophageal and cervical cancers. Compared to APIs of California, SA population experienced more cancers of oesophagus, gall bladder, prostate, breast, ovary and uterus, as well as lymphomas, leukemias and multiple myelomas. Compared to NHW population of California, SAs experienced more cancers of the stomach, liver and bile duct, gall bladder, cervix and multiple myelomas. Significantly increasing time trends were observed in colon and breast cancer incidence. CONCLUSION: SA population of California experiences unique patterns of cancer incidence most likely associated with acculturation, screening and tobacco habits. There is need for early diagnosis of leading cancers in SA. If necessary steps are not taken to curb the growth of breast, colon and lung cancer, rates in SA will soon approximate those of the NHW population of California. [Abstract/Link to Full Text]

Bergheim I, Wolfgarten E, Bollschweiler E, H�lscher AH, Bode CH, Parlesak A
Role of retinoic acid receptors in squamous-cell carcinoma in human esophagus.
J Carcinog. 2005 Nov 8;420.
BACKGROUND: Worldwide, cancer in the esophagus ranks among the 10 most common cancers. Alterations of retinoic acid receptors (e.g. RARalpha, beta, gamma, and RXRalpha, beta, gamma) expression is considered to play an important role in development of squamous-cell carcinoma (SCC), which is the most common esophageal cancer. Alcohol consumption and smoking, which can alter retinoic acid receptor levels, have been identified as key risk factors in the development of carcinoma in the aero-digestive tract. Therefore, the aim of the present study was to evaluate protein levels of retinoic acid receptors (i.e. RARalpha, beta, gamma, and RXRbeta) in esophageal SCC and surrounding normal tissue of patients with untreated SCC and controls. METHODS: All study participants completed a questionnaire concerning smoking and alcohol drinking habits as well as anthropometrical parameters. Protein levels of RARalpha, beta, gamma, and RXRbeta were determined by Western Blot in normal esophageal tissue and tissue obtained from SCC of 21 patients with newly diagnosed esophageal SCC and normal esophageal tissue of 10 controls. RESULTS: Protein levels of RARgamma were significantly lower by approximately 68% in SCC compared to normal surrounding tissue in patients with SCC that smoked and/or consumed elevated amounts of alcohol. Furthermore, RARalpha protein levels were significantly lower (approximately- 45%) in SCC in comparison to normal esophageal mucosa in patients with elevated alcohol intake. When comparing protein levels of retinoic acid receptors between normal tissue of patients with SCC and controls, RARgamma protein levels were found to be significantly higher (approximately 2.7-fold) in normal esophageal tissue of SCC patients than in esophageal tissue obtained from controls. No differences were found for RARalpha, beta, and RXRbeta protein levels between normal esophageal tissue of patients and that of controls. CONCLUSION: In conclusion, results of the present study suggest that alterations of retinoic acid receptors protein may contribute in the development of SCC in esophagus and that in some patients life style (e.g. smoking and alcohol consumption) may be a critical component in the alteration of retinoic acid receptor levels in esophagus. [Abstract/Link to Full Text]

Pereira PR, Odashiro AN, Marshall JC, Correa ZM, Belfort R, Burnier MN
The role of c-kit and imatinib mesylate in uveal melanoma.
J Carcinog. 2005 Oct 19;419.
BACKGROUND: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, leading to metastasis in 40% of the cases and ultimately to death in 10 years, despite local and/or systemic treatment. The c-kit protein (CD117) is a membrane-bound tyrosine kinase receptor and its overexpression has been observed in several neoplasms. Imatinib mesylate is a FDA approved compound that inhibits tyrosine quinase receptors, as well as c-kit. Imatinib mesylate controls tumor growth in up to 85% of advanced gastrointestinal stromal tumors, a neoplasia resistant to conventional therapy. METHODS: Fifty-five specimens of primary UM selected from the archives of the Ocular Pathology Laboratory, McGill University, Montreal, Canada, were immunostained for c-kit. All cells displaying distinct immunoreactivity were considered positive. Four human UM cell lines and 1 human uveal transformed melanocyte cell line were tested for in vitro proliferation Assays (TOX-6) and invasion assay with imatinib mesylate (concentration of 10 microM). RESULTS: The c-kit expression was positive in 78.2% of the UM. There was a statistical significant decrease in the proliferation and invasion rates of all 5 cell lines. CONCLUSION: The majority of UM expressed c-kit, and imatinib mesylate does decrease the proliferation and invasion rates of human UM cell lines. These results justify the need for a clinical trial to investigate in vivo the response of UM to imatinib mesylate. [Abstract/Link to Full Text]

Simpson DA, Livanos E, Heffernan TP, Kaufmann WK
Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G1 checkpoint function.
J Carcinog. 2005 Oct 6;418.
BACKGROUND: Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10-20 doublings. During this time chromosomal aberrations seen in mitotic cells increase while DNA damage and decatenation checkpoint functions in G2 cells decrease. METHODS: To explore this complex interplay between chromosomal instability and checkpoint dysfunction, human fibroblast lines were derived that expressed HPV16E6 oncoprotein or dominant-negative alleles of p53 (A143V and H179Q) with or without the catalytic subunit of telomerase. RESULTS: Cells with normal p53 function displayed 86-93% G1 arrest after exposure to 1.5 Gy ionizing radiation (IR). Expression of HPV16E6 or p53-H179Q severely attenuated G1 checkpoint function (3-20% arrest) while p53-A143V expression induced intermediate attenuation (55-57% arrest) irrespective of telomerase expression. All cell lines, regardless of telomerase expression or p53 status, exhibited a normal DNA damage G2 checkpoint response following exposure to 1.5 Gy IR prior to the senescence checkpoint. As telomerase-negative cells bypassed senescence, the frequencies of chromosomal aberrations increased generally congruent with attenuation of G2 checkpoint function. Telomerase expression allowed cells with defective p53 function to grow >175 doublings without chromosomal aberrations or attenuation of G2 checkpoint function. CONCLUSION: Thus, chromosomal instability in cells with defective p53 function appears to depend upon telomere erosion not loss of the DNA damage induced G1 checkpoint. [Abstract/Link to Full Text]

Elkak AE, Meligonis G, Salhab M, Mitchell B, Blake JR, Newbold RF, Mokbel K
hTERT protein expression is independent of clinicopathological parameters and c-Myc protein expression in human breast cancer.
J Carcinog. 2005 Oct 4;417.
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. The hTERT (human telomerase reverse transcriptase) subunit seems to be the rate-limiting determinant of telomerase and knowledge of factors controlling hTERT transcription may be useful in therapeutic strategies. The hTERT promoter contains binding sites for c-Myc and there is some experimental and in vitro evidence that c-Myc may increase hTERT expression. We previously reported no correlation between c-Myc mRNA expression and hTERT mRNA or telomerase activity in human breast cancer. This study aims to examine the correlation between hTERT expression as determined by immunohistochemistry and c-Myc expression, lymph node status, and tumour size and grade in human breast cancer. MATERIALS AND METHODS: The immunohistochemical expression of hTERT and c-Myc was investigated in 38 malignant breast tumours. The expression of hTERT was then correlated with the lymph node status, c-Myc expression and other clinicopathological parameters of the tumours. RESULTS: hTERT expression was positive in 27 (71%) of the 38 tumours. 15 (79%) of 19 node positive tumours were hTERT positive compared with 11 (63%) of 19 node negative tumours. The expression was higher in node positive tumours but this failed to reach statistical significance (p = 0.388). There was no significant association with tumour size, tumour grade or c-Myc expression. However, hTERT expression correlated positively with patients' age (correlation coefficient = 0.415, p = 0.0097). CONCLUSION: hTERT protein expression is independent of lymph node status, tumour size and grade and c-Myc protein expression in human breast cancer. [Abstract/Link to Full Text]

Pangburn HA, Kraus H, Ahnen DJ, Rice PL
Sulindac metabolites inhibit epidermal growth factor receptor activation and expression.
J Carcinog. 2005 Sep 2;416.
BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased mortality from colorectal cancer (CRC). NSAIDs induce apoptotic cell death in colon cancer cells in vitro and inhibit growth of neoplastic colonic mucosa in vivo however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2) signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF) receptor (EGFR). METHODS: HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068), total EGFR, phosphorylated ERK1/2 (pERK1/2), total ERK1/2, activated caspase-3, and alpha-tubulin. RESULTS: EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation. CONCLUSION: These results suggest that downregulation of EGFR signaling by sulindac metabolites may occur, at least in part, by inhibiting activation and expression of EGFR. Inhibition of EGFR signaling may account for part of the growth inhibitory and chemopreventive effects of these compounds. [Abstract/Link to Full Text]

Jenny M, Schwaiger W, Bernhard D, Wrulich OA, Cosaceanu D, Fuchs D, Ueberall F
Apoptosis induced by the Tibetan herbal remedy PADMA 28 in the T cell-derived lymphocytic leukaemia cell line CEM-C7H2.
J Carcinog. 2005 Sep 2;415.
The Tibetan herbal remedy PADMA 28 revealed promising results to support treatment of atherosclerosis, Charot syndrome (intermittent claudication), chronic active hepatitis and infection of the respiratory tract. The remedy was confirmed to be closely linked with anti- and pro-oxidative properties in vitro. In this study, apoptogenic and survival effects of PADMA 28 were investigated in the T cell-derived lymphocytic leukaemia cell line CEM-C7H2. PADMA 28 led to a concentration-dependent inhibition of cell proliferation accompanied by the accumulation of CEM-C7H2 cells in subG1 phase, fragmentation of poly (ADP-ribose) polymerase (PARP) and nuclear body formation. Treatment with PADMA 28 rescued to some extent cells over-expressing Bcl-2 from apoptosis. This finding suggests that the mechanism of action of PADMA 28 may be via interference with Bcl-2 triggered survival pathways. [Abstract/Link to Full Text]

Wada R, Yamaguchi T, Tanizaki T
Mucin phenotypic expression and p53 gene abnormality of gastric super-minute well-differentiated adenocarcinoma: re-evaluation with relationship between histogenesis of well-differentiated adenocarcinoma and intestinal metaplasia in distal stomach.
J Carcinog. 2005 Sep 1;414.
BACKGROUND: Although the gastric well-differentiated adenocarcinoma in the distal stomach has been thought to develop via a intestinal metaplasia-carcinoma sequence, there are some disproofs from new mucin examinations for minute-size lesions in same type carcinoma. The current study was performed and pointed out the new findings for the solution to the problem according to the point described above. METHODS: 12 super-minute lesions (less than 1 mm in maximum diameter) of well-differentiated adenocarcinoma in distal stomach (SMCa), which were detected from the pathological examinations of 210 surgically resected stomach specimens, and the mucosa adjacent to these carcinoma lesions, were examined by immunohistochemical mucin stainings (MUC2 and CD-10: intestinal phenotype, 45M1 and MUC6: gastric phenotype) and p53-overexpression. And the analyses of the replication error of the microsatellites in chromosome 17 related p53 gene (TP53 and D17S786) (RER-p53MS) were performed in SMCa lesions, adjacent mucosa to each lesion and other gastric mucosa with intestinal metaplasia, because all SMCa lesions showed p53-overexpression immunohistochemically, described below. RESULTS: 1. The carcinoma cells in all SMCa lesions were positive for 45M1 and p53. On the other hand, no positive carcinoma cells for MUC6 were seen although the pyloric glands and the remnant pyloric gland in the SMCa lesions in the same slides were positive for MUC6. Ten lesions (83%) had intestinal phenotypic mucin (10 lesions: MUC2 (+), 4 lesions: CD10 (+)). Two lesions (17%) were positive for only 45M1 (gastric phenotypic mucin). 2. All of the mucosa adjacent to SMCa showed intestinal metaplasia (complete type: 7 regions, incomplete type: 5 regions). 3. RER-p53MS was confirmed in 42% (5/12 regions) of SMCa, in 42% (5/12 regions) of the mucosa adjacent to SMCa and 14% (6/42 regions) of the other intestinal metaplasia mucosa. CONCLUSION: Most of the super-minute well-differentiated adenocarcinoma lesions in the distal stomach, which had both gastric and intestinal phenotypic mucin, are considered to develop from the tubular proliferative zone with the incomplete type of the intestinal metaplasia and p53 gene abnormality, while a part of them, which had only gastric phenotypic mucin, may derive from the gastric native tubules (non-metaplastic epithelium) with p53 gene abnormality. [Abstract/Link to Full Text]

Hoyal CR, Kammerer S, Roth RB, Reneland R, Marnellos G, Kiechle M, Schwarz-Boeger U, Griffiths LR, Ebner F, Rehbock J, Nelson MR, Braun A
Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases.
J Carcinog. 2005 Aug 19;413.
BACKGROUND: Several studies have identified rare genetic variations responsible for many cases of familial breast cancer but their contribution to total breast cancer incidence is relatively small. More common genetic variations with low penetrance have been postulated to account for a higher proportion of the population risk of breast cancer. METHODS AND RESULTS: In an effort to identify genes that influence non-familial breast cancer risk, we tested over 25,000 single nucleotide polymorphisms (SNPs) located within approximately 14,000 genes in a large-scale case-control study in 254 German women with breast cancer and 268 age-matched women without malignant disease. We identified a marker on chromosome 14q24.3-q31.1 that was marginally associated with breast cancer status (OR = 1.5, P = 0.07). Genotypes for this SNP were also significantly associated with indicators of breast cancer severity, including presence of lymph node metastases (P = 0.006) and earlier age of onset (P = 0.01). The association with breast cancer status was replicated in two independent samples (OR = 1.35, P = 0.05). High-density association fine mapping showed that the association spanned about 80 kb of the zinc-finger gene DPF3 (also known as CERD4). One SNP in intron 1 was found to be more strongly associated with breast cancer status in all three sample collections (OR = 1.6, P = 0.003) as well as with increased lymph node metastases (P = 0.01) and tumor size (P = 0.01). CONCLUSION: Polymorphisms in the 5' region of DPF3 were associated with increased risk of breast cancer development, lymph node metastases, age of onset, and tumor size in women of European ancestry. This large-scale association study suggests that genetic variation in DPF3 contributes to breast cancer susceptibility and severity. [Abstract/Link to Full Text]

Mukherjee B, Ghosh S, Das T, Doloi M
Characterization of insulin-like-growth factor II (IGF II) mRNA positive hepatic altered foci and IGF II expression in hepatocellular carcinoma during diethylnitrosamine-induced hepatocarcinogenesis in rats.
J Carcinog. 2005 Aug 10;412.
BACKGROUND: Insulin-like-growth factor II (IGF II) has been implicated in the pathogenesis of neoplasm of different tissues, including liver of rats and men. This growth factor is believed to exert its effect during cellular proliferation. During the process of development of hepatocellular carcinoma (HCC), different hepatic altered foci appear. They are believed to be the putative precursors of HCC in rats and in men. Thus, to study the role of the gene in a defined model of hepatocarcinogenesis was the target to elucidate its role in various cancer phenotypes during the entire development stage of cancer, right from earlier preneoplastic lesions to HCC. METHODS: Antisense in situ hybridization technique was used here to characterize the type(s) of foci in which IGF II mRNA had expressed during the development of hepatocarcinogenesis-induced by diethylnitrosamine and promoted by phenobarbital in rats. Various focal lesions have been categorized depending on the stages and sizes along with IGF II expression patterns in them. Immunohistochemical detection for proliferating cell nuclear antigen (PCNA) was made to detect the role of the gene in preneoplastic and neoplastic cellular proliferation. RESULTS: IGF II expression was located in the glycogen-storage acidophilic cell foci maximally followed by mixed cell lesions and the least in basophilic lesions. The expression of IGF II was found to be predominant in the HCC. The expression of gene was also located at the peripheral cells of spongiosis hepatis which are believed to be the precursor of ito cell carcinoma. It was noted that there is a direct correlation between IGF II expression and immunohistochemical detection for PCNA. CONCLUSION: It may be concluded that IGF II gene expression plays an important role during the development of neoplasia and the gene expresses in the sequence of events leading from glycogen-rich-acidophilic lesions to glycogen poor basophilic lesions to HCC with an expression pattern of "high-low-high" in terms of degree of expression. Moreover, the essential role of the gene at the immediate initiation stage of carcinogenesis (first few weeks) and during HCC development cannot be ignored. Thus this expression can be used as a suitable marker for very early detection of the cancerous process and can save numbers of future cancer victims by very early detection of this disease. [Abstract/Link to Full Text]

Dahle J, Kvam E, Stokke T
Bystander effects in UV-induced genomic instability: antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation.
J Carcinog. 2005 Aug 9;411.
BACKGROUND: Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. METHODS: Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt) gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. RESULTS: The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequencies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24%. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. CONCLUSION: The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of glutathione. Previously, we have shown that ultraviolet induced delayed mutations may be induced via a bystander effect and that this effect is 5-fold higher for UVB radiation than for UVA radiation. Therefore, we propose that the antioxidants inhibit an ultraviolet radiation-induced bystander effect and that the effect is transmitted via the medium and via an internal transfer between cells, like gap junctional intercellular communication, for UVB radiation and only by the latter mechanism for UVA radiation. [Abstract/Link to Full Text]

Rivera JA, Alturaihi H, Kumar U
Differential regulation of somatostatin receptors 1 and 2 mRNA and protein expression by tamoxifen and estradiol in breast cancer cells.
J Carcinog. 2005 Jul 14;4(1):10.
Somatostatin (SST) inhibition of hormone hypersecretion from tumors is mediated by somatostatin receptors (SSTRs). SSTRs also play an important role in controlling tumor growth through specific antiproliferative actions. These receptors are well expressed in numerous normal and tumor tissues and are susceptible to regulation by a variety of factors. Estradiol, a potent trophic and mitogenic hormone in its target tissues, is known to modulate the expression of SST and its receptors. Accordingly, in the present study, we determined the effects of tamoxifen, a selective estrogen receptor (ER) modulator (SERM), and estradiol on SSTR1 and SSTR2 expression at the mRNA and protein levels in ER-positive and -negative breast cancer cells. We found that SSTR1 was upregulated by tamoxifen in a dose-dependent manner but no effect was seen with estradiol. In contrast, SSTR2 was upregulated by both tamoxifen and estradiol. Combined treatment caused suppression of SSTR1 below control levels but had no significant effect on SSTR2. Treatment with SSTR1-specific agonist was significantly more effective in suppressing cell proliferation of cells pre-treated with tamoxifen. Taking these data into consideration, we suggest that tamoxifen and estradiol exert variable effects on SSTR1 and SSTR2 mRNA and protein expression and distributional pattern of the receptors. These changes are cell subtype-specific and affect the ability of SSTR agonists to inhibit cell proliferation. [Abstract/Link to Full Text]

Wada R, Ogawa K, Yamaguchi T, Tanizaki T, Matsumoto M
Intercalated duct cell is starting point in development of pancreatic ductal carcinoma?
J Carcinog. 2005 Jul 14;49.
BACKGROUND: Although it is well known that the pancreatic ductal carcinoma may develop having a relationship to the mucous gland hyperplasia (MGH) with atypia (PanIN-1B by PanIN system), the starting point of this atypical MGH is unclear. To know it, we examined the pancreas tissue using many methods described below. METHODS: 1. Twenty-seven surgically resected pancreas tissue specimens, including pancreatic ductal carcinomas (PDC), chronic pancreatitis and normal pancreas, were investigated using immunohistochemical stainings for MUC1, MUC6, 45M1, Ki67 and p53. 2. DNA extraction and analysis of K-ras mutation at codon 12 using microdissection method: The paraffin blocks with 16 regions including the intercalated duct cell (IC) adjacent to the atypical MGH were prepared for DNA extraction. Mutation of K-ras codon 12 was analyzed and compared in enriched polymerase chain reaction-enzyme-linked mini sequence assay (PCR-ELMA). RESULTS: 1. In the normal pancreas, although no positive cell was seen in 45M1, p53, Ki67, the cytoplasm of IC were always positive for MUC1 and sometimes positive for MUC6. In the pancreas with fibrosis or inflammation, MGH was positive for MUC6 and 45M1. And atypical MGH was positive for MUC1, MUC6 and 45M1. Some IC adjacent to the atypical MGH was positive for Ki67 as well as atypical MGH. The carcinoma cells in all cases of PDC were diffusely positive for MUC1, 45M1, p53 and Ki67, and focally positive for MUC6. 2. In K-ras mutation, we examined the regions including IC adjacent to the atypical MGH, because the immunohistochemical apomucin stainings of these regions resembled those of PDC as described above. And K-ras mutation was confirmed in 12 of 16 regions (75%). All mutations were a single mutation, in 6 regions GTT was detected, in 4 regions GAT was detected and in 2 region AGT was detected. CONCLUSION: Some intercalated duct cell may be the starting point of the pancreatic ductal carcinoma, because the exhibitions of mucin expressions, Ki67, p53 and K-ras mutation in some intercalated duct cell resembled those of mucous gland hyperplasia or pancreatic ductal carcinoma. [Abstract/Link to Full Text]

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Quirt I, Verma S, Petrella T, Bak K, Charette M
Temozolomide for the treatment of metastatic melanoma: a systematic review.
Oncologist. 2007 Sep;12(9):1114-23.
BACKGROUND: This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to 2005. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. RESULTS: Two randomized phase III trials and three randomized phase II trials were located. In addition, 21 phase I or II trials investigating single-agent temozolomide, temozolomide plus interferon-alpha, and temozolomide plus thalidomide were reviewed. A direct comparison of temozolomide and dacarbazine demonstrated equal efficacy for response rates and overall survival; however, no significant difference was reported. A second phase III study comparing single-agent temozolomide with temozolomide combined with interferon-alpha indicated a significantly higher response rate for the combination treatment arm, but no difference in overall survival was noted. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and interferon-alpha or thalidomide. CONCLUSION: Our review of the available literature suggests that temozolomide demonstrates comparable activity to the current standard treatment, dacarbazine, with the additional benefit of being a convenient oral treatment that penetrates the blood-brain barrier. [Abstract/Link to Full Text]

Penson RT, Gu F, Harris S, Thiel MM, Lawton N, Fuller AF, Lynch TJ
Hope.
Oncologist. 2007 Sep;12(9):1105-13.
Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery that provides hope to the patient, support to caregivers, and encourages the healing process. The Center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. A patient with recurrent ovarian cancer, now in a 12-year remission after recurrence, and her surgeon, discussed their experiences and feelings around the hopes and fears of cancer and its treatment. Hope sustains many through dark times, and is at the core of the wonderful resilience of many who wrestle with cancer. Concerns about false hope, unrealistic expectations, assumptions, engaging in realistic hopefulness, and the joys and stresses embodied in hope and how they frame the caregiver-patient relationship are discussed. The literature and limited evidence base are reviewed. [Abstract/Link to Full Text]

Lally BE, Urbanic JJ, Blackstock AW, Miller AA, Perry MC
Small cell lung cancer: have we made any progress over the last 25 years?
Oncologist. 2007 Sep;12(9):1096-104.
Twenty-five years ago, small cell lung cancer was widely considered to be the next cancer added to the list of "curable cancers." This article attempts to summarize the progress made toward that goal since then. Clinical trials have provided landmarks in the therapy of limited-stage small cell lung cancer (LS-SCLC). These are: (a) the proof that thoracic radiation therapy adds to systemic chemotherapy, (b) the superiority of twice-daily radiation therapy over daily fractionation, and (c) the need for prophylactic central nervous system radiation (prophylactic cranial irradiation). Each of these innovations adds about 5%-10% to the overall survival rate. In extensive-stage disease, irinotecan plus cisplatin may be a possible alternative to the "standard" etoposide-cisplatin chemotherapy doublet, but there has been little progress otherwise. It is imperative that, whenever possible, patients be given the opportunity to participate in future clinical trials so that the survival for these patients can continue to improve. [Abstract/Link to Full Text]

Strome SE, Sausville EA, Mann D
A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects.
Oncologist. 2007 Sep;12(9):1084-95.
Several monoclonal antibodies are now in clinical use for cancer therapy, and many others are currently undergoing clinical evaluation. These agents offer unique specificity against key molecular targets on tumor cells or in the tumor microenvironment. The clinical efficacy of monoclonal antibodies is generally attributed to target-specific mechanisms resulting from neutralizing or inhibiting a growth factor or receptor that drives cell proliferation and tumor growth. Several targets, including CD20, human epidermal growth factor receptor 2, vascular endothelial growth factor, and epidermal growth factor receptor, have been validated in specific malignancies on the basis of monoclonal antibody efficacy. However, monoclonal antibodies also have the potential to activate immune-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. These functions result from interactions involving the Fc domain of the antibody, and, consequently, may vary by antibody, isotype, and Fc modification, such as changes in glycosylation. Accordingly, all monoclonal antibodies directed against a given target should not be considered equivalent in their ability to stimulate immune-mediated effector functions. [Abstract/Link to Full Text]

Superfin D, Iannucci AA, Davies AM
Commentary: Oncologic drugs in patients with organ dysfunction: a summary.
Oncologist. 2007 Sep;12(9):1070-83.
There are few prospective data regarding the pharmacokinetics and clinical toxicity of commonly used chemotherapeutics in cancer patients with organ dysfunction. Although increasing numbers of studies are investigating newer chemotherapeutics in patients with liver or kidney dysfunction, most guidelines for dosing, especially for established agents, remain empiric. This review describes the available data (both prospective and case study) evaluating the impact of renal and hepatic dysfunction on toxicity and dosing of commonly used chemotherapeutics and provides a practical summary for their use in this setting. [Abstract/Link to Full Text]

Moore HC, Theriault RL
Commentary: Ovarian function does not equal fertility does not equal babies.
Oncologist. 2007 Sep;12(9):1067-9. [Abstract/Link to Full Text]

Blumenfeld Z
How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries.
Oncologist. 2007 Sep;12(9):1044-54.
The possibilities to preserve fertility in women exposed to chemotherapy are: in vitro fertilization plus embryo cryopreservation, ovarian cryopreservation, unfertilized ova cryopreservation, and the administration of a gonadotropin-releasing hormone (GnRH) agonist. Because none of these methods is ideal, combination of several methods should be considered. Because the chances of preserving gonadal function following combined-modality treatment are significantly better for girls than for boys, simulation of a prepubertal milieu was applied only to women of reproductive age. The administration of GnRH agonists to women with Hodgkin's disease, breast cancer, and other malignancies, or to patients with lupus nephropathy, in parallel with chemotherapy, by others and by us, has demonstrated a significantly lower rate of premature ovarian failure in survivors than in nonrandomized controls. Several prospective, randomized studies are ongoing. A recent meta-analysis found that the administration of a GnRH agonist, in addition to chemotherapy, to patients with breast cancer was associated with less recurrence and superior survival. Several possibilities to explain the beneficial effect of GnRH agonists to minimize chemotherapy-associated gonadotoxicity are suggested: (a) The hypogonadotropic milieu decreases the number of primordial follicles entering the differentiation stage, which is more vulnerable to chemotherapy; (b) The hypoestrogenic state decreases ovarian perfusion and delivery of chemotherapy to the ovaries; (c) A direct effect of the GnRH agonist on the ovary occurs independently of the gonadotropin level; (d) GnRH agonists may upregulate an intragonadal antiapoptotic molecule such as sphingosine-1-phosphate; (e) The GnRH agonist may protect ovarian germline stem cells. [Abstract/Link to Full Text]

Oktay K, S�nmezer M, Oktem O, Fox K, Emons G, Bang H
Absence of conclusive evidence for the safety and efficacy of gonadotropin-releasing hormone analogue treatment in protecting against chemotherapy-induced gonadal injury.
Oncologist. 2007 Sep;12(9):1055-66.
Every year, an increasing number of women with malignant and nonmalignant diseases is successfully treated with cytotoxic chemotherapy and/or radiotherapy. Many of these patients suffer from infertility and gonadal failure as a result of these treatments. At present, these patients may resort to assisted-reproduction techniques to protect their future childbearing potential before the implementation of cytotoxic therapy. While embryo cryopreservation is an established technology, oocyte and ovarian tissue freezing techniques are still investigational. Nevertheless both of these techniques have resulted in live births. Apart from assisted-reproduction techniques, it has been extensively debated whether administration of gonadotropin-releasing hormone (GnRH) analogues in conjunction with chemotherapy can protect ovarian reserve against cytotoxic insult. In this manuscript, we debate the rationale for the effectiveness of GnRH analogue coadministration in preservation of fertility by reviewing the literature, and provide preliminary data to support our views. [Abstract/Link to Full Text]

Lipton A, Cook RJ, Major P, Smith MR, Coleman RE
Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity.
Oncologist. 2007 Sep;12(9):1035-43.
OBJECTIVE: Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer. METHODS: This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX < 64 nmol/mmol creatinine) or elevated (NTX > or = 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models. RESULTS: Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels. CONCLUSIONS: These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings. [Abstract/Link to Full Text]

Littlewood TJ
Response to "Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia".
Oncologist. 2007 Aug;12(8):1031-2; author reply 1032-4. [Abstract/Link to Full Text]

Lappin TR, Maxwell AP, Johnston PG
Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia.
Oncologist. 2007 Apr;12(4):362-5. [Abstract/Link to Full Text]

Courtney DM, Aldeen AZ, Gorman SM, Handler JA, Trifilio SM, Parada JP, Yarnold PR, Bennett CL
Cancer-associated neutropenic fever: clinical outcome and economic costs of emergency department care.
Oncologist. 2007 Aug;12(8):1019-26.
Purpose. Febrile neutropenia (FN) is a common, costly, and potentially fatal complication in oncology. While FN in the inpatient setting has been extensively studied, only one study has evaluated emergency department (ED) care for FN cancer patients. That study found that 96% of patients survived the complication. We evaluated clinical and economic outcomes for cancer patients with chemotherapy-associated FN treated in an ED. Methods. ED records for consecutive oncology patients with FN were reviewed for information on death, intensive care unit (ICU) use, blood cultures, and costs. Results. Forty-eight patients (n = 57 visits) were evaluated. Six patients died from FN (12%) and four received ICU care within 2 weeks and survived (8%). Blood cultures were positive for 37% of the ED visits. The median ED time was 3.3 hours. In 91% of visits, i.v. antibiotics were administered in the ED, ordered at a median of 1.7 hours from triage (interquartile range [IQR], 1.2-2.8 hours). All patients with death or ICU in 2 weeks and all but one patient with positive blood cultures received antibiotics. The median per patient ED costs were $1,455 (IQR, $1,300-$1,579)-42.4% for hospital/nursing, 23.5% for radiology, 20.8% for physician services, 10.9% for diagnostic tests, and 2.4% for antibiotics. Conclusions. Cancer patients with FN in this sample presenting to the ED frequently had no identified source of infection. One third of the patients had positive ED blood cultures and one fifth died or required ICU care within 2 weeks. Costs of ED care were similar to the cost of a single day of inpatient care. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Wan X, Helman LJ
The biology behind mTOR inhibition in sarcoma.
Oncologist. 2007 Aug;12(8):1007-18.
Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Maki RG
Gemcitabine and docetaxel in metastatic sarcoma: past, present, and future.
Oncologist. 2007 Aug;12(8):999-1006.
Objective. In the era of oral molecular kinase inhibitors, cytotoxic chemotherapy agents are somewhat overlooked, but remain the backbone of treatment for most cancers. Patients with non-gastrointestinal stromal tumor sarcomas, such as leiomyosarcoma, liposarcoma, and undifferentiated high-grade pleomorphic sarcoma (formerly called malignant fibrous histiocytoma), have received doxorubicin and ifosfamide as the backbone of their treatment for over 15 years or more. The goal of this article is to review the data that have led to the use of gemcitabine and docetaxel as a useful combination for patients with metastatic sarcomas, and to comment on possible synergy of the combination. Methods and results. The literature regarding the use of gemcitabine, docetaxel, or both, is reviewed, with emphasis on patients with metastatic sarcoma. Results. Activity of gemcitabine and docetaxel is observed in leiomyosarcoma and undifferentiated high-grade pleomorphic sarcoma. There is apparent schedule dependence of the combination in other cancers; it is unclear if schedule matters in patients with sarcomas. The dose and schedule of gemcitabine and docetaxel examined in phase II studies are probably too high for routine practice. Conclusions. The combination of gemcitabine and docetaxel is an effective option for patients with metastatic sarcoma, increasing the armamentarium for the practicing oncologist in treating this heterogeneous group of diseases. Given the low response rate to docetaxel as a single agent, it is likely that there is true clinical synergy of the combination. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R
FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL).
Oncologist. 2007 Aug;12(8):991-8.
On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ; hereafter, O) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. O was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1-9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar; Merck, Whitehouse Station, NJ; hereafter, E) or O along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. O, at a dose of 2,500 IU/m(2), was administered i.m. on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. E, at a dose of 6,000 IU/m(2), was administered i.m. three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of O and E for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious O efficacy effect. Following induction and DI treatment there was complete (</=1 microM) or moderate (1-10 microM) depletion of serum asparagine levels in the large majority of samples tested over the 4-week period in both O-treated and E-treated subjects. Similarly, depletion of cerebrospinal fluid asparagine levels during induction was similar between O-treated and E-treated subjects. The number of days asparaginase activity exceeded >0.03 IU/ml in O-treated subjects was greater than the number of days in E-treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant. Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) O subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) E subjects tested at any time during the study had antiasparaginase antibodies. In both study arms EFS was in the range of 80% at 3 years. The most serious, sometimes fatal, O toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Manochakian R, Miller KC, Chanan-Khan AA
Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma.
Oncologist. 2007 Aug;12(8):978-90.
Standard frontline therapy for multiple myeloma comprises cytoreductive therapy with or without consolidative high-dose therapy plus stem cell transplantation (HDT-SCT). Despite therapeutic advances, the disease remains incurable; most patients relapse following frontline treatment and die within 5 years of diagnosis. New options are required to enhance and prolong response, and improve survival, particularly for elderly patients and those with renal dysfunction. Preclinical studies have demonstrated the ability of bortezomib to enhance the activity of commonly used myeloma agents, an observation validated through clinical studies in both the relapsed and frontline settings. This review focuses on the growing body of clinical evidence showing the effectiveness of bortezomib and bortezomib-based combinations in newly diagnosed patients, characterized by high overall response rates and consistently high rates of complete response. A number of studies incorporating bortezomib as part of induction therapy have demonstrated no adverse impact of bortezomib on stem cell harvest and engraftment in patients proceeding to transplantation. The higher rates of complete response typically associated with bortezomib treatment may potentially improve clinical outcomes in this setting. Final results from ongoing phase III studies of bortezomib-based combinations versus standard regimens will help define the optimal use of bortezomib as a standard component of frontline therapy for multiple myeloma. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Eisbruch A
Commentary: induction chemotherapy for head and neck cancer: hypothesis-based rather than evidence-based medicine.
Oncologist. 2007 Aug;12(8):975-7. [Abstract/Link to Full Text]

Posner M
Evolving strategies for combined-modality therapy for locally advanced head and neck cancer.
Oncologist. 2007 Aug;12(8):967-74.
Despite continual advances in the treatment of head and neck cancer, disease-free survival, functional outcome, toxicity of therapy, and overall survival remain less than optimal. While traditional treatment has focused on surgical resection with or without radiation and chemoradiotherapy, newer combined-modality regimens may offer patients a better prognosis, organ preservation, and less morbidity. In this paper, single agents and doublet therapy are reviewed, as are emerging data on the utility of induction therapy, chemoradiotherapy, and surgery as a sequential treatment regimen. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Fehrmann RS, Li XY, van der Zee AG, de Jong S, Te Meerman GJ, de Vries EG, Crijns AP
Profiling studies in ovarian cancer: a review.
Oncologist. 2007 Aug;12(8):960-6.
Ovarian cancer is a heterogeneous disease with respect to histopathology, molecular biology, and clinical outcome. In advanced stages, surgery and chemotherapy result in an approximately 25% overall 5-year survival rate, pointing to a strong need to identify subgroups of patients that may benefit from targeted innovative molecular therapy. This review summarizes: (a) microarray research identifying gene-expression profiles in ovarian cancer; (b) the methodological flaws in the available microarray studies; and (c) applications of pathway analysis to define new molecular subgroups. Microarray technology now permits the analysis of expression levels of thousands of genes. So far seven studies have aimed to identify a genetic profile that can predict survival/clinical outcome and/or response to platinum-based therapy. To date, the clinical evidence of prognostic microarray studies has only reached the level of small retrospective studies, and there are other issues that may explain the nonreproducibility among the reported prognostic profiles, such as overfitting, technical platform differences, and accuracy of measurements. We consider pathway analysis a promising new strategy. The accumulation of small differential expressions within a meaningful molecular regulatory network might lead to a critical threshold level, resulting in ovarian cancer. Microarray technologies have already provided valuable expression data for classifying ovarian cancer and the first clues about which molecular changes in ovarian cancer could be exploited in new treatment strategies. Further improvements in technology as well as in study design, combined with pathway analysis, will allow us to detect even more subtle tumor expression differences among subgroups of ovarian cancer patients. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Dellapasqua S, Colleoni M, Castiglione M, Goldhirsch A
New criteria for selecting elderly patients for breast cancer adjuvant treatment studies.
Oncologist. 2007 Aug;12(8):952-9.
About 50% of breast cancers occur in women aged 65 years and older, and both the incidence and prevalence of breast cancer among older women are expected to increase in the future. Aging implies a reduction in life expectancy and tolerance to treatments that should be considered in elderly patients with early breast cancer. In fact, treatment options often carry short-term risks and toxicities that might be tempered by long-term survival gains. The choice of adjuvant treatment for elderly patients should be based on the same criteria that are currently used for younger patients: endocrine responsiveness and assessment of risk of relapse. Adjuvant endocrine therapy should be considered for women with endocrine-responsive disease, regardless of age. The value of adjuvant chemotherapy is controversial. Older women are frequently undertreated with adjuvant chemotherapy and are underrepresented in clinical trials. In particular, no convincing data are available on the role of adjuvant chemotherapy in endocrine nonresponsive tumors, partly because most of the time these tumors represent a relatively small subset in adjuvant studies focusing on the elderly population. Several phase III trials are currently ongoing in elderly patients with early breast cancer to evaluate different options of adjuvant treatments. Only one trial, coordinated by the International Breast Cancer Study Group, is investigating the role of adjuvant chemotherapy for postmenopausal women of advanced age with endocrine nonresponsive early breast cancer. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Greenblatt DY, Vaccaro AM, Jaskula-Sztul R, Ning L, Haymart M, Kunnimalaiyaan M, Chen H
Valproic acid activates notch-1 signaling and regulates the neuroendocrine phenotype in carcinoid cancer cells.
Oncologist. 2007 Aug;12(8):942-51.
Carcinoid tumors are neuroendocrine malignancies that frequently metastasize and secrete hormones that cause debilitating symptoms in patients. In this study we report the effects of valproic acid (VPA), a drug long used for the treatment of epilepsy, on the growth and neuroendocrine phenotype of human carcinoid cancer cells. VPA treatment of gastrointestinal and pulmonary carcinoid cells resulted in a dose-dependent inhibition of cancer cell growth. Western blot analysis revealed degradation of cyclin D1 and an increase in cyclin-dependent kinases p21 and p27 with VPA treatment. Flow cytometry confirmed that the mechanism of VPA-induced growth inhibition is G(1) phase cell cycle arrest. Furthermore, VPA suppressed expression of the neuroendocrine tumor marker chromogranin A. In addition to these effects, VPA also increased levels of full-length Notch-1 and the active Notch-1 intracellular domain. Luciferase reporter assays incorporating the centromere-binding factor 1 (CBF-1) binding site and the achaete-scute complex-like 1 (ASCL-1) promoter confirmed the functional activity of VPA-induced Notch-1. Transfection of Notch-1 small-interfering RNA into carcinoid tumor cells blocked the effects of VPA on Notch-1 activation, ASCL-1 suppression, p21 induction, and cell growth inhibition. VPA also suppressed growth of carcinoid tumors in vivo in a mouse tumor xenograft experiment. These findings confirm the important role of Notch-1 in regulating the growth and neuroendocrine phenotype of carcinoid tumor cells. On the basis of this study, a clinical trial of VPA for patients with advanced carcinoid cancer will be conducted. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Marchetti S, Mazzanti R, Beijnen JH, Schellens JH
Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein).
Oncologist. 2007 Aug;12(8):927-41.
The importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported. Inhibition or induction of P-gp by coadministered drugs or food as well as herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or undertreatment. On the other hand, modulation of P-gp expression and/or activity may be a useful strategy to improve the pharmacological profile of anticancer P-gp substrate drugs. In recent years, the use of complementary and alternative medicine (CAM), like herbs, food, and vitamins, by cancer patients has increased significantly. CAM use substantially increases the risk for interactions with anticancer drugs, especially because of the narrow therapeutic window of these compounds. However, for most CAMs, it is unknown whether they affect metabolizing enzymes and/or drug transporter activity. Clinically relevant interactions are reported between St John's wort or grapefruit juice and anticancer as well as nonanticancer drugs. CAM-drug interactions could explain, at least in part, the large interindividual variation in efficacy and toxicity associated with drug therapy in both cancer and noncancer patients. The study of drug-drug, food-drug, and herb-drug interactions and of genetic factors affecting pharmacokinetics and pharmacodynamics is expected to improve drug safety and will enable individualized drug therapy. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Hempel G, Boos J
Flat-fixed dosing versus body surface area based dosing of anticancer drugs: there is a difference.
Oncologist. 2007 Aug;12(8):924-6. [Abstract/Link to Full Text]

Mathijssen RH, de Jong FA, Loos WJ, van der Bol JM, Verweij J, Sparreboom A
Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference?
Oncologist. 2007 Aug;12(8):913-23.
The current practice of using body-surface area (BSA) in dosing anticancer agents was implemented in clinical oncology half a century ago. By correcting for BSA, it was generally assumed that cancer patients would receive a dose of a particular cytotoxic drug associated with an acceptable degree of toxicities without reducing the agent's therapeutic effect. More recently, doubt has arisen to this hypothesis, and for many drugs, the effects of BSA on the pharmacokinetics of these agents have therefore been studied retrospectively. In (by far) most cases, use of BSA does not reduce the interindividual variation in the pharmacokinetics of adults, and thus, a logical rationale for further use of this tool in dosing adults is lacking. As a result, alternative dosing strategies have been proposed in order to replace BSA-based dosing. Flat-fixed dosing regimens have been suggested, thereby avoiding potential dose calculation mistakes. As flat-fixed dosing does not typically lead to greater pharmacokinetic variability, it does not seem worse than using BSA-based dosing. While it provides a simplification, it can, however, be questioned whether to call this an improvement or not. The implementation of so-called genotyping and phenotyping strategies, and therapeutic drug monitoring, may probably be of more clinical value. In the end, the nonscientifically based BSA-based dosing strategy should be replaced by alternative strategies. Despite the lack of basic fundamentals, BSA-based dosing still seems "untouchable" in clinical oncology. Even when alternatives will be shown to be indisputably better, many hurdles will probably have to be overcome before physicians will be willing to ban BSA-based dosing. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Gonzalez-Angulo AM, Hennessy BT, Broglio K, Meric-Bernstam F, Cristofanilli M, Giordano SH, Buchholz TA, Sahin A, Singletary SE, Buzdar AU, Hortob�gyi GN
Trends for inflammatory breast cancer: is survival improving?
Oncologist. 2007 Aug;12(8):904-12.
The purpose of this study was to evaluate whether the survival of women with inflammatory breast cancer (IBC) treated at our institution has improved over the past 30 years. Three-hundred ninety-eight patients with IBC were treated between 1974 and 2005. Patient characteristics and outcomes were tabulated and compared among decades of diagnosis. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared among groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient and disease characteristics and treatments received. The median follow-up was 5.8 years (range, 0.3-23.8 years). There were 238 recurrences and 236 deaths. The median recurrence-free survival (RFS) duration was 2.3 years and the median overall survival (OS) time was 4.2 years. In the models for RFS and OS, after adjustment for patient and disease characteristics, increasing year of diagnosis was not associated with a decrease in the risk for recurrence (hazard ratio, [HR], 1.00; 95% confidence interval [CI], 0.97-1.04) or death (HR, 0.97; 95% CI, 0.94-1.01). Our data show that there has not been an important change in the prognosis of patients with IBC in the last 30 years. Clinical trials focusing on the management of this aggressive disease are warranted. Disclosure of potential conflicts of interest is found at the end of this article. [Abstract/Link to Full Text]

Chabner BA
Orange alert for oncologists.
Oncologist. 2007 Aug;12(8):902-3. [Abstract/Link to Full Text]

Eichler AF, Loeffler JS
Multidisciplinary management of brain metastases.
Oncologist. 2007 Jul;12(7):884-98.
Metastatic brain tumors are the most common intracranial neoplasms in adults. The incidence of brain metastases appears to be rising as a result of superior imaging modalities, earlier detection, and more effective treatment of systemic disease. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Treatment decisions must take into account clinical prognostic factors in order to maximize survival and neurologic function whilst avoiding unnecessary treatments. The goal of this article is to review important prognostic factors that may guide treatment selection, discuss the roles of surgery, radiation, and chemotherapy in the treatment of patients with brain metastases, and present new directions in brain metastasis therapy under active investigation. In the future, patients will benefit from a multidisciplinary approach focused on the integration of surgical, radiation, and chemotherapeutic options with the goal of prolonging survival, preserving neurologic and neurocognitive function, and maximizing quality of life. [Abstract/Link to Full Text]

Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, Canniff PC, Sharma A, Gomez-Navarro J
Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.
Oncologist. 2007 Jul;12(7):873-83.
Tremelimumab (CP-675,206) is a fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) in clinical development for patients with cancer. Blocking the CTLA-4 negative costimulatory receptor with the antagonistic antibody tremelimumab results in immune activation. Administration of tremelimumab to patients with locally advanced and metastatic melanoma has resulted in a subset of patients with durable objective tumor regressions. Its IgG(2) isotype minimizes the possibility of cytotoxic effects on activated T lymphocytes and cytokine release syndrome. Preclinical testing in vitro and in large animal models predicted the target concentrations of circulating antibody in humans necessary for a pharmacodynamic effect. Phase I clinical trials provided evidence of dose- or exposure-related effects consistent with the anticipated mechanism of action. Further clinical development has led to two ongoing registration trials in patients with metastatic melanoma: a phase III randomized trial of tremelimumab versus dacarbazine or temozolomide in previously untreated patients with advanced melanoma and a phase II trial of tremelimumab in previously treated patients with advanced melanoma. [Abstract/Link to Full Text]

Weber J
Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events.
Oncologist. 2007 Jul;12(7):864-72.
The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. Preclinical and early clinical studies of patients with advanced melanoma show that ipilimumab promotes antitumor activity as monotherapy and in combination with treatments such as chemotherapy, vaccines, or cytokines. Emerging data on the kinetics of response to ipilimumab and associated adverse events are increasing our understanding about how to manage patients treated with this therapy. For example, short-term tumor progression prior to delayed regression has been observed in ipilimumab-treated patients, and objective responses may be of prolonged duration. In some patients clinical improvement manifests as stable disease, which may also extend for months or years. Immune-related adverse events (IRAEs) have been observed in patients after CTLA-4 blockade and most likely reflect the drug mechanism of action and corresponding effects on the immune system. Early clinical data suggest a correlation between IRAEs and response to ipilimumab treatment. This paper briefly reviews the results from several ongoing and completed ipilimumab clinical trials, provides a synopsis of current trials, and presents several cases that demonstrate the kinetics of antitumor responses and the relationship to IRAEs in patients receiving ipilimumab. [Abstract/Link to Full Text]

Ceresoli GL, Gridelli C, Santoro A
Multidisciplinary treatment of malignant pleural mesothelioma.
Oncologist. 2007 Jul;12(7):850-63.
The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease. [Abstract/Link to Full Text]

Gridelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F
Erlotinib in non-small cell lung cancer treatment: current status and future development.
Oncologist. 2007 Jul;12(7):840-9.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Standard treatment approaches such as chemotherapy, radiotherapy, and surgery have reached a plateau in this disease. Therefore, alternatives to conventional treatment, such as new molecular-targeted therapies, are needed. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. There are two EGFR tyrosine kinase inhibitors approved for the treatment of advanced NSCLC: gefitinib and erlotinib. Of these, erlotinib has shown a significant improvement in median survival, quality of life, and related symptoms in an unselected population of advanced and metastatic NSCLC patients in the second- or third-line setting. Furthermore, erlotinib has significant antitumor activity in first-line treatment. Moreover, factors that predict the efficacy of erlotinib, including clinical, pathologic, and molecular features, have been investigated. A series of studies is planned to contribute to our understanding of the role of erlotinib in NSCLC treatment. Major areas of clinical research are the assessment of erlotinib: in adjuvant treatment, combined with chemotherapy and/or radiotherapy in locally advanced disease, in the first-line therapy of advanced disease, and in combination and/or sequence with cytotoxic treatments and/or other molecular target agents. [Abstract/Link to Full Text]

Recent Articles in CA: A Cancer Journal for Clinicians

Yates JW
Food and Drug Administration, partner in drug development.
CA Cancer J Clin. 2006 Nov-Dec;56(6):321-2. [Abstract/Link to Full Text]

Fertility guidelines address often-ignored treatment side effect.
CA Cancer J Clin. 2006 Sep-Oct;56(5):251-3. [Abstract/Link to Full Text]

A call for more vitamin D research.
CA Cancer J Clin. 2006 Sep-Oct;56(5):250-1. [Abstract/Link to Full Text]

HPV vaccine fights cervical cancer.
CA Cancer J Clin. 2006 Sep-Oct;56(5):249-50. [Abstract/Link to Full Text]

Choices for good health: American Cancer Society Guidelines for Nutrition and Physical Activity for cancer prevention.
CA Cancer J Clin. 2006 Sep-Oct;56(5):310-2. [Abstract/Link to Full Text]

Kushi LH, Byers T, Doyle C, Bandera EV, McCullough M, McTiernan A, Gansler T, Andrews KS, Thun MJ
American Cancer Society Guidelines on Nutrition and Physical Activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity.
CA Cancer J Clin. 2006 Sep-Oct;56(5):254-81; quiz 313-4.
The American Cancer Society (ACS) publishes Nutrition and Physical Activity Guidelines to serve as a foundation for its communication, policy, and community strategies and ultimately, to affect dietary and physical activity patterns among Americans. These Guidelines, published every 5 years, are developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and as such, they represent the most current scientific evidence related to dietary and activity patterns and cancer risk. The ACS Guidelines include recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or interferes with healthy behaviors. Community efforts are essential to create a social environment that promotes healthy food choices and physical activity. Therefore, this committee presents one key recommendation for community action to accompany the four recommendations for individual choices to reduce cancer risk. This recommendation for community action recognizes that a supportive social environment is indispensable if individuals at all levels of society are to have genuine opportunities to choose healthy behaviors. The ACS Guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion, as defined by the Department of Health and Human Services' 2005 Dietary Guidelines for Americans. [Abstract/Link to Full Text]

Chen SL, Iddings DM, Scheri RP, Bilchik AJ
Lymphatic mapping and sentinel node analysis: current concepts and applications.
CA Cancer J Clin. 2006 Sep-Oct;56(5):292-309; quiz 316-7.
Since the introduction of sentinel node biopsy in 1990 as a minimally invasive surgical technique for the diagnosis of melanoma lymphatic metastases, the number of applications has expanded. We review applications and the current status of sentinel node biopsy in melanoma, breast, colon, gastric, esophageal, head and neck, thyroid, and lung cancer. Variations on techniques specific to each organ are explained, and the current role of sentinel node biopsy in diagnosis and treatment is discussed. [Abstract/Link to Full Text]

Kotilingam D, Lev DC, Lazar AJ, Pollock RE
Staging soft tissue sarcoma: evolution and change.
CA Cancer J Clin. 2006 Sep-Oct;56(5):282-91; quiz 314-5.
Soft tissue sarcoma (STS) is an extremely heterogeneous group of rare tumors that share a putative mesenchymal cell origin. STS can occur in any soft tissue in the body, yet all share a common feature of primarily disseminating hematogenously, particularly to the lungs. Staging for STS is particularly useful in prognosis, design of effective multimodality treatment programs, and comparing treatment outcomes from different centers and different eras. The current iteration of AJCC STS staging includes Tumor, Grade, Node, and Metastasis with "a" indicating superficial and "b" indicating deep designations. Further opportunities to improve this process exist, particularly as molecular considerations become more apparent, and future evolution into an even more useful STS staging system can be anticipated. [Abstract/Link to Full Text]

Sharkey RM, Goldenberg DM
Targeted therapy of cancer: new prospects for antibodies and immunoconjugates.
CA Cancer J Clin. 2006 Jul-Aug;56(4):226-43.
Immunotherapy of cancer has been explored for over a century, but it is only in the last decade that various antibody-based products have been introduced into the management of patients with diverse cancers. At present, this is one of the most active areas of clinical research, with eight therapeutic products already approved in oncology. Antibodies against tumor-associated markers have been a part of medical practice in immunohistology and in vitro immunoassays for several decades, have even been used as radioconjugates in diagnostic imaging, and are now becoming increasingly recognized as important biological agents for the detection and treatment of cancer. Molecular engineering has improved the prospects for such antibody-based therapeutics, resulting in different constructs and humanized/human antibodies that can be administered frequently. Consequently, a renewed interest in the development of antibodies conjugated with radionuclides, drugs, and toxins has emerged. We review how antibodies and immunoconjugates have influenced cancer detection and therapy, and also describe promising new developments and challenges for broader applications. [Abstract/Link to Full Text]

Hendriks YM, de Jong AE, Morreau H, Tops CM, Vasen HF, Wijnen JT, Breuning MH, Br�cker-Vriends AH
Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians.
CA Cancer J Clin. 2006 Jul-Aug;56(4):213-25.
ABSTRACT diagnostic workup of familial colorectal cancer is an elaborate and time consuming process in which the family and several medical specialists closely collaborate. However, establishing a diagnosis can be very rewarding. If a mutation is detected in the family, a satisfactory explanation can be provided for an accumulation of tumors at young age, and often of untimely death. Appropriate presymptomatic testing can be offered to reduce mortality among at-risk family members, and relatives not at risk can avoid uncertainty and needlessly intensive surveillance. We show the differential diagnostic considerations when an individual with a family history of colorectal carcinoma is encountered, with emphasis on Lynch syndrome (Hereditary Nonpolyposis Colorectal Carcinoma [HNPCC]). Practical recommendations for laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis are given. Furthermore, the clinical management after a molecular diagnosis has been made is described. The diagnostic scheme presented here allows efficient and effective analysis of colorectal carcinoma cases with (suspected) Lynch syndrome, making optimal use of currently available technology. [Abstract/Link to Full Text]

Christ GH, Christ AE
Current approaches to helping children cope with a parent's terminal illness.
CA Cancer J Clin. 2006 Jul-Aug;56(4):197-212.
Much has been learned about childhood bereavement in the last few decades as studies have increasingly focused on the direct interviewing of children about their recovery from the tragic loss of a parent. It has been shown that children do indeed mourn, although differently from adults. Important moderating and mediating variables have been identified that impact their recovery from the loss of a parent, which can be the focus of intervention. When death is expected, the terminal phase of an illness has been found to be particularly stressful for children, yet seldom investigated. Similarly, few studies have explored the impact of development on children's experience and expression of grief. We present research findings that clarify phases in children's experience during the terminal illness, hospital visits, the death, and its immediate aftermath, as well as how the parent is mourned and issues in longer term reconstitution. Variations in children's responses in these phases are described as they were experienced by 87 children from 3 different developmental groupings: 3 to 5 years, 6 to 8 years, and 9 to 11 years. Recommendations are suggested for parents and professionals about ways to understand and support children during the terminal illness, at the time of death, and during the phase of reconstitution. [Abstract/Link to Full Text]

Smigal C, Jemal A, Ward E, Cokkinides V, Smith R, Howe HL, Thun M
Trends in breast cancer by race and ethnicity: update 2006.
CA Cancer J Clin. 2006 May-Jun;56(3):168-83.
In this article, the American Cancer Society (ACS) provides estimates of new breast cancer cases and deaths in 2006 and describes trends in incidence, mortality, and survival for female breast cancer in the United States. These estimates are based on incidence data from the National Cancer Institute (NCI) and the North American Association of Central Cancer Registries, which includes state data from NCI and the National Program of Cancer Registries of the Centers for Disease Control and Prevention and mortality data from the National Center for Health Statistics for the most recent years available (1975 to 2002). This article also shows trends in screening mammography. Approximately 212,920 new cases of invasive breast cancer, 61,980 in situ cases, and 40,970 deaths are expected to occur among US women in 2006. As previously reported, breast cancer incidence rates increased rapidly among women of all races from 1980 to 1987, a period when there was increasing uptake of mammography by a growing proportion of US women, and then continued to increase, but at a much slower rate, from 1987 to 2002. Trends in incidence vary by age, race, socioeconomic status, and stage. The continuing increase in incidence (all stages combined) is limited to White women age 50 and older; recent trends are stable for African American women age 50 and older and White women under age 50 years and are decreasing for African American women under age 50 years. Although incidence rates (all races combined) are substantially higher for women age 50 and older (375.0 per 100,000 females) compared with women younger than 50 years (42.5 per 100,000 females), approximately 23% of breast cancers are diagnosed in women younger than 50 years because those women represent 73% of the female population. For women age 35 and younger, age-specific incidence rates are slightly higher among African Americans compared with Whites but then cross over so that Whites have substantially higher incidence at all later ages. Among women of all races and ages, breast cancer mortality rates declined at an average rate of 2.3% per year between 1990 and 2002, a trend that reflects progress in both early detection and treatment. However, death rates in African American women remain 37% higher than in Whites, despite lower incidence rates. Although, in national surveys, approximately 70% of women age 40 years and older report having had a mammogram in the past 2 years, rates vary by race/ethnicity and are markedly lower among women with lower levels of education, without health insurance, and in recent immigrants. Furthermore, a recent study suggests that the true percentage of women having regular mammography is lower than reported in survey data. Encouraging patients age 40 years and older to have annual mammography and clinical breast exam is the single most important step that clinicians can take to reduce suffering and death from breast cancer. Clinicians should also ensure that patients at high risk of breast cancer are identified and offered appropriate referrals and treatment. Continued progress in the control of breast cancer will require sustained and increased efforts to provide high-quality screening, diagnosis, and treatment to all segments of the population. [Abstract/Link to Full Text]

Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH, Brooks D, Burt RW, Byers T, Fletcher RH, Hyman N, Johnson D, Kirk L, Lieberman DA, Levin TR, O'Brien MJ, Simmang C, Thorson AG, Winawer SJ
Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer.
CA Cancer J Clin. 2006 May-Jun;56(3):160-7; quiz 185-6.
Patients with resected colorectal cancer are at risk for recurrent cancer and metachronous neoplasms in the colon. This joint update of guidelines by the American Cancer Society (ACS) and US Multi-Society Task Force on Colorectal Cancer addresses only the use of endoscopy in the surveillance of these patients. Patients with endoscopically resected Stage I colorectal cancer, surgically resected Stage II and III cancers, and Stage IV cancer resected for cure (isolated hepatic or pulmonary metastasis) are candidates for endoscopic surveillance. The colorectum should be carefully cleared of synchronous neoplasia in the perioperative period. In nonobstructed colons, colonoscopy should be performed preoperatively. In obstructed colons, double contrast barium enema or computed tomography colonography should be done preoperatively, and colonoscopy should be performed 3 to 6 months after surgery. These steps complete the process of clearing synchronous disease. After clearing for synchronous disease, another colonoscopy should be performed in 1 year to look for metachronous lesions. This recommendation is based on reports of a high incidence of apparently metachronous second cancers in the first 2 years after resection. If the examination at 1 year is normal, then the interval before the next subsequent examination should be 3 years. If that colonoscopy is normal, then the interval before the next subsequent examination should be 5 years. Shorter intervals may be indicated by associated adenoma findings (see Postpolypectomy Surveillance Guideline). Shorter intervals are also indicated if the patient's age, family history, or tumor testing indicate definite or probable hereditary nonpolyposis colorectal cancer. Patients undergoing low anterior resection of rectal cancer generally have higher rates of local cancer recurrence, compared with those with colon cancer. Although effectiveness is not proven, performance of endoscopic ultrasound or flexible sigmoidoscopy at 3- to 6-month intervals for the first 2 years after resection can be considered for the purpose of detecting a surgically curable recurrence of the original rectal cancer. [Abstract/Link to Full Text]

Winawer SJ, Zauber AG, Fletcher RH, Stillman JS, O'brien MJ, Levin B, Smith RA, Lieberman DA, Burt RW, Levin TR, Bond JH, Brooks D, Byers T, Hyman N, Kirk L, Thorson A, Simmang C, Johnson D, Rex DK
Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society.
CA Cancer J Clin. 2006 May-Jun;56(3):143-59; quiz 184-5.
Adenomatous polyps are the most common neoplastic findings uncovered in people who undergo colorectal screening or have a diagnostic workup for symptoms. It was common practice in the 1970s for these patients to have annual follow-up surveillance examinations to detect additional new adenomas as well as missed synchronous adenomas. As a result of the National Polyp Study report in 1993, which demonstrated clearly in a randomized design that the first postpolypectomy examination could be deferred for 3 years, guidelines published by a gastrointestinal consortium in 1997 recommended that the first follow-up surveillance be 3 years after polypectomy for most patients. In 2003, these guidelines were updated, colonoscopy was recommended as the only follow-up examination, and stratification at baseline into lower and higher risk for subsequent adenomas was suggested. The 1997 and 2003 guidelines dealt with both screening and surveillance. However, it has become increasingly clear that postpolypectomy surveillance is now a large part of endoscopic practice, draining resources from screening and diagnosis. In addition, surveys have demonstrated that a large proportion of endoscopists are conducting surveillance examinations at shorter intervals than recommended in the guidelines. In the present paper, a careful analytic approach was designed addressing all evidence available in the literature to delineate predictors of advanced pathology, both cancer and advanced adenomas, so that patients can be more definitely stratified at their baseline colonoscopy into those at lower or increased risk for a subsequent advanced neoplasia. People at increased risk have either three or more adenomas, or high-grade dysplasia, or villous features, or an adenoma > or =1 cm in size. It is recommended that they have a 3-year follow-up colonoscopy. People at lower risk who have one or two small (< 1 cm) tubular adenomas with no high-grade dysplasia can have a follow-up in 5 to 10 years, whereas people with hyperplastic polyps only should have a 10-year follow-up as average-risk people. Recent papers have reported a significant number of missed cancers by colonoscopy. However, high-quality baseline colonoscopy with excellent patient preparation and adequate withdrawal time should minimize this and reduce clinicians' concerns. These guidelines were developed jointly by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society to provide a broader consensus and thereby increase utilization of the recommendations by endoscopists. Adoption of these guidelines nationally can have a dramatic impact on shifting available resources from intensive surveillance to screening. It has been shown that the first screening colonoscopy and polypectomy produces the greatest effects on reducing the incidence of colorectal cancer in patients with adenomatous polyps. [Abstract/Link to Full Text]

Cokkinides V, Bandi P, Ward E, Jemal A, Thun M
Progress and opportunities in tobacco control.
CA Cancer J Clin. 2006 May-Jun;56(3):135-42.
Much progress has been made in reducing tobacco use in the United States. Despite the continuing challenges of tobacco control and the massive burden of illness, death, and economic costs caused by tobacco products, there are now unprecedented opportunities to prevent and treat tobacco dependence through a combination of interventions that have proven effective at both the population and individual levels. This report briefly reviews population trends in tobacco use by youth and adults, describes some of the policy measures that have proven effective in comprehensive tobacco control, and discusses the role of clinicians in the diagnosis and treatment of tobacco dependence in patients. [Abstract/Link to Full Text]

Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ
Cancer statistics, 2006.
CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,399,790 new cancer cases and 564,830 deaths from cancer are expected in the United States in 2006. When deaths are aggregated by age, cancer has surpassed heart disease as the leading cause of death for those younger than age 85 since 1999. Delay-adjusted cancer incidence rates stabilized in men from 1995 through 2002, but continued to increase by 0.3% per year from 1987 through 2002 in women. Between 2002 and 2003, the actual number of recorded cancer deaths decreased by 778 in men, but increased by 409 in women, resulting in a net decrease of 369, the first decrease in the total number of cancer deaths since national mortality record keeping was instituted in 1930. The death rate from all cancers combined has decreased by 1.5% per year since 1993 among men and by 0.8% per year since 1992 among women. The mortality rate has also continued to decrease for the three most common cancer sites in men (lung and bronchus, colon and rectum, and prostate) and for breast and colon and rectum cancers in women. Lung cancer mortality among women continues to increase slightly. In analyses by race and ethnicity, African American men and women have 40% and 18% higher death rates from all cancers combined than White men and women, respectively. Cancer incidence and death rates are lower in other racial and ethnic groups than in Whites and African Americans for all sites combined and for the four major cancer sites. However, these groups generally have higher rates for stomach, liver, and cervical cancers than Whites. Furthermore, minority populations are more likely to be diagnosed with advanced stage disease than are Whites. Progress in reducing the burden of suffering and death from cancer can be accelerated by applying existing cancer control knowledge across all segments of the population. [Abstract/Link to Full Text]

Chochinov HM
Dying, dignity, and new horizons in palliative end-of-life care.
CA Cancer J Clin. 2006 Mar-Apr;56(2):84-103; quiz 104-5.
Palliative care practitioners are now better able than ever before to ameliorate end-of-life symptom distress. What remains less developed, however, is the knowledge base and skill set necessary to recognize, assess, and compassionately address the psychosocial, existential, and spiritual aspects of the patient's dying experience. This review provides an overview of these areas, focusing primarily on empirical data that has examined these issues. A brief overview of psychiatric challenges in end-of-life care is complemented with a list of resources for readers wishing to explore this area more extensively. The experience of spiritual or existential suffering toward the end of life is explored, with an examination of the conceptual correlates of suffering. These correlates include: hopelessness, burden to others, loss of sense of dignity, and desire for death or loss of will to live. An empirically-derived model of dignity is described in some detail, with practical examples of diagnostic questions and therapeutic interventions to preserve dignity. Other interventions to reduce existential or spiritual suffering are described and evidence of their efficacy is presented. The author concludes that palliative care must continue to develop compassionate, individually tailored, and effective responses to the mounting vulnerability and increasingly difficult physical, psychosocial, and spiritual challenges facing persons nearing the end of life. [Abstract/Link to Full Text]

Schottenfeld D, Beebe-Dimmer J
Chronic inflammation: a common and important factor in the pathogenesis of neoplasia.
CA Cancer J Clin. 2006 Mar-Apr;56(2):69-83.
A causal link between chronic inflammation and carcinogenesis is explored by reviewing illustrative examples of specific cancers and causal agents and mechanisms. The causal agents or pathologic conditions include microbial agents, gastroesophageal reflux, chronic cholecystitis and cholelithiasis, inflammatory bowel disease, and specific agents that cause chronic obstructive or diffuse interstitial lung disease. The proportion of total cancer deaths attributable to infectious agents is estimated to be about 20% to 25% in developing countries and 7% to 10% in more industrialized countries. Recurrent or persistent inflammation may induce, promote, or influence susceptibility to carcinogenesis by causing DNA damage, inciting tissue reparative proliferation, and/or creating a stromal "soil" that is enriched with cytokines and growth factors. Future research on the complex cascade of cellular and humoral factors participating in the chronic inflammatory process will further understanding of the pathogenesis of various cancers and potentially provide a rationale for targeted chemopreventive interventions. [Abstract/Link to Full Text]

Singletary SE, Connolly JL
Breast cancer staging: working with the sixth edition of the AJCC Cancer Staging Manual.
CA Cancer J Clin. 2006 Jan-Feb;56(1):37-47; quiz 50-1.
The sixth edition of the AJCC Cancer Staging Manual contains some of the most extensive and significant revisions that have ever been made in the breast cancer staging system. The principal changes are related to the size, number, location, and method of detection of regional metastases to the lymph nodes. Some changes are related to the growing use of new technology (eg, sentinel lymph node biopsy, immunohistochemical staining, reverse transcriptase-polymerase chain reaction), whereas others are amendments of prior staging criteria, reflecting recent clinical evidence or widespread clinical consensus. Available data did not support the addition of new prognostic indicators such as histologic tumor grade to the tumor-node-metastasis system at this time. Future developments in determining breast cancer prognosis will most likely incorporate new approaches to identifying the genetic fingerprint of individual tumors. [Abstract/Link to Full Text]

Jimbo M, Nease DE, Ruffin MT, Rana GK
Information technology and cancer prevention.
CA Cancer J Clin. 2006 Jan-Feb;56(1):26-36; quiz 48-9.
Information technology is rapidly advancing and making its way into many primary care settings. The technology may provide the means to increase the delivery of cancer preventive services. The aim of this systematic review is to examine the literature on information technology impacts on the delivery of cancer preventive services in primary care offices. Thirty studies met our selection criteria. Technology interventions studied to date have been limited to some type of reminder to either patients or providers. Patient reminders have been mailed before appointments, mailed unrelated to an appointment, mailed after a missed appointment, or given at the time of an appointment. Telephone call interventions have not used technology to automate the calls. Provider interventions have been primarily computer-generated reminders at the time of an appointment. However, there has been limited use of computer-generated audits, feedback, or report cards. The effectiveness of information technology on increasing cancer screening was modest at best. The full potential of information technology to unload the provider-patient face-to-face encounter has not been examined. There is critical need to study these new technologic approaches to understand the impact and acceptance by providers and patients. [Abstract/Link to Full Text]

Smith RA, Cokkinides V, Eyre HJ
American Cancer Society guidelines for the early detection of cancer, 2006.
CA Cancer J Clin. 2006 Jan-Feb;56(1):11-25; quiz 49-50.
Each January, the American Cancer Society (ACS) publishes a summary of its recommendations for early cancer detection, including guideline updates, emerging issues that are relevant to screening for cancer, and a summary of the most current data on cancer screening rates for US adults. In 2005, there were no updates to ACS guidelines. In this issue of the journal, we summarize the guidelines, discuss recent evidence and policy changes that have implications for cancer screening, and provide an update of the most recent data pertaining to participation rates in cancer screening by age, sex, and insurance status from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System. [Abstract/Link to Full Text]

Runowicz CD
Investment in cancer control and research: a sure bet.
CA Cancer J Clin. 2006 Jan-Feb;56(1):9-10. [Abstract/Link to Full Text]

Armitage JO
Staging non-Hodgkin lymphoma.
CA Cancer J Clin. 2005 Nov-Dec;55(6):368-76.
Non-Hodgkin Lymphomas are always treatable and frequently curable malignancies. However, choosing the most appropriate therapy requires accurate diagnosis and a careful staging evaluation. New patients with non-Hodgkin Lymphoma should have their tumors classified using the World Health Organization classification. The specific choice of therapy is dependent on a careful staging evaluation. Patients with non-Hodgkin Lymphoma are assigned an anatomic stage using the Ann Arbor system. However, patients should also be classified using the International Prognostic Index. New insights into the biology of the lymphomas in the coming years might well improve our ability to evaluate patients and choose therapy. [Abstract/Link to Full Text]

Yang GY, Wagner TD, Fuss M, Thomas CR
Multimodality approaches for pancreatic cancer.
CA Cancer J Clin. 2005 Nov-Dec;55(6):352-67.
The role of combined-modality therapy for pancreatic cancer is evolving with the recent development and completion of major, multi-institutional clinical trials. One of the challenges for the busy clinician is to appreciate the variation in staging, surgical expertise, and application of either definitive chemoradiotherapy or adjuvant chemoradiotherapy for local and/or regionally advanced disease. Our aim is to summarize the current state-of-the-art management and future directions regarding the multimodality approach to pancreatic cancer. [Abstract/Link to Full Text]

Souza RF, Spechler SJ
Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach.
CA Cancer J Clin. 2005 Nov-Dec;55(6):334-51.
For decades, the incidence rates for squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have been declining while the rates for adenocarcinomas of the esophagus and gastric cardia have increased profoundly. Recent studies have shown that the gastroesophageal junction (GEJ) is regularly exposed to concentrated gastric acid and to a variety of nitrosating species, noxious agents that may contribute to carcinogenesis in this region. For adenocarcinomas that straddle the GEJ, it can be difficult to determine whether the tumor originated in the esophagus or in the gastric cardia. This classification problem hampers studies on the epidemiology and pathogenesis of GEJ tumors. Current concepts in the prevention of cancers of the distal esophagus and proximal stomach have emerged from advances in our understanding of the specific molecular events that occur during the evolution of these tumors. This report reviews those events and focuses on current concepts in the prevention of adenocarcinomas at the GEJ. The similarities and differences in risk factors, molecular pathogenesis, and in preventive strategies for adenocarcinomas of the esophagus and gastric cardia are highlighted. [Abstract/Link to Full Text]

D'Andrea GM
Use of antioxidants during chemotherapy and radiotherapy should be avoided.
CA Cancer J Clin. 2005 Sep-Oct;55(5):319-21.
Many patients being treated for cancer use dietary supplements, particularly antioxidants, in the hope of reducing the toxicity of chemotherapy and radiotherapy. Some researchers have claimed, furthermore, that antioxidants also increase the effectiveness of cytotoxic therapy and have explicitly recommended their use. However, mechanistic considerations suggest that antioxidants might reduce the effects of conventional cytotoxic therapies. Preclinical data are currently inconclusive and a limited number of clinical studies have not found any benefit. Clinicians should advise their patients against the use of antioxidant dietary supplements during chemotherapy or radiotherapy. Such caution should be seen as the standard approach for any unproven agent that may be harmful. [Abstract/Link to Full Text]

Pienta KJ, Smith DC
Advances in prostate cancer chemotherapy: a new era begins.
CA Cancer J Clin. 2005 Sep-Oct;55(5):300-18; quiz 323-5.
Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely. In 2004, two landmark studies demonstrated a survival advantage in androgen-independent prostate cancer patients utilizing docetaxel chemotherapy, setting a new standard of care for this disease. In addition, treatments with the bisphosphonate zoledronic acid and systemic radioisotopes have also been shown to have palliative benefits in this population. Building on these advances, several new traditional chemotherapeutic agents as well as new targeted therapies are under development. [Abstract/Link to Full Text]

Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML
Pharmacotherapy for nicotine dependence.
CA Cancer J Clin. 2005 Sep-Oct;55(5):281-99; quiz 322-3, 325.
Approximately 50% of long-term cigarette smokers die prematurely from the adverse effects of smoking, including on cancer, cardiovascular disease, lung disease, or other illness. This risk can be substantially reduced by smoking cessation, with greater benefits occurring the earlier in the smoking career that cessation occurs. However, cessation provides benefits at any stage, including after the onset of smoking-related disease, by improving the prognosis and quality of life. Clinicians can have a significant impact on reducing tobacco use by their patients by following the US Public Health Service Clinical Practice Guidelines. Proven strategies include structured methods of advising cigarette smokers to quit and guidance to facilitate their efforts, as well as the use of various pharmacotherapies. Pharmacotherapies for tobacco dependence include nicotine replacement medications in the form of gum, transdermal patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler formulations. The only nonnicotine medication that has been approved by the US Food and Drug Administration is bupropion. Combination therapies, long-term medication therapies, and harm reduction strategies may further improve outcome with approved medications. Further, new medications such as varenicline and rimonabant are likely to reach tobacco users who are refractory to current treatments. Increasing the treatment options, increasing availability, and reducing the perceived cost of these medications may have an additional public health impact. [Abstract/Link to Full Text]

Hoffman B
Cancer survivors at work: a generation of progress.
CA Cancer J Clin. 2005 Sep-Oct;55(5):271-80.
Before the 1970s, a substantial percentage of cancer survivors faced blatant employment discrimination with little legal recourse, a paucity of support services, and limited medical options for curative treatment. Since then, survivors have benefited from improvements in cancer treatment, the passage of state and federal antidiscrimination laws, and a sea change in perceptions about living with and beyond cancer. Consequently, cancer survivors now face fewer barriers to employment opportunities. Because millions of cancer survivors, more than ever before, are now working age adults, advocacy efforts should shift from expanding legal protection from cancer-based discrimination to providing resources to help survivors meet their individual employment-related concerns. [Abstract/Link to Full Text]

Patel SG, Shah JP
TNM staging of cancers of the head and neck: striving for uniformity among diversity.
CA Cancer J Clin. 2005 Jul-Aug;55(4):242-58; quiz 261-2, 264.
The sixth edition of the tumor-node-metastasis staging system for head and neck cancers incorporates some significant shifts in philosophy. As treatment paradigms shift and data from ongoing clinical and basic research become available, further revisions may be expected in the future. The purpose of this review is to highlight the complexities involved in developing a user-friendly staging system and to report the major changes in the new version. The authors also discuss some areas of current interest that may have the potential to lead to future modifications. [Abstract/Link to Full Text]

Recent Articles in Cancer Control: Journal of the Moffitt Cancer Center

Rezania D, Sokol L, Cualing HD
Classification and treatment of rare and aggressive types of peripheral T-cell/natural killer-cell lymphomas of the skin.
Cancer Control. 2007 Apr;14(2):112-23.
BACKGROUND: The classification of cutaneous lymphomas has been contentious. Two major competing classifications were the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). The principal authors met for a consensus meeting resulted in a combined classification called WHO-EORTC Classification of Cutaneous Lymphoma. METHODS: We review the classification of "mature" or peripheral T-cell lymphoma (PTCL) with high predilection to the skin as published by the WHO-EORTC. We also highlight new information and changes from the previous classifications of cutaneous PTCL according to the WHO classification or the EORTC classification. Finally, the salient findings are compared with similar-looking nodal PTCLs with a high frequency of skin involvement. RESULTS: This review focuses on a rare group of cutaneous PTCLs other than mycosis fungoides or its variants. Changes from the previous classifications are discussed, and the rare group of nodal PTCLs with high predilection to the skin are presented. The salient findings, diagnostic features, and treatments are included, along with summary tables and clinical-histopathologic images. CONCLUSIONS: This review may serve as a guide for hematologists, oncologists and dermatologists in the diagnosis and management of these rare, aggressive, and often difficult to diagnose lymphomas. Although cutaneous lymphomas are morphologically identical to systemic lymphomas, the former behave differently, require divergent management, and should be recognized as separate entities. The consensus WHO-EORTC classification presents unified terminology and definitions to promote conformity in diagnosing and treating these cases, to foster a multidisciplinary approach to these often-obscure diseases, and to lead to more advances in identifying molecular targets specific to these entities. [Abstract/Link to Full Text]

Keehn CA, Belongie IP, Shistik G, Fenske NA, Glass LF
The diagnosis, staging, and treatment options for mycosis fungoides.
Cancer Control. 2007 Apr;14(2):102-11.
BACKGROUND: Cutaneous T-cell lymphoma (CTCL) represents a spectrum of diseases composed of malignant T lymphocytes. The most common type is mycosis fungoides (MF). An accurate diagnosis of early MF may be difficult because of the varied clinical and histologic expressions of the disease. METHODS: The authors review the epidemiology, possible risk factors, clinical manifestations, diagnostic techniques, staging, prognosis, and treatment options for MF. RESULTS: The varied and often nonspecific clinical and histologic presentations of MF may delay diagnosis and staging, thus necessitating further studies such as immunophenotyping and T-cell receptor gene rearrangement analysis. CONCLUSIONS: A multidisciplinary approach to the diagnosis, staging, and treatment of MF assists in optimizing outcomes from management of patients with this disease. [Abstract/Link to Full Text]

Lee J, Demissie K, Lu SE, Rhoads GG
Cancer incidence among Korean-American immigrants in the United States and native Koreans in South Korea.
Cancer Control. 2007 Jan;14(1):78-85.
BACKGROUND: While previous studies demonstrated contrasting patterns of cancer risk among migrant populations from different ethnic groups in the United States, few studies have focused on the Korean-American population. This study compares cancer incidence rates between Korean-Americans, whites, and blacks in the United States and native Koreans. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) program and International Association for Research on Cancer were used to calculate age-standardized incidence rates among whites, blacks, and Korean Americans in the United States and native Koreans. RESULTS: The risk of stomach, liver, gallbladder, larynx, and esophageal cancer has sharply declined in Korean-American men compared with their native counterparts while prostate, colon, and rectum cancer risk has increased. In women, stomach, liver, gallbladder, and cervical cancers have declined, and breast, lung, colon, rectum, and endometrial cancers have increased. Cancer rates for stomach, liver, gallbladder, and esophagus are higher in native Koreans compared to US whites. Recently, cancer rates for Korean-American immigrants have increased for prostate, breast, colon, and rectal cancers. CONCLUSIONS: The study provides evidence that the risk of cancers common in Western countries is higher for Korean Americans than for their native counterparts. Recent trends among Korean Americans also revealed a stronger Western profile. [Abstract/Link to Full Text]

Meade CD, Menard J, Martinez D, Calvo A
Impacting health disparities through community outreach: utilizing the CLEAN look (culture, literacy, education, assessment, and networking).
Cancer Control. 2007 Jan;14(1):70-7.
BACKGROUND: Community outreach programs are important vehicles for reducing the discovery-delivery disconnect by bringing cancer education and screening services directly to community members. Such programs are consistent with the priority areas of the Department of Health and Human Services' initiatives for reducing health disparities by 2010, and they support the use of culturally, linguistically, and literacy-specific approaches for eliminating cancer health disparities. METHODS: This article reviews the important tenets of culture and literacy when developing community outreach programs for medically underserved populations, examines a health education empowerment model for community program planning, and describes the use of the CLEAN Look Checklist (in which CLEAN is an easy-to-remember mnemonic of culture, literacy, education, assessment, and networking) for identifying cues and strategies to achieve relevant outreach. RESULTS: This article illustrates the application of this approach with an example of outreach strategies for reaching at-risk Haitian American women in our community. CONCLUSIONS: Meeting the challenge of a strong health disparities agenda requires integration of cultural and literacy considerations in outreach program, message, and intervention development. The use of a checklist may help clinicians, educators, and researchers create a sustainable model of community outreach guided by a paradigm that incorporates a multilevel approach to address cancer outcomes for disenfranchised populations. [Abstract/Link to Full Text]

Balasubramanian BA, Gandhi SK, Demissie K, August DA, Kohler B, Osinubi OY, Rhoads GG
Use of adjuvant systemic therapy for early breast cancer among women 65 years of age and older.
Cancer Control. 2007 Jan;14(1):63-8.
BACKGROUND: The National Institutes of Health (NIH) consensus statement recommends adjuvant therapy for early breast cancer irrespective of age. However, the actual use of such therapy is not well documented among women over 65 years of age. METHODS: We studied the frequency of use of adjuvant therapy and report the receipt of this therapy among 200 women aged > or = 65 years diagnosed with early breast cancer who were identified from the New Jersey State Cancer Registry. RESULTS: In this population, 28% of patients received chemotherapy alone or in combination with hormonal therapy, whereas 42% received hormonal therapy alone. Less than half of the women with estrogen receptor-negative tumors received chemotherapy alone or in combination with hormonal treatment. Adjuvant therapy was not prescribed in 30% of patients. CONCLUSIONS: Despite NIH recommendations, the frequency of use of adjuvant therapy in New Jersey is low among women over 65 years of age, regardless of their receptor status. [Abstract/Link to Full Text]

Gridelli C, Maione P, Comunale D, Rossi A
Adjuvant chemotherapy in elderly patients with non-small-cell lung cancer.
Cancer Control. 2007 Jan;14(1):57-62.
BACKGROUND: More than two thirds of patients who die of lung cancer in the United States are over 65 years of age. More than 50% of lung cancer patients are diagnosed over the age of 65 and about 30% over the age of 70. METHODS: The authors review recent data from large randomized trials on adjuvant chemotherapy in patients with NSCLC. They discuss age-related changes in organ function, comorbidities and frailty in the elderly, and chemotherapy treatment in elderly patients with NSCLC. RESULTS: Randomized trials suggest that postoperative chemotherapy improves survival after surgery in patients with stage IB to IIIA NSCLC, and awareness of the efficacy of this approach is growing in the scientific community. Clinical data obtained in the young population cannot be automatically adopted in the elderly counterpart. Elderly patients tolerate chemotherapy poorly because of comorbidity and organ failure, and after lung surgery they are considered at higher risk of chemotherapy-induced toxicity. The survival benefit obtained with platin-based chemotherapy may vanish or decrease in the elderly due to a potential higher toxic death rate or lower compliance to treatment. CONCLUSIONS: Modified schedules or attenuated dose of platin-containing chemotherapy should be investigated in the adjuvant setting by specifically designed trials. Specifically designed prospective trials are needed to elucidate the role of this approach in the elderly. [Abstract/Link to Full Text]

Wedding U, Honecker F, Bokemeyer C, Pientka L, H�ffken K
Tolerance to chemotherapy in elderly patients with cancer.
Cancer Control. 2007 Jan;14(1):44-56.
BACKGROUND: Due to demographic changes, the number of elderly people with cancer will increase in the next decades. In the past, elderly patients with cancer were often excluded from clinical trials. Chronological age has been considered a risk factor for increased toxicity and reduced tolerance to chemotherapy. METHODS: We present a review on toxicity of chemotherapy and factors associated with toxicity in elderly patients with cancer, and we discuss chemotherapeutic agents and treatment options in treating this patient population. RESULTS: Age is a risk factor for increased toxicity to chemotherapy and decreased tolerance. However, few trials have been reported with adjustment for age-associated changes such as impairment of functional status and increased comorbidity, which also show an independent association with increased toxicity. Published data may include several biases, such as referral and publication bias. CONCLUSIONS: Decision making in elderly cancer patients should be based on the results of a geriatric assessment. Patients with few or no limitations should be treated as younger patients are treated. Data with a high level of evidence are unavailable for patients showing moderate or severe limitations in a geriatric assessment. [Abstract/Link to Full Text]

Hurria A, Lichtman SM
Pharmacokinetics of chemotherapy in the older patient.
Cancer Control. 2007 Jan;14(1):32-43.
BACKGROUND: The number of individuals aged 65 years and older is growing rapidly, and the majority of cancers are diagnosed in this age group. Age-related changes in physiology can affect chemotherapy pharmacokinetics and pharmacodynamics in older patients. METHODS: We review the literature regarding the impact of age on the pharmacokinetics of commonly used chemotherapy drugs and discuss age-related changes in physiology and pharmacology that can affect chemotherapy tolerance in older patients. RESULTS: The data on age-related changes in chemotherapy pharmacokinetics are conflicting. While a few studies report age-related differences in chemotherapy pharmacokinetics, most found no significant difference or subtle differences in pharmacokinetics with aging. A difference in pharmacodynamics was commonly seen, however, with older patients at increased risk of myelosuppression and toxicity from age-related decline in organ function. The majority of these studies were performed in a small cohort of patients, thus limiting the generalizability of these results. CONCLUSIONS: Additional studies are needed to address the pharmacokinetics and pharmacodynamics of cancer therapies in the older patient. Multicenter pharmacokinetic studies of adequate sample size, which include a thorough evaluation of physiologic factors and geriatric assessment parameters, would provide further insight into the factors affecting treatment tolerance. These studies would also help to guide appropriate chemotherapy dosing and interventions in order to maximize efficacy and minimize toxicity in the older patient. [Abstract/Link to Full Text]

Anisimov VN
Biology of aging and cancer.
Cancer Control. 2007 Jan;14(1):23-31.
BACKGROUND: The incidence of cancer increases with age in both humans and laboratory animals. A clear understanding of the causes of the age-related increase in cancer incidence is needed to develop a strategy for primary cancer prevention. METHODS: We summarized the data available in the literature and our own experience in hormonal metabolic shifts in organisms and disturbances at tissue and cellular levels observed in natural aging and in different types of carcinogenesis in vivo. RESULTS: There are incongruent patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by at least two mechanisms: tissue accumulation of cells in late stages of carcinogenesis and alterations in internal homeostasis, in particular, alterations in immune and endocrine system. Increased susceptibility to the effects of tumor promoters is found in both aged animals and aged humans, as predicted by the multistage model of carcinogenesis. CONCLUSIONS: Aging is associated with a number of events at the molecular, cellular and physiologic levels that influence carcinogenesis and subsequent cancer growth. A clearer understanding of these events will help in predicting and treating cancer more effectively. [Abstract/Link to Full Text]

Extermann M
Interaction between comorbidity and cancer.
Cancer Control. 2007 Jan;14(1):13-22.
BACKGROUND: Older patients have an average of three comorbidities in addition to their cancer. Oncologic studies have usually ignored this aspect when adjusting for confounders. There is mounting evidence that comorbidity interacts with risk, survival, disease progression, and treatment of elderly patients with cancer. The strength of many of these interactions increases with age. METHODS: A review of the literature was undertaken regarding two of these interactions: cancer risk and prognosis. RESULTS: In older patients, the risk and behavior of cancer can be strongly affected by comorbidities and their related treatment. Rather than a blanket effect, this effect might be attached to groups of syndromes with common pathophysiologic mechanisms. This is notably true for metabolic disorders and inflammatory diseases. CONCLUSIONS: In addition to focusing on the influence of cancer treatment on comorbidity or on the effect of comorbidity in delivering cancer treatment, future endeavors will need to consider the direct impact of comorbidity on the risk and the behavior of the cancer in elderly patients. [Abstract/Link to Full Text]

Balducci L
Aging, frailty, and chemotherapy.
Cancer Control. 2007 Jan;14(1):7-12.
BACKGROUND: In many cases, elderly individuals have not been offered life-saving interventions due to the assumption that these treatments would be too toxic to tolerate. METHODS: This article offers an overview of the biology of aging, reviews the assessment of an individual's physiologic age, and explores the medical definition of frailty and its implications in cancer treatment. RESULTS: The definition of frailty is controversial. Rather than chronologic age, a more accurate assessment relies on individual estimates of life expectancy and functional reserve, including serum levels of interleukin 6 and D-dimer, the levels of a number of inflammatory cytokines, and the circulating level of C-reacting protein. Decision making for optimal cancer treatment in the older-aged patient benefits from a comprehensive geriatric assessment, a functional test, and a laboratory evaluation to determine a patient's life expectancy and functional reserve. CONCLUSIONS: Most older patients appear to benefit from cancer treatment to an extent comparable to that of younger individuals, and only a minority of these patients should be excluded from treatment due to reduced tolerance. [Abstract/Link to Full Text]

Kurtin S, Sokol L
Practical considerations in the use of lenalidomide therapy for myelodysplastic syndromes.
Cancer Control. 2006 Dec;13 Suppl26-31.
Lenalidomide has been approved by the US Food and Drug Administration for the treatment of patients with myelodysplastic syndromes (MDS) with an interstitial deletion of the long arm of chromosome 5 and, more recently, in combination with dexamethasone for multiple myeloma in patients who received at least one prior therapy. This discussion examines several clinically relevant, practical considerations regarding dosing, monitoring, follow-up evaluation, adverse events, and available support for lenalidomide recipients and their prescribing physicians in the MDS setting. [Abstract/Link to Full Text]

Goss TF, Szende A, Schaefer C, Totten PJ, Knight R, J�dersten M, Hellstr�m-Lindberg E, List AF
Cost effectiveness of lenalidomide in the treatment of transfusion-dependent myelodysplastic syndromes in the United States.
Cancer Control. 2006 Dec;13 Suppl17-25.
Lenalidomide has been approved for the treatment of transfusion-dependent low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We evaluated the cost effectiveness of lenalidomide versus best supportive care (BSC) in these patients. We developed a decision analytic model to compare costs and outcomes of lenalidomide with BSC without recombinant erythropoietin (EPO) versus BSC with EPO over 1 year. Outcome measures were transfusion independence and quality-adjusted life years (QALYs) gained. The model incorporated costs of medications, transfusions, chelation, laboratory tests, office visits, and other resources associated with each therapy. Lenalidomide therapy was associated with an estimated incremental 0.53 transfusion-free and 0.25 QALY gain compared to BSC at 1 year. The costs of lenalidomide therapy were substantially offset by reduced blood transfusion and EPO costs. One-year total treatment costs were estimated at $63,385 for lenalidomide and $54,940 for BSC. The incremental cost-effectiveness ratio for lenalidomide vs BSC was estimated at $16,066 per transfusion-free year and $35,050 per QALY gained, values within the acceptable cost-effectiveness ranges for a new therapy. Results suggest that oral lenalidomide is cost effective in the United States in the treatment of transfusion-dependent, low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality. Confirmation of these findings awaits results of an ongoing randomized phase III trial (MDS-004 study). [Abstract/Link to Full Text]

List AF
Evolving applications of lenalidomide in the management of anemia in myelodysplastic syndromes.
Cancer Control. 2006 Dec;13 Suppl12-6.
Lenalidomide has emerged as an effective therapeutic alternative for the management of anemia in lower-risk myelodysplastic syndromes (MDS). Compelling results from phase I and phase II clinical studies prompted the US Food and Drug Administration to approve lenalidomide for the treatment of transfusion-dependent MDS patients with interstitial deletion of chromosome 5q [del(5q)]. Subsequently, the National Comprehensive Cancer Network (NCCN) has incorporated lenalidomide into their current treatment algorithm for the treatment of lower-risk del(5q) patients. This discussion examines the current NCCN guidelines for the treatment of these patients, including the management of anemia in lower-risk MDS, and discusses the potential future therapeutic applications of lenalidomide in this disease. [Abstract/Link to Full Text]

List AF, Baker AF, Green S, Bellamy W
Lenalidomide: targeted anemia therapy for myelodysplastic syndromes.
Cancer Control. 2006 Dec;13 Suppl4-11.
Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected. [Abstract/Link to Full Text]

List AF
Lenalidomide: from bench to bedside (part 1).
Cancer Control. 2006 Dec;13 Suppl2-3. [Abstract/Link to Full Text]

McKinney MM, Weiner BJ, Carpenter WR
Building community capacity to participate in cancer prevention research.
Cancer Control. 2006 Oct;13(4):295-302. [Abstract/Link to Full Text]

Gaissert HA, Mark EJ
Tracheobronchial gland tumors.
Cancer Control. 2006 Oct;13(4):286-94.
BACKGROUND: Tracheal tumors are uncommon, making up only 0.2% of all respiratory malignancies in the United States. One consequence of this low incidence is that few centers accumulate meaningful experience. Another is the lack of awareness of effective therapy. Bronchial gland tumors demonstrate oncologic diversity and include benign, low-grade, and high-grade malignant tumors. METHODS: We reviewed the present knowledge of bronchial gland tumors of the trachea, carina, and bronchi, including the epidemiology, presentation, evaluation, tumor types, and treatment options. RESULTS: The malignant bronchial gland tumors, adenoid cystic carcinoma and mucoepidermoid carcinoma, are far more common than benign mucinous cystadenoma or pleomorphic adenoma. Complete resection of localized tumors has excellent long-term results in symptomatic benign tumors. The disease-free survival after resection of malignant tumors is limited by distant metastasis and regional disease, while local recurrence is uncommon. Postoperative mediastinal radiation is now accepted adjuvant therapy. Experience at our institute demonstrates a significant survival advantage for patients with complete resection compared to unresectable patients. CONCLUSIONS: Expanding knowledge of diagnostic evaluation and surgical therapy can improve the long-term survival of patients with tracheobronchial gland tumors. [Abstract/Link to Full Text]

Taveira-DaSilva AM, Steagall WK, Moss J
Lymphangioleiomyomatosis.
Cancer Control. 2006 Oct;13(4):276-85.
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by proliferation of abnormal smooth muscle-like cells (LAM cells), which leads to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics, and abdominal tumors. It primarily affects women. METHODS: The authors present a review of large series, registries, and protocols to highlight the prevalence, pathology, clinical features, diagnosis, and treatment options for patients with LAM. RESULTS: LAM commonly presents with progressive breathlessness or with recurrent pneumothorax, chylothorax, or sudden abdominal hemorrhage. Computed tomography (CT) scans show numerous thin-walled cysts throughout the lungs, abdominal angiomyolipomas, and lymphangioleiomyomas. Pulmonary function tests show decreased forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO). Exercise testing shows gas-exchange abnormalities, ventilatory limitation, and hypoxemia that may occur with near-normal lung function. CONCLUSIONS: No effective treatment currently exists for this progressive disorder. However, recent progress in cancer and smooth muscle cell biology and a better understanding of the factors regulating angiogenesis and lymphangiogenesis may provide a foundation for the development of new therapeutic strategies. [Abstract/Link to Full Text]

Fernandez FG, Battafarano RJ
Large-cell neuroendocrine carcinoma of the lung.
Cancer Control. 2006 Oct;13(4):270-5.
BACKGROUND: Large-cell neuroendocrine carcinoma (LCNEC) of the lung displays morphologic and immunohistochemical characteristics common to neuroendocrine tumors and morphologic features of large-cell carcinomas. Because surgical resection of LCNEC in many series has been described with 5-year actuarial survival that is far worse than that reported for other histologic variants of non-small-cell lung cancer (NSCLC), considerable debate has emerged as to whether these tumors should be classified and treated as NSCLC or small-cell lung cancer. METHODS: The initial evaluation and diagnosis, tumor classification, surgical treatment, results of therapy, and long-term prognosis of patients with LCNEC based on our experience are discussed, and a review of the literature is presented. RESULTS: Patients with LCNEC are more likely to develop recurrent lung cancer and have shorter actuarial survival than patients with other histologic types of NSCLC, even in those with stage I disease. CONCLUSIONS: Accurate differentiation of LCNEC from other types of NSCLC is important because it identifies those patients at highest risk for developing recurrent disease. Efforts to identify effective adjuvant therapies are needed to improve treatment outcomes with this aggressive type of lung cancer. [Abstract/Link to Full Text]

Robinson LA
Solitary fibrous tumor of the pleura.
Cancer Control. 2006 Oct;13(4):264-9.
BACKGROUND: The solitary fibrous tumor of the pleura (SFTP) is a rare primary tumor arising from mesenchymal cells in the areolar tissue subjacent to the mesothelial-lined pleura. Only about 800 cases have been reported in the medical literature. The tumor appears to be unrelated to malignant pleural mesothelioma, the most common primary tumor of the pleura. METHODS: In just over half of these cases, the neoplasm presents as an asymptomatic mass, is often quite large, and is benign in 78% to 88% of patients. The initial evaluation and diagnosis, tumor classification, surgical treatment, results of therapy, and long-term prognosis are reviewed, based on a selective review of the literature from MEDLINE beginning 1980. RESULTS: Complete en bloc surgical resection is the preferred treatment of benign and malignant varieties of the tumor. The pedunculated tumors attached to the visceral pleura can be effectively treated with a wedge resection of lung. Sessile tumors arising on the lung require a larger lung resection. Sessile tumors on the chest wall require wide local excision, often with chest wall resection because of their propensity for local recurrence. Adjuvant therapy remains controversial in SFTP. CONCLUSIONS: Benign SFTP has a high cure rate and an 8% local recurrence rate that is usually amenable to curative re-excision. Malignant SFTP, especially the more common sessile type, has a 63% recurrence rate even with complete resection. The majority of patients with recurrent disease die of the tumor within 2 years. Nevertheless, the overall long-term cure rate for all patients is 88% to 92%. [Abstract/Link to Full Text]

Ismail-Khan R, Robinson LA, Williams CC, Garrett CR, Bepler G, Simon GR
Malignant pleural mesothelioma: a comprehensive review.
Cancer Control. 2006 Oct;13(4):255-63.
BACKGROUND: The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively. METHODS: The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma. RESULTS: When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized. Effects on underlying structures limit application of radiation therapy, but some systemic agents are beginning to enhance survival. CONCLUSIONS: The disease is expected to increase in incidence till 2020, so awareness of this entity as a possible diagnosis should be heightened. In patients with advanced disease, several newer antitumor agents are already showing a capability of extending survival so it is not unreasonable to expect further progress in this area. [Abstract/Link to Full Text]

Tanvetyanon T
Understanding the uncommon thoracic tumors.
Cancer Control. 2006 Oct;13(4):252-3. [Abstract/Link to Full Text]

Strickland CJ
Challenges in community-based participatory research implementation: experiences in cancer prevention with Pacific Northwest American Indian tribes.
Cancer Control. 2006 Jul;13(3):230-6.
BACKGROUND: Much has been written about community-based participatory research (CBPR) history and principles, but few have addressed challenges in implementation in transcultural situations. The goal of this discussion is to address CBPR implementation issues in cancer prevention research with American Indian tribal communities in the Pacific Northwest. METHOD: Information in this discussion is drawn from qualitative research conducted over a 10-year period in which CBPR was employed in cancer prevention research with Pacific Northwest Indian tribes. CBPR principles provide the framework for the discussion: establishing trusting relationships, assuring participation, sharing power, and communicating. RESULTS: In this work, we found that CBPR is appropriate for use in Pacific Northwest Indian tribal communities and is compatible with cultural values. We also found that there are many challenges. Recommendations are provided on needed institutional and structural changes. CONCLUSIONS: CBPR is an important research approach in addressing cancer prevention health disparities among American Indian tribal communities. Continued effort needs to be directed toward creating systems and structures to support researchers in utilizing this method. Findings are of value to researchers aiming to implement CBPR in Indian communities and to practitioners, policy makers, and administrators who make decisions about CBPR funding and support structures. [Abstract/Link to Full Text]

Rogers ES, Wallace LS, Weiss BD
Misperceptions of medical understanding in low-literacy patients: implications for cancer prevention.
Cancer Control. 2006 Jul;13(3):225-9.
BACKGROUND: Patients with limited literacy skills often have difficulty understanding medical information, are less likely to undergo cancer screening, and present with cancer at later stages than patients with better literacy skills. Since primary care physicians are responsible for performing or initiating the majority of cancer screening in the United States, they need to be able to not only identify patients who might not understand medical information but also communicate effectively with them about cancer prevention and screening. METHODS: To determine whether family medicine residents could identify patients who might have difficulty understanding medical information because of limited literacy, we measured the literacy skills of patients in a university-based family medicine clinic using the short form of the Test of Functional Health Literacy in Adults (S-TOFHLA). After the patients completed their office visits with a physician, we asked family medicine residents to rate the patients' ability to understand medical information. RESULTS: Among 140 patients who met with 18 family medicine resident physicians, 24% had limited literacy skills based on testing with the S-TOFHLA. Residents identified only about half of these patients as having poor or below average understanding of medical information. CONCLUSIONS: IN many cases, family medicine residents are unable to identify patients who, based on assessment of their literacy skills, are likely to have difficulty understanding medical information. When working with residents, medical educators should promote the habit of taking poor literacy into account when communicating with patients. [Abstract/Link to Full Text]

Andrews S, Robinson L, Cantor A, DeConti RC
Survival after surgical resection of isolated pulmonary metastases from malignant melanoma.
Cancer Control. 2006 Jul;13(3):218-23.
BACKGROUND: The overall prognosis for patients with metastatic malignant melanoma remains poor. However, careful staging and identification of patients with limited metastatic disease offers the opportunity for surgical salvage and improved survival for selected patients. METHODS: We reviewed the experience over the last 17 years at our institute with isolated pulmonary metastasectomy in 86 patients with advanced malignant melanoma. RESULTS: Our data demonstrate an overall median time to relapse of approximately 8.4 months and a median survival of 35 months. The 5-year survival rate is estimated at 33%, and 16% remain continuously free of disease after a median follow-up of 35 months. Resection of properly staged and evaluated patients with limited pulmonary metastases appears to convey a significant survival benefit. Patients with a single metastasis fare best. CONCLUSIONS: These encouraging results offer a rationale for the careful follow-up of resected patients. One third of all relapses will be limited and additional surgery contributes to their overall survival. [Abstract/Link to Full Text]

Khan MA, Andrews S, Ismail-Khan R, Munster PN, Brem S, King J, Reintgen DS, Sondak VK, Daud AI
Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database.
Cancer Control. 2006 Jul;13(3):211-7.
BACKGROUND: Many new agents are currently in trial in melanoma. It remains unclear, however, what the benefit of a given therapy may be since information on progression-free and overall survival of untreated patients is limited. Since few trials in melanoma have had a non-treated cohort, it remains unclear what survival can be expected in patients who are not treated with chemotherapy. METHODS: To help develop parameters for future trials, we analyzed treatment history and survival in 212 patients with metastatic melanoma seen at our institution between January 1998 and September 2003. A retrospective analysis was done using a database created for melanoma patients at our center. Patient survival information was determined from this database, tumor registry, Social Security index, and direct patient calls. Patient staging information was determined according to the 2001 guidelines. Non-chemotherapy-treated patients with M1c disease were used as "controls." RESULTS: The median survival of stage M1c melanoma was 6.0 months. Survival was longer for stage M1a and M1b and shorter in older patients. No significant differences were found in survival based on gender. Among chemotherapy-treated patients, those with progressive disease on treatment or with increased lactate dehydrogenase (LDH) fared worse than those with a clinical response or normal LDH, respectively. Patients treated with either biochemotherapy or temozolomide and thalidomide survived longer than those who received no chemotherapy treatment. Dacarbazine (DTIC) treatment did not prolong survival. CONCLUSIONS: In this retrospective review of patients treated at a single institution, those treated with multiagent chemotherapy but not with single-agent DTIC appeared to have had a survival benefit. [Abstract/Link to Full Text]

Rodriguez A, Sexton WJ
Management of locally advanced renal cell carcinoma.
Cancer Control. 2006 Jul;13(3):199-210.
BACKGROUND: Renal cell carcinoma accounts for approximately 3% of adult malignancies and over 90% of primary renal tumors. Recurrence rates for patients with locally advanced renal cell carcinoma (LARCC) remain high. METHODS: The authors review literature regarding prognostic factors, potential biomarkers, surgical strategies, and adjuvant therapy trials for patients with LARCC. RESULTS: Molecular tumor markers may improve existing staging systems for predicting prognosis. Surgery is the best initial treatment for most patients with clinically localized renal tumors, although complete surgical resection can be challenging for patients with large tumors, bulky regional lymph node involvement, or inferior vena cava tumor thrombus. Significant recurrence rates for patients with LARCC undergoing nephrectomy indicate the presence of undetected micrometastases at the time of surgery. Adjuvant radiation, chemotherapy, and immunotherapy have been ineffective. Other trials of adjuvant therapy are ongoing. CONCLUSIONS: Aggressive surgical resection alone for LARCC is not sufficient to prevent disease recurrence in a significant number of patients. Adjuvant therapies are needed to improve cancer-specific survival. [Abstract/Link to Full Text]

Tan WW
Novel agents and targets in managing patients with metastatic prostate cancer.
Cancer Control. 2006 Jul;13(3):194-8.
BACKGROUND: Docetaxel has recently been found to improve survival in patients with metastatic androgen-independent prostate cancer (AIPC). Chemotherapy as a first-line option leaves room for improvement, while second-line options are multiple and somewhat controversial. METHODS: Clinically relevant articles focusing on chemotherapy drugs for metastatic prostate cancer and their mechanism of action and efficacy were reviewed from January 2004 through April 2006. RESULTS: Docetaxel is the standard of care for AIPC. However, for doublets with docetaxel or second-line chemotherapy, multiple studies have shown interesting and promising results with calcitriol, thalidomide, bevacizumab, satraplatin, vaccines, ixabepilone, and atrasentan. CONCLUSIONS: Docetaxel should be considered for first-line treatment of metastatic AIPC. Due to its progression-free survival of only 6 months, more effective drugs and drug combinations need to be developed to treat patients with AIPC. Combination treatments with docetaxel and other new agents are promising, but adequately powered phase III trials need to be conducted with survival as the principal endpoint for these promising drug combinations. [Abstract/Link to Full Text]

Torres-Roca JF
The role of external-beam radiation therapy in the treatment of clinically localized prostate cancer.
Cancer Control. 2006 Jul;13(3):188-93.
BACKGROUND: The treatment of clinically localized prostate cancer is controversial. Options include radical prostatectomy, external-beam radiation therapy (EBRT), brachytherapy, cryotherapy, and watchful waiting. METHODS: The author reviews EBRT as treatment for clinically localized prostate cancer, with particular emphasis on the technological advances that have allowed dose escalation and fewer therapy-related side effects. RESULTS: Technological advances in the last two decades have significantly improved the delivery of EBRT to the prostate. This has resulted in an overall increase in the total dose that can be safely delivered to the prostate, which has led to modest improvements in biochemical outcome. An alternative approach of combining androgen suppression therapy and EBRT has also been successful in improving clinical outcomes. However, establishing the optimal therapy for prostate cancer remains controversial. CONCLUSIONS: Recent progress has led to improvements in clinical outcomes in patients treated with EBRT for prostate cancer. It is hoped that the next decades will bring continued advances in the development of biologicals that will further improve current clinical outcomes. [Abstract/Link to Full Text]

Recent Articles in Pathology Oncology Research

R�nyi I, B�rdi E, Udvardi E, Kov�cs G, Bartyik K, Kajt�r P, Mas�t P, Nagy K, Gal�ntai I, Kiss C
Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin's lymphoma.
Pathol Oncol Res. 2007;13(1):57-62.
To prevent acute renal failure in children at risk for developing tumor lysis syndrome due to acute lymphoblastic leukemia or non-Hodgkin's lymphoma treated according to international BFM protocols, we investigated recombinant urate oxidase (rasburicase) in the first Central European openlabeled, prospective, multicenter phase IV trial. Rasburicase was administered intravenously, at 0.2 mg/kg for 5 consecutive days to 36 patients. Blood levels of uric acid, creatinine, phosphorus, calcium, lactate dehydrogenase and complete blood count were measured daily during rasburicase treatment and on days 6, 7 and 12. Initial uric acid level decreased significantly by 4 hours (from 343 micromol/L to 58 micromol/L, p<0.001), except for one steroid-resistant patient who required hemodialysis on day 14 after having introduced combined cytostatic treatment. Comparing the data of a subgroup of 12 patients receiving rasburicase with that of a historic cohort of 14 patients treated with allopurinol indicated the superiority of rasburicase over allopurinol in prophylaxis and treatment of hyperuricemia in children with leukemia and lymphoma. [Abstract/Link to Full Text]

Magyari L, Bene J, Koml�si K, Tali�n G, Farag� B, Cs�ngei V, J�romi L, S�fr�ny E, Sipeky C, Lakner L, Varga M, Gasztonyi B, Melegh B
Prevalence of SLC22A4 1672T and SLC22A5 -207C combination defined TC haplotype in Hungarian ulcerative colitis patients.
Pathol Oncol Res. 2007;13(1):53-6.
Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract. The aim of this study was to verify the prevalence rate of the haplotype called TC, determined by combination of two functional alleles of OCTN cation transporter genes (SLC22A4 1672T and SLC22A5 -207C combination variants) in ulcerative colitis patients and unrelated healthy controls. The "TC haplotype" has recently been suggested to confer risk for UC. A total of 121 unrelated Hungarian subjects with UC and 110 matched controls were genotyped for the two single nucleotide polymorphisms. The genotypes were determined by using PCR/RFLP assay and direct sequencing. The SLC22A4 1672T allele frequency was 46.7% in the patients with UC and 46.4% in the controls, whereas the SLC22A5 -207C allele occurred in 48.8% of the patients and 51.4% of the controls. The prevalence of the TC haplotype was 19% in the patient group and 22.7% in controls. Since there was no accumulation of the TC haplotype in the patient group, our observation suggests that carrying the TC haplotype is not associated with a higher risk for UC in the Hungarian population. [Abstract/Link to Full Text]

Amirzargar AA, Khosravi F, Dianat SS, Alimoghadam K, Ghavamzadeh F, Ansaripour B, Moradi B, Nikbin B
Association of HLA class II allele and haplotype frequencies with chronic myelogenous leukemia and age-at-onset of the disease.
Pathol Oncol Res. 2007;13(1):47-51.
Chronic myelogenous leukemia (CML) is characterized by the presence of Philadelphia chromosome resulting from bcr/abl translocation. To clarify the association between HLA class II allele and haplotype frequencies in CML, 50 patients referred to Hematology Oncology and Bone Marrow Transplantation (BMT) center, Shariaty Hospital, Tehran, Iran, were randomly selected and compared with a group of 80 unrelated healthy blood donor subjects. HLA class II alleles were determined by PCR-SSP method. The results showed that the frequencies of DQB1*03011 (P=0.01) and DQA1*0505 (P=0.05) were higher, while that of DQB1*03032 (P=0.04) was lower in patients than in the controls. Regarding age-at-onset, the frequency of HLA-DRB1*07 (P=0.03) and -DQA1*0201 (P=0.03) alleles were higher in patients younger than 35 years. The most frequent haplotypes in our CML patients were HLA-DRB1*11/-DQB1*03011/-DQA1*0505 (P=0.01) and HLA-DRB1*04/-DQB1*0302/-DQA1*03011 (P=0.02). In conclusion, it is suggested that positive and negative association in certain HLA alleles and haplotypes exist in Iranian patients with CML. [Abstract/Link to Full Text]

Arslantas A, Artan S, Oner U, M�sl�manoglu MH, Ozdemir M, Durmaz R, Arslantas D, Vural M, Cosan E, Atasoy MA
Genomic alterations in low-grade, anaplastic astrocytomas and glioblastomas.
Pathol Oncol Res. 2007;13(1):39-46.
To extend our understanding of potential stepwise genetic alterations that may underlie tumor progression from low-grade astrocytomas to glioblastomas, histopathologic and comparative genomic hybridization analyses were performed on tumor specimens from 68 primary lesions, including 40 glioblastomas, 10 anaplastic and 18 low-grade astrocytomas. The number of aberrations per case increased towards the higher grade tumors (grade II: 1.66+/-1.49; grade III: 2.80+/-1.68; grade IV: 3.02+/-1.07; F=6.955, p=0.002). A gain of 7/7q was common and the most frequently seen aberration in low-grade astrocytomas, whereas loss of 10q was the most frequently seen anomaly in anaplastic astrocytomas and glioblastomas. Chromosome 7p amplification was only detected in glioblastomas. Chromosome 10/10q deletion and combination of 1p, 19q and 17p deletions were specific to high-grade astrocytic tumors. Sequences of chromosome 7 and 10 seem to have pivotal roles in the biology of human gliomas. The genomic copy deletions of chromosomes 1p and 19q might provide an alternative mechanism in the genesis of astrocytomas. [Abstract/Link to Full Text]

Park HR, Park YK
Differential expression of runx2 and Indian hedgehog in cartilaginous tumors.
Pathol Oncol Res. 2007;13(1):32-7.
Runx2-Cbfa1, a Runt transcription factor, plays important roles during skeletal development. In its absence, chondrocyte hypertrophy is severely impaired and there is no vascularization of cartilage templates during skeletal development. In addition, Indian hedgehog (Ihh) signaling molecules control the space and timing of chondrocyte differentiation. Our goal was to gain a better understanding of the molecular process underlying the development of chondrosarcoma and to investigate whether there is a biological difference among variable types of chondrosarcomas. To accomplish this we collected a series of 10 enchondromas and 57 chondrosarcomas (conventional, n = 17; mesenchymal, n = 20; clear cell, n = 20), and investigated the expression of Runx2 and Ihh in these cartilaginous tumors by immunohistochemistry. Cellular and matrix-rich areas were evaluated separately. Runx2 was expressed in 100% of conventional, mesenchymal, and clear cell chondrosarcomas, and in 30% of enchondromas. Higher levels of expression of Runx2 were found in cellular areas than in matrixrich areas. Expression levels increased with increasing histological grade in conventional chondrosarcoma, suggesting involvement in tumor progression. Ihh was expressed in 100% of conventional and clear cell chondrosarcomas, especially in matrix-rich areas. Mesenchymal chondrosarcomas revealed only focal expression of Ihh in matrix-rich areas. Small cell areas were negative. Ihh was absent or focally expressed in enchondromas. These findings demonstrate that Runx2 expression is active in variable chondrosarcomas compared to enchondromas, suggesting its importance in growth and differentiation of neoplastic cartilage. Ihh expression is considered a marker of the hypertrophic stage of differentiation in these tumor cells. [Abstract/Link to Full Text]

Kiss J, T�m�r J, Somlai B, Gilde K, Fej�s Z, Gaudi I, Lad�nyi A
Association of microvessel density with infiltrating cells in human cutaneous malignant melanoma.
Pathol Oncol Res. 2007;13(1):21-31.
Vascularization and host response to malignant tumors may have common molecular regulators, therefore, we analyzed the relationship between microvessel density (MVD) and tumor infiltrating cells in cutaneous malignant melanoma. Density of lymphocyte subpopulations, macrophages, dendritic cells and CD34(+) microvessels was determined by immunohistochemistry in primary tumor samples from fifty-two patients with melanoma thicker than 1 mm. Intratumoral MVD did not show significant association with infiltration for any of these cell types. In the case of peritumoral reactive cell densities analyzed in the whole patient population, a positive correlation of MVD was found with CD3(+) T cell density. This association was stronger in melanomas >4.0 mm and in visceral metastatic tumors. In these subgroups similar phenomenon was observed for CD8(+) cells. We found significant correlation of MVD with CD68(+) macrophage density only in the highest thickness category, and weak associations with B-cell and dendritic cell infiltration in visceral metastatic cases. MVD did not vary significantly in tumors categorized according to thickness, localization, ulceration or histological type. However, both intratumoral MVD and macrophage infiltration were significantly higher in male patients compared to females. The correlation of immune cell density with tumor vascularization and gender differences in vascularity and macrophage infiltration of melanoma deserve further attention. [Abstract/Link to Full Text]

Wincewicz A, Sulkowska M, Koda M, Sulkowski S
Clinicopathological significance and linkage of the distribution of HIF-1alpha and GLUT-1 in human primary colorectal cancer.
Pathol Oncol Res. 2007;13(1):15-20.
HIF-1alpha induces GLUT-1 expression, and their presence has been evaluated in colorectal cancer. However, the expressions of GLUT-1 and HIF-1alpha have not been investigated together with reference to clinicopathological characteristics in human colorectal cancer. The aim of our study was to compare the expression of HIF-1alpha and GLUT-1 with various clinicopathological features of colorectal cancer. The presence of HIF-1alpha and GLUT-1 was visualized immunohistochemically in 123 primary tumors. Membranous localization of GLUT-1 was found in multifocally necrotizing cancer samples, while pure cytoplasmic perinuclear, mostly supranuclear GLUT-1 accumulation was characteristic of cancer fields with lack of necrosis. HIF-1alpha was located in the cytoplasm and occasionally in the nuclei of cancer cells. Immunoreactivity to GLUT-1 was significantly higher in node-positive cancers compared with nodenegative ones (p=0.04), confirming our earlier results obtained on a larger number of patients. Non-mucinous adenocarcinomas expressed GLUT-1 and HIF-1alpha with significantly greater frequency than mucinous adenocarcinomas (p=0.002, p=0.0002, respectively). GLUT-1 and HIF-1alpha expression did not differ in relation to tumor stage, location, or patients' age or gender. In contrast to that of GLUT-1, expression of HIF-1alpha correlated with grade (p=0.00003) without difference with regard to pN status. HIF-1alpha expression correlated with GLUT-1 expression in the whole patient population, as well as in all clinicopathological groups except for the pT1+pT2 group. Although the coexpression of cytoplasmic HIF-1alpha and GLUT-1 does not directly prove the dependence between HIF-1 as a nuclear transcriptional factor and GLUT-1 as its downstream protein, it is evidence of their simultaneous upregulation. The extranuclear accumulation of HIF-1alpha and GLUT-1 requires further studies to explain its significance in colorectal cancer. [Abstract/Link to Full Text]

Cserni G, Bianchi S, Vezzosi V, Arisio R, Bori R, Peterse JL, Sapino A, Castellano I, Drijkoningen M, Kulka J, Eusebi V, Foschini MP, Bellocq JP, Marin C, Thorstenson S, Amendoeira I, Reiner-Concin A, Decker T, Lacerda M, Figueiredo P, Fejes G
Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study.
Pathol Oncol Res. 2007;13(1):5-14.
Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated. [Abstract/Link to Full Text]

Merkli H, P�l E, G�ti I
Asymmetric calf hypertrophy of neurogenic origin.
Pathol Oncol Res. 2006;12(4):254-6.
A 47-year-old male presented with painful swelling of the right calf. His medical history was negative, except for a herniation of disc LIV-V 5 years before. Physical examination revealed unilateral calf hypertrophy with moderate weakness of plantarflexion, mild paresis of dorsiflexion. Electromyography showed a peripheral neurogenic lesion in the right anterior tibial muscle, but normal findings were obtained from the unaffected quadriceps muscle. Histological examination of the right gastrocnemic muscle showed neurogenic changes with typical targetoid fibers, but no pathological changes were present in the quadriceps muscle. Chronic asymmetric spinal muscular atrophy is an infrequent neuromuscular disease and because of asymmetric appearance, it might be difficult to distinguish from other, acquired neurogenic muscle diseases such as radiculopathy caused by intervertebral disc herniation. Our case confirms that muscular hypertrophy can follow partial denervation in humans. [Abstract/Link to Full Text]

Kondo T, Tanaka Y
Malignant pilomatricoma in the parietal area.
Pathol Oncol Res. 2006;12(4):251-3.
A 27-year-old Japanese woman presented with a 2.5-cm nodular subcutaneous lesion in the parietal area. The nodule was well demarcated and situated in the dermis and subcutis. Histologically, the tumor was diagnosed as malignant pilomatricoma. The tumor was excised, the postoperative course was uneventful, no evidence of local recurrence or distant metastasis was observed, and the patient continues to be under close follow-up. Malignant pilomatricoma, a locally aggressive counterpart of benign pilomatricoma, is also referred to as pilomatrix carcinoma. Most cases are excised as benign tumors; however, when the excision is incomplete local recurrence is likely, and distant metastases have also been reported. Histologically, the diagnosis can be challenging because no clear histologic criteria are available. Because of the rarity of malignant pilomatricoma, no welldefined standards in the surgical management of this neoplasm have been established. Moreover, since distant metastases have been described, close followup of the lesion is requisite. [Abstract/Link to Full Text]

Pappa L, Machera M, Tsanou E, Damala C, Peschos D, Bafa M, Malamou-Mitsi V
Subcutaneous metastasis of peritoneal mesothelioma diagnosed by fine-needle aspiration.
Pathol Oncol Res. 2006;12(4):247-50.
Mesothelioma is a rare malignant neoplasm of the serosal membranes, which can give distant metastases in various organs in advanced stages of its course. Subcutaneous tissue is an unusual metastatic site. In the literature, only one case of metastatic mesothelioma to the skin of the face has been reported. We present a case of a 60-year-old female with a prior history of peritoneal malignant mesothelioma, who 6 months after the initial diagnosis presented with a subcutaneous nodule in the lateral chest wall. Cytological examination of the material obtained by FNA from the nodule revealed metastatic mesothelioma. Although subcutaneous metastasis of malignant mesothelioma is a rare entity, one must always keep this possibility in mind and proceed to further investigation of such lesions. In these cases, FNA is a simple diagnostic procedure for the identification of metastatic disease in patients with a prior history of malignancy. [Abstract/Link to Full Text]

Derecskei K, Moldvay J, Bogos K, T�m�r J
Protocol modifications influence the result of EGF receptor immunodetection by EGFR pharmDx in paraffin-embedded cancer tissues.
Pathol Oncol Res. 2006;12(4):243-6.
EGF receptor (EGFR) became a useful target for several recently introduced therapies of various cancer types including colorectal, lung, head and neck cancers and glioblastoma. The successful clinical application of these novel molecularly targeted therapies requires the expression of their target, EGFR, determined by nucleic acid based or immunohistochemical techniques. However, until now, immunohistochemistry has not become a reliable diagnostic approach for this purpose. The golden standard for the determination of EGFR protein expression in paraffin-embedded cancer tissues is the EGFR pharmDxTM kit. Here we show that the recommended protocol may not be optimal for EGFR immunodetection. Microwave antigen retrieval and extended primary antibody incubation time converted four out of eight EGFR-negative tumors into EGFR-positive in a study of 50 lung adenocarcinoma cases. Accordingly, we recommend retesting cases negative for EGFR with EGFR pharmDxTM using protocol modifications optimizing antigen retrieval and the incubation periods. [Abstract/Link to Full Text]

Alberth M, Majoros L, Kovalecz G, Borb�s E, Szegedi I, J M�rton I, Kiss C
Significance of oral Candida infections in children with cancer.
Pathol Oncol Res. 2006;12(4):237-41.
Candidiasis is common in children with cancer, particularly during periods of severe immunosuppression and neutropenia. Our aim was to study the microbiological changes in the oral cavity of children with newly diagnosed cancer. The study group consisted of 30 consecutive children and adolescents, 16 with acute lymphoblastic leukemia and 14 with solid tumors. Oral cultures to detect fungi and bacteria were conducted for all patients before treatment, during and after neutropenic episodes. In 23 patients developing fever simultaneous throat, urine and blood sampling was carried out. No pathogens were found in the cultures taken before the outset (30 cultures) or after recovery from (30 cultures) the neutropenic episodes. In the 45 oral cultures taken during the neutropenic episodes 38 (84.4%) proved positive. Fungi were the most frequently isolated oral pathogens: 33/38 yeast and 6/38 bacterial infections were identified. There was no association between the underlying malignancy and the occurrence of the positive cultures. Of the 30 patients, all 23 (76.7%) who have developed moderate-to-severe neutropenia, developed oral fungal colonization or clinically obvious fungal infection at least on one occasion during the study. In addition to oral samples, fungi were identified in 9/23 pharyngeal swabs, 6/23 urine and 1/23 blood cultures. The initial fungal pathogen was exclusively (33/33) Candida albicans. In extended severe neutropenic states, C. albicans was replaced by non-albicans species (C. kefyr, C. lusitaniae, C. sake, C. tropicalis) in 5 patients between 4 to 6 days of the neutropenic episodes. Four of the nonalbicans Candida strains were resistant to azole-type antifungal agents. Neutropenic episodes of children with cancer are associated with an increased risk of developing oral and even systemic infections with C. albicans that can be replaced by azole-resistant nonalbicans strains in prolonged neutropenia contributing to morbidity of these patients. [Abstract/Link to Full Text]

S�le N, T�sz�s A, K�lm�n E, Szigeti R, Miseta A, Kellermayer R
Lithium suppresses epidermal SERCA2 and PMR1 levels in the rat.
Pathol Oncol Res. 2006;12(4):234-6.
Autosomal dominant mutations in the genes encoding the calcium ATPases SERCA2 and PMRI/SPCA1 cause the genodermatoses Darier disease (DD) and Hailey-Hailey disease (HHD), respectively. Recent observations indicated that the level of the pathogenic proteins greatly decreases in the affected areas of the epidermis in these disorders. Here we addressed how lithium, a recognized exacerbating factor in Darier disease, affects the epidermal expression of SERCA2 and PMR1/SPCA1 in the rat as a model. Standard histologic and immunohistochemical methods were utilized in 3 lithium-treated and 3 control animals. A significant suppression of epidermal SERCA2 and PMR1 levels were observed as a result of lithium therapy in addition to marked qualitative and quantitative changes in the stratum corneum and the granular layer of the epidermis in the treated animals. Our findings suggest that exacerbating factors in calcium ATPase disorders of the skin suppress epidermal SERCA2 and PMR1 levels, further decreasing the already haploinsufficient protein expression to a potentially critical level in Darier disease and Hailey-Hailey disease, respectively. Lithium therapy should specifically be avoided not only in Darier disease, but Hailey-Hailey disease as well. [Abstract/Link to Full Text]

K�mory E, Tanyi M, Kolacsek O, Olasz L, T�th L, Damjanovich L, Csuka O
Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history.
Pathol Oncol Res. 2006;12(4):228-33.
The Bethesda guidelines may offer more useful criteria in patients' selection for germline mismatch repair gene mutation analysis than guidelines merely based on family background. An early onset double primary colorectal cancer patient with poor family history with MSI-H status was investigated for MLH1 promoter methylation, expression of the MLH1 and MSH2 gene by immunohistochemistry and mutations in the MLH1 and MSH2 genes. The index patient carried two germline alterations, the p.Val716Met in MLH1 and the c.2210+1G>C in MSH2 genes, and both tumors failed to express MLH1 and MSH2 proteins. After subsequent analysis of the whole family of the index patient, the p.Val716Met variant can be defined as a rare polymorphism with the possible contribution of pathogenicity to tumor formation and c.2210+1G>C as a true pathogenic mutation causing an out-of-frame deletion of exon 13. [Abstract/Link to Full Text]

Kiani J, Khan A, Khawar H, Shuaib F, Pervez S
Estrogen receptor alpha-negative and progesterone receptor-positive breast cancer: lab error or real entity?
Pathol Oncol Res. 2006;12(4):223-7.
Aretrospective study comparing the estrogen receptor (ER) alpha subtype and progesterone receptor (PR) profile of breast carcinomas amongst 1625 cases over 2.5 years was carried out. Strictly speaking it is generally believed that breast carcinomas can biochemically express PR only if they are ER-positive. However, a few ERalpha-PR+ cases do exist paradoxically. This class of tumors was the focus of our study in which we looked at the possible reasons for such an immunophenotype and compared it with a group of ERalpha+PR+ breast carcinomas. An internationally recognized immunohistochemical method employing monoclonal antibodies against estrogen and progesterone receptors was used. Correlations with established risk factors i.e. menopausal status, grade, tumor size and lymph node status were analyzed for our study group (ERalpha-PR+) and compared with a control (ERalpha+PR+). Out of the total 1625 cases, 29.91% (486) were ERalpha+PR+, 5.11% (83) were ERalpha+PR-, 56.86% (924) were ERalpha-PR- and 8.12% (132) were ERalpha-PR+. Patients' age was significantly lower in the ERalpha-PR+ group (P=0.002). Statistical analysis of the grading between the two study groups revealed no significant difference (P=0.091), although the ERalpha-PR+ group contained significantly more poorly differentiated tumors than the ERalpha+PR+ one (P=0.032). Tumor size was also significantly larger in the ERalpha-PR+ than in the ERalpha+PR+ group (P=0.046). The frequency of lymph node metastases was independent of receptor profile. In conclusion, our study group does exhibit characteristics which are suggestive of a distinct breast cancer phenotype (ERalpha-PR+) with a different etiology and prognosis. [Abstract/Link to Full Text]

Cserni G, Orosz Z, Kulka J, S�pi Z, K�lm�n E, Bori R
Divergences in diagnosing nodular breast lesions of noncarcinomatous nature.
Pathol Oncol Res. 2006;12(4):216-21.
Nodular breast lesions of noncarcinomatous origin are often of fibroepithelial origin. They may cause classification problems when they are hypocellular or hypercellular; the latter setting may also raise the differential diagnosis of phyllodes tumors. Thirty equivocal nodular breast lesions were collected and one hematoxylin and eosin slide from each was assessed by six pathologists with special interest in breast pathology. The overall reproducibility of classifying these lesions into categories of fibroadenoma, phyllodes tumor or anything else was moderate (kappa value: 0.48). The lack of a uniform nomenclature was not felt disturbing for hypocellular lesions, but the discordant diagnosis of tumors resembling or representing phyllodes tumors was acknowledged to require intervention, such as more obvious implication of guidelines and quality assurance programs aiming at assessing diagnoses and prognostic parameters. [Abstract/Link to Full Text]

Sahin FI, Yilmaz Z, Yagmurdur MC, Atac FB, Ozdemir BH, Karakayali H, Demirhan B, Haberal M
Clinical findings and HER-2/neu gene amplification status of breast carcinoma patients.
Pathol Oncol Res. 2006;12(4):211-5.
The study group was derived from the archival materials of 48 invasive intraductal breast cancer patients who had undergone partial mastectomy/ axillary dissection. All patients included in the study had clinically T1-2N0M0 invasive ductal carcinoma. To detect HER-2/neu status, fluorescent in situ hybridization was performed using a HER-2/neu locus-specific probe. Signals were counted and patients were classified in three groups according to signal ratios: signal ratio <2, group 1 (n=31); signal ratio 2-4, group 2 (n=11); signal ratio >4, group 3 (n=6). Ratios of axillary metastatic lymph nodes to dissected total lymph nodes were 17%, 23% and 83% in groups 1, 2 and 3 respectively (P=0.003). The number of metastatic axillary lymph nodes, and the ratio of microscopic metastatic lymph nodes were highest in group 3 (P=0.001 and P=0.008, respectively). No significant difference was observed between groups for distant metastasis in a 5-year follow-up period. Signal ratios decreased with estrogen receptor expression (P=0.03). Histopathologically, an irregular growth pattern of the tumor was observed in 100% of the patients in group 3, and in 54% and 60% in groups 1 and 2, respectively (P=0.04). Lymphovascular invasion of the tumor was significantly higher in group 3 compared to the other two groups (P=0.01). The extensive intraductal component ratio was the highest in group 3 (P=0.04). The appearance of desmoplastic reaction and lymphocyte infiltration did not show significant difference between the groups. Our results show that HER-2/neu signal ratio increases with lymphovascular invasion, an extensive intraductal component, irregular growth pattern and axillary metastasis in clinically T1-2N0M0 invasive ductal carcinoma of the breast. [Abstract/Link to Full Text]

Kruslin B, Tomas D, Cviko A, Cupic H, Odak L, Belicza M
Periacinar Clefting and p63 Immunostaining in Prostatic Intraepithelial Neoplasia and Prostatic Carcinoma.
Pathol Oncol Res. 2006;12(4):205-9.
The aim of the present study was to correlate the presence and extent of retraction clefting and the expression of p63 in neoplastic glands and glands with prostatic intraepithelial neoplasia (PIN) in needle core biopsies. We analyzed needle core biopsies from 28 patients with PIN and 41 patients with adenocarcinoma. Neoplastic glands and those with PIN were analyzed on high power field (400x) and classified in three groups according to the extent of clefting. Immunohistochemical staining was performed following Microwave Streptavidin ImmunoPeroxidase (MSIP) protocol on DAKO TechMate Horizon automated immunostainer. Periacinar retraction clefting was significantly more prominent in prostatic carcinoma compared to PIN (p<0.0001) and nonneoplastic glands (p<0.0001). There was no difference between normal glands and PIN regarding clefting (p=0.8064). p63 was positive around the whole circumference in 12 out of 28 cases with PIN, and discontinuously positive in remaining 16 PIN cases suggesting initial disruption of the basal cell layer. p63 immunostaining was also positive in all nonneoplastic glands, and negative in all carcinomas. We conclude that retraction clefting was associated with cancer and lack of basal cells, but not with PIN. The relationship between clefting and p63 immunostaining in prostatic cancer should be further analyzed. [Abstract/Link to Full Text]

Kulka J, T�k�s AM, Kaposi-Nov�k P, Udvarhelyi N, Keller A, Schaff Z
Detection of HER-2/neu gene amplification in breast carcinomas using quantitative real-time PCR - a comparison with immunohistochemical and FISH results.
Pathol Oncol Res. 2006;12(4):197-204.
The aim of our study was to evaluate the value of quantitative real-time-PCR (qPCR) in the determination of HER-2/neu amplification status of human breast carcinomas by comparing qPCR, FISH and immunohistochemistry results from the same samples. A total of 210 breast carcinomas were examined. Ready-to-use CB11 antibody was applied to detect HER-2/neu oncoprotein expression. In 76 out of 210 cases FISH was performed, and 162 cases were investigated with qPCR. Seventy-five tumors were 2+ or 3+ positive with immunohistochemistry, while 135 samples were either completely negative or 1+. In 45 cases results from all three methods were available. Out of these, in twenty negative and sixteen positive cases both FISH and qPCR led to similar results. The mean qPCR amplification ratio in the concordant positive cases was 5.424 while in the qPCR+/FISH- group the mean ratio was 2.765. Out of 121 samples with scores of 0 or 1+ immunohistochemical result, analyzed also with qPCR, 26 showed HER-2/neu gene amplification. In these cases the mean amplification ratio was 2.53. Comparison of FISH and qPCR together with immunohistochemistry shows that qPCR is more sensitive to detect HER-2/neu gene amplification in tumors scored as 2+ with immunohistochemistry, but the diagnostic cut-off ratio should be defined above 2.7 to avoid high number of false positive cases. Amongst the immunohistochemistry score 2+ cases, 10 of 18 showed gene amplification by qPCR while 10 of 26 by FISH. In conclusion, a well calibrated HER-2/neu qPCR assay may serve as useful alternative to FISH in breast cancer patients. [Abstract/Link to Full Text]

Avninder SP, Saxena S
Infiltrating ductal carcinoma of the breast, metastatic to axillary lymph nodes harboring primary tuberculous lymphadenitis.
Pathol Oncol Res. 2006;12(3):188-9.
A 46-year-old female presented with lump in the left breast. Fine-needle aspiration cytology (FNAC) from breast and axillary lymph node revealed infiltrating ductal carcinoma with metastasis in axillary node. The patient underwent radical mastectomy with axillary lymph node dissection. Histopathological examination showed concomitant presence of metastatic tumor deposits and tubercular lymphadenitis in 8/18 nodes. The case is presented for its rarity and illustrates that FNAC can fail to detect mixed lesions unless multiple punctures from many sites are performed. [Abstract/Link to Full Text]

Coutts MA, Borthwick NJ, Hungerford JL, Cree IA
Post-menopausal bleeding: a rare presentation of metastatic uveal melanoma.
Pathol Oncol Res. 2006;12(3):184-7.
Uveal melanoma differs from cutaneous melanoma in many ways, including its pattern of metastasis, and exhibits latency with clinical evidence of metastasis sometimes appearing many years after primary diagnosis. Most patients develop metastasis within the liver, but some may present with metastasis to other sites. We report a case of uveal melanoma that presented with post-menopausal bleeding due to metastasis. Further investigation revealed widespread metastatic disease and the patient was not fit for chemotherapy. She died two months after presentation: autopsy revealed metastases in many sites, including the uterus, right ovarian fibroma, kidney, mesentery, liver, lung, thyroid, bone marrow and skin. The immediate cause of death was cardiac tamponade due to a malignant effusion secondary to cardiac metastasis. This case illustrates the widespread metastatic potential of uveal melanoma and highlights the potential for unusual presentation of metastatic disease from this eye tumor. [Abstract/Link to Full Text]

Elek G, Lapis K
A path or a new road in laboratory diagnostics? Biological mass spectrometry: facts and perspectives.
Pathol Oncol Res. 2006;12(3):178-83.
Proteins in tissues and biofluids and their many attributes define the proteome. Proteome can be directly correlated to known diseases and histological regions allowing the diagnosis and monitoring of disease progression as well predicting the patient's response to specific treatments. Proteomics performs large-scale, high-throughput characterization of the human proteome, among others by biological mass spectrometry. Proteinchip technology coupled with bioinformatics is able to screen any protein source for putative disease biomarkers from a small sample volume (microliter range) by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). This article discusses on a basic level both the technology and reliability of these methods. [Abstract/Link to Full Text]

Helal Tel A, Fadel MT, El-Sayed NK
Human papilloma virus and p53 expression in bladder cancer in Egypt: relationship to schistosomiasis and clinicopathologic factors.
Pathol Oncol Res. 2006;12(3):173-8.
The aim of the current study was to compare the role of p53 and human papillomavirus (HPV) in schistosomiasis-related and schistosomiasis-unrelated carcinoma of the urinary bladder. To achieve this aim, we investigated 114 bladder carcinomas for p53 oncoprotein expression by immunohistochemistry and for human papillomavirus by in situ hybridization technique. The results revealed that 64 tumors (56.1%) were schistosomiasis-associated. Sixty seven (58.8%) were transitional cell carcinomas and 32 (28%) were squamous cell carcinomas. The remaining 15 tumors (13.2%) included adenocarcinomas and sarcomatoid carcinomas. In both schistosomiasis-associated and non-associated carcinomas, p53 oncoprotein expression was significantly higher in poorly differentiated tumors. However, it was significantly higher in locally more invasive tumors in the schistosomal carcinomas only. HPV types 16/18 could be detected in 1 of the 114 bladder carcinomas (0.95%), which was schistosomiasis-related squamous cell carcinoma in situ. These results suggest that p53 immunohistochemistry can be a prognostic factor in both schistosomal and nonschistosomal bladder cancer. More importantly, HPV does not seem to play a role in the pathogenesis of either type of bladder cancer in our country. [Abstract/Link to Full Text]

Malik A, Deb P, Sharma MC, Sarkar C
Neuropathological spectrum of pilocytic astrocytoma: an Indian series of 120 cases.
Pathol Oncol Res. 2006;12(3):164-71.
Pilocytic astrocytomas (PAs) are generally well circumscribed, slowly growing, cystic tumors, occurring in the pediatric age group. Our aims were to retrospectively analyze the neuropathological spectrum of PA, and correlate it with various clinicopathological features. A total of 120 PAs, diagnosed and managed at this center during a 5-year period, were included. The study population had a mean age of 18.9 years, with male predominance (68.3%), and demonstrated predilection for posterior fossa (61.7%). On histopathology, biphasic pattern (89.2%) along with Rosenthal fibers (66.7%) and eosinophilic granular bodies (60%) were present in the majority of cases. Vascular features were characterized by perivascular hyalinization (51.7%), angiomatous proliferation (21.7%) and glomeruloid changes (21.7%). Hemosiderin-laden macrophages were noted in 37.1% of cases. Further, 60.8% showed lymphoplasmacytic infiltration, while atypia and necrosis were present in 25.8% and 1.7% of cases, respectively. Statistical evaluation revealed significant correlation of angiomatous proliferation with age (< or =12 and >12-year age groups) (p=0.011); and of hemosiderin deposition with angiomatous proliferation (p=0.006), perivascular hyalinization (p=0.035), and age (< or =12 and >12-year age groups) (p=0.028). This study emphasizes that though PAs generally display classical histomorphology, diagnosis may be challenging in patients with unusual clinicopathological features, e.g. in older patients, uncommon location, absence of biphasic pattern, or presence of nuclear atypia, mitotic figures and necrosis, and also in cases of small biopsies. In the absence of diagnostic histology enumerated above, vascular features like angiomatous proliferation, glomeruloid changes and perivascular hyalinization, along with hemosiderinladen macrophages and perivascular lymphocytic infiltration should be considered as surrogate histological markers of PA. [Abstract/Link to Full Text]

Szegedi I, Kiss C, Kar�szi E, V�mosi G, Sz�ll�si J, Kov�cs P, Benk� I
Differential regulation of umbilical cord blood and leukemic B cells by interferon-alpha (IFN-alpha): observations in cultured cells.
Pathol Oncol Res. 2006;12(3):159-63.
The exact mechanism of the beneficial therapeutic action of interferon-a (IFN-alpha) in B-cell-lineage malignancies has not been adequately explained. Here we report on the differential effect of IFN-alpha2b on non-malignant B cells of umbilical cord blood and leukemic B-cell lines JY, BL-41 and BCBL-1. Leukemic cell proliferation was characterized by colony assay, whereas apoptosis was investigated by flow cytometry of propidium iodide-stained cells. The degree of differentiation was evaluated by measuring the expression level of Fcgamma receptor-II (FcgammaRII) labeled with anti-CD32-FITC monoclonal antibody using flow cytometry. IFN-alpha protected umbilical cord blood CD19-positive B lymphocytes from apoptotic cell death in vitro. IFN-alpha significantly decreased colony formation of all three cell lines, and in contrast to normal cells, induced apoptosis in JY and BL-41 and excessive necrosis in HHV-8 infected BCBL-1 cells. FcgammaRII was upregulated both in normal and in leukemic B cells as indicated by an increase both in the proportion of CD32-positive cells and the mean fluorescence intensity. From our results it seems that antiproliferative, apoptotic and differentiative effects of IFN-alpha are interrelated but distinct cellular events, which are differentially regulated in normal, leukemic and virus-infected cells of the B-cell lineage. [Abstract/Link to Full Text]

Nogueira MC, Guedes Neto Ede P, Rosa MW, Zettler E, Zettler CG
Immunohistochemical expression of p16 and p53 in vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva.
Pathol Oncol Res. 2006;12(3):153-7.
This study was undertaken to examine the expression of p16 and p53 in vulvar intraepithelial neoplasia (VIN) and squamous cell carcinoma (SCC) of the vulva. We also analyzed the relationship between p16 and p53 immunoexpression in women younger vs. older than 55 years of age. Seventyseven histologic samples of vulvar tissue, treated surgically between June 2000 and November 2004 at the Complexo Hospitalar Santa Casa (Porto Alegre, Brazil), were investigated. We analyzed 28 cases of VIN, 37 cases of SCC and 12 normal vulvar tissues. The percentage of immunohistochemical positivity for p16 had the following distribution across the groups: VIN: 21.4% (6/28), cancer: 24.3% (9/37) and control: absent (p=0.202). p53 expression showed the following percentages: VIN: 60.7% (17/28), cancer: 18.9% (7/37) and control: 8.3% (1/12) (p=0.01). p16 expression in the cancer group (mean age: 63.4 years) was positive in 6 and 3 cases of women younger or older than 55 years, respectively (54.5% vs. 11.5%, p=0.01). p53 expression was not detected in young females with cancer, while it was expressed in 7/26 (26.9%) cases of the group of females older than 55 years of age (p=0.08). Our results suggest an increase in the immunohistochemical expression of p16 protein in young women with squamous cell carcinoma of the vulva, and a possible association with a low expression of p53. [Abstract/Link to Full Text]

L�rincz T, T�th J, Badalian G, T�m�r J, Szendr�i M
HER-2/neu genotype of breast cancer may change in bone metastasis.
Pathol Oncol Res. 2006;12(3):149-52.
The genotype of breast cancer (BRC) is considered to be relatively stable during tumor progression, accordingly, determination of the estrogen receptor and HER-2/neu status is currently based on the primary tumor. However, recent data suggest that the gene expression profile of the metastatic lesion can be different compared to that of the primary BRC. Accordingly, it is possible that the HER-2/neu status is different in the metastatic lesion and the primary BRC. Since the bone is the most frequent metastatic site during the progression of BRC, we have analyzed the HER-2/neu status of 48 bone metastatic BRC cases by immunohistochemistry and fluorescent in situ hybridization, and it was possible to compare it to the primary site in 23 cases. The frequency of HER-2/neu amplification of BRC in the primary tumors was found to be 17.4% compared to 10.5% in bone metastases. Half of BRC cases with HER-2/neu amplification lost this genotype in bone metastases (4/23 versus 2/23, respectively) and even in the 2 cases where HER-2/neu amplification was retained in the metastases, the copy number was found to be decreased compared to the primary tumor. Based on our data and previous reports in the literature, we suggest to perform HER-2/neu testing both on primary tumor and samples obtained from BRC metastases, at least in case of primary tumors with HER-2/neu amplification, before introduction of HER-2/neu-targeting therapy. [Abstract/Link to Full Text]

Johannessen AL, Torp SH
The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas.
Pathol Oncol Res. 2006;12(3):143-7.
The current WHO classification of human astrocytomas has limitations in predicting prognosis and diagnosis, and there is a need for additional factors. Several studies have investigated the clinical value of proliferative activity in these tumors, especially the Ki-67/MIB-1 labeling index (LI). The aim of this study was to review the literature on this topic to get a survey of the current experience. All studies show increasing values of Ki-67/MIB-1 LI with increasing grade of malignancy. Most of them demonstrate that MIB-1 LI differentiates well between diffuse astrocytomas WHO grade II (AII) and anaplastic astrocytomas (AA) and between AII and glioblastomas (GM), but not between AA and GM. There is, however, considerable overlap of indices between the different malignancy groups. Further, in most studies positive correlations between MIB-1 LI and survival are found, though the proposed cut-off values vary substantially between the reports. The studies reviewed report MIB-1 LI as an important prognostic factor in human astrocytomas. Due to the great spread of values between the various tumor grades, however, MIB-1 LI cannot be used as a diagnostic factor alone but should be used in combination with established criteria of histological malignancy. It may be especially useful in cases where histology reveals a low-grade astrocytoma whereas other parameters indicate a more malignant neoplasm. Thus, it is our opinion that MIB-1 LI should be a part of the routine investigation in patients with astrocytic tumors. Until larger multicenter studies based on standardized immunohistopathological procedures have been completed, each laboratory has to establish its own practice. [Abstract/Link to Full Text]

Nagy K, Sz�kely-Sz�ts K, Izeradjene K, Douglas L, Tillman M, Barti-Juh�sz H, Dominici M, Spano C, Luca Cervo G, Conte P, Houghton JA, Mihalik R, Kopper L, Pet�k I
Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria.
Pathol Oncol Res. 2006;12(3):133-42.
The synergistic interaction between proteasome inhibitors and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising approach to induce cell death in tumor cells. However, the molecular and biochemical mechanisms of this synergism have been proven to be cell type specific. We therefore focused our investigation on TRAIL-resistant colon carcinoma cells in this study. DNA fragmentation, mitochondrial membrane depolarization and increased caspase-3-like enzyme activity was exclusively induced only by combined treatment with proteasome inhibitors (epoxomicin, MG132, bortezomib/PS-341) and TRAIL. The expression level of anti-apoptotic proteins (XIAP, survivin, Bcl-2, Bcl-XL), regulated by NF-kappaB transcription factor, was not effected by any of these treatments. TRAIL alone induced only partial activation of caspase-3 (p20), while the combination of TRAIL and proteasome inhibition led to the full proteolytic activation of caspase-3 (p17). Only the combination treatment induced marked membrane depolarization and the release of cytochrome c, HtrA2/Omi and Smac/DIABLO. Apoptosis-inducing factor (AIF) was not released in any of these conditions. These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment. This molecular mechanism, independent of the inhibition NF-kappaB activity, may provide rationale for the combination treatment of colon carcinomas with proteasome inhibitors and recombinant TRAIL or agonistic antibody of TRAIL receptors. [Abstract/Link to Full Text]