Free Full Text Journal Articles: Cancer -- Neurotransmitter.net

Recent Articles in Molecular Cancer

Ribeiro FR, Henrique R, Hektoen M, Berg M, Jer�nimo C, Teixeira MR, Lothe RA
Comparison of chromosomal and array-based comparative genomic hybridization for the detection of genomic imbalances in primary prostate carcinomas.
Mol Cancer. 2006;533.
BACKGROUND: In order to gain new insights into the molecular mechanisms involved in prostate cancer, we performed array-based comparative genomic hybridization (aCGH) on a series of 46 primary prostate carcinomas using a 1 Mbp whole-genome coverage platform. As chromosomal comparative genomic hybridization (cCGH) data was available for these samples, we compared the sensitivity and overall concordance of the two methodologies, and used the combined information to infer the best of three different aCGH scoring approaches. RESULTS: Our data demonstrate that the reliability of aCGH in the analysis of primary prostate carcinomas depends to some extent on the scoring approach used, with the breakpoint estimation method being the most sensitive and reliable. The pattern of copy number changes detected by aCGH was concordant with that of cCGH, but the higher resolution technique detected 2.7 times more aberrations and 15.2% more carcinomas with genomic imbalances. We additionally show that several aberrations were consistently overlooked using cCGH, such as small deletions at 5q, 6q, 12p, and 17p. The latter were validated by fluorescence in situ hybridization targeting TP53, although only one carcinoma harbored a point mutation in this gene. Strikingly, homozygous deletions at 10q23.31, encompassing the PTEN locus, were seen in 58% of the cases with 10q loss. CONCLUSION: We conclude that aCGH can significantly improve the detection of genomic aberrations in cancer cells as compared to previously established whole-genome methodologies, although contamination with normal cells may influence the sensitivity and specificity of some scoring approaches. Our work delineated recurrent copy number changes and revealed novel amplified loci and frequent homozygous deletions in primary prostate carcinomas, which may guide future work aimed at identifying the relevant target genes. In particular, biallelic loss seems to be a frequent mechanism of inactivation of the PTEN gene in prostate carcinogenesis. [Abstract/Link to Full Text]

Cabrera G, Porvasnik SL, DiCorleto PE, Siemionow M, Goldman CK
Intra-arterial adenoviral mediated tumor transfection in a novel model of cancer gene therapy.
Mol Cancer. 2006;532.
BACKGROUND: The aim of the present study was to develop and characterize a novel in vivo cancer gene therapy model in which intra-arterial adenoviral gene delivery can be characterized. In this model, the rat cremaster muscle serves as the site for tumor growth and provides convenient and isolated access to the tumor parenchyma with discrete control of arterial and venous access for delivery of agents. RESULTS: Utilizing adenovirus encoding the green fluorescent protein we demonstrated broad tumor transfection. We also observed a dose dependent increment in luciferase activity at the tumor site using an adenovirus encoding the luciferase reporter gene. Finally, we tested the intra-arterial adenovirus dwelling time required to achieve optimal tumor transfection and observed a minimum time of 30 minutes. CONCLUSION: We conclude that adenovirus mediated tumor transfection grown in the cremaster muscle of athymic nude rats via an intra-arterial route could be achieved. This model allows definition of the variables that affect intra-arterial tumor transfection. This particular study suggests that allowing a defined intra-tumor dwelling time by controlling the blood flow of the affected organ during vector infusion can optimize intra-arterial adenoviral delivery. [Abstract/Link to Full Text]

Marampon F, Ciccarelli C, Zani BM
Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors.
Mol Cancer. 2006;531.
BACKGROUND: Expression of c-myc proto-oncogene is inappropriate in a wide range of human tumors, and is a downstream target of Ras/Raf/ERK pathway, which promotes c-Myc stability by enhancing c-Myc expression and activity.The aim of this study was to investigate whether the oncogenic phenotype in the human muscle-derived Rhabdomyosarcoma (RD) cell line and in non muscle-derived human tumor cell lines (SW403, IGR39 and PC3) can be blocked by disrupting the c-Myc pathway either by means of pharmacological MEK/ERK inhibition or by direct inactivation of the c-Myc protein. RESULTS: We demonstrate that, in all the tumor cell lines used, the MEK/ERK inhibitor U0126 rapidly induces c-Myc de-phosphorylation, which is followed by a marked reduction in its expression level, by inhibition of proliferation and by reversion of anchorage-independent growth. These data suggest that the targeting of pathways controlling c-Myc expression or stability reverses deregulated growth of different tumor-derived cell lines. Indeed, in RD cells, we found a marked down-regulation of cyclins E2, A and B and CDK2, all of which are known to be targets of c-Myc. Moreover, ectopic MadMyc chimera, a c-Myc function antagonist, causes dramatic growth arrest, CDK and cyclin modulation as well as inhibition of anchorage-independent growth in RD cells, as occurs in U0126-treated cells. In particular, we found that the mere inhibition of c-Myc by MadMyc chimera rescues the myogenic program, MHC expression and the acquisition of the myogenic-like phenotype in RD cells. CONCLUSION: Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest and transformation phenotype of Rhabdomyosarcoma and of non muscle-derived tumor cell lines. In fact, MEK/ERK inhibitor, U0126, induces growth arrest, anchorage-dependent growth of these cell lines. In addition, the results of this study demonstrate that the direct inactivation of c-Myc by Mad/Myc chimera rescues myogenic program and leads to the reversal of the Rhabdomyosarcoma phenotype. In conclusion these data strongly suggest that the targeting of c-Myc by means of the MEK inhibitor can be tested as a promising strategy in anti-cancer therapy. [Abstract/Link to Full Text]

Nindl I, Dang C, Forschner T, Kuban RJ, Meyer T, Sterry W, Stockfleth E
Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling.
Mol Cancer. 2006;530.
BACKGROUND: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). RESULTS: Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. CONCLUSION: The majority of identified differentially expressed genes in cutaneous SCC were previously not described. [Abstract/Link to Full Text]

Bandr�s E, Cubedo E, Agirre X, Malumbres R, Z�rate R, Ramirez N, Abajo A, Navarro A, Moreno I, Monz� M, Garc�a-Foncillas J
Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues.
Mol Cancer. 2006;529.
MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes.In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor.Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia. [Abstract/Link to Full Text]

Das PM, Ramachandran K, Vanwert J, Ferdinand L, Gopisetty G, Reis IM, Singal R
Methylation mediated silencing of TMS1/ASC gene in prostate cancer.
Mol Cancer. 2006;528.
BACKGROUND: Transcriptional silencing associated with aberrant promoter methylation has been established as an alternate pathway for the development of cancer by inactivating tumor suppressor genes. TMS1 (Target of Methylation induced Silencing), also known as ASC (Apoptosis Speck like protein containing a CARD) is a tumor suppressor gene which encodes for a CARD (caspase recruitment domain) containing regulatory protein and has been shown to promote apoptosis directly and by activation of downstream caspases. This study describes the methylation induced silencing of TMS1/ASC gene in prostate cancer cell lines. We also examined the prevalence of TMS1/ASC gene methylation in prostate cancer tissue samples in an effort to correlate race and clinico-pathological features with TMS1/ASC gene methylation. RESULTS: Loss of TMS1/ASC gene expression associated with complete methylation of the promoter region was observed in LNCaP cells. Gene expression was restored by a demethylating agent, 5-aza-2'deoxycytidine, but not by a histone deacetylase inhibitor, Trichostatin A. Chromatin Immunoprecipitation (ChIP) assay showed enrichment of MBD3 (methyl binding domain protein 3) to a higher degree than commonly associated MBDs and MeCP2. We evaluated the methylation pattern in 66 prostate cancer and 34 benign prostatic hyperplasia tissue samples. TMS1/ASC gene methylation was more prevalent in prostate cancer cases than controls in White patients (OR 7.6, p 0.002) while no difference between the cases and controls was seen in Black patients (OR 1.1, p 0.91). CONCLUSION: Our study demonstrates that methylation-mediated silencing of TMS1/ASC is a frequent event in prostate cancer, thus identifying a new potential diagnostic and prognostic marker for the treatment of the disease. Racial differences in TMS1/ASC methylation patterns implicate the probable role of molecular markers in determining in susceptibility to prostate cancer in different ethnic groups. [Abstract/Link to Full Text]

Perez-Plasencia C, Duenas-Gonzalez A
Can the state of cancer chemotherapy resistance be reverted by epigenetic therapy?
Mol Cancer. 2006;527.
BACKGROUND: Transcriptome analysis shows that the chemotherapy innate resistance state of tumors is characterized by: poorly dividing tumor cells; an increased DNA repair; an increased drug efflux potential by ABC-transporters; and a dysfunctional ECM. Because chemotherapy resistance involves multiple genes, epigenetic-mediated changes could be the main force responsible of this phenotype. Our hypothesis deals with the potential role of epigenetic therapy for affecting the chemotherapy resistant phenotype of malignant tumors. PRESENTATION OF THE HYPOTHESIS: Recent studies reveal the involvement of DNA methylation and histone modifications in the reprogramming of the genome of mammalian cells in cancer. In this sense, it can be hypothesized that epigenetic reprogramming can participate in the establishment of an epigenetic mark associated with the chemotherapy resistant phenotype. If this were correct, then it could be expected that agents targeting DNA methylation and histone deacetylation would by reverting the epigenetic mark induce a global expression profile that mirror the observed in untreated resistant cells. TESTING THE HYPOTHESIS: It is proposed to perform a detailed analysis using all the available databases where the gene expression of primary tumors was analyzed and data correlated with the therapeutic outcome to determine whether a transcriptome profiling of "resistance" is observed. Assuming an epigenetic programming determines at some level the intrinsic resistant phenotype, then a similar pattern of gene expression dictated by an epigenetic mark should also be found in cell acquiring drug resistance. If these expectations are meet, then it should be further investigated at the genomic level whether these phenotypes are associated to certain patterns of DNA methylation and chromatin modification. Once confirmed the existence of an epigenetic mark associated to either the intrinsic or acquired chemotherapy resistant phenotype, then a causal association should be investigated. These preclinical findings should also be tested in a clinical setting. IMPLICATIONS OF THE HYPOTHESIS: Our hypothesis on the ability of epigenetic therapy to revert the epigenetic changes leading to a transcritome profile that defines the resistant state will eventually be a more rational and effective way to treat malignant tumors. [Abstract/Link to Full Text]

Brown MA, Sims RJ, Gottlieb PD, Tucker PW
Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex.
Mol Cancer. 2006;526.
BACKGROUND: Disrupting the balance of histone lysine methylation alters the expression of genes involved in tumorigenesis including proto-oncogenes and cell cycle regulators. Methylation of lysine residues is commonly catalyzed by a family of proteins that contain the SET domain. Here, we report the identification and characterization of the SET domain-containing protein, Smyd2. RESULTS: Smyd2 mRNA is most highly expressed in heart and brain tissue, as demonstrated by northern analysis and in situ hybridization. Over-expressed Smyd2 localizes to the cytoplasm and the nucleus in 293T cells. Although accumulating evidence suggests that methylation of histone 3, lysine 36 (H3K36) is associated with actively transcribed genes, we show that the SET domain of Smyd2 mediates H3K36 dimethylation and that Smyd2 represses transcription from an SV40-luciferase reporter. Smyd2 associates specifically with the Sin3A histone deacetylase complex, which was recently linked to H3K36 methylation within the coding regions of active genes in yeast. Finally, we report that exogenous expression of Smyd2 suppresses cell proliferation. CONCLUSION: We propose that Sin3A-mediated deacetylation within the coding regions of active genes is directly linked to the histone methyltransferase activity of Smyd2. Moreover, Smyd2 appears to restrain cell proliferation, likely through direct modulation of chromatin structure. [Abstract/Link to Full Text]

Paulsen MT, Starks AM, Derheimer FA, Hanasoge S, Li L, Dixon JE, Ljungman M
The p53-targeting human phosphatase hCdc14A interacts with the Cdk1/cyclin B complex and is differentially expressed in human cancers.
Mol Cancer. 2006;525.
BACKGROUND: The evolutionary conserved cyclin-dependent kinase phosphatase hCdc14A has been shown to play potential roles in the regulation of mitotic exit and in the centrosome duplication cycle. We have recently shown that hCdc14A also can interact with the tumor suppressor p53 both in vitro and in vivo and specifically dephosphorylates the ser315 site of p53 in vitro. In this study we developed antibodies against hCdc14A to investigate the expression and regulation of hCdc14A in human tissues and cancer cells. RESULTS: We show that hCdc14A is differentially expressed in human tissues and in 75 cancer cell lines examined. Treatments with the histone deacetylase inhibitor TSA, the demethylating agent 5-aza-2'-deoxycytodine or the proteasome inhibitor MG132 significantly induced expression of hCdc14A in cell lines expressing low or undetectable levels of hCdc14A. There was a strong bias for low expression of hCdc14A in cancer cell lines harboring wild-type p53, suggesting that high Cdc14A expression is not compatible with wild-type p53 expression. We present evidence for a role for hCdc14A in the dephosphorylation of the ser315 site of p53 in vivo and that hCdc14A forms a complex with Cdk1/cyclin B during interphase but not during mitosis. CONCLUSION: Our results that hCdc14A is differentially expressed in human cancer cells and that hCdc14A can interact with both p53 and the Cdk1/cyclin B complex may implicate that dysregulation of hCdc14A expression may play a role in carcinogenesis. [Abstract/Link to Full Text]

Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK, Fedele V, Ginzinger D, Getts R, Haqq C
Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies.
Mol Cancer. 2006;524.
BACKGROUND: Recent studies indicate that microRNAs (miRNAs) are mechanistically involved in the development of various human malignancies, suggesting that they represent a promising new class of cancer biomarkers. However, previously reported methods for measuring miRNA expression consume large amounts of tissue, prohibiting high-throughput miRNA profiling from typically small clinical samples such as excision or core needle biopsies of breast or prostate cancer. Here we describe a novel combination of linear amplification and labeling of miRNA for highly sensitive expression microarray profiling requiring only picogram quantities of purified microRNA. RESULTS: Comparison of microarray and qRT-PCR measured miRNA levels from two different prostate cancer cell lines showed concordance between the two platforms (Pearson correlation R2 = 0.81); and extension of the amplification, labeling and microarray platform was successfully demonstrated using clinical core and excision biopsy samples from breast and prostate cancer patients. Unsupervised clustering analysis of the prostate biopsy microarrays separated advanced and metastatic prostate cancers from pooled normal prostatic samples and from a non-malignant precursor lesion. Unsupervised clustering of the breast cancer microarrays significantly distinguished ErbB2-positive/ER-negative, ErbB2-positive/ER-positive, and ErbB2-negative/ER-positive breast cancer phenotypes (Fisher exact test, p = 0.03); as well, supervised analysis of these microarray profiles identified distinct miRNA subsets distinguishing ErbB2-positive from ErbB2-negative and ER-positive from ER-negative breast cancers, independent of other clinically important parameters (patient age; tumor size, node status and proliferation index). CONCLUSION: In sum, these findings demonstrate that optimized high-throughput microRNA expression profiling offers novel biomarker identification from typically small clinical samples such as breast and prostate cancer biopsies. [Abstract/Link to Full Text]

Debauve G, Nonclercq D, Ribaucour F, Wiedig M, Gerbaux C, Leo O, Laurent G, Journ� F, Belayew A, Toubeau G
Early expression of the Helicase-Like Transcription Factor (HLTF/SMARCA3) in an experimental model of estrogen-induced renal carcinogenesis.
Mol Cancer. 2006;523.
BACKGROUND: The Helicase-Like Transcription Factor (HLTF/SMARCA3) belongs to the family of SWI/SNF proteins that use the energy of ATP hydrolysis to remodel chromatin in a variety of cellular processes. Several SWI/SNF genes are disrupted in cancer, suggesting a role of tumor suppressor. Similarly, the HLTF gene was recently found to be inactivated by hypermethylation in a number of advanced colon and gastric tumors. However, other evidences indicated a 20-fold HLTF overexpression in cell lines derived from various neoplasms (ovary, breast, cervix, kidney...). RESULTS: In the present study, we investigated HLTF expression by immunohistochemistry in a model of kidney tumors induced by continuous administration of diethylstilbestrol to male Syrian golden hamsters. A strong labeling was already detected in small tumor buds, making HLTF an early cancer marker in this model. Although every cell stained for HLTF at this early stage, the number of HLTF-positive cells decreased to 10% with cancer progression, and these positive cells were dispersed in the tumor mass. HLTF expression was conserved in the HKT-1097 cell line established from kidney tumors, but again only 10% of positive cells were found in xenografts produced by HKT-1097 cells in nude mice. CONCLUSION: In conclusion, our data suggest that HLTF gene activation is linked to initial steps of carcinogenesis in this model and should be investigated in early stages of other neoplasms. [Abstract/Link to Full Text]

Han SS, Peng L, Chung ST, DuBois W, Maeng SH, Shaffer AL, Sporn MB, Janz S
CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms.
Mol Cancer. 2006;522.
BACKGROUND: Gene-targeted iMycEmu mice that carry a His6-tagged mouse Myc(c-myc)cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Emu, are prone to B cell and plasma cell neoplasms, such as lymphoblastic B-cell lymphoma (LBL) and plasmacytoma (PCT). Cell lines derived from Myc-induced neoplasms of this sort may provide a good model system for the design and testing of new approaches to prevent and treat MYC-driven B cell and plasma cell neoplasms in human beings. To test this hypothesis, we used the LBL-derived cell line, iMycEmu-1, and the newly established PCT-derived cell line, iMycEmu-2, to evaluate the growth inhibitory and death inducing potency of the cancer drug candidate, CDDO-imidazolide (CDDO-Im). METHODS: Morphological features and surface marker expression of iMycEmu-2 cells were evaluated using cytological methods and FACS, respectively. mRNA expression levels of the inserted MycHis and normal Myc genes were determined by allele-specific RT-PCR and qPCR. Myc protein was detected by immunoblotting. Cell cycle progression and apoptosis were analyzed by FACS. The expression of 384 "pathway" genes was assessed with the help of Superarray cDNA macroarrays and verified, in part, by RT-PCR. RESULTS: Sub-micromolar concentrations of CDDO-Im caused growth arrest and apoptosis in iMycEmu-1 and iMycEmu-2 cells. CDDO-Im-dependent growth inhibition and apoptosis were associated in both cell lines with the up-regulation of 30 genes involved in apoptosis, cell cycling, NFkappaB signaling, and stress and toxicity responses. Strongly induced (> or = 10 fold) were genes encoding caspase 14, heme oxygenase 1 (Hmox1), flavin-containing monooxygenase 4 (Fmo4), and three members of the cytochrome P450 subfamily 2 of mixed-function oxygenases (Cyp2a4, Cyp2b9, Cyp2c29). CDDO-Im-dependent gene induction coincided with a decrease in Myc protein. CONCLUSION: Growth arrest and killing of neoplastic mouse B cells and plasma cells by CDDO-Im, a closely related derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, appears to be caused, in part, by drug-induced stress responses and reduction of Myc. [Abstract/Link to Full Text]

Lejeune D, Hasanuzzaman M, Pitcock A, Francis J, Sehgal I
The superoxide scavenger TEMPOL induces urokinase receptor (uPAR) expression in human prostate cancer cells.
Mol Cancer. 2006;521.
There is little understanding of the effect that reactive oxygen metabolites have on cellular behavior during the processes of invasion and metastasis. These oxygen metabolites could interact with a number of targets modulating their function such as enzymes involved in basement membrane dissolution, adhesion molecules involved in motility or receptors involved in proliferation. We investigated the effect of increased scavenging of superoxide anions on the expression of the urokinase receptor (uPAR) in PC-3M human prostate cancer cells. Urokinase receptor is a GPI-linked cell surface molecule which mediates multiple functions including adhesion, proliferation and pericellular proteolysis. Addition of the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) to PC-3M cultures stimulated expression of uPAR protein peaking between 48 and 72 hours. Cell surface expression of the uPAR was also increased. Surprisingly, uPAR transcript levels increased only slightly and this mild increase did not coincide with the striking degree of protein increase. This disparity indicates that the TEMPOL effect on uPAR occurs through a post-transcriptional mechanism. TEMPOL presence in PC-3M cultures reduced intracellular superoxide-type species by 75% as assayed by NBT dye conversion; however this reduction significantly diminished within hours following TEMPOL removal. The time gap between TEMPOL treatment and peak uPAR protein expression suggests that reduction of reactive oxygen metabolites in prostate cancer cells initiates a multistep pathway which requires several hours to culminate in uPAR induction. These findings reveal a novel pathway for uPAR regulation involving reactive oxygens such as superoxide anion. [Abstract/Link to Full Text]

De Angelis PM, Svendsrud DH, Kravik KL, Stokke T
Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery.
Mol Cancer. 2006;520.
BACKGROUND: Treatment of cells with the anti-cancer drug 5-fluorouracil (5-FU) causes DNA damage, which in turn affects cell proliferation and survival. Two stable wild-type TP53 5-FU-resistant cell lines, ContinB and ContinD, generated from the HCT116 colon cancer cell line, demonstrate moderate and strong resistance to 5-FU, respectively, markedly-reduced levels of 5-FU-induced apoptosis, and alterations in expression levels of a number of key cell cycle- and apoptosis-regulatory genes as a result of resistance development. The aim of the present study was to determine potential differential responses to 8 and 24-hour 5-FU treatment in these resistant cell lines. We assessed levels of 5-FU uptake into DNA, cell cycle effects and apoptosis induction throughout treatment and recovery periods for each cell line, and alterations in expression levels of DNA damage response-, cell cycle- and apoptosis-regulatory genes in response to short-term drug exposure. RESULTS: 5-FU treatment for 24 hours resulted in S phase arrests, p53 accumulation, up-regulation of p53-target genes on DNA damage response (ATF3, GADD34, GADD45A, PCNA), cell cycle-regulatory (CDKN1A), and apoptosis-regulatory pathways (FAS), and apoptosis induction in the parental and resistant cell lines. Levels of 5-FU incorporation into DNA were similar for the cell lines. The pattern of cell cycle progression during recovery demonstrated consistently that the 5-FU-resistant cell lines had the smallest S phase fractions and the largest G2(/M) fractions. The strongly 5-FU-resistant ContinD cell line had the smallest S phase arrests, the lowest CDKN1A levels, and the lowest levels of 5-FU-induced apoptosis throughout the treatment and recovery periods, and the fastest recovery of exponential growth (10 days) compared to the other two cell lines. The moderately 5-FU-resistant ContinB cell line had comparatively lower apoptotic levels than the parental cells during treatment and recovery periods and a recovery time of 22 days. Mitotic activity ceased in response to drug treatment for all cell lines, consistent with down-regulation of mitosis-regulatory genes. Differential expression in response to 5-FU treatment was demonstrated for genes involved in regulation of nucleotide binding/metabolism (ATAD2, GNL2, GNL3, MATR3), amino acid metabolism (AHCY, GSS, IVD, OAT), cytoskeleton organization (KRT7, KRT8, KRT19, MAST1), transport (MTCH1, NCBP1, SNAPAP, VPS52), and oxygen metabolism (COX5A, COX7C). CONCLUSION: Our gene expression data suggest that altered regulation of nucleotide metabolism, amino acid metabolism, cytoskeleton organization, transport, and oxygen metabolism may underlie the differential resistance to 5-FU seen in these cell lines. The contributory roles to 5-FU resistance of some of the affected genes on these pathways will be assessed in future studies. [Abstract/Link to Full Text]

Pyrko P, Soriano N, Kardosh A, Liu YT, Uddin J, Petasis NA, Hofman FM, Chen CS, Chen TC, Sch�nthal AH
Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo.
Mol Cancer. 2006;519.
BACKGROUND: 2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) that lacks COX-2-inhibitory function. However, despite its inability to block COX-2 activity, DMC is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that both of these drugs are able to involve targets other than COX-2 to exert their recognized cytotoxic effects. However, the molecular components that are involved in mediating these drugs' apoptosis-stimulatory consequences are incompletely understood. RESULTS: We present evidence that celecoxib and DMC are able to down-regulate the expression of survivin, an anti-apoptotic protein that is highly expressed in tumor cells and known to confer resistance of such cells to anti-cancer treatments. Suppression of survivin is specific to these two drugs, as other coxibs (valdecoxib, rofecoxib) or traditional NSAIDs (flurbiprofen, indomethacin, sulindac) do not affect survivin expression at similar concentrations. The extent of survivin down-regulation by celecoxib and DMC in different tumor cell lines is somewhat variable, but closely correlates with the degree of drug-induced growth inhibition and apoptosis. When combined with irinotecan, a widely used anticancer drug, celecoxib and DMC greatly enhance the cytotoxic effects of this drug, in keeping with a model that suppression of survivin may be beneficial to sensitize cancer cells to chemotherapy. Remarkably, these effects are not restricted to in vitro conditions, but also take place in tumors from drug-treated animals, where both drugs similarly repress survivin, induce apoptosis, and inhibit tumor growth in vivo. CONCLUSION: In consideration of survivin's recognized role as a custodian of tumor cell survival, our results suggest that celecoxib and DMC might exert their cytotoxic anti-tumor effects at least in part via the down-regulation of survivin - in a manner that does not require the inhibition of cyclooxygenase-2. Because inhibition of COX-2 appears to be negligible, it might be worthwhile to further evaluate DMC's potential as a non-coxib alternative to celecoxib for anti-cancer purposes. [Abstract/Link to Full Text]

Liu H, Ippolito GC, Wall JK, Niu T, Probst L, Lee BS, Pulford K, Banham AH, Stockwin L, Shaffer AL, Staudt LM, Das C, Dyer MJ, Tucker PW
Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells.
Mol Cancer. 2006;518.
BACKGROUND: Chromosomal aberrations of BCL11A at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development. RESULTS: Alternative pre-mRNA splicing of BCL11A produces multiple isoforms sharing a common N-terminus. The most abundant isoform we have identified in human lymphoid samples is BCL11A-XL, the longest transcript produced at this locus, and here we report the conservation of this major isoform and its functional characterization. We show that BCL11A-XL is a DNA-sequence-specific transcriptional repressor that associates with itself and with other BCL11A isoforms, as well as with the BCL6 proto-oncogene. Western blot data for BCL11A-XL expression coupled with data previously published for BCL6 indicates that these genes are expressed abundantly in germinal-center-derived B cells but that expression is extinguished upon terminal differentiation to the plasma cell stage. Although BCL11A-XL/BCL6 interaction can modulate BCL6 DNA binding in vitro, their heteromeric association does not alter the homomeric transcriptional properties of either on model reporter activity. BCL11A-XL partitions into the nuclear matrix and colocalizes with BCL6 in nuclear paraspeckles. CONCLUSION: We propose that the conserved N-terminus of BCL11A defines a superfamily of C2HC zinc-finger transcription factors involved in hematopoietic malignancies. [Abstract/Link to Full Text]

Costello LC, Franklin RB
The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots.
Mol Cancer. 2006;517.
BACKGROUND: The genetic and molecular mechanisms responsible for and associated specifically with the development and progression of malignant prostate cells are largely unidentified. In addition, despite its implication in virtually all malignant cells, the role of altered cellular metabolism as an essential factor in prostate malignancy has been largely ignored. Moreover, the intermediary metabolism of normal prostate as well as malignant prostate cells is among the least studied and most poorly understood of all mammalian cells. Some important factors, especially the role of zinc, have been identified and implicated in the development and progression of prostate malignancy. In this review, we provide a current and updated integrated assessment of the relationships of intermediary metabolism in normal prostate and in prostate cancer. The experimental and clinical evidence that leads to the formulation of concepts of normal and malignant prostate metabolism is presented. The evidence for a concept of zinc as a tumor suppressor agent and Zip1 zinc transporter as a tumor-suppressor gene is described. RESULTS: The specialized function of the normal prostate glandular epithelium to produce and secrete enormously high levels of citrate involves and requires unique intermediary metabolism activities that are not generally associated with other normal mammalian cells. The accumulation of zinc by these cells is an essential factor in this unique metabolic relationship. In malignancy, the normal zinc-accumulating citrate-producing epithelial cells are metabolically transformed to citrate-oxidizing cells that lose the ability to accumulate zinc. A genetic alteration in the expression of ZIP1 zinc transporter is associated with this metabolic transformation. These genetic/metabolic relationships have important consequences on citrate-related metabolism, bioenergetics, cell proliferation and invasive capabilities of the malignant cells, which result in tumor-suppression characteristics. CONCLUSION: The genetic/metabolic relationships in normal prostate glandular epithelium are driven by the unique function to accumulate and secrete citrate. The genetic/metabolic transformation of the prostate malignant cells is driven by the metabolic/bioenergetic, growth/proliferative, and invasive/migration requirements of the malignant process. Zinc is critical to these relationships. An understanding of these genetic/metabolic relationships provides new directions and opportunities for development of regimens for the prevention and treatment of prostate cancer. Important insight into the genetic/metabolic requirements of the prostate malignant process is now evolving. Most importantly at this time, an appreciation and recognition of the genetic/metabolic significance and implications in the development of prostate malignancy is imperative; and much needed research in this area is essential. Hopefully, this review will help to achieve these goals. [Abstract/Link to Full Text]

Narayan G, Goparaju C, Arias-Pulido H, Kaufmann AM, Schneider A, D�rst M, Mansukhani M, Pothuri B, Murty VV
Promoter hypermethylation-mediated inactivation of multiple Slit-Robo pathway genes in cervical cancer progression.
Mol Cancer. 2006;516.
BACKGROUND: Cervical Cancer (CC) exhibits highly complex genomic alterations. These include hemizygous deletions at 4p15.3, 10q24, 5q35, 3p12.3, and 11q24, the chromosomal sites of Slit-Robo pathway genes. However, no candidate tumor suppressor genes at these regions have been identified so far. Slit family of secreted proteins modulates chemokine-induced cell migration of distinct somatic cell types. Slit genes mediate their effect by binding to its receptor Roundabout (Robo). These genes have shown to be inactivated by promoter hypermethylation in a number of human cancers. RESULTS: To test whether Slit-Robo pathway genes are targets of inactivation at these sites of deletion, we examined promoter hypermethylation of SLIT1, SLIT2, SLIT3, ROBO1, and ROBO3 genes in invasive CC and its precursor lesions. We identified a high frequency of promoter hypermethylation in all the Slit-Robo genes resulting in down regulated gene expression in invasive CC, but the inhibitors of DNA methylation and histone deacetylases (HDACs) in CC cell lines failed to effectively reactivate the down-regulated expression. These results suggest a complex mechanism of inactivation in the Slit-Robo pathway in CC. By analysis of cervical precancerous lesions, we further show that promoter hypermethylation of Slit-Robo pathway occurs early in tumor progression. CONCLUSION: Taken together, these findings suggest that epigenetic alterations of Slit-Robo pathway genes (i) play a role in CC development, (ii) further delineation of molecular basis of promoter methylation-mediated gene regulation provides a potential basis for epigenetic-based therapy in advanced stage CC, and (iii) form epigenetic signatures to identify precancerous lesions at risk to progression. [Abstract/Link to Full Text]

Yin W, Cheepala S, Roberts JN, Syson-Chan K, DiGiovanni J, Clifford JL
Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions.
Mol Cancer. 2006;515.
BACKGROUND: Squamous cell carcinoma (SCC) of the skin is the most aggressive form of non-melanoma skin cancer (NMSC), and is the single most commonly diagnosed cancer in the U.S., with over one million new cases reported each year. Recent studies have revealed an oncogenic role of activated signal transducer and activator of transcription 3 (Stat3) in many human tumors, especially in those of epithelial origin, including skin SCC. Stat3 is a mediator of numerous growth factor and cytokine signaling pathways, all of which activate it through phosphorylation of tyrosine 705. RESULTS: To further address the role of Stat3 in skin SCC tumorigenesis, we have analyzed a panel of human skin-derived cell lines ranging from normal human epidermal keratinocytes (NHEK), to non-tumorigenic transformed skin cells (HaCaT), to highly tumorigenic cells (SRB1-m7 and SRB12-p9) and observed a positive correlation between Stat3 phosphorylation and SCC malignancy. We next determined the role of Stat3 activity in cell proliferation and viability under serum-free culture conditions. This was accomplished by suppressing Stat3 activity in the SRB12-p9 cells through stable expression of a dominant negative acting form of Stat3beta, which contains a tyrosine 705 to phenylalanine mutation (S3DN). The S3DN cells behaved similar to parental SRB12-p9 cells when cultured in optimal growth conditions, in the presence of 10% fetal calf serum. However, unlike the SRB12-p9 cells, S3DN cells underwent apoptotic cell death when cultured in serum-free medium (SFM). This was evidenced by multiple criteria, including accumulation of sub-G1 particles, induced PARP cleavage, and acquisition of the characteristic morphological changes associated with apoptosis. CONCLUSION: This study provides direct evidence for a role for Stat3 in maintaining cell survival in the conditions of exogenous growth factor deprivation produced by culture in SFM. We also propose that delivery of the S3DN gene or protein to tumor cells could induce apoptosis and/or sensitize those cells to the apoptotic effects of cancer therapeutic agents, raising the possibility of using S3DN as an adjunct for treatment of skin SCC. [Abstract/Link to Full Text]

Singh KK, Desouki MM, Franklin RB, Costello LC
Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues.
Mol Cancer. 2006;514.
BACKGROUND: In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. RESULTS: The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. CONCLUSION: The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells. [Abstract/Link to Full Text]

Saidi SA, Holland CM, Charnock-Jones DS, Smith SK
In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer.
Mol Cancer. 2006;513.
Fenofibrate, an agonist of PPAR-alpha, in doses above 25 microM, inhibits proliferation and induces apoptosis in Ishikawa endometrial cancer cells. We show that these effects are potentiated by retinoic acid, an agonist of the retinoid-X-receptor. DNA content analysis shows that G1/S phase progression through the cell cycle is inhibited. Independent Component Analysis of gene microarray experiments demonstrated downregulation of Cyclin D1 (CCND1) and associated changes in cell cycle gene expression. Expression of PPAR-alpha mRNA was reduced by >75% using RNA-interference but this resulted in only minor changes in biological effects. A nude mouse model of endometrial carcinoma was used to investigate the effect of fenofibrate in vivo but failed to show consistent inhibition of tumour growth. CONCLUSION: The combination of fenofibrate and retinoic acid is a potent inhibitor of Ishikawa endometrial cancer cell growth in vitro. [Abstract/Link to Full Text]

Kupumbati TS, Cattoretti G, Marzan C, Farias EF, Taneja R, Mira-y-Lopez R
Dominant negative retinoic acid receptor initiates tumor formation in mice.
Mol Cancer. 2006;512.
BACKGROUND: Retinoic acid suppresses cell growth and promotes cell differentiation, and pharmacological retinoic acid receptor (RAR) activation is anti-tumorigenic. This begs the question of whether chronic physiological RAR activation by endogenous retinoids is likewise anti-tumorigenic. RESULTS: To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARalpha (RARalphaG303E) was under the control of the mouse mammary tumor virus (MMTV) promoter. The transgene was expressed in the lymphoid compartment and in the mammary epithelium. Observation of aging mice revealed that transgenic mice, unlike their wild type littermates, developed B cell lymphomas at high penetrance, with a median latency of 40 weeks. MMTV-RARalphaG303E lymphomas were high grade Pax-5+, surface H+L Ig negative, CD69+ and BCL6- and cytologically and phenotypically resembled human adult high grade (Burkitt's or lymphoblastic) lymphomas. We postulated that mammary tumors might arise after a long latency period as seen in other transgenic models of breast cancer. We tested this idea by transplanting transgenic epithelium into the cleared fat pads of wild type hosts, thus bypassing lymphomagenesis. At 17 months post-transplantation, a metastatic mammary adenocarcinoma developed in one of four transplanted glands whereas no tumors developed in sixteen of sixteen endogenous glands with wild type epithelium. CONCLUSION: These findings suggest that physiological RAR activity may normally suppress B lymphocyte and mammary epithelial cell growth and that global RAR inactivation is sufficient to initiate a stochastic process of tumor development requiring multiple transforming events. Our work makes available to the research community a new animal resource that should prove useful as an experimental model of aggressive sporadic lymphoma in immunologically uncompromised hosts. We anticipate that it may also prove useful as a model of breast cancer. [Abstract/Link to Full Text]

Mehrotra R, Gupta A, Singh M, Ibrahim R
Application of cytology and molecular biology in diagnosing premalignant or malignant oral lesions.
Mol Cancer. 2006;511.
Early detection of a premalignant or cancerous oral lesion promises to improve the survival and the morbidity of patients suffering from these conditions. Cytological study of oral cells is a non-aggressive technique that is well accepted by the patient, and is therefore an attractive option for the early diagnosis of oral cancer, including epithelial atypia and squamous cell carcinoma. However its usage has been limited so far due to poor sensitivity and specificity in diagnosing oral malignancies. Lately it has re-emerged due to improved methods and it's application in oral precancer and cancer as a diagnostic and predictive method as well as for monitoring patients. Newer diagnostic techniques such as "brush biopsy" and molecular studies have been developed. Recent advances in cytological techniques and novel aspects of applications of scraped or exfoliative cytology for detecting these lesions and predicting their progression or recurrence are reviewed here. [Abstract/Link to Full Text]

Babu SD, Jayanthi V, Devaraj N, Reis CA, Devaraj H
Expression profile of mucins (MUC2, MUC5AC and MUC6) in Helicobacter pylori infected pre-neoplastic and neoplastic human gastric epithelium.
Mol Cancer. 2006;510.
BACKGROUND: Helicobacter pylori (H. pylori) causes gastritis and intestinal metaplasia (IM) that may evolve to gastric carcinoma. The objective of this study was to compare the profile of mucins in the progressive stages of H. pylori infected pre-neoplastic and neoplastic human gastric epithelium. We used a panel of monoclonal antibodies with well-defined specificities of MUC2, MUC5AC and MUC6 to characterize the expression pattern of mucins by immunohistochemistry. METHODS: RUT and ELISA were down for H. pylori confirmation. Human gastric biopsy sections were stained using immunohistochemistry with MUC2, MUC5AC and MUC6 antibodies. RESULTS: MUC5AC was expressed in the superficial epithelium and the upper part of the gastric pits. MUC6 expression was detected in the lower part of the gastric glands. MUC2 was expressed in intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the progressive stages of H. pylori infected human gastric epithelium allows the identification of intestinal metaplasia, which is characterized by a decreased expression of the gastric mucins (MUC5AC and MUC6) and de novo expression of MUC2. CONCLUSION: In conclusion, our results suggest that there is altered expression of MUC5AC and MUC6 together with the aberrant expression of MUC2 in intestinal metaplasia, during the process of gastric carcinogenesis. The present study indicates that the MUC2 mucin expression pattern is a reliable marker of intestinal metaplasia, which appears in the context of H. pylori infected individuals. [Abstract/Link to Full Text]

Datta MW, Hernandez AM, Schlicht MJ, Kahler AJ, DeGueme AM, Dhir R, Shah RB, Farach-Carson C, Barrett A, Datta S
Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway.
Mol Cancer. 2006;59.
BACKGROUND: Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer. RESULTS: Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling. CONCLUSION: We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects. [Abstract/Link to Full Text]

Alao JP, Stavropoulou AV, Lam EW, Coombes RC, Vigushin DM
Histone deacetylase inhibitor, trichostatin A induces ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells.
Mol Cancer. 2006;58.
BACKGROUND: Cyclin D1 is an important regulator of G1-S phase cell cycle transition and has been shown to be important for breast cancer development. GSK3beta phosphorylates cyclin D1 on Thr-286, resulting in enhanced ubiquitylation, nuclear export and degradation of the cyclin in the cytoplasm. Recent findings suggest that the development of small-molecule cyclin D1 ablative agents is of clinical relevance. We have previously shown that the histone deacetylase inhibitor trichostatin A (TSA) induces the rapid ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells prior to repression of cyclin D1 gene (CCND1) transcription. TSA treatment also resulted in accumulation of polyubiquitylated GFP-cyclin D1 species and reduced levels of the recombinant protein within the nucleus. RESULTS: Here we provide further evidence for TSA-induced ubiquitin-dependent degradation of cyclin D1 and demonstrate that GSK3beta-mediated nuclear export facilitates this activity. Our observations suggest that TSA treatment results in enhanced cyclin D1 degradation via the GSK3beta/CRM1-dependent nuclear export/26S proteasomal degradation pathway in MCF-7 cells. CONCLUSION: We have demonstrated that rapid TSA-induced cyclin D1 degradation in MCF-7 cells requires GSK3beta-mediated Thr-286 phosphorylation and the ubiquitin-dependent 26S proteasome pathway. Drug induced cyclin D1 repression contributes to the inhibition of breast cancer cell proliferation and can sensitize cells to CDK and Akt inhibitors. In addition, anti-cyclin D1 therapy may be highly specific for treating human breast cancer. The development of potent and effective cyclin D1 ablative agents is therefore of clinical relevance. Our findings suggest that HDAC inhibitors may have therapeutic potential as small-molecule cyclin D1 ablative agents. [Abstract/Link to Full Text]

Alao JP, Gamble SC, Stavropoulou AV, Pomeranz KM, Lam EW, Coombes RC, Vigushin DM
The cyclin D1 proto-oncogene is sequestered in the cytoplasm of mammalian cancer cell lines.
Mol Cancer. 2006;57.
BACKGROUND: The cyclin D1 proto-oncogene is an important regulator of G1 to S-phase transition and an important cofactor for several transcription factors in numerous cell types. Studies on neonatal cardiomyocytes and postmitotic neurons indicate that the activity of cyclin D1 may be regulated through its cytoplasmic sequestration. We have demonstrated previously, that TSA induces the ubiquitin-dependent degradation of cyclin D1 in MCF-7 breast cancer cells. Additional studies were initiated in order to further investigate the effect of TSA on cyclin D1 regulation using sub-cellular fractionation techniques. RESULTS: Our studies revealed cyclin D1 to be localized predominantly within the cytoplasmic fraction of all cell lines tested. These observations were confirmed by confocal microscopy. GSK3beta was found to be localized within both the nucleus and cytoplasm throughout the cell cycle. Inhibition of GSK3beta or CRM1-dependent nuclear export resulted in only modest nuclear accumulation, suggesting that the cytoplasmic localization of cyclin D1 results from the inhibition of its nuclear import. CONCLUSION: We have shown by several different experimental approaches, that cyclin D1 is in fact a predominantly cytoplasmic protein in mammalian cancer cell lines. Recent studies have shown that the cytoplasmic sequestration of cyclin D1 prevents apoptosis in neuronal cells. Our results suggest that cytoplasmic sequestration may additionally serve to regulate cyclin D1 activity in mammalian cancer cells. [Abstract/Link to Full Text]

Grandics P
The cancer stem cell: evidence for its origin as an injured autoreactive T cell.
Mol Cancer. 2006;56.
This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing. The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response. As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, we recommend a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system. [Abstract/Link to Full Text]

Hunter F, Xie J, Trimble C, Bur M, Li KC
Rhodamine-RCA in vivo labeling guided laser capture microdissection of cancer functional angiogenic vessels in a murine squamous cell carcinoma mouse model.
Mol Cancer. 2006;55.
BACKGROUND: Cancer growth, invasion and metastasis are highly related to tumor-associated neovasculature. The presence and progression of endothelial cells in cancer is chaotic, unorganized, and angiogenic vessels are less functional. Therefore, not all markers appearing on the chaotic endothelial cells are accessible if a drug is given through the vascular route. Identifying endothelial cell markers from functional cancer angiogenic vessels will indicate the accessibility and potential efficacy of vascular targeted therapies. RESULTS: In order to quickly and effectively identify endothelial cell markers on the functional and accessible tumor vessels, we developed a novel technique by which tumor angiogenic vessels are labeled in vivo followed by Laser Capture Microdissection of microscopically isolated endothelial cells for genomic screening. Female C3H mice (N = 5) with established SCCVII tumors were treated with Rhodamine-RCA lectin by tail vein injection, and after fluorescence microscopy showed a successful vasculature staining, LCM was then performed on frozen section tissue using the PixCell II instrument with CapSure HS caps under the Rhodamine filter. By this approach, the fluorescent angiogenic endothelial cells were successfully picked up. As a result, the total RNA concentration increased from an average of 33.4 ng/ul +/- 24.3 (mean +/- S.D.) to 1913.4 ng/ul +/- 164. Relatively pure RNA was retrieved from both endothelial and epithelial cells as indicated by the 260/280 ratios (range 2.22-2.47). RT-PCR and gene electrophoresis successfully detected CD31 and Beta-Actin molecules with minimal Keratin 19 expression, which served as the negative control. CONCLUSION: Our present study demonstrates that in vivo Rhodamine RCA angiogenic vessel labeling provided a practical approach to effectively guide functional endothelial cell isolation by laser capture microdissection with fluorescent microscopy, resulting in high quality RNA and pure samples of endothelial cells pooled for detecting genomic expression. [Abstract/Link to Full Text]

Jiang W, Newsham IF
The tumor suppressor DAL-1/4.1B and protein methylation cooperate in inducing apoptosis in MCF-7 breast cancer cells.
Mol Cancer. 2006 Jan 18;5(1):4.
ABSTRACT: BACKGROUND: DAL-1 (Differentially Expressed in Adenocarcinoma of the Lung)/4.1B is a member of the protein 4.1 superfamily that has been shown to suppress growth in lung, breast and brain tumor cells. In the case of the caspase-3 deficient MCF-7 breast cancer cells, this growth suppression has been shown to be partially mediated by the induction of apoptosis. However the exact mechanism of action of DAL-1/4.1B is unknown. Recently, protein arginine N-methyltransferase 3 (PRMT3) was identified as a DAL-1/4.1B interacting protein. Protein arginine methyltransferases (PRMTs) posttranslationally methylate the arginine residues of proteins, a modification which has been implicated in the regulation of multiple cellular processes including nuclear-cytoplasmic transport, signal transduction, and transcription. RESULTS: To investigate the role of protein methylation in cell death induced by DAL-1/4.1B, DAL-1/4.1B-inducible MCF-7 cells were examined for apoptosis and caspase activation in the absence and presence of the protein methylation inhibitor adenosine dialdehyde (AdOX). Flow cytometry analysis revealed that apoptosis was primarily associated with the activation of caspase 8, and inhibition of this activation blocked the ability of DAL-1/4.1B to induce cell death. Furthermore, AdOX treatment enhanced DAL-1/4.1B-associated apoptosis. CONCLUSIONS: These results suggest that protein methylation cooperates with DAL-1/4.1B-associated caspase 8-specific activation to induce apoptosis in breast cancer cells . [Abstract/Link to Full Text]

Recent Articles in Cancer Cell International

Strauss BE, Fontes RB, Lotfi CF, Skorupa A, Bartol I, Cipolla-Neto J, Costanzi-Strauss E
Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats.
Cancer Cell Int. 2002 Apr 4;2(1):2.
BACKGROUND: The p16INK4A gene product halts cell proliferation by preventing phosphorylation of the Rb protein. The p16INK4a gene is often deleted in human glioblastoma multiforme, contributing to unchecked Rb phosphorylation and rapid cell division. We show here that transduction of the human p16INK4a cDNA using the pCL retroviral system is an efficient means of stopping the proliferation of the rat-derrived glioma cell line, C6, both in tissue culture and in an animal model. C6 cells were transduced with pCL retrovirus encoding the p16INK4a, p53, or Rb genes. These cells were analyzed by a colony formation assay. Expression of p16INK4a was confirmed by immunohistochemistry and Western blot analysis. The altered morphology of the p16-expressing cells was further characterized by the senescence-associated beta-galactosidase assay. C6 cells infected ex vivo were implanted by stereotaxic injection in order to assess tumor formation. RESULTS: The p16INK4a gene arrested C6 cells more efficiently than either p53 or Rb. Continued studies with the p16INK4a gene revealed that a large portion of infected cells expressed the p16INK4a protein and the morphology of these cells was altered. The enlarged, flat, and bi-polar shape indicated a senescence-like state, confirmed by the senescence-associated beta-galactosidase assay. The animal model revealed that cells infected with the pCLp16 virus did not form tumors. CONCLUSION: Our results show that retrovirus mediated transfer of p16INK4a halts glioma formation in a rat model. These results corroborate the idea that retrovirus-mediated transfer of the p16INK4a gene may be an effective means to arrest human glioma and glioblastoma. [Abstract/Link to Full Text]

Szende B, Tyih�k E, Tr�zl L
Role of arginine and its methylated derivatives in cancer biology and treatment.
Cancer Cell Int. 2001 Dec 17;1(1):3.
Both L-arginine supplementation and deprivation influence cell proliferation. The effect of high doses on tumours is determined by the optical configuration: L-arginine is stimulatory, D-arginine inhibitory. Arginine-rich hexapeptides inhibited tumour growth. Deprivation of L-arginine from cell cultures enhanced apoptosis. The pro-apoptotic action of NO synthase inhibitors, like NG-monomethyl-L-arginine, is manifested through inhibition of the arginase pathway. NG-hydroxymethyl-L-arginines caused apoptosis in cell cultures and inhibited the growth of various transplantable mouse tumours. These diverse biological activities become manifest through formaldehyde (HCHO) because guanidine group of L-arginine in free and bound form can react rapidly with endogenous HCHO, forming NG-hydroxymethylated derivatives. L-arginine is a HCHO capturer, carrier and donor molecule in biological systems. The role of formaldehyde generated during metabolism of NG-methylated and hydroxymethylated arginines in cell proliferation and death can be shown. The supposedly anti-apoptotic homozygous Arg 72-p53 genotype may increase susceptibility of some cancers. The diverse biological effects of L-arginine and its methylated derivatives call for further careful studies on their possible application in chemoprevention and cancer therapy. [Abstract/Link to Full Text]

Poirier F, Bourin P, Bladier D, Joubert-Caron R, Caron M
Effect of 5-azacytidine and galectin-1 on growth and differentiation of the human b lymphoma cell line bl36.
Cancer Cell Int. 2001 Dec 17;1(1):2.
BACKGROUND: 5-AzaCytidine (AzaC) is a DNA demethylating drugs that has been shown to inhibit cell growth and to induce apoptosis in certain cancer cells. Induced expression of the galectin1 (Gal1) protein, a galactoside-binding protein distributed widely in immune cells, has been described in cultured hepatoma-derived cells treated with AzaC and this event may have a role in the effect of the drug. According to this hypothesis, we investigated the effect of AzaC and Gal1 on human lymphoid B cells phenotype. METHODS: The effect of AzaC and Gal1 on cell growth and phenotype was determined on the Burkitt lymphoma cell line BL36. An immunocytochemical analysis for detection of Gal1 protein expression was performed in AzaC-treated cells. To investigate the direct effects of Gal1, recombinant Gal1 was added to cells. RESULTS: Treatment of lymphoid B cells with AzaC results in: i) a decrease in cell growth with an arrest of the cell cycle at G0/G1 phase, ii) phenotypic changes consistent with a differentiated phenotype, and iii) the expression of p16, a tumor-suppressor gene whose expression was dependent of its promoter demethylation, and of Gal1. A targeting of Gal 1 to the plasma membrane follows its cytosolic expression. To determine which of the effects of AzaC might be secondary to the induction of Gal1, recombinant Gal1 was added to BL36 cells. Treated cells displayed growth inhibition and phenotypic changes consistent with a commitment toward differentiation. CONCLUSIONS: Altered cell growth and expression of the cell surface plasma cell antigen, CD138 are detectable in BL36 cells treated by AzaC as well as by Gal1. It seems that AzaC-induced Gal1 expression and consequent binding of Gal1 on its cell membrane receptor may be, in part, involved in AzaC-induced plasmacytic differentiation. [Abstract/Link to Full Text]

Erenpreisa J, Cragg MS
Mitotic death: a mechanism of survival? A review.
Cancer Cell Int. 2001 Nov 23;1(1):1.
Mitotic death is a delayed response of p53 mutant tumours that are resistant to genotoxic damage. Questions surround why this response is so delayed and how its mechanisms serve a survival function. After uncoupling apoptosis from G1 and S phase arrests and adapting these checkpoints, p53 mutated tumour cells arrive at the G2 compartment where decisions regarding survival and death are made. Missed or insufficient DNA repair in G1 and S phases after severe genotoxic damage results in cells arriving in G2 with an accumulation of point mutations and chromosome breaks. Double strand breaks can be repaired by homologous recombination during G2 arrest. However, cells with excessive chromosome lesions either directly bypass the G2/M checkpoint, starting endocycles from G2 arrest, or are subsequently detected by the spindle checkpoint and present with the features of mitotic death. These complex features include apoptosis from metaphase and mitosis restitution, the latter of which can also facilitate transient endocycles, producing endopolyploid cells. The ability of cells to initiate endocycles during G2 arrest and mitosis restitution most likely reflects their similar molecular environments, with down-regulated mitosis promoting factor activity. Resulting endocycling cells have the ability to repair damaged DNA, and although mostly reproductively dead, in some cases give rise to mitotic progeny. We conclude that the features of mitotic death do not simply represent aberrations of dying cells but are indicative of a switch to amitotic modes of cell survival that may provide additional mechanisms of genotoxic resistance. [Abstract/Link to Full Text]

Recent Articles in Breast Cancer Research

Schindlbeck C, Kampik T, Janni W, Rack B, Jeschke U, Krajewski S, Sommer H, Friese K
Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas.
Breast Cancer Res. 2005;7(6):R1174-85.
INTRODUCTION: The prognostic significance of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has been demonstrated in many studies. Yet, it is not clear which of the primary tumors' biological factors predict hematogenous dissemination. We therefore examined 'tissue micro arrays' (TMAs) of 265 primary breast carcinomas from patients with known bone marrow (BM) status for HER2, Topoisomerase IIalpha (Top IIa), Ki 67, and p53. METHODS: BM analysis was performed by cytospin preparation and immunocytochemical staining for cytokeratin (CK). TMAs were examined by immunohistochemistry (IHC) for HER2, Top IIa, Ki 67 and p53, and fluorescence in situ hybridization (FISH) for HER2. RESULTS: HER2 (2+/3+) was positive in 35/167 (21%) cases (FISH 24.3%), Top IIa (>10%) in 87/187 (46%), Ki 67 in 52/184 (28%) and p53 (>5%) in 61/174 cases (34%). Of 265 patients, 68 (25.7%) showed DTC-BM with a median of 2/2 x 106 cells (1 to 1,500). None of the examined factors significantly predicted BM positivity. Significant correlation was seen between HER2 IHC and Top IIa (p = 0.06), Ki 67 (p = 0.031), and p53 (p < .001). Top IIa correlated with Ki 67 and p53, and Ki 67 also with p53 (p = 0.004). After a median follow-up of 60.5 months (7 to 255), the presence of DTC-BM showed prognostic relevance for overall survival (p = 0.03), whereas HER2 (IHC, p = 0.04; FISH, p = 0.03) and Ki 67 (p = 0.04) correlated with disease free survival, and HER2 with distant disease free survival (IHC, p = 0.06; FISH, p = 0.05). DISCUSSION: The congruence of the examined factors' expression rates indicates a causal line of suppressor, proliferation, and mitosis markers, and growth factor receptors. Hematogenous tumor cell spread seems to be an independent process. The examination of these factors on DTC-BM is the aim of ongoing research. [Abstract/Link to Full Text]

Patel AV, Calle EE, Pavluck AL, Feigelson HS, Thun MJ, Rodriguez C
A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk.
Breast Cancer Res. 2005;7(6):R1168-73.
INTRODUCTION: The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA. METHODS: Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer. RESULTS: We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk. CONCLUSION: Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes. [Abstract/Link to Full Text]

Dalenc F, Giamarchi C, Petit M, Poirot M, Favre G, Faye JC
Farnesyl-transferase inhibitor R115,777 enhances tamoxifen inhibition of MCF-7 cell growth through estrogen receptor dependent and independent pathways.
Breast Cancer Res. 2005;7(6):R1159-67.
INTRODUCTION: We have previously shown that FTI-277, a farnesyl transferase inhibitor (FTI), enhances the efficacy of tamoxifen (Tam) in inhibiting the proliferation of the estrogen dependent MCF-7 cell line. As the cellular response to Tam is the result of an inhibition of both estrogen receptor-dependent and -independent pathways, we have used the estrogen receptor selective anti-estrogen ICI182,780 and N-pyrrolidine(-phenylmethyl-phenoxy)-ethanamine-HCl (PBPE), a selective ligand of anti-estrogen binding site (AEBS), to dissect out the mechanism(s) associated with the observed additivity resulting from combination treatment with FTI-277 and Tam. Moreover, for these studies, FTI-277 has been replaced by R115,777, a FTI currently in phase III clinical trials. METHODS: The quantitative sulphorhodamine B (SRB) colorimetric assay was used to determine the growth inhibitory effect of agents on MCF-7 cells. Dose response interactions between R115,777-Tam, R115,777-ICI182,780 and R115,777-PBPE were evaluated, at the IC50 point, using the isobologram method. Apoptotic cell death (DNA fragmentation, nucleus condensation and cytokeratin 18 cleavage) and inhibition of the mevalonate pathway (western blot) were also determined. RESULTS: Combinations of the specific FTI R115,777 with either ICI182,780 or PBPE exhibit a synergistic effect on MCF-7 cell growth inhibition, while its combination with Tam is additive, as previously reported for FTI-277. Apoptosis is detected after treatment with combinations of R115,777 with either Tam or PBPE but not with ICI182,780, suggesting that each combination inhibits cell proliferation by different mechanisms. Even though the ER pathway has not yet been deciphered, it is shown here that the AEBS pathway is able to interfere with the mevalonate pathway at the level of protein farnesylation. CONCLUSION: Overall, this work reveals that combinations of R115,777 with either selective ER ligands or a selective AEBS ligand are able to induce large increases in their anti-proliferative activities on MCF-7 cells. Moreover, these results suggest that it may be of definite interest to evaluate combinations of R115,777 with different anti-estrogens in the treatment of ER positive breast tumours. Based on these experimental data, such combinations may prove beneficial in different clinical scenarios or when used in specific sequences; studying the combination of R115,777 with ICI182,780 for early treatment and reserving combinations with either Tam or a selective AEBS ligand, such as BMS-217380-01, for more resistant disease. [Abstract/Link to Full Text]

Esserman LJ, Ozanne EM, Dowsett M, Slingerland JM
Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis.
Breast Cancer Res. 2005;7(6):R1153-8.
INTRODUCTION: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. METHODS: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. RESULTS: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. CONCLUSION: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection. [Abstract/Link to Full Text]

Stoff-Khalili MA, Stoff A, Rivera AA, Banerjee NS, Everts M, Young S, Siegal GP, Richter DF, Wang M, Dall P, Mathis JM, Zhu ZB, Curiel DT
Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system.
Breast Cancer Res. 2005;7(6):R1141-52.
INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin. METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver. RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells. CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast. [Abstract/Link to Full Text]

Shilkaitis A, Green A, Punj V, Steele V, Lubet R, Christov K
Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism.
Breast Cancer Res. 2005;7(6):R1132-40.
INTRODUCTION: Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17beta-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. METHODS: Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. RESULTS: Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects. [Abstract/Link to Full Text]

Mitchell G, Antill YC, Murray W, Kirk J, Salisbury E, Lindeman GJ, Di Iulio J, Milner AD, Devereaux L, Phillips KA
Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation.
Breast Cancer Res. 2005;7(6):R1122-31.
INTRODUCTION: The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk. METHODS: Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit. RESULTS: Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P <or= 0.001). CONCLUSION: It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer. [Abstract/Link to Full Text]

Lamb CA, Helguero LA, Giulianelli S, Soldati R, Vanzulli SI, Molinolo A, Lanari C
Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice.
Breast Cancer Res. 2005;7(6):R1111-21.
INTRODUCTION: Previous data from our laboratory suggested that progesterone receptors (PRs) are involved in progestin-independent growth of mammary carcinomas. To investigate this possibility further, we studied the effects of PR antisense oligodeoxynucleotides (asPR) on in vivo tumor growth. METHOD: BALB/c mice with subcutaneous 25 mm2 mammary carcinomas expressing estrogen receptor-alpha and PR were either injected intraperitoneally with 1 mg asPR every 24 or 12 hours for 5-10 days, or subcutaneously with RU 486 (6.5 mg/kg body weight) every 24 hours. Control mice received vehicle or scPR. RESULTS: Significant inhibition of tumor growth as well as a significant decrease in bromodeoxyuridine uptake was observed in asPR-treated mice, which correlated with histological signs of regression and increased apoptosis. Mice treated with RU 486 experienced almost complete tumor regression. No differences were detected between vehicle-treated and scPR-treated mice. Anti-progestin-treated and asPR-treated mice were in a continuous estrous/meta-estrous state. Decreased phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2 levels and estrogen receptor-alpha expression were observed as late events in RU 486-treated and asPR-treated mice with regressing tumors. CONCLUSION: We demonstrate, for the first time, inhibition of tumor growth in vivo using asPR. Our results provide further evidence for a critical and hierarchical role of the PR pathway in mammary carcinomas. [Abstract/Link to Full Text]

Kasukabe T, Okabe-Kado J, Kato N, Sassa T, Honma Y
Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts.
Breast Cancer Res. 2005;7(6):R1097-110.
INTRODUCTION: Rapamycin, an inhibitor of the serine/threonine kinase target of rapamycin, induces G1 arrest and/or apoptosis. Although rapamycin and its analogues are attractive candidates for cancer therapy, their sensitivities with respect to growth inhibition differ markedly among various cancer cells. Using human breast carcinoma cell line MCF-7 as an experimental model system, we examined the growth-inhibitory effects of combinations of various agents and rapamycin to find the agent that most potently enhances the growth-inhibitory effect of rapamycin. METHOD: We evaluated the growth-inhibitory effect of rapamycin plus various agents, including cotylenin A (a novel inducer of differentiation of myeloid leukaemia cells) to MCF-7 cells, using either MTT assay or trypan blue dye exclusion test. The cell cycle was analyzed using propidium iodide-stained nuclei. Expressions of several genes in MCF-7 cells with rapamycin plus cotylenin A were studied using cDNA microarray analysis and RT-PCR. The in vitro results of MCF-7 cells treated with rapamycin plus cotylenin A were further confirmed in vivo in a mouse xenograft model. RESULTS: We found that the sensitivity of rapamycin to MCF-7 cells was markedly affected by cotylenin A. This treatment induced growth arrest of the cells at the G1 phase, rather than apoptosis, and induced senescence-associated beta-galactosidase activity. We examined the gene expression profiles associated with exposure to rapamycin and cotylenin A using cDNA microarrays. We found that expressions of cyclin G2, transforming growth factor-beta-induced 68 kDa protein, BCL2-interacting killer, and growth factor receptor-bound 7 were markedly induced in MCF-7 cells treated with rapamycin plus cotylenin A. Furthermore, combined treatment with rapamycin and cotylenin A significantly inhibited the growth of MCF-7 cells as xenografts, without apparent adverse effects. CONCLUSION: Rapamycin and cotylenin A cooperatively induced growth arrest in breast carcinoma MCF-7 cells in vitro, and treatment with rapamycin and cotylenin A combined more strongly inhibited the growth of MCF-7 cells as xenografts in vivo than treatment with rapamycin or cotylenin A alone, suggesting that this combination may have therapeutic value in treating breast cancer. We also identified several genes that were markedly modulated in MCF-7 cells treated with rapamycin plus cotylenin A. [Abstract/Link to Full Text]

Gathani T, Bull D, Green J, Reeves G, Beral V
Breast cancer histological classification: agreement between the Office for National Statistics and the National Health Service Breast Screening Programme.
Breast Cancer Res. 2005;7(6):R1090-6.
INTRODUCTION: Epidemiological studies rely on data supplied by central cancer registration sources to be timely, accurate and complete. Validation studies of such data at a national level are limited. Data collected for the Million Women Study was used to compare the level of agreement between the Office for National Statistics (ONS) and the National Health Service Breast Screening Programme (NHSBSP) in the recording of incident screen-detected breast cancer histology between 1996 and 2001. METHODS: 1.3 million women aged 50 to 64 years were recruited into the Million Women Study cohort via the NHSBSP. Incident screen-detected breast cancer histologies were notified separately by the ONS and NHSBSP. ICD-10 and ICD-02 ONS codes and NHSBSP histology data were similarly coded to allow for comparison in terms of cancer invasiveness and morphology. The statistical outcome measures are percentage agreement and the kappa statistic. RESULTS: A total of 5,886 incident screen-detected breast cancers were available for analysis. Of the 5,886 screen-detected cancers reported by the ONS and NHSBSP, 5,684 (96.6%, kappa = 0.9) agreed in terms of the degree of invasiveness. Of the 5,458 cancers that had been assigned a specific morphology code, there was exact agreement between the ONS and the NHSBSP in 4,922 cases (90.2%, kappa = 0.8). CONCLUSION: There is an excellent level of agreement between the ONS and NHSBSP in the recording of the histology of screen-detected breast cancer. From these results it is not possible to comment on which source of data is the more or less accurate, although the differences are very small. [Abstract/Link to Full Text]

Zhang Y, Pan Q, Zhong H, Merajver SD, Kleer CG
Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells.
Breast Cancer Res. 2005;7(6):R1080-9.
INTRODUCTION: CCN6/WISP3 belongs to the CCN (Cyr61, CTGF, Nov) family of genes that contains a conserved insulin-like growth factor (IGF) binding protein motif. CCN6 is a secreted protein lost in 80% of the aggressive inflammatory breast cancers, and can decrease mammary tumor growth in vitro and in vivo. We hypothesized that inhibition of CCN6 might result in the loss of a growth regulatory function that protects mammary epithelial cells from the tumorigenic effects of growth factors, particularly IGF-1. METHOD: We treated human mammary epithelial (HME) cells with a CCN6 hairpin short interfering RNA. RESULTS: CCN6-deficient cells showed increased motility and invasiveness, and developed features of epithelial-mesenchymal transition (EMT). Inhibition of CCN6 expression promoted anchorage-independent growth of HME cells and rendered them more responsive to the growth effects of IGF-1, which was coupled with the increased phosphorylation of IGF-1 receptor and insulin receptor substrate-1 (IRS-1). CONCLUSION: Specific stable inhibition of CCN6 expression in HME cells induces EMT, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1. [Abstract/Link to Full Text]

Wilson CA, Cajulis EE, Green JL, Olsen TM, Chung YA, Damore MA, Dering J, Calzone FJ, Slamon DJ
HER-2 overexpression differentially alters transforming growth factor-beta responses in luminal versus mesenchymal human breast cancer cells.
Breast Cancer Res. 2005;7(6):R1058-79.
INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-beta) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-beta1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-beta on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-beta1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-beta signaling pathway was assessed using TGF-beta1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-beta1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-beta in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-beta. In contrast, HER-2 and TGF-beta signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model. [Abstract/Link to Full Text]

Morikawa A, Williams TY, Dirix L, Colpaert C, Goodman M, Lyles RH, Zhong D, Zhou W
Allelic imbalances of chromosomes 8p and 18q and their roles in distant relapse of early stage, node-negative breast cancer.
Breast Cancer Res. 2005;7(6):R1051-7.
INTRODUCTION: Identification of breast cancer patients at risk for postoperative distant relapse is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors. METHODS: Using 'counting alleles', a novel experimental method, we determined allelic status of chromosomes 8p and 18q in a case-control study with 65 early stage, node negative, invasive ductal carcinomas (IDCs). The association between allelic imbalance (AI) of both chromosomal markers and distant relapses was examined. RESULTS: Eighty percent of tumors contained 8pAI and sixty-eight percent of tumors contained 18qAI. However, none of the tumor samples retained both chromosome 8p and 18q alleles. More importantly, tumors with 8pAI but not 18qAI were more likely to have distant relapse compared to tumors with 18qAI but not 8pAI. CONCLUSION: Our finding suggests that differential allelic loss of chromosomes 8p and 18q may represent subtypes of early stage IDC with different tumor progression behaviors. [Abstract/Link to Full Text]

Ghatge RP, Jacobsen BM, Schittone SA, Horwitz KB
The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells.
Breast Cancer Res. 2005;7(6):R1036-50.
INTRODUCTION: Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells. METHOD: A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor. RESULTS: In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous. CONCLUSION: Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor. [Abstract/Link to Full Text]

Dimitrakakis C, Zhou J, Wang J, Matyakhina L, Mezey E, Wood JX, Wang D, Bondy C
Co-expression of estrogen receptor-alpha and targets of estrogen receptor action in proliferating monkey mammary epithelial cells.
Breast Cancer Res. 2006;8(1):R10.
INTRODUCTION: Failure to detect co-expression of estrogen receptor-alpha (ERalpha) and proliferation 'markers' such as Ki67 in human mammary epithelium led to the view that estrogen acts indirectly to stimulate mammary epithelial proliferation. The mitotic index was so low in prior studies, however, that transient co-expression of ERalpha and Ki67 during the cell cycle could have been below detection limits. METHODS: Immunohistochemistry was used on mammary tissue sections from estrogen treated rhesus monkeys to investigate co-expression of ERalpha and the proliferation antigen Ki67. Using the same methods, we investigated the cell localization of proteins involved in estrogen-induced proliferation, including cyclin D1, stromal cell-derived factor (SDF)-1, and MYC. RESULTS: ERalpha was co-expressed with the proliferation marker Ki67 as well as with SDF-1, MYC and cyclin D1 in mammary epithelial cells from estrogen-treated monkeys. CONCLUSION: ERalpha is expressed in proliferating mammary epithelial cells together with the estrogen-induced proteins MYC, cyclin D1 and SDF-1, consistent with a direct mitogenic action by estrogen in primate mammary epithelium. [Abstract/Link to Full Text]

Sleeman KE, Kendrick H, Ashworth A, Isacke CM, Smalley MJ
CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells.
Breast Cancer Res. 2006;8(1):R7.
INTRODUCTION: Breast cancer is thought to arise in mammary epithelial stem cells. There is, therefore, a large amount of interest in identifying these cells. The breast is a complex tissue consisting of two epithelial layers (an outer myoepithelial/basal layer and an inner luminal epithelial layer) as well as a large non-epithelial component (fibroblasts, endothelial cells, lymphocytes, adipocytes, neurons and myocytes). The definitive identification of a mammary epithelial stem cell population is critically dependent on its purity. To date, this has been hampered by the lack of suitable markers to separate out the two epithelial layers, and to remove contaminating non-epithelial cells. METHODS: Mouse mammary glands were dissociated and stained with CD24. Cells were sorted into separate populations based on CD24 expression and assessed for luminal epithelial and myoepithelial/basal markers by direct fluorescent microscopy and real time PCR. The stem/progenitor potential of these cell populations was assessed in vivo by cleared mammary fat pad transplantation. RESULTS: Three populations of CD24 expressing cells were identified: CD24Negative, CD24Low and CD24High. Staining of these cells with cytokeratin markers revealed that these populations correspond to non-epithelial, myoepithelial/basal and luminal epithelial cells, respectively. Cell identities were confirmed by quantitative PCR. Cleared mammary fat pad transplantation of these cell populations revealed that extensive mammary fat pad repopulation capacity segregates with the CD24Low cells, whilst CD24High cells have limited repopulation capacity. CONCLUSION: Differential staining of mammary epithelial cells for CD24 can be used to simultaneously isolate pure populations of non-epithelial, myoepithelial/basal and luminal epithelial cells. Furthermore, mammary fat pad repopulation capacity is enriched in the CD24Low population. As separation is achieved using a single marker, it will be possible to incorporate additional markers to further subdivide these populations. This will considerably facilitate the further analysis of mammary epithelial subpopulations, whilst ensuring high purity, which is key for understanding mammary epithelial stem cells in normal tissue biology and carcinogenesis. [Abstract/Link to Full Text]

Shadeo A, Lam WL
Comprehensive copy number profiles of breast cancer cell model genomes.
Breast Cancer Res. 2006;8(1):R9.
INTRODUCTION: Breast cancer is the most commonly diagnosed cancer in women worldwide and consequently has been extensively investigated in terms of histopathology, immunochemistry and familial history. Advances in genome-wide approaches have contributed to molecular classification with respect to genomic changes and their subsequent effects on gene expression. Cell lines have provided a renewable resource that is readily used as model systems for breast cancer cell biology. A thorough characterization of their genomes to identify regions of segmental DNA loss (potential tumor-suppressor-containing loci) and gain (potential oncogenic loci) would greatly facilitate the interpretation of biological data derived from such cells. In this study we characterized the genomes of seven of the most commonly used breast cancer model cell lines at unprecedented resolution using a newly developed whole-genome tiling path genomic DNA array. METHODS: Breast cancer model cell lines MCF-7, BT-474, MDA-MB-231, T47D, SK-BR-3, UACC-893 and ZR-75-30 were investigated for genomic alterations with the submegabase-resolution tiling array (SMRT) array comparative genomic hybridization (CGH) platform. SMRT array CGH provides tiling coverage of the human genome permitting break-point detection at about 80 kilobases resolution. Two novel discrete alterations identified by array CGH were verified by fluorescence in situ hybridization. RESULTS: Whole-genome tiling path array CGH analysis identified novel high-level alterations and fine-mapped previously reported regions yielding candidate genes. In brief, 75 high-level gains and 48 losses were observed and their respective boundaries were documented. Complex alterations involving multiple levels of change were observed on chromosome arms 1p, 8q, 9p, 11q, 15q, 17q and 20q. Furthermore, alignment of whole-genome profiles enabled simultaneous assessment of copy number status of multiple components of the same biological pathway. Investigation of about 60 loci containing genes associated with the epidermal growth factor family (epidermal growth factor receptor, HER2, HER3 and HER4) revealed that all seven cell lines harbor copy number changes to multiple genes in these pathways. CONCLUSION: The intrinsic genetic differences between these cell lines will influence their biologic and pharmacologic response as an experimental model. Knowledge of segmental changes in these genomes deduced from our study will facilitate the interpretation of biological data derived from such cells. [Abstract/Link to Full Text]

Lee S, Mohsin SK, Mao S, Hilsenbeck SG, Medina D, Allred DC
Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer.
Breast Cancer Res. 2006;8(1):R6.
INTRODUCTION: The hyperplastic enlarged lobular unit (HELU) is a common alteration in adult female human breast and is the earliest histologically identifiable lesion with premalignant potential. Growth and differentiation in normal epithelium are regulated by estrogen and progesterone, whose effects are mediated through estrogen receptor (ER)-alpha and progesterone receptor (PR). We assessed correlations between growth (proliferation and apoptosis), endogenous hormone levels (using age as a surrogate for menopausal/estrogen status), and ER-alpha/PR expression in HELUs versus adjacent normal terminal duct lobular units (TDLUs) to gain insight into potentially premalignant hyperplasia. METHODS: Proliferation (Ki67 antigen), ER-alpha, and PR were assessed by immunohistochemistry, apoptosis using the TUNEL (terminal transferase-mediated dUTP nick end-labeling) assay, and nuclear colocalization of ER-alpha and Ki67 by dual-labeled immunofluorescence in HELUs and adjacent TDLUs (n = 100-584, depending on the factor) from 324 breasts. All factors were quantified under direct microscopic visualization. ER-alpha/PR expression was semiquantified by estimating the proportion of positive cells (0 = none, 1 = or <1/100, 2 = 1/100 to 1/10, 3 = 1/10 to 1/3, 4 = 1/3 to 2/3, and 5 = or >2/3). Ki67, TUNEL, and colocalization of ER-alpha and Ki67 were scored by absolute counting (%positive). RESULTS: ER-alpha and PR expression were significantly elevated in HELUs versus adjacent TLDUs (average score: 4.5 versus 3.1 and 3.5 versus 2.1; P < 0.0001). Proliferation was also significantly higher in HELUs versus TDLUs (average 6.3% versus 2.0%; P < 0.0001). In contrast, apoptosis was significantly lower in HELUs versus TDLUs (average 0.61% versus 0.22%; P < 0.0001). Changes in proliferation and receptor expression were similar between premenopausal and postmenopausal TDLUs and HELUs, suggesting that hyperplastic cells remain responsive to regulation by estrogen. The proportion of ER-positive/proliferating cells was much higher in HELUs than TDLUs (27.6% vs. 4.9%; P < .0001). CONCLUSION: Development of HELUs is associated with increased proliferation and decreased cell death relative to normal cells. ER-alpha and PR are highly elevated in HELUs, which may contribute to the hyperplasia because they mediate hormonal regulation of growth. An understanding of the fundamental causes of increased levels of receptors and growth may lead to new strategies to prevent breast cancer. [Abstract/Link to Full Text]

Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, Nol� F
Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy.
Breast Cancer Res. 2006;8(1):R4.
INTRODUCTION: The amounts of estrogen receptor (ER) and progesterone receptor (PgR) in a primary tumor are predictive of the response to endocrine therapies of breast cancer. Several patients with ER-positive primary tumors relapse after adjuvant endocrine therapy with no ER expression in the recurrent tissue; much fewer with a recurrent disease after an ER-negative primary tumor may become endocrine responsive. These sequences of events indicate that a phenotype based on ER expression may not be a permanent feature of breast cancer. METHODS: Ten patients with advanced breast cancer whose tumors overexpressed HER-2, but not ER or PgR, were treated with weekly trastuzumab at standard doses with or without chemotherapy. RESULTS: Three out of 10 patients showed overexpression of ERs first appearing after 9, 12 and 37 weeks, respectively, from the initiation of trastuzumab. Two of these patients were subsequently treated with endocrine therapy alone: one of them received letrozole for 3 years without evidence of progression. CONCLUSION: Therapeutic targets enabling the appearance of an endocrine responsive disease may increase treatment options for patients with breast cancer. Furthermore, these clinical data suggest that an ER-negative phenotype is a multi-step process with a reversible repression modality, and that some ER-negative tumors may either revert to an ER-positive phenotype, allowing an endocrine treatment to be effective. [Abstract/Link to Full Text]

Antoniou AC, Durocher F, Smith P, Simard J, Easton DF
BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families.
Breast Cancer Res. 2006;8(1):R3.
INTRODUCTION: Several genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated. We used data from French-Canadian families to evaluate the mutation predictions given by the BRCAPRO and BOADICEA models. We also used this data set to estimate the age-specific risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. METHODS: A total of 195 families with multiple affected individuals with breast or ovarian cancer were recruited through the INHERIT (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility) BRCAs research program. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BOADICEA and BRCAPRO models. The models were assessed using Brier scores, attributes diagrams and receiver operating characteristic curves. Log relative risks for breast and ovarian cancer in mutation carriers versus population risks were estimated by maximum likelihood, using a modified segregation analysis implemented in the computer program MENDEL. Twenty-five families were eligible for inclusion in the BRCA1 penetrance analysis and 27 families were eligible for the BRCA2 penetrance analysis. RESULTS: The BOADICEA model predicted accurately the number of BRCA1 and BRCA2 mutations for the various groups of families, and was found to discriminate well at the individual level between carriers and noncarriers. BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations. It significantly overestimated the carrier frequency for high predicted probabilities. However, it discriminated well between carriers and noncarriers. Receiver operating characteristic (ROC) curves indicate similar sensitivity and specificity for BRCAPRO and BOADICEA. The estimated risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers were consistent with previously published estimates. CONCLUSION: The BOADICEA model predicts accurately the carrier probabilities in French-Canadian families and may be used for counselling in this population. None of the penetrance estimates was significantly different from previous estimates, suggesting that previous estimates may be appropriate for counselling in this population. [Abstract/Link to Full Text]

Banks E, Reeves G, Beral V, Bull D, Crossley B, Simmonds M, Hilton E, Bailey S, Barrett N, Briers P, English R, Jackson A, Kutt E, Lavelle J, Rockall L, Wallis MG, Wilson M, Patnick J
Hormone replacement therapy and false positive recall in the Million Women Study: patterns of use, hormonal constituents and consistency of effect.
Breast Cancer Res. 2006;8(1):R8.
INTRODUCTION: Current and recent users of hormone replacement therapy (HRT) have an increased risk of being recalled to assessment at mammography without breast cancer being diagnosed ('false positive recall'), but there is limited information on the effects of different patterns of HRT use on this. The aim of this study is to investigate in detail the relationship between patterns of use of HRT and false positive recall. METHODS: A total of 87,967 postmenopausal women aged 50 to 64 years attending routine breast cancer screening at 10 UK National Health Service Breast Screening Units from 1996 to 1998 joined the Million Women Study by completing a questionnaire before screening and were followed for their screening outcome. RESULTS: Overall, 399 (0.5%) participants were diagnosed with breast cancer and 2,629 (3.0%) had false positive recall. Compared to never users of HRT, the adjusted relative risk (95% CI) of false positive recall was: 1.62 (1.43-1.83), 1.80 (1.62-2.01) and 0.76 (0.52-1.10) in current users of oestrogen-only HRT, oestrogen-progestagen HRT and tibolone, respectively (p (heterogeneity) < 0.0001); 1.65 (1.43-1.91), 1.49 (1.22-1.81) and 2.11 (1.45-3.07) for current HRT used orally, transdermally or via an implant, respectively (p (heterogeneity) = 0.2); and 1.84 (1.67-2.04) and 1.75 (1.49-2.06) for sequential and continuous oestrogen-progestagen HRT, respectively (p (heterogeneity) = 0.6). The relative risk of false positive recall among current users appeared to increase with increasing time since menopause, but did not vary significantly according to any other factors examined, including duration of use, hormonal constituents, dose, whether single- or two-view screening was used, or the woman's personal characteristics. CONCLUSION: Current use of oestrogen-only and oestrogen-progestagen HRT, but not tibolone, increases the risk of false positive recall at screening. [Abstract/Link to Full Text]

Journe F, Chaboteaux C, Magne N, Duvillier H, Laurent G, Body JJ
Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines.
Breast Cancer Res. 2006;8(1):R2.
INTRODUCTION: Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. METHODS: We examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens. RESULTS: Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC50: 10(-4) M for MCF-7 and IBEP-2 cells; 3 x 10(-4) M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17beta-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists. CONCLUSION: These data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer. [Abstract/Link to Full Text]

Crowe DL, Lee MK
New role for nuclear hormone receptors and coactivators in regulation of BRCA1-mediated DNA repair in breast cancer cell lines.
Breast Cancer Res. 2006;8(1):R1.
INTRODUCTION: The breast cancer susceptibility gene BRCA1 is involved in the repair of double-strand breaks induced by ionizing radiation and chemotherapy drugs. BRCA1 interacts with coactivators such as p300 and CREB-binding protein (CBP) to activate target gene transcription. Estrogen and retinoic acid receptors (ER and RAR) also require coactivator proteins for their ligand-dependent functions. Few studies have suggested a role for nuclear hormone receptors in DNA repair. METHODS: DNA damage and repair activity were quantified with the use of single-cell gel electrophoresis and plasmid end-joining assays. Cell cycle progression and apoptosis were determined by bromodeoxyuridine and TdT-mediated dUTP nick end labelling assays. Stable transfection was accomplished with the lipofection procedure. Protein interaction and expression were determined by immunoprecipitation and western blotting. RESULTS: 17beta-estradiol (E2) and all-trans retinoic acid (RA) had opposing effects on DNA damage and breast cancer cell survival after double-strand break damage. Treatment with E2, but not with RA, resulted in complex formation between ERalpha, CBP, and BRCA1 in ER-positive cell lines. Mutant BRCA1 reduced the expression and activity of DNA damage repair proteins but did not block nuclear hormone-dependent effects. Mutant BRCA1 failed to form complexes with ERalpha and CBP, which correlated with its ability to exert E2-independent effects on DNA repair. Mutant BRCA1 inhibited cell cycle progression and produced increased survival in cells with double-strand breaks. Ectopic ERalpha expression reproduced the E2-mediated effects on DNA damage, repair, and survival. CONCLUSION: The present study proposes a new mechanism by which ER and RAR regulate BRCA1-mediated DNA repair by means of CBP. [Abstract/Link to Full Text]

Pinzon-Charry A, Maxwell T, McGuckin MA, Schmidt C, Furnival C, L�pez JA
Spontaneous apoptosis of blood dendritic cells in patients with breast cancer.
Breast Cancer Res. 2006;8(1):R5.
INTRODUCTION: Dendritic cells (DCs) are key antigen-presenting cells that play an essential role in initiating and directing cellular and humoral immunity, including anti-tumor responses. Due to their critical role in cancer, induction of DC apoptosis may be one of the central mechanisms used by tumors to evade immune recognition. METHODS: Spontaneous apoptosis of blood DCs (lineage negative HLA-DR positive cells) was assessed in peripheral blood mononuclear cells (PBMCs) using Annexin-V and TUNEL assays immediately after blood collection. The role of tumor products was assessed by culturing cells with supernatants derived from breast cancer cell lines (TDSN) or PBMCs (PBMC-SN, as a control). The capacity of DC stimulation to prevent apoptosis was assessed by incubating DC with inflammatory cytokines, poly I:C, IL-12 or CD40 ligand (CD40L) prior to culture with TDSN. Apoptosis was determined by flow cytometry and microscopy, and Bcl-2 expression determined by intracellular staining. RESULTS: In this study we document the presence of a significantly higher proportion of apoptotic (Annexin-V+ and TUNEL+) blood DCs in patients with early stage breast cancer (stage I to II; n = 13) compared to healthy volunteers (n = 15). We examined the role of tumor products in this phenomenon and show that supernatants derived from breast cancer lines induce apoptosis of blood DCs in PBMC cultures. Aiming to identify factors that protect blood DC from apoptosis, we compared a range of clinically available maturation stimuli, including inflammatory cytokines (tumor necrosis factor-alpha, IL-1beta, IL-6 and prostaglandin (PG)E2 as a cytokine cocktail), synthetic double-stranded RNA (poly I:C) and soluble CD40 ligand. Although inflammatory cytokines and poly I:C induced robust phenotypic maturation, they failed to protect blood DCs from apoptosis. In contrast, CD40 stimulation induced strong antigen uptake, secretion of IL-12 and protected blood DCs from apoptosis through sustained expression of Bcl-2. Exogenous IL-12 provided similar Bcl-2 mediated protection, suggesting that CD40L effect is mediated, at least in part, through IL-12 secretion. CONCLUSION: Cumulatively, our results demonstrate spontaneous apoptosis of blood DCs in patients with breast cancer and confirm that ex vivo conditioning of blood DCs can protect them from tumor-induced apoptosis. [Abstract/Link to Full Text]

Lenahan C, Avigan D
Dendritic cell defects in patients with cancer: mechanisms and significance.
Breast Cancer Res. 2006;8(1):101.
Dendritic cells (DCs) are a complex network of antigen-presenting cells that have an essential role in the modulation of primary immunity. There has been increasing evidence that DCs isolated from patients with malignancy demonstrate functional deficiencies that inhibit the capacity to mount an effective anti-tumor response. In this issue of Breast Cancer Research, Pinzon-Charry and colleagues investigate one of the possible mechanisms by which tumors induce DC dysfunction to evade host immune surveillance. They demonstrate that DCs isolated from the circulation of patients with early-stage breast cancer exhibit increased rates of spontaneous apoptosis. In vitro studies suggest that a soluble factor secreted by breast cancer cells is responsible for this phenomenon. In contrast, ex vivo conditioning of DCs with CD-40 ligand and IL-12 was protective against tumor-induced apoptosis. [Abstract/Link to Full Text]

Reis-Filho JS, Milanezi F, Carvalho S, Simpson PT, Steele D, Savage K, Lambros MB, Pereira EM, Nesland JM, Lakhani SR, Schmitt FC
Metaplastic breast carcinomas exhibit EGFR, but not HER2, gene amplification and overexpression: immunohistochemical and chromogenic in situ hybridization analysis.
Breast Cancer Res. 2005;7(6):R1028-35.
INTRODUCTION: Metaplastic breast carcinomas constitute a heterogeneous group of neoplasms, accounting for less than 1% of all invasive mammary carcinomas. Approximately 70-80% of metaplastic breast carcinomas overexpress the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor (HER)2 and EGFR have attracted much attention in the medical literature over the past few years owing to the fact that humanized monoclonal antibodies against HER2 and therapies directed against the extracellular ligand-binding domain or the intracellular tyrosine kinase domain of EGFR have proven successful in treating certain types of human cancer. We investigated whether HER2 and EGFR overexpression was present and evaluated gene amplification in a series of metaplastic breast carcinomas. METHOD: Twenty-five metaplastic breast carcinomas were immunohistochemically analyzed using a monoclonal antibody (31G7) for EGFR and two antibodies for HER2 (Herceptest and CB11) and scored using the Herceptest scoring system. Gene amplification was evaluated by chromogenic in situ hybridization using Zymed Spot-Light EGFR and HER2 amplification probe. The results were evaluated by bright field microscopy under 40x and 63x objective lenses. RESULTS: Nineteen (76%) metaplastic breast carcinomas exhibited EGFR ovexpression, and among these EGFR amplification (defined either by large gene clusters or >5 signals/nucleus in >50% of neoplastic cells) was detected in seven cases (37%): three carcinomas with squamous differentiation and four spindle cell carcinomas. One case exhibited HER2 overexpression of grade 2+ (>10% of cells with weak to moderate complete membrane staining), but HER2 gene amplification was not detected. CONCLUSION: Metaplastic breast carcinomas frequently overexpressed EGFR, which was associated with EGFR gene amplification in one-third of cases. Our findings suggest that some patients with metaplastic breast carcinomas might benefit from novel therapies targeting EGFR. Because most metaplastic breast carcinomas overexpress EGFR without gene amplification, further studies to evaluate EGFR activating mutations are warranted. [Abstract/Link to Full Text]

G�rski B, Narod SA, Lubinski J
A common missense variant in BRCA2 predisposes to early onset breast cancer.
Breast Cancer Res. 2005;7(6):R1023-7.
INTRODUCTION: Mutations in the BRCA2 gene are one of the two major causes of hereditary breast cancer. Protein-truncating mutations of BRCA2 are usually deleterious and increase the risk of breast cancer up to 80% over a lifetime. A few missense mutations in BRCA2 are believed to have a similarly high penetrance, apart from more common neutral polymorphisms. It is often difficult to classify a particular sequence variant as a mutation or a polymorphism. For a deleterious variant, one would expect a greater allele frequency in breast cancer cases than in ethnic-matched controls. In contrast, neutral polymorphic variants should be equally frequent in the two groups. METHODS: We genotyped 3,241 cases of breast cancer diagnosed at under 51 years of age, unselected for family history, from 18 hospitals throughout Poland and 2,791 ethnic-matched controls for a single BRCA2 C5972T variant. RESULTS: The variant was present in approximately 6% of the Polish population. In the study, 13 women (11 cases and two controls (OR = 4.7; p = 0.02)) were homozygous for the variant allele. The overall odds ratio for breast cancer in women with a single copy of the BRCA2 C5972T variant was 1.1 (p = 0.7); however, the effect was significant for patients diagnosed at or before age 40 (OR = 1.4; p = 0.04). We reviewed the association between the BRCA2 variant in different histologic subgroups and found the effect most pronounced in women who had ductal carcinoma in situ (DCIS) with micro-invasion (OR = 2.8; p < 0.0001). CONCLUSION: The BRCA2 C5972T allele is a common variant in Poland that increases the risk of DCIS with micro-invasion. The homozygous state is rare but increases the risk of breast cancer five-fold. [Abstract/Link to Full Text]

van Wezel T, Lombaerts M, van Roon EH, Philippo K, Baelde HJ, Szuhai K, Cornelisse CJ, Cleton-Jansen AM
Expression analysis of candidate breast tumour suppressor genes on chromosome 16q.
Breast Cancer Res. 2005;7(6):R998-1004.
INTRODUCTION: Chromosome arm 16q is the second most frequent target of loss of heterozygosity in breast cancer and is, therefore, a candidate to contain one or more classic tumour suppressor genes (TSGs). E-cadherin at 16q22 was identified as a TSG in lobular breast cancer, but TSGs in ductal breast cancer remain elusive. Several genes have been suggested as potential candidates (e.g. CBFA2T3, CTCF and WWOX) but no inactivating mutations could be identified in these genes and they thus fail to fit the classic two-hit model for a TSG. With the completion of the human transcriptome, new candidate genes can be distinguished. Besides mutational inactivation, a TSG could, at least in a subset of the tumours, be transcriptionally suppressed or even inactivated. Studying candidate genes for expression and somatic mutations could thus identify the TSGs. METHODS: Possible candidates CBFA2T3, TERF2 and TERF2IP, FBXL8 and LRRC29 and FANCA were studied for insertion and deletion mutations and for expression differences using quantitative RT-PCR in a panel of tumour cell lines and primary tumours with and without loss of 16q. RESULTS: None of the genes showed mutations or obvious expression differences. FANCA expression increased with tumour grade. CONCLUSION: Apparently, the underlying genetics at chromosome 16q are complex or the TSGs remain to be identified. Multiple mechanisms, such as mutations, promoter hypermethylation or haploinsufficiency, might lead to the inactivation of a TSG. [Abstract/Link to Full Text]

Lewis AG, Flanagan J, Marsh A, Pupo GM, Mann G, Spurdle AB, Lindeman GJ, Visvader JE, Brown MA, Chenevix-Trench G
Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer.
Breast Cancer Res. 2005;7(6):R1005-16.
INTRODUCTION: Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. We hypothesized that germline mutations in FANCD2, BRIP1/BACH1, LMO4 and SFN may account for some of the unexplained multiple-case breast cancer families. METHODS: The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I). RESULTS: DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity. CONCLUSION: There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk. [Abstract/Link to Full Text]

Higgins SA, Matloff ET, Rimm DL, Dziura J, Haffty BG, King BL
Patterns of reduced nipple aspirate fluid production and ductal lavage cellularity in women at high risk for breast cancer.
Breast Cancer Res. 2005;7(6):R1017-22.
INTRODUCTION: Nipple aspiration is a noninvasive technique for obtaining breast fluids from the duct openings of the nipple for the evaluation of abnormalities associated with breast cancer. Nipple aspirate fluid (NAF) can be elicited from 48 to 94% of healthy women, and its production has been linked to an increased relative risk for breast cancer development. NAF production has been used in studies to guide the selection of ducts for ductal lavage, a procedure in which ducts are cannulated and flushed with saline to collect cells. In a previous multicenter trial to evaluate intraductal approaches in women at high-risk for breast cancer, NAF production was observed in 84% of the subjects. However, we observed a significantly lower proportion of fluid-yielding subjects in a similar series of high-risk women. The purpose of the present study was to identify variables associated with this reduction. METHOD: Nipple aspiration was performed on 33 high-risk women (defined as having a 5-year Gail model index of more than 1.7, a personal or family history of breast cancer, and/or a BRCA1 or BRCA2 germline mutation) to identify ductal orifices for lavage procedures. Lavage was performed on all fluid-yielding ducts and on nine non-fluid-yielding ducts. RESULTS: Fluid-yielding ducts were identified in 12 of 33 (36%) of the subjects in the present series, compared with 16 of 19 (84%) of the subjects undergoing identical procedures at our facility during a multicenter trial (P = 0.001). Reduced NAF yields were associated with postmenopausal status (P = 0.02), BRCA germline mutations (P = 0.004), and risk reduction therapies, including bilateral salpingo-oophorectomy (BSO) and/or selective estrogen receptor modulators (SERMs; P = 0.009). All nine (100%) of the ductal lavage specimens collected from non-fluidyielding ducts were acellular, in comparison with 3 of 13 specimens from fluid-yielding ducts (P < .001). CONCLUSION: Analysis of high-risk women in the present series revealed patterns of reduced NAF production and ductal lavage cellularity compared with a previous multicenter trial. The present series included more BRCA-positive women, many of whom had undergone BSO and/or were using SERMs. Our data suggest that endocrine mechanisms associated with these risk-reducing therapies may be related to patterns of diminished breast fluid production. [Abstract/Link to Full Text]

Price KN, Goldhirsch A
Clinical trial update: International Breast Cancer Study Group.
Breast Cancer Res. 2005;7(6):252-4.
The International Breast Cancer Study Group (IBCSG) has been conducting large, phase III clinical trials since 1978. Prior to 1986, these activities were carried out under the name of Ludwig Breast Cancer Study Group. Seven trials of adjuvant therapies are currently open for patient accrual, five of which are described in this report. The IBCSG has been a leader in the field of tailored treatment approaches for specific subpopulations of patients with breast cancer, believing that what is best for the majority may not be best for a defined minority. [Abstract/Link to Full Text]

Metsola K, Kataja V, Sillanp�� P, Siivola P, Heikinheimo L, Eskelinen M, Kosma VM, Uusitupa M, Hirvonen A
XRCC1 and XPD genetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study.
Breast Cancer Res. 2005;7(6):R987-97.
INTRODUCTION: It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking. METHODS: The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1-399 Gln allele (OR 2.33, 95% CI 1.30-4.19, pint 0.025) or XPD-751 Gln/Gln genotype (OR 2.52, 95% CI 1.27-5.03, pint 0.011) compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66-10.3) and 4.41 (95% CI 1.62-12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00-2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes. CONCLUSION: Our results do not indicate a major role for XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women. [Abstract/Link to Full Text]

Segersten U, Holm PK, Bj�rklund P, Hessman O, Nordgren H, Binderup L, Akerstr�m G, Hellman P, Westin G
25-Hydroxyvitamin D3 1alpha-hydroxylase expression in breast cancer and use of non-1alpha-hydroxylated vitamin D analogue.
Breast Cancer Res. 2005;7(6):R980-6.
INTRODUCTION: The cytochrome P450 mitochondrial enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) of renal tubule cells hydroxylates the major circulating form of vitamin D (25(OH)D3) to the active systemic hormone 1,25(OH)2D3. Local production of 1,25(OH)2D3 appears to occur also at other sites where 1alpha-hydroxylase is expressed for autocrine/paracrine regulation. To reduce risks of hypercalcemia during treatment with vitamin D, we have previously suggested use of non-1alpha-hydroxylated vitamin D analogues to target tissues where 1alpha-hydroxylase is expressed, including the parathyroid glands in secondary hyperparathyroidism. The present study was undertaken to examine expression of 1alpha-hydroxylase in breast cancer and to investigate whether a non-1alpha-hydroxylated vitamin D analogue displayed biological function. In addition, expression of the 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) and the vitamin D receptor (VDR) was investigated. METHODS: The expression of 1alpha-hydroxylase, 24-hydroxylase and VDR was investigated in breast cancer specimens (n = 19) and normal breast tissues (n = 10) by immunohistochemistry and/or RT-PCR. Consecutive cryosections of 6 mum essentially free of immune cells were used in the analyses. The effect of vitamin D analogues on transcriptional activation was analyzed in transiently transfected MCF-7 breast cancer cells. RESULTS: 1alpha-hydroxylase protein was demonstrated in 79% and 100% of breast cancer specimens and normal breast, respectively. The overall relative mRNA levels of 1alpha-hydroxylase and 24-hydroxylase in normal breast compared to breast tumors were: 1alpha-hydroxylase, 1 +/- 0.07 versus 0.7 +/- 0.05, respectively (p < 0.001); 24-hydroxylase, 1 +/- 0.08 verus 2.1 +/- 0.2, respectively (p < 0.001). The VDR was expressed in 95% of the tumors as expected, with mRNA levels of 1 +/- 0.09 and 1.4 +/- 0.12 (p < 0.05) in breast cancer and normal breast, respectively. The ketoconazole-sensitive transcription activation potential of the non-1alpha-hydroxylated vitamin D analogue prodrug of EB1089 (EB1285) was demonstrated in MCF-7 cells, which express 1alpha-hydroxylase. The activity of EB1285 was about 20% of 1,25(OH)2D3. CONCLUSION: These results demonstrate nearly normal expression levels of 1alpha-hydroxylase, 24-hydroxylase and VDR in the majority of investigated breast cancer specimens. A non-1alpha-hydroxylated vitamin D analogue displayed activity in breast cancer cells. Such analogues may present future therapeutic options for proliferative disorders where 1alpha-hydroxylase is expressed. [Abstract/Link to Full Text]

Hinck L, Silberstein GB
Key stages in mammary gland development: the mammary end bud as a motile organ.
Breast Cancer Res. 2005;7(6):245-51.
In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-beta acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed. [Abstract/Link to Full Text]

Rae JM, Johnson MD
What does an orphan G-protein-coupled receptor have to do with estrogen?
Breast Cancer Res. 2005;7(6):243-4.
Estrogen affects multiple aspects of human physiology, including the normal growth and development of female reproductive tissues, bone integrity, cardiovascular and central nervous system functions, and plays a central role in normal mammary development and breast pathogenesis. It modulates diverse cell signaling pathways, some of which appear to be independent of the known estrogen receptors (ERs). Although many of estrogen's actions can be explained by the nuclear ERs (ER-alpha and ER-beta) functioning as ligand-activated RNA transcription factors, there are numerous rapid biochemical and physiological responses that cannot be explained by the classical genomic effects of estrogen signaling. It has long been postulated that the rapid effects of estrogen are due to a membrane-bound ER, and two recent reports suggest that it is in fact a G-protein-coupled receptor named 'GPR30'. [Abstract/Link to Full Text]

Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF
Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells.
Breast Cancer Res. 2005;7(6):R965-74.
INTRODUCTION: The metastatic progression of cancer is a direct result of the disregulation of numerous cellular signaling pathways, including those associated with adhesion, migration, and invasion. Members of the Rac family of small GTPases are known to act as regulators of actin cytoskeletal structures and strongly influence the cellular processes of integrin-mediated adhesion and migration. Even though hyperactivated Rac proteins have been shown to influence metastatic processes, these proteins have never been directly linked to metastatic progression. METHODS: To investigate a role for Rac and Cdc42 in metastatic breast cancer cell invasion and migration, relative endogenous Rac or Cdc42 activity was determined in a panel of metastatic variants of the MDA-MB-435 metastatic human breast cancer cell line using a p21-binding domain-PAK pull down assay. To investigate the migratory and invasive potential of the Rac isoforms in human breast cancer, namely Rac1 and the subsequently cloned Rac3, we stably expressed either dominant active Rac1 or dominant active Rac3 into the least metastatic cell variant. Dominant negative Rac1 or dominant negative Rac3 were stably expressed in the most metastatic cell variant. Cell lines expressing mutant Rac1 or Rac3 were analyzed using in vitro adhesion, migration and invasion assays. RESULTS: We show that increased activation of Rac proteins directly correlates with increasing metastatic potential in a panel of cell variants derived from a single metastatic breast cancer cell line (MDA-MB-435). The same correlation could not be found with activated Cdc42. Expression of a dominant active Rac1 or a dominant active Rac3 resulted in a more invasive and motile phenotype. Moreover, expression of either dominant negative Rac1 or dominant negative Rac3 into the most metastatic cell variant resulted in decreased invasive and motile properties. CONCLUSION: This study correlates endogenous Rac activity with high metastatic potential and implicates Rac in the regulation of cell migration and invasion in metastatic breast cancer cells. Taken together, these results suggest a role for both the Rac1 and Rac3 GTPases in human breast cancer progression. [Abstract/Link to Full Text]

Pachmann K, Camara O, Kavallaris A, Schneider U, Sch�nemann S, H�ffken K
Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring.
Breast Cancer Res. 2005;7(6):R975-9.
INTRODUCTION: In adjuvant treatment for breast cancer there is no tool available with which to measure the efficacy of the therapy. In contrast, in neoadjuvant therapy reduction in tumour size is used as an indicator of the sensitivity of tumour cells to the agents applied. If circulating epithelial (tumour) cells can be shown to react to therapy in the same way as the primary tumour, then this response may be exploited to monitor the effect of therapy in the adjuvant setting. METHOD: We used MAINTRAC analysis to monitor the reduction in circulating epithelial cells during the first three to four cycles of neoadjuvant therapy in 30 breast cancer patients. RESULTS: MAINTRAC analysis revealed a patient-specific response. Comparison of this response with the decline in size of the primary tumour showed that the reduction in number of circulating epithelial cells accurately predicted final tumour reduction at surgery if the entire neoadjuvant regimen consisted of chemotherapy. However, the response of the circulating tumour cells was unable to predict the response to additional antibody therapy. CONCLUSION: The response of circulating epithelial cells faithfully reflects the response of the whole tumour to adjuvant therapy, indicating that these cells may be considered part of the tumour and can be used for therapy monitoring. [Abstract/Link to Full Text]

Recent Articles in International Seminars in Surgical Oncology

No recent articles are currently available.

Recent Articles in World Journal of Surgical Oncology

Haraguchi M, Kinoshita H, Koori M, Tsuneoka N, Kosaka T, Ito Y, Furui J, Kanematsu T
Multiple rectal carcinoids with diffuse ganglioneuromatosis.
World J Surg Oncol. 2007;519.
BACKGROUND: Rectal carcinoids comprise only about 1% of all anorectal neoplasms. In addition, ganglioneuroma of the gastrointestinal tract is a rare tumor composed ganglion cells, nerve fibers, and supporting cells. Multiple carcinoid tumors with diffuse ganglioneuromatosis limited to the rectum are quite unusual. CASE PRESENTATION: A 69-year-old man was referred to us because of about 100 small submucosal rectal tumors. He underwent abdominoperineal resection. Pathology revealed carcinoid tumors for about 30 submucosal nodules and diffuse ganglioneuromotosis. To date (6 months later) he remains well with no recurrence. CONCLUSION: Although the optimal treatment for the multiple rectal carcinoids remains to be clearly established, it is believed that not all patients with multiple rectal carcinoids (measuring less than 1 cm in diameter) need to have a radical operation. However, the treatment plan for each case should be individualized and a careful follow-up is mandatory. [Abstract/Link to Full Text]

Povoski SP, Young DC, Walker MJ, Carson WE, Yee LD, Agnese DM, Farrar WB
Re-emphasizing the concept of adequacy of intraoperative assessment of the axillary sentinel lymph nodes for identifying nodal positivity during breast cancer surgery.
World J Surg Oncol. 2007;518.
BACKGROUND: Although sentinel lymph node (SLN) biopsy is a standard of care for the evaluation of the axillary lymph nodes during breast cancer surgery, a substantial degree of variation exists among individual surgeons as to what represents an adequate assessment. The aim of the current study was to assess when metastatic disease was first identified within consecutively harvested SLN candidates for invasive breast cancers demonstrating a positive SLN. METHODS: We retrospectively analyzed a series of 400 breast cancers from a recently published prospective randomized clinical trial. A combined radiocolloid and blue dye technique was used. All potential SLN candidates, containing counts of at least 10% of the hottest SLN and/or containing blue dye, were harvested and were consecutively numbered in the order of the decreasing level of counts (with the hottest SLN representing SLN #1). RESULTS: Among 371 invasive breast cancers, a SLN was identified within 353 cases (95%). Mean number of SLNs identified was 2.5 (range, 1 to 9), with a single SLN identified in 104 (29%) cases, two identified in 110 (31%), three identified in 73 (21%), four identified in 35 (10%), five identified in 16 (5%), and six or more identified in 15 (4%). A positive SLN was found in 104 (29%) cases. SLN #1 was the first positive SLN in 86 (83%). SLN #2 was the first positive SLN in 15 (14%). SLN #3, SLN #4, and SLN #5 were the first positive SLN in one case (1%) each. A positive SLN was found in 18% (19/104) of cases when a single SLN was identified, as compared to in 34% (85/249) when two or more SLNs were identified (P = 0.003). CONCLUSION: The accurate and optimal assessment of the axilla during breast cancer surgery requires persistence and diligence for attempting to identify all potential SLN candidates in order to avoid failing to recognize a positive SLN. The scenario in which only a single negative SLN candidate is intraoperatively identified is one that should raise some concern to the operating surgeon. [Abstract/Link to Full Text]

Kim SH, Das K, Noreen S, Coffman F, Hameed M
Prognostic implications of immunohistochemically detected YKL-40 expression in breast cancer.
World J Surg Oncol. 2007;517.
BACKGROUND: YKL-40 has been implicated as a mediator of collagen synthesis and extracellular matrix re-modeling as well as mitogenesis. Elevated serum levels of YKL-40 have been associated with worse survival in a variety of malignancies including breast cancer. We wished to determine if immunohistochemically detected expression had prognostic implications in breast cancer. METHODS: A prospectively collected database of breast cancer patients treated at the University Hospital of Newark was used for analysis. Immunohistochemistry was performed on archived tumor tissue from 109 patients for whom full clinical information and follow up was available. RESULTS: YKL-40 expression was noted in 37 patients (34%). YKL-40 immunoreactivity significantly correlated with larger tumor size, poorer tumor differentiation, and a greater likelihood of being estrogen and/or progesterone receptor negative. No significant correlation was demonstrated between YKL-40 status and nodal stage. At a mean follow up of 3.2 years, disease-free survival was significantly worse in the subset of patients whose tumors demonstrated YKL-40 expression compared to the non-expressors. In multivariate analysis, YKL-40 status was independent of T-stage and N-stage in predicting disease recurrence. CONCLUSION: Immunoreactivity for YKL-40 was a significant predictor of breast cancer relapse in this subset of patients. This was independent of T or N-stage and suggests that tumor immunohistochemistry for this protein may be a valuable prognostic marker in breast cancer. [Abstract/Link to Full Text]

Denzinger S, Otto W, Burger M, Hammerschmied C, Junker K, Hartmann A, Wieland WF, Walter B
Sporadic renal cell carcinoma in young and elderly patients: are there different clinicopathological features and disease specific survival rates?
World J Surg Oncol. 2007;516.
BACKGROUND: Sporadic renal cell carcinoma (RCC) is rare in young adults. In the present retrospective study we reviewed clinicopathological features and disease specific survival rates in young patients (< or = 45 years) with RCC and compared them to old patients (> or = 75 years) with RCC. METHODS: Between 1992 and 2005 a total of 1042 patients were treated for RCC at our institution. We found 70 patients 45 years or younger (YP) and 150 patients 75 years or older (OP) at time of diagnosis. There were no differences in therapeutical approaches between both groups. Clinical and biologic parameters at diagnosis were compared and subjected to uni- and multivariate analysis to study cancer specific survival and progression rate. Mean postoperative follow-up in both groups was 50.1 months. RESULTS: Mean age was 39 years in YP and 80 years in OP, respectively. YP demonstrated significantly lower stage (pT1-pT2 N0 M0, p = 0.03), lower tumor grade (p = 0.01) and higher male-to-female ratio (p < 0.001). The rate of lymph node metastases or distant metastatic disease at presentation did not differ significantly between both groups. In multivariate analysis young age was independently associated with a higher 5-year cancer specific survival (95.2% vs. 72.3%, p = 0.009) and a lower 5-year progression rate (11.3% vs. 42.5%, p = 0.002). CONCLUSION: Sporadic RCC in young patients have lower tumor stages and grades and a better outcome compared to elderly. Age < or = 45 years was an independent prognostic factor for survival and progression. [Abstract/Link to Full Text]

Daigeler A, Vogt PM, Busch K, Pennekamp W, Weyhe D, Lehnhardt M, Steinstraesser L, Steinau HU, Kuhnen C
Elastofibroma dorsi--differential diagnosis in chest wall tumours.
World J Surg Oncol. 2007;515.
BACKGROUND: Elastofibromas are benign soft tissue tumours mostly of the infrascapular region between the thoracic wall, the serratus anterior and the latissimus dorsi muscle with a prevalence of up to 24% in the elderly. The pathogenesis of the lesion is still unclear, but repetitive microtrauma by friction between the scapula and the thoracic wall may cause the reactive hyperproliferation of fibroelastic tissue. METHODS: We present a series of seven cases with elastofibroma dorsi with reference to clinical findings, further clinical course and functional results after resection, as well as recurrence. Data were obtained retrospectively by clinical examination, phone calls to the patients' general practitioners and charts review. Follow-up time ranged from four months to nine years and averaged 53 months. RESULTS: The patients presented with swelling of the infrascapular region or snapping scapula. In three cases, the lesion was painful. The ratio men/women was 2/5 with a mean age of 64 years. The tumor sizes ranged from 3 to 13 cm. The typical macroscopic aspect was characterized as poorly defined fibroelastic soft tissue lesion with a white and yellow cut surface caused by intermingled remnants of fatty tissue. Microscopically, the lesions consisted of broad collagenous strands and densely packed enlarged and fragmented elastic fibres with mostly round shapes. In all patients but one, postoperative seroma (which had to be punctuated) occurred after resection; however, at follow-up time, no patient reported any decrease of function or sensation at the shoulder or the arm of the operated side. None of the patients experienced a relapse. CONCLUSION: In differential diagnosis of soft tissue tumors located at this specific site, elastofibroma should be considered as likely diagnosis. Due to its benign behaviour, the tumor should be resected only in symptomatic patients. [Abstract/Link to Full Text]

Slam KD, Calkins S, Cason FD
LaPlace's law revisited: cecal perforation as an unusual presentation of pancreatic carcinoma.
World J Surg Oncol. 2007;514.
BACKGROUND: Pancreatic cancer is often locally and distally aggressive, but initial presentation as cecal perforation is uncommon. CASE PRESENTATION: We describe a patient presenting with pneumoperitoneum, found at initial exploration to have a cecal perforation believed to be secondary to a large cecal adenoma, after palpation of the remainder of the colon revealed hard stool but no distal obstruction. Postoperatively, however, the patient progressed to large bowel obstruction and upon reexploration, a mass could now be delineated, encompassing the splenic flexure, splenic hilum, and distal pancreas. Histological evaluation determined this was locally invasive pancreatic adenocarcinoma, and therefore the true etiology of the original cecal perforation. CONCLUSION: Any perforation localized to the cecum must be highly suspicious for a distal obstruction, as dictated by the law of LaPlace. [Abstract/Link to Full Text]

Cavanna L, Lazzaro A, Vallisa D, Civardi G, Artioli F
Role of image-guided fine-needle aspiration biopsy in the management of patients with splenic metastasis.
World J Surg Oncol. 2007;513.
BACKGROUND: Splenic metastases are very rare and are mostly diagnosed at the terminal phase of the disease or at the time of autopsy. The cytohistological diagnosis, when done, is made prevalently by splenectomy. Reports on splenic percutaneous biopsies in the diagnosis of splenic metastasis are fragmentary and very poor. The aims of this study are to analyse retrospectively the accuracy, safety and the clinical impact of ultrasound (US)-guided fine-needle aspiration biopsy (UG-FNAB) in patients with suspected splenic metastasis. METHODS: A retrospective analysis of 1800 percutaneous abdominal biopsies performed at our institute during the period from 1993 to 2003 was done and 160 patients that underwent splenic biopsy were found. Among these 160 patients, 12 cases with the final diagnosis of solitary splenic metastases were encountered and they form the basis of this report. The biopsies were performed under US guidance using a 22-gauge Chiba needle. All the patients underwent laboratory tests, CT examination of the abdomen and chest, US examination of abdomen and pelvis. RESULTS: There were 5 women and 7 men, median age 65 years (range 48-80). Eight patients had a known primary cancer at the time of the diagnosis of splenic metastasis: 3 had breast adenocarcinoma, 2 colon adenocarcinoma, 2 melanoma and 1 lung adenocarcinoma. Four patients were undiagnosed at the time of the appearance of splenic metastasis and subsequent investigations showed adenocarcinoma of the lung in 2 patients and colon adenocarcinoma in the remaining 2. There was a complete correspondence between the US and Computed Tomography (CT) in detecting focal lesions of the spleen. The splenic biopsies allowed a cytological diagnosis of splenic metastasis in all the 12 patients and changed clinical management in all cases. Reviewing the 160 patients that underwent UG-FNAB of the spleen we found no complications related to the biopsies. CONCLUSION: These results indicate that UG-FNAB is a successful technique for diagnosis of splenic metastasis allowing an adequate treatment of the affected patients. [Abstract/Link to Full Text]

Pandey M, Rao LP, Das SR, Mathews A, Chacko EM, Naik BR
Patterns of mandibular invasion in oral squamous cell carcinoma of the mandibular region.
World J Surg Oncol. 2007;512.
BACKGROUND: Mandibular resections are routinely carried out for achieving a R0 resection for oral cancers. However, the need of mandibular resection to achieve this has always been questioned. The present study was carried out to define the pattern of mandibular involvement in carcinoma of the mandibular region. PATIENTS AND METHODS: A total of 25 consecutive patients who had undergone mandibular resection and were found to have mandibular invasion were studied in a prospective open fashion. After decalcification the specimens were serially sectioned at 1 cm interval to identify invasion of mandibular bone. Type of invasion, route of spread and host cell reactions were also recorded. RESULTS: The mandibular involvement was infiltrative in 14(56%) and erosive in 11(44%). It was cortical in 5(20%), marrow involvement was seen in 15(60%) while 5(20%) had spread through the inferior alveolar canal. Of the 25, 24(96%) lesions were located with in 1 cm of the mandible. CONCLUSION: The possibility of mandibular involvement is higher in patients where tumours are located with in 1 cm of the mandible. Involvement of mandible through the canal of inferior alveolar nerve in the present study was relatively high (20%). Therefore it is recommended that before a decision is taken to preserve the mandible it should be thoroughly screened for possible involvement. [Abstract/Link to Full Text]

Qureshi SS, Ahmed QG, Yadav PS
Successful reconstruction of large oropharyngeal defect with pectoralis major myocutaneous flap in a four-year-old boy with recurrent fibromatosis.
World J Surg Oncol. 2007;511.
BACKGROUND: Pectoralis major myocutaneous (PMMC) flap continues to be the workhorse in head and neck reconstruction. Although free tissue transfer has revolutionized the reconstruction in cancers of the oral region, PMMC is still considered a readily accessible source of vascularized soft tissue available to the reconstructive surgeon and especially in most developing nations where due to the cost, time, expertise, or infrastructural constraints free flaps cannot be generally offered. Although commonly used in adults, it has been hardly described for reconstruction in children. CASE PRESENTATION: We present a 4-year-old child with recurrent fibromatosis of the oropharyngeal region where the PMMC was used for reconstruction of the surgical defect and to the best of our knowledge is the youngest patient undergoing reconstruction with PMMC for neoplastic lesion of the head and neck. CONCLUSION: The PMMC flap is justifiably a popular flap that continues to command an important place in the head and neck surgeon's reconstructive armamentarium. [Abstract/Link to Full Text]

Filippakis GM, Zografos G
Contraindications of sentinel lymph node biopsy: are there any really?
World J Surg Oncol. 2007;510.
BACKGROUND: One of the most exciting and talked about new surgical techniques in breast cancer surgery is the sentinel lymph node biopsy. It is an alternative procedure to standard axillary lymph node dissection, which makes possible less invasive surgery and side effects for patients with early breast cancer that wouldn't benefit further from axillary lymph node clearance. Sentinel lymph node biopsy helps to accurately evaluate the status of the axilla and the extent of disease, but also determines appropriate adjuvant treatment and long-term follow-up. However, like all surgical procedures, the sentinel lymph node biopsy is not appropriate for each and every patient. METHODS: In this article we review the absolute and relative contraindications of the procedure in respect to clinically positive axilla, neoadjuvant therapy, tumor size, multicentric and multifocal disease, in situ carcinoma, pregnancy, age, body-mass index, allergies to dye and/or radio colloid and prior breast and/or axillary surgery. RESULTS: Certain conditions involving host factors and tumor biologic characteristics may have a negative impact on the success rate and accuracy of the procedure. The overall fraction of patients unsuitable or with multiple risk factors that may compromise the success of the sentinel lymph node biopsy, is very small. Nevertheless, these patients need to be successfully identified, appropriately advised and cautioned, and so do the surgeons that perform the procedure. CONCLUSION: When performed by an experienced multi-disciplinary team, the SLNB is a highly effective and accurate alternative to standard level I and II axillary clearance in the vast majority of patients with early breast cancer. [Abstract/Link to Full Text]

Candelaria M, Hurtado-Monroy R, Vargas-Viveros P, Carrillo-Mu�noz S, Duenas-Gonzalez A
Tamoxifen-associated vasculitis in a breast cancer patient.
World J Surg Oncol. 2007;59.
BACKGROUND: Estrogen plays a critical role in breast cancer. Thereafter, endocrine therapy is a standard of care in patients with breast carcinoma, expressing ER or PR. CASE PRESENTATION: Herein we report the case of a 53-year old patient, who developed cholestasis and vasculitis during the treatment with tamoxifen. This toxicity was reversable after the removal of the drug. Thereafter she continued adjuvant treatment for breast carcinoma with anastrazole. Since tamoxifen has been widely indicated for patients with breast carcinoma, we did a literature review, looking for other cases with this type of toxicity. CONCLUSION: This case is the third with vasculitis informed in the literature, but the first one that additionally developed cholestasis and arthritis. Although it is rare, we discuss the indication of this drug in the actual era, where aromatase inhibitors offer a better security profile. [Abstract/Link to Full Text]

Marone U, Carac� C, Chiofalo MG, Botti G, Mozzillo N
Resection in the popliteal fossa for metastatic melanoma.
World J Surg Oncol. 2007;58.
BACKGROUND: Traditionally metastatic melanoma of the distal leg and the foot metastasize to the lymph nodes of the groin. Sometimes the first site of nodal disease can be the popliteal fossa. This is an infrequent event, with rare reports in literature and when it occurs, radical popliteal node dissection must be performed. CASE PRESENTATION: We report a case of a 36-year old man presented with diagnosis of 2 mm thick, Clark's level II-III, non ulcerated melanoma of the left heel, which developed during the course of the disease popliteal node metastases, after a superficial and deep groin dissection for inguinal node involvement. Five months after popliteal lymph node dissection he developed systemic disease, therefore he received nine cycles of dacarbazine plus fotemustine. To date (56 months after prior surgery and 11 months after chemotherapy) he is alive with no evidence of disease. CONCLUSION: In case of groin metastases from melanoma of distal lower extremities, clinical and ultrasound examination of ipsilateral popliteal fossa is essential. When metastatic disease is found, radical popliteal dissection is the standard of care. Therefore knowledge of anatomy and surgical technique about popliteal lymphadenectomy are required to make preservation of structures that if injured, can produce a permanent, considerable disability. [Abstract/Link to Full Text]

Anand A, Tsapakis EM, Narvani AA, Alhakim A, Cannon SR, Tsiridis E
"Pseudosarcoma" in a pregnant woman.
World J Surg Oncol. 2007;57.
BACKGROUND: Intravascular fasciitis (IVF) is a rare benign condition characterised by reactive myofibroblastic proliferation arising from the superficial or deep fascia and involving arteries and/or veins. It is a distinct variant of the more common condition of nodular fasciitis, which possesses similar clinical and histological features to IVF, but lacks vascular invasion. A thorough review of the literature revealed 26 reported cases of IVF. CASE PRESENTATION: We report a case of IVF in a 16-week pregnant lady affecting the hypothenar eminence of the hand associated with the ulnar artery. CONCLUSION: The characteristic involvement of muscular arteries and veins by reactive myofibroblastic proliferation in IVF suggests a malignant component and often leads to an inappropriate diagnosis for this benign condition. We propose that hormone-related changes associated with pregnancy may play an important role in the aetiopathogenesis of this myofibroblastic lesion. [Abstract/Link to Full Text]

Todoroki T, Sano T, Yamada S, Hirahara N, Toda N, Tsukada K, Motojima R, Motojima T
Clear cell carcinoid tumor of the distal common bile duct.
World J Surg Oncol. 2007;56.
BACKGROUND: Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. CASE PRESENTATION: A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2nd portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 x 0.6 x 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. CONCLUSION: Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct. [Abstract/Link to Full Text]

de Le�n DC, P�rez-Montiel D, Chanona-Vilchis J, Due�as-Gonz�lez A, Villavicencio-Valencia V, Zavala-Casas G
Primary retroperitoneal mucinous cystadenocarcinoma: report of two cases.
World J Surg Oncol. 2007;55.
BACKGROUND: Retroperitoneal cystadenocarcinomas are rare lesions, the majority of cases presented as one-patient reports. METHODS: We present two cases of retroperitoneal cystadenocarcinoma, both in women of reproductive age: one with aggressive behavior, and the remaining case, with a more indolent clinical evolution. RESULTS: One case presented as pelvic tumor, was treated with surgical resection of the disease, but manifested with recurrent disease a few months later despite use of chemotherapy. The second case involved a patient with diagnosis of abdominal tumor; during laparotomy, a retroperitoneal tumor was found and was totally removed. At follow-up, the patient is disease-free with no other treatment. CONCLUSION: The behavior and treatment of retroperitoneal cystadenocarcinoma are controversial. We suggest aggressive surgery including radical hysterectomy and bilateral salpingoopherectomy with adjuvant chemotherapy in these cases. [Abstract/Link to Full Text]

Saied GM, El-Metenawy WH, Elwan MS, Dessouki NR
Urine carcinoembryonic antigen levels are more useful than serum levels for early detection of Bilharzial and non-Bilharzial urinary bladder carcinoma: observations of 43 Egyptian cases.
World J Surg Oncol. 2007;54.
BACKGROUND: Both urinary bilharziasis and urothelial neoplasia are associated with increased production of tissue carcinoembryonic antigen (CEA). PATIENTS AND METHODS: Urine and serum CEA were determined in 43 patients with urinary bladder carcinoma including 22 post bilharzial and 21 nonbiharzial cases, in addition to 10 normal control cases. RESULTS: A significant increase was detected in both urine and serum CEA levels with bladder carcinoma compared to control cases. Urinary CEA was significantly elevated in 86% of bilharzial, versus 62% in nonbilharzial bladder carcinoma. Only 10.5% of control cases had urinary CEA elevation. The mean urinary CEA in bilharzial, was higher than that of nonbilharzial carcinoma, but the difference was not statistically significant. There was a definite relationship between urine CEA and the stage of malignancy; the higher the stage, the higher the level of urine CEA. No relationship could be detected between the stage of malignancy and serum CEA, or between the grades of malignancy and urine or serum CEA levels. CONCLUSION: Urinary CEA is more useful than serum CEA in the early detection of urotherlial carcinoma particularly if provoked by bilharziasis. Its level is also correlated with the tumor stage. [Abstract/Link to Full Text]

Venkitaraman R, George MK, Ramanan SG, Sagar TG
A single institution experience of combined modality management of extra skeletal Ewings sarcoma.
World J Surg Oncol. 2007;53.
BACKGROUND: Extraskeletal Ewings sarcoma are rare tumors for which there is no consensus on optimal management. METHODS: A retrospective review of the clinical features, treatment and outcome of patients with extraskeletal Ewings sarcoma who reported to a single institution between January 1992-December 2003 is reported. RESULTS: A total of 19 patients with extraskeletal Ewings sarcoma were identified. Of these, 4 patients had metastatic disease at presentation and 15 patients with non-metastatic disease received combined modality treatment with primary combination chemotherapy followed by local treatment with radiotherapy or surgery. Disease free survival and overall survival for patients with non metastatic disease after combined modality treatment were 60% and 30% respectively. The significant predictors for prolonged disease free survival and overall survival were high haemoglobin (p = 0.002), low lactate dehydrogenase (p = 0.028), chemotherapy with Vincristine, Adriamycin, Cyclophosphamide, Ifosfamide and Etoposide regime (p = 0.008) and complete response to chemotherapy (p = 0.001). CONCLUSION: Aggressive combination chemotherapy followed by complete surgery or radiotherapy to a dose of more than 50 Gy is essential to confer optimal outcome for patients with extraskeletal Ewings sarcoma. [Abstract/Link to Full Text]

Kabeer MA, Lloyd-Davies E, Maskell G, Hohle R, Mathew J
Metastatic prostate cancer masquerading clinically and radiologically as a primary caecal carcinoma.
World J Surg Oncol. 2007;52.
BACKGROUND: Prostatic carcinoma is the second most common cause of cancer-related deaths in males in the West. Approximately 20% of patients present with metastatic disease. We describe the case of a patient with metastatic prostate cancer to the bowel presenting clinically and radiologically as a primary caecal cancer. CASE PRESENTATION: A 72 year-old man presented with abdominal discomfort and a clinically palpable caecal mass and a firm nodule on his thigh, the latter behaving clinically and radiologically as a lipoma. Computed tomographic (CT) scan showed a luminally protuberant caecal mass with regional nodal involvement. The patient was being treated (Zoladex) for prostatic cancer diagnosed 6 years previously and was known to have bony metastases. On admission his PSA was 245.4 nmol/ml. The patient underwent a right hemicolectomy. Histology showed a poorly differentiated adenocarcinoma which was PSA positive, confirming metastatic prostatic adenocarcinoma to the caecum. The patient underwent adjuvant chemotherapy and is free from recurrence a year later. CONCLUSION: Metastasis of prostatic carcinoma to the bowel is a very rare occurrence and presents a challenging diagnosis. The diagnosis is supported by immunohistochemistry for PSA. The treatment for metastatic prostate cancer is mainly palliative. [Abstract/Link to Full Text]

Omranipour R, Alavion M
Cervical mature teratoma 17 years after initial treatment of testicular teratocarcinoma: report of a late relapse.
World J Surg Oncol. 2007;51.
BACKGROUND: Late relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma. CASE PRESENTATION: A 20-year-old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma. CONCLUSION: This is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life. [Abstract/Link to Full Text]

Sand M, Gelos M, Sand D, Bechara FG, Bonhag G, Welsing E, Mann B
Serum calcitonin negative medullary thyroid carcinoma.
World J Surg Oncol. 2006;497.
BACKGROUND: Medullary thyroid carcinomas (MTC) constitute about 5 to 7% of thyroid neoplasms. They originate from parafollicular C cells which produce Calcitonin, a hormone which has an impact on calcium metabolism and represents the biochemical activity of MTC. In rare cases pre-operative serum calcitonin can be negative. CASE PRESENTATION: We report on a 73-year-old female patient with a rare case of a serum calcitonin negative medullary thyroid carcinoma who suffered fulminant post-operative course and died of multiple metastasis. CONCLUSION: This case shows that in very rare cases MTCs do not secrete calcitonin making diagnosis and tumour follow-up difficult. To this date, only few reports describing this combination of circumstances were found in the English literature. [Abstract/Link to Full Text]

Bhama PK, Chugh R, Baker LH, Doherty GM
Gardner's syndrome in a 40-year-old woman: successful treatment of locally aggressive desmoid tumors with cytotoxic chemotherapy.
World J Surg Oncol. 2006;496.
BACKGROUND: Desmoid tumors that present as a part of Gardener's syndrome can present very difficult management problems. CASE PRESENTATION: We report a case of intra-abdominal desmoid tumor causing distal small bowel obstruction that complicated the management of a more proximal enterocutaneous fistula from the jejunum. After failure of more conventional management options including imatinib, the patient's disease responded to doxorubicin and ifosfamide. The response resolved the bowel obstruction and allowed small intestinal resection to resolve the enterocutaneous fistula. CONCLUSION: Systemic cytotoxic therapy with doxorubicin and ifosfamide can be useful for patients with complications from intra-abdominal desmoid tumor. [Abstract/Link to Full Text]

Ruparelia N, Ahmadi H, Cobiella C
Metastatic adenocarcinoma of the colon presenting as a monarthritis of the hip in a young patient.
World J Surg Oncol. 2006;495.
BACKGROUND: Malignant arthritis is a rare manifestation of metastatic disease. We describe the case of a previously well 28 year old man in whom hip pain was the presenting symptom of disease. We describe the case and discuss the aetiology of colorectal cancer in young patients. We then review the literature and discuss the investigation and management of malignant joint arthritis. CASE PRESENTATION: We present the case of a 28 year old man who presented to the emergency department with an acute monoarthritis of the hip. He had an unremarkable past medical history and was systemically well. A diagnosis of malignant joint effusion was reached after a heightened index of clinical suspicion, magnetic resonance imaging and cytological evaluation of the synovial fluid. Computed tomography and bone scan confirmed widespread metastatic disease from a primary colonic adenocarcinoma. The patient tolerated three cycles of oxaliplatin and capecitabine but died 4 months after presentation. CONCLUSION: The metastatic spread of cancer to the joint and the synovium is one of the rarest manifestations of malignant disease and has not been previously reported as the presenting symptom of disease. The diagnosis is a difficult one to reach and is associated with a poor prognosis. This case illustrates the importance of thorough investigation in reaching this diagnosis and entertaining the possibility in individuals who do not respond to conventional management of acute monoarthritis, even in young patients and individuals who do not display any other symptoms of disease. [Abstract/Link to Full Text]

Mizokami K, Kakeji Y, Oda S, Maehara Y
Relationship of hypoxia-inducible factor 1alpha and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer.
World J Surg Oncol. 2006;494.
BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in oxygen homeostasis. The expression of HIF-1alpha-inducible genes is associated with tumor progression. p21 mediates cell cycle arrest and is one of the downstream genes targeted by HIF-1. PATIENTS AND METHODS: We examined the relationship between HIF-1alpha and p21 expression, apoptosis and tumor progression using tissue specimens obtained surgically from 126 patients with gastric cancer. RESULTS: Immunohistochemical analysis indicated that loss of p21 expression correlated positively with patient age and tumor size. Lymph node metastasis was significantly more frequent in tumors with loss of p21 expression (P = 0.022). HIF-1alpha-positive/p21-negative tumors had a lower apoptotic index than any other tumor samples, and patients with HIF-1alpha-positive/p21-negative tumors also had a significantly poorer prognosis than the other patient populations. CONCLUSION: These results suggest that loss of HIF-1alpha-dependent p21 expression results in decreased apoptosis, increased cell survival and more aggressive tumors. [Abstract/Link to Full Text]

Marchena-Gomez J, Conde-Martel A, Hemmersbach-Miller M, Alonso-Fernandez A
Metachronic malignant transformation of small bowel and rectal endometriosis in the same patient.
World J Surg Oncol. 2006;493.
BACKGROUND: Malignant transformation of intestinal endometriosis is a rare event with an unknown rate of incidence. Metachronous progression of endometriosis to adenocarcinoma from two distant intestinal foci happening in the same patient has not been previously reported. CASE PRESENTATION: We describe a case of metachronic transformation of ileal and rectal endometriosis into an adenocarcinoma occurring in a 45-year-old female without macroscopic pelvic involvement of her endometriosis. First, a right colectomy was performed due to intestinal obstruction by an ileal mass. Pathological examination revealed an ileal endometrioid adenocarcinoma and contiguous microscopic endometriotic foci. Twenty months later, a rectal mass was discovered. An endoscopic biopsy revealed an adenocarcinoma. En bloc anterior rectum resection, hysterectomy and bilateral salpingectomy were performed. A second endometrioid adenocarcinoma arising from a focus of endometriosis within the wall of the rectum was diagnosed. CONCLUSION: Intestinal endometriosis should be considered a premalignant condition in premenopausal women. [Abstract/Link to Full Text]

Khalifa MA, Rowsell CH, Gladdy R, Ko YJ, Hanna S, Smith A, Law C
Is EGFR expression altered following postoperative chemotherapy for colorectal adenocarcinoma?
World J Surg Oncol. 2006;492.
BACKGROUND: There is immunohistochemical evidence to suggest that expression of epidermal growth factor receptor (EGFR) in primary colorectal adenocarcinoma predicts its expression in recurrent disease. This study investigates whether postoperative chemotherapy affects the degree of concordance between EGFR statuses of the two tumors. METHODS: Thirty-three patients were identified from the files of Sunnybrook Health Sciences Center from July 1994 to June 2005. All patients had resection of their primary tumors and their distant recurrences. Eighteen patients received postoperative chemotherapy, 3 of which also received postoperative radiation therapy. Representative primary and recurrent tumor sections were stained using mouse anti-EGFR antibodies and only membranous staining of malignant cells was recorded. Results were reported as negative (no staining), 1+ (positivity in <50% of cells) or 2+ (positivity in >50% of cells). RESULTS: EGFR immunostaining in the 15 patients, who received no postoperative chemotherapy, was decreased in 3 recurrences, remained the same in 10 and increased in 2. In the group of 18 patients who received postoperative chemotherapy, EGFR immunostaining was decreased in 6 recurrences, remained the same in 9 and increased in 3 (p = 0.6598). In patients who received postoperative chemotherapy, the odds ratio for a recurrence to show lower levels of EGFR immunostaining compared to its originally resected primary was 4.75 (CI = 0.94-26.73). CONCLUSION: These preliminary data suggest that recurrences following postoperative chemotherapy are likely to have lower levels of EGFR expression compared to cases who receive no chemotherapy. Although the difference of immunostaining profiles between the two groups was not statistically significant, this observation might impact the management of these patients by targeted biologic therapies and its practical implications need further validation in larger series. [Abstract/Link to Full Text]

Avninder S, Rakheja D, Bhatnagar A
Clear cell odontogenic carcinoma: a diagnostic and therapeutic dilemma.
World J Surg Oncol. 2006;491.
BACKGROUND: Clear cell odontogenic carcinoma is a rare odontogenic tumor occurring in the anterior region of the mandible in 5th-7th decades and shows a female preponderance. It is potentially aggressive, capable of frequent recurrences and loco-regional and distant metastases. CASE PRESENTATION: A 45-year-old woman presented with a radiolucent left mandibular swelling associated with loss of teeth. Left cervical lymph nodes were enlarged on palpation. The patient underwent resection of the tumor but consequent to resected margins being positive for tumor cells underwent left hemimandibulectomy with ipsilateral functional neck dissection and was free of recurrence at 8 months follow-up. CONCLUSION: Clear cell odontogenic carcinoma should be considered in the differential diagnosis of jaw tumors with conspicuous clear cell component. Curettage or conservative resection inevitably results in recurrences and/or metastasis and more radical resection is warranted in these tumors, especially when they are large and show soft tissue invasion. [Abstract/Link to Full Text]

Ogundiran TO, Ademola SA, Oluwatosin OM, Akang EE, Adebamowo CA
Primary osteogenic sarcoma of the breast.
World J Surg Oncol. 2006;490.
BACKGROUND: Primary extra-osseous osteogenic sarcomas have been reported in many tissues of the body but their occurrence in the breast is extremely rare. It can arise as a result of osseous metaplasia in a pre-existing benign or malignant neoplasm of the breast or as non-phylloides sarcoma from the soft tissue of a previously normal breast. CASE PRESENTATION: A 40 year-old Nigerian woman was clinically diagnosed to have carcinoma of the left breast. The histology report of core-needle biopsy of the mass showed a malignant neoplasm comprising islands of chondroblastic and osteoblastic stromal cells. This report changed the diagnosis from carcinoma to osteogenic sarcoma of the breast. She had a left modified radical mastectomy, however there was significant post surgery skin deficit. A latissimus dorsi musculocutaneous flap was used to cover the anterior chest wall defect. Sections from the mastectomy specimen confirmed the diagnosis of osteogenic sarcoma. She died six months after mastectomy. CONCLUSION: A diagnosis of osteogenic sarcoma of the breast was made based on histology report and after excluding an osteogenic sarcoma arising from underlying ribs and sternum. This is the second documented case of primary osteogenic sarcoma of the breast coming from Nigeria. [Abstract/Link to Full Text]

Hussain BM, Geetha N, Lali V, Pandey M
Rituximab induced hypoglycemia in non-Hodgkin's lymphoma.
World J Surg Oncol. 2006;489.
BACKGROUND: Hypoglycemia is a vary rare toxicity of rituximab. The exact mechanism of rituximab induced hypoglycemia is not clear. CASE PRESENTATION: A 50 year old female presented with a left tonsillar non Hodgkin's lymphoma and was started on R-CHOP chemotherapy. Twenty four hours after the first rituximab infusion, she developed hypoglycemia which was managed by IV glucose infusion. CONCLUSION: Hypoglycemia following rituximab administration is rare. Possibilities of hypoglycemia should be kept in mind in patients developing symptoms like fatigue, restlessness, and sweating while on rituximab therapy. [Abstract/Link to Full Text]

Vieni S, Cabibi D, Cipolla C, Fricano S, Graceffa G, Latteri MA
Secretory breast carcinoma with metastatic sentinel lymph node.
World J Surg Oncol. 2006;488.
BACKGROUND: Secretory mammary carcinoma is a rare breast neoplasia originally described in children but sometimes also found in adults. It presents a more favourable outcome than more common histological types of breast carcinoma; published literature in fact reports only a few cases with axillary lymph node metastases and only four cases with distant metastases. CLINICAL PRESENTATION: In this paper we report a rare case of secretory breast carcinoma with axillary lymph node metastases in a 33-year-old woman. To our knowledge, this is the first case of secretory carcinoma involving biopsy of the sentinel lymph node and investigation of the e-cadherin expression.We found positivity for e-cadherin, which would support the hypothesis that this type of tumour is a variant of the infiltrating ductal carcinoma. CONCLUSION: After a careful analysis of reported data, we have come to the conclusion that the treatment of choice for patients with secretory breast carcinoma should be conservative surgery with sentinel lymph node biopsy, followed by accurate follow-up. We are of the opinion that while post-operative radiotherapy is indicated in adult patients who have undergone quadrantectomy, it should not be used in children. Although several cases of secretory carcinoma have been treated with adjuvant chemotherapy, there are still no reliable data regarding the real value of such a choice. [Abstract/Link to Full Text]

Head CS, Luu Q, Sercarz J, Saxton R
Photodynamic therapy and tumor imaging of hypericin-treated squamous cell carcinoma.
World J Surg Oncol. 2006;487.
BACKGROUND: Conventional cancer therapy including surgery, radiation, and chemotherapy often are physically debilitating and largely ineffective in previously treated patients with recurrent head and neck squamous cell carcinoma (SCC). A natural photochemical, hypericin, could be a less invasive method for laser photodynamic therapy (PDT) of these recurrent head and neck malignancies. Hypericin has powerful photo-oxidizing ability, tumor localization properties, and fluorescent imaging capabilities as well as minimal dark toxicity. The current study defined hypericin PDT in vitro with human SCC cells before the cells were grown as tumor transplants in nude mice and tested as a model for hypericin induced tumor fluorescence and PDT via laser fiberoptics. METHODS: SNU squamous carcinoma cells were grown in tissue culture, detached from monolayers with trypsin, and incubated with 0.1 microg to 10 microg/ml of hypericin before exposure to laser light at 514, 550, or 593 nm to define optimal dose, time, and wavelength for PDT of tumor cells. The SCC cells also were injected subcutaneously in nude mice and grown for 6-8 weeks to form tumors before hypericin injection and insertion of fiberoptics from a KTP532 surgical laser to assess the feasibility of this operating room instrument in stimulating fluorescence and PDT of tumors. RESULTS: In vitro testing revealed a hypericin dose of 0.2-0.5 microg/ml was needed for PDT of the SCC cells with an optimal tumoricidal response seen at the 593 nm light absorption maximum. In vivo tumor retention of injected hypericin was seen for 7 to 10 days using KTP532 laser induced fluorescence and biweekly PDT via laser fiberoptics led to regression of SCC tumor transplants under 0.4 cm2 diameter, but resulted in progression of larger size tumors in the nude mice. CONCLUSION: In this preclinical study, hypericin was tested for 514-593 nm dye laser PDT of human SCC cells in vitro and for KTP532 surgical laser targeting of SCC tumors in mice. The results suggest hypericin is a potent tumor imaging agent using this surgical laser that may prove useful in defining tumor margins and possibly in sterilizing post-resection margins. Deeply penetrating pulsed infrared laser emissions will be needed for PDT of larger and more inaccessible tumors. [Abstract/Link to Full Text]

Recent Articles in Journal of Carcinogenesis

No recent articles are currently available.

Recent Articles in The Oncologist

Jamali FR, Darwiche SS, El-Kinge N, Tawil A, Soweid AM
Disease progression following imatinib failure in gastrointestinal stromal tumors: role of surgical therapy.
Oncologist. 2007 Apr;12(4):438-42.
Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal neoplasms of the GI tract. The optimal management of GISTs has been evolving rapidly over the past 5 years and depends on proper histopathologic and radiologic diagnosis as well as appropriate multidisciplinary medical and surgical treatments. Complete surgical resection of primary localized GIST with negative margins remains the best therapeutic option today. In the setting of locally advanced or metastatic disease, imatinib mesylate has emerged as the initial treatment of choice, administered either as cytoreductive or as definitive treatment. Surgery or ablative modalities in this setting are becoming increasingly employed, particularly when all disease becomes amenable to gross resection or destruction, or to manage complications arising from the disease following imatinib failure. We report on the surgical management of an unusual and clinically significant complication following progression of disease secondary to imatinib resistance. The role of surgical therapy in the management of GIST complications following resistance to imatinib and the integration of surgical and molecular therapy of locally advanced or metastatic GISTs are discussed. [Abstract/Link to Full Text]

Strumberg D, Clark JW, Awada A, Moore MJ, Richly H, Hendlisz A, Hirte HW, Eder JP, Lenz HJ, Schwartz B
Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.
Oncologist. 2007 Apr;12(4):426-37.
Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer. [Abstract/Link to Full Text]

Pentheroudakis G, Briasoulis E, Pavlidis N
Cancer of unknown primary site: missing primary or missing biology?
Oncologist. 2007 Apr;12(4):418-25.
Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths and represents both a diagnostic and a management challenge. In CUP, the regression or dormancy of the primary tumor, the development of early, uncommon, systemic metastases, and the resistance to therapy are hallmarks of this heterogeneous clinical entity. Still, no consensus exists on whether CUP is simply a group of metastatic tumors with unidentified primaries or a distinct entity with specific genetic/phenotypic aberrations that define it as "primary metastatic disease." In this review, we present karyotypic analyses as well as the single-gene, single-protein studies done on the expression of oncogenes, tumor- or metastasis-suppressor genes, as well as angiogenesis effectors. These studies show frequent expression of oncoproteins, lack of activating epidermal growth factor receptor/c-Kit mutations or amplification, uncommon presence of tumor- or metastasis-suppressor gene mutations and highly active angiogenesis in CUP. Informative as they may be, these data have been observed in several solid tumors of known primary and failed to identify a CUP-specific molecular signature. The latter, if it exists, probably consists of a multigene expression pattern not captured by single-gene studies. Gene and protein microarray technologies offer promise for the unraveling of complex genetic programs that would either identify each CUP's primary tissue of origin or instead define the CUP-specific molecular signature. Confirmation of one of the two hypotheses would either improve primary disease-oriented therapy or develop CUP-oriented treatments targeting molecular aberrations that drive neoplastic growth/dissemination. [Abstract/Link to Full Text]

Hirasaki S, Noguchi T, Mimori K, Onuki J, Morita K, Inoue H, Sugihara K, Mori M, Hirano T
BAC clones related to prognosis in patients with esophageal squamous carcinoma: an array comparative genomic hybridization study.
Oncologist. 2007 Apr;12(4):406-17.
PURPOSE: The prognosis of patients with esophageal carcinoma is poor. To identify genomic alterations associated with poor patient prognosis, we analyzed whole DNA copy number profiles of esophageal squamous carcinomas (ESCs) using array-based comparative genomic hybridization (aCGH). MATERIALS AND METHODS: Twenty-one operated and two biopsied cases of esophageal squamous cancer were examined for study. Each sample was laser microdissected to obtain pure cancer cell populations. The extracted DNA was analyzed using aCGH. RESULTS: One of the most representative alterations was a previously reported amplification at 11q13.3. In addition, some novel alterations, such as deletion of 16p13.3, were identified. Of the 19 patients who were reassessed more than 5 years after the operation, nine were still living and 10 had died from disease recurrence. When aCGH profiles from the surviving group and the deceased group were compared, significant differences were recognized in 68 of 4,030 bacterial artificial chromosome (BAC) clones. Almost half of these clones were present at nine limiting regions in 4q, 13q, 20q, and Xq. For 22 of these 68 BAC clones, there also was a significant difference in the Kaplan-Meier survival curve, using the log-rank test, when comparing patients who had an alteration in a particular clone with those who did not. CONCLUSIONS: aCGH study of esophageal squamous cancer clearly identified BAC clones that are related to the prognosis of patients. These clones give us the opportunity to determine specific genes that are associated with cancer progression. [Abstract/Link to Full Text]

J�rgensen JT, Nielsen KV, Ejlertsen B
Pharmacodiagnostics and targeted therapies - a rational approach for individualizing medical anticancer therapy in breast cancer.
Oncologist. 2007 Apr;12(4):397-405.
The selection of therapy for a particular breast cancer patient is traditionally based on average results from randomized clinical trials. Rational pharmacotherapy is in essence about selecting the right drug(s) for the right patient, and in order to guide this selection process pharmacodiagnostic tests are indispensable. A number of tests have been developed or are under development for targeted therapies, such as antiestrogens, human epidermal growth factor receptor 2 inhibitors, and topoisomerase inhibitors. Based on a biopsy from the tumor, the tests are able to identify patients with a high probability to benefit from these therapies. The detection of the predictive biomarkers is based on different technologies, such as immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization. Pharmacodiagnostic tests will play an important role in the further development of targeted therapies and may be seen as a prerequisite for the introduction of individualized medicine in oncology. [Abstract/Link to Full Text]

Penault-Llorca F, Abrial C, Mouret-Reynier MA, Raoelfils I, Durando X, Leheurteur M, Gimbergues P, Tortochaux J, Cur� H, Chollet P
Achieving higher pathological complete response rates in HER-2-positive patients with induction chemotherapy without trastuzumab in operable breast cancer.
Oncologist. 2007 Apr;12(4):390-6.
Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2-positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti-HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2-positive patients (23.5%) than for HER-2-negative patients (7%). The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2-negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2-negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2-positive patients who achieved a pCR compared with HER-2-positive patients who did not. [Abstract/Link to Full Text]

Tripathy D
Capecitabine in combination with novel targeted agents in the management of metastatic breast cancer: underlying rationale and results of clinical trials.
Oncologist. 2007 Apr;12(4):375-89.
At present there is no established standard of care for metastatic breast cancer and prognosis remains poor, although the use of newer chemotherapeutic regimens has led to modest improvements in survival. Capecitabine, an oral prodrug of 5-fluorouracil, is a promising addition to these approaches, having already shown single-agent activity against metastatic breast cancer. Following a pivotal trial demonstrating that capecitabine confers increased survival when used in combination with docetaxel, it is being investigated intensively in combined regimens using other standard chemotherapeutic agents, as well as with novel molecularly targeted therapies. Among the novel agents, the most intensively studied in combination with capecitabine is trastuzumab. Despite preclinical data suggesting that these two agents might not show additive effects, clinical trials have been very encouraging for both heavily pretreated patients and for patients receiving first-line therapy in the metastatic setting. This work is being further extended in an ongoing trial in the neoadjuvant setting. An initial trial in combination with bevacizumab, enrolling heavily pretreated patients, was less successful, but following the example of the E2100 trial, this combination is being re-examined in less heavily treated patients. In addition, this review discusses ongoing trials with an array of newer molecularly targeted agents. Significant improvement in time to progression has already been demonstrated in the combination of lapatinib and capecitabine compared with capecitabine monotherapy; for the most part, however, these trials are still in early stages. [Abstract/Link to Full Text]

Stanway SJ, Delavault P, Purohit A, Woo LW, Thurieau C, Potter BV, Reed MJ
Steroid sulfatase: a new target for the endocrine therapy of breast cancer.
Oncologist. 2007 Apr;12(4):370-4.
Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women. [Abstract/Link to Full Text]

Koop CE
Health and health care for the 21st century: for all the people.
Oncologist. 2007 Apr;12(4):366-9. [Abstract/Link to Full Text]

Koop CE
Health and health care for the 21st century: for all the people.
Am J Public Health. 2006 Dec;96(12):2090-2. [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]

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]

Cohen MH, Gootenberg J, Keegan P, Pazdur R
FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer.
Oncologist. 2007 Mar;12(3):356-61.
On June 20, 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), administered in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) for the second-line treatment of metastatic carcinoma of the colon or rectum. Efficacy and safety were demonstrated in one Eastern Cooperative Oncology Group (ECOG) open-label, multicenter, randomized, three-arm, active-controlled trial enrolling 829 adult patients. Patients had received a fluoropyrimidine- and irinotecan-based regimen as initial therapy for metastatic disease; or they had received prior adjuvant irinotecan-based chemotherapy and had recurred within 6 months of completing therapy. Treatments included bevacizumab, 10 mg/kg, as a 90-minute i.v. infusion on day 1, every 2 weeks, either alone or in combination with FOLFOX4, or FOLFOX4 alone. The bevacizumab monotherapy arm was closed to accrual after an interim efficacy analysis suggested a possibly shorter survival in that arm. Overall survival (OS), the primary study endpoint, was significantly longer for patients receiving bevacizumab in combination with FOLFOX4 than for those receiving FOLFOX4 alone. The objective response rate was significantly higher in the FOLFOX4 plus bevacizumab arm than in the FOLFOX4 alone arm. The duration of response was approximately 6 months for both treatment arms. Patients treated with the bevacizumab combination were also reported, based on investigator assessment, to have significantly longer progression-free survival. There were no new bevacizumab safety signals. The most serious, and sometimes fatal, bevacizumab toxicities are gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure. [Abstract/Link to Full Text]

Meshinchi S, Arceci RJ
Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia.
Oncologist. 2007 Mar;12(3):341-55.
Acute myeloid leukemia (AML) has posed significant therapeutic challenges to pediatric oncologists. Despite intensive therapy, half of the children with AML relapse and die from their disease. Efforts to identify risk factors in AML are directed toward defining populations who may benefit from alternative therapies. Patients at lower risk for relapse may benefit from treatment de-escalation, sparing them adverse side effects. Management of high-risk patients may prove more difficult, as the nearly myeloablative nature of AML therapy leaves little room for therapy escalation short of stem cell transplantation. This review evaluates prognostic factors in pediatric AML and discusses the feasibility of using these factors in risk-adapted therapy regimens. [Abstract/Link to Full Text]

Hayslip J, Fenning R
Safe administration of iodine-131 tositumomab after repeated infusion-related reactions to rituximab.
Oncologist. 2007 Mar;12(3):338-40.
Infusion-related reactions during administration of monoclonal antibody therapy are often mild and unlikely to recur with subsequent treatment. If patients experience another severe reaction upon reattempting treatment, future treatments with the same agent are typically not pursued. It is unclear whether different monoclonal antibodies that bind the same tumor cell or antigen are likely to induce similar infusion reactions. Here, we report the case of a patient with repeated severe infusion reactions with rituximab who subsequently safely received treatment with iodine-131 tositumomab and discuss the relevant literature. [Abstract/Link to Full Text]

Wakelee H, Dubey S, Gandara D
Optimal adjuvant therapy for non-small cell lung cancer--how to handle stage I disease.
Oncologist. 2007 Mar;12(3):331-7.
The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration. [Abstract/Link to Full Text]

Sequist LV
Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.
Oncologist. 2007 Mar;12(3):325-30.
Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strategy for treating non-small cell lung cancer (NSCLC) patients and the first generation of agents developed for this purpose, gefitinib and erlotinib, stimulated a unique escalation in both biologic and clinical research within the field. Second-generation EGFR-targeted agents that aim to further improve patient outcomes are now in preclinical and clinical trials. This review discusses four promising agents that are currently being studied in NSCLC: EKB-569, HKI-272, CI-1033, and ZD6474. [Abstract/Link to Full Text]

Ishikawa K, Sasaki A, Haraguchi N, Yoshikawa Y, Mori M
A case of an alpha-fetoprotein-producing intrahepatic cholangiocarcinoma suggests probable cancer stem cell origin.
Oncologist. 2007 Mar;12(3):320-4.
Recent evidence suggests that some cancers may originate from cancer stem cells, which may derive from carcinogenesis of normal stem cells. A hepatic progenitor cell population, which gives rise to hepatocytes and cholangiocytes, has been suggested in humans, though whether these cells can give rise to malignant tumors has not been confirmed. We report here a case of an alpha-fetoprotein (AFP)-producing intrahepatic cholangiocarcinoma (ICC) in an 81-year-old woman with chronic hepatitis C viral infection, suggesting malignant transformation of hepatic stem cells as a mechanism for hepatic neoplasia. Abdominal computed tomography revealed a low-density mass with surrounding enhancement measuring 5 cm x 5 cm in segments IV and VIII of the liver. The preoperative serum levels of tumor markers were 1.7 ng/ml of carcinoembryonic antigen, 22 mAU/ml of protein induced by vitamin K absence or antagonist II, 43.4 U/ml of carbohydrate antigen 19-9, and 1,560 ng/ml of AFP. Following central bisegmentectomy of the liver, serum AFP levels decreased dramatically. Histologically, the tumor cells showed indistinct glandular structures with abundant fibrous stroma. Immunohistochemical analysis demonstrated that the neoplastic cells reacted strongly to antibodies against AFP and cytokeratin (CK) 7. In addition, cancer cells showed partially positive reaction to anti-CK14, a liver stem cell marker, and to anticluster designation (CD) 133, a hematopoietic stem cell marker, and negative reaction to antihepatocyte paraffin (HepPar) 1. These data may indicate that the tumor was derived from a normal liver stem cell that underwent oncogenic transformation. [Abstract/Link to Full Text]

Wang WS, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Chiou TJ, Liu JH, Yen CC, Chen PM
Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients.
Oncologist. 2007 Mar;12(3):312-9.
Oxaliplatin is effective in the treatment of metastatic colorectal cancer (MCRC) patients; however, severe neurotoxicity develops frequently. To assess the efficacy of oral glutamine for preventing neuropathy induced by oxaliplatin, a pilot study was performed. A total of 86 patients with MCRC treated at Taipei Veterans General Hospital were enrolled. Oxaliplatin (85 mg/m(2), days 1 and 15) plus weekly bolus 5-fluorouracil (5-FU; 500 mg/m(2)) and folinic acid (FA; 20 mg/m(2)) on days 1, 8, and 15 were given every 28 days as first-line treatment. Patients were randomized to receive (glutamine group; n = 42) or not receive (control group; n = 44) glutamine (15 g twice a day for seven consecutive days every 2 weeks starting on the day of oxaliplatin infusion). Efficacy of chemotherapy, neurological toxicity, and electrophysiological alterations were assessed. A lower percentage of grade 1-2 peripheral neuropathy was observed in the glutamine group (16.7% versus 38.6%) after two cycles of treatment, and a significantly lower incidence of grade 3-4 neuropathy was noted in the glutamine group after four cycles (4.8% versus 18.2%) and six cycles (11.9% versus 31.8%). By adding glutamine, interference with activities of daily living was lower (16.7% versus 40.9%), and need for oxaliplatin dose reduction was lower (7.1% versus 27.3%). There were no significant between-group differences in response to chemotherapy (52.4% versus 47.8%), electrophysiological abnormalities, grade 3-4 non-neurological toxicities (26.2% versus 22.8%), or survival. These data indi-cate that oral glutamine significantly reduces the incidence and severity of peripheral neuropathy of MCRC patients receiving oxaliplatin without affecting response to chemotherapy and survival. [Abstract/Link to Full Text]

Ioannidis JP
Is molecular profiling ready for use in clinical decision making?
Oncologist. 2007 Mar;12(3):301-11.
Molecular profiling, the classification of tissue or other specimens for diagnostic, prognostic, and predictive purposes based on multiple gene expression, is a technology that holds major promise for optimizing the management of patients with cancer. However, the use of these tests for clinical decision making presents many challenges to overcome. Assay development and data analysis in this field have been largely exploratory, and leave numerous possibilities for the introduction of bias. Standardization of profiles remains the exception. Classifier performance is usually overinterpreted by presenting the results as p-values or multiplicative effects (e.g., relative risks), while the absolute sensitivity and specificity of classification remain modest at best, especially when tested in large validation samples. Validation has often been done with suboptimal attention to methodology and protection from bias. The postulated classifier performance may be inflated compared to what these profiles can achieve. With the exception of breast cancer, we have little evidence about the incremental discrimination that molecular profiles can provide versus classic risk factors alone. Clinical trials have started to evaluate the utility of using molecular profiles for breast cancer management. Until we obtain data from these trials, the impact of these tests and the net benefit under real-life settings remain unknown. Optimal incorporation into clinical practice is not straightforward. Finally, cost-effectiveness is difficult to appreciate until these other challenges are addressed. Overall, molecular profiling is a fascinating and promising technology, but its incorporation into clinical decision making requires careful planning and robust evidence. [Abstract/Link to Full Text]

Engels FK, de Jong FA, Sparreboom A, Mathot RA, Loos WJ, Kitzen JJ, de Bruijn P, Verweij J, Mathijssen RH
Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel.
Oncologist. 2007 Mar;12(3):291-300.
OBJECTIVE: To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. PATIENTS AND METHODS: Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. RESULTS: Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). CONCLUSION: Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments. [Abstract/Link to Full Text]

Armand JP, Burnett AK, Drach J, Harousseau JL, L�wenberg B, San Miguel J
The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib.
Oncologist. 2007 Mar;12(3):281-90.
As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer. [Abstract/Link to Full Text]

Cortes J, Baselga J
Targeting the microtubules in breast cancer beyond taxanes: the epothilones.
Oncologist. 2007 Mar;12(3):271-80.
Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer. [Abstract/Link to Full Text]

Colozza M, de Azambuja E, Personeni N, Lebrun F, Piccart MJ, Cardoso F
Achievements in systemic therapies in the pregenomic era in metastatic breast cancer.
Oncologist. 2007 Mar;12(3):253-70.
Over the last decades, the introduction of several new agents into clinical practice has significantly improved disease control and obtained some, albeit rare, survival benefits in metastatic breast cancer (MBC). Despite these results, the choice of treatment for the majority of patients is still empirically based, since the only two predictive factors with level 1 evidence for clinical use are hormonal receptor status for endocrine therapy and HER-2 status for trastuzumab therapy. Important improvements in the endocrine therapy of both pre- and postmenopausal women with hormone-responsive disease have been achieved. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogs combined with tamoxifen has become the standard treatment, although aromatase inhibitors plus ovarian function suppression are under evaluation. In postmenopausal patients, aromatase inhibitors have proved to be superior to standard endocrine therapies in either first- or second-line treatment and a novel antiestrogen compound, fulvestrant, has been introduced in clinical practice. Chemotherapy remains the treatment of choice for hormone unresponsive or resistant patients. Anthracyclines and taxanes have been used either alone or in combination as first-line chemotherapy, but with the more frequent use of these agents in the adjuvant setting, new standards are needed for first-line chemotherapy, and new and more efficacious treatments are required. In the subgroup of patients with tumors that overexpress HER-2, the use of trastuzumab alone or in combination with chemotherapy has modified the natural history of these tumors, even if only about one out of two patients obtains a clinical response. In this review we summarize the main achievements and the currently available treatment options for patients with MBC. [Abstract/Link to Full Text]

Zerhouni EA, Sanders CA, von Eschenbach AC
The Biomarkers Consortium: public and private sectors working in partnership to improve the public health.
Oncologist. 2007 Mar;12(3):250-2. [Abstract/Link to Full Text]

Chabner BA, Roberts TG
The FDA in 2006: reasons for optimism.
Oncologist. 2007 Mar;12(3):247-9. [Abstract/Link to Full Text]

Johnston PG
Bruce Chabner awarded the Bob Pinedo Prize: a celebration of translational research and patient care excellence.
Oncologist. 2007 Mar;12(3):244-6. [Abstract/Link to Full Text]

Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR
Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy.
Oncologist. 2007 Feb;12(2):231-42.
PURPOSE: To evaluate the safety and efficacy of intravenous (IV) sodium ferric gluconate complex (FG), oral ferrous sulfate, or no iron to increase hemoglobin (Hb) in anemic cancer patients receiving chemotherapy and epoetin alfa. PATIENTS AND METHODS: In this open-label, multicenter trial, 187 patients with chemotherapy-related anemia (Hb <11 g/dl; serum ferritin > or =100 ng/ml or transferrin saturation > or =15%) scheduled to receive chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate three times daily, or no iron. The primary outcome was a change in Hb from baseline to endpoint, first whole-blood or red blood cell transfusion, or study withdrawal. RESULTS: One hundred twenty-nine patients were evaluable for efficacy (FG, n = 41; oral iron, n = 44; no iron, n = 44). Mean increase in Hb was 2.4 g/dl (95% confidence interval [CI], 2.1-2.7) for FG (p = .0092 vs. oral iron; p = .0044 vs. no iron), 1.6 g/dl (95% CI, 1.1-2.1) for oral iron (p =.7695 vs. no iron), and 1.5 g/dl (95% CI, 1.1-1.9) for no iron. Hb response (increase > or =2 g/dl) was 73% for FG (p = .0099 vs. oral iron; p = .0029 vs. no iron), 46% for oral iron (p = .6687 vs. no iron), and 41% for no iron. FG was well tolerated. CONCLUSION: For cancer patients with chemotherapy-related anemia receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients. [Abstract/Link to Full Text]

Lai YH, Shun SC, Hsiao YL, Chiou JF, Wei LL, Tsai JT, Kao CY
Fatigue experiences in hepatocellular carcinoma patients during six weeks of stereotactic radiotherapy.
Oncologist. 2007 Feb;12(2):221-30.
PURPOSE: To compare fatigue experiences and related factors during the first 6 weeks of stereotactic radiotherapy (SRT) for liver cancer patients with and without fatigue before SRT. PATIENTS AND METHODS: Subjects (n = 91) were liver cancer patients receiving SRT at two teaching hospitals in northern Taiwan. Data were collected at seven times: the week before SRT (T0) and the end of each of the first 6 weeks of SRT (T1, T2, T3, T4, T5, and T6). Study variables were fatigue intensity, fatigue interference (with patients' daily life), functional status, symptom distress, sleep disturbance, depressive status, radiation dose, stage of cancer, and selected laboratory data. RESULTS: Subjects were divided at T0 into two groups by fatigue level: those without (group 1, n = 32) and with (group 2, n = 59) pretreatment fatigue distress. Patients in group 2 had higher levels of fatigue intensity and interference than did patients in group 1. Both groups had similar patterns of fatigue interference, peaking at T5. However, patterns of average fatigue intensity differed slightly. In group 2, fatigue intensity remained constant until T3 and then increased to a peak at T5. In group 1, fatigue intensity increased to a peak between T4 and T5. Generalized estimating equation analysis showed significant differences between groups in fatigue intensity and interference across 6 weeks. Examination of factors related to fatigue after SRT indicated that sleep disturbance significantly predicted both fatigue intensity and interference in group 1, but depressive status, overall symptom distress, and education level predicted fatigue intensity and interference for group 2. CONCLUSION: Liver cancer patients with or without fatigue before treatment had different fatigue experiences across 6 weeks of radiation therapy. Fatigue experiences of liver cancer patients receiving SRT can be better understood through future studies exploring patients' long-term fatigue changes and responses to fatigue-management interventions. [Abstract/Link to Full Text]

Toschi L, Cappuzzo F
Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors.
Oncologist. 2007 Feb;12(2):211-20.
The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy. [Abstract/Link to Full Text]

Ara�jo A, Ribeiro R, Azevedo I, Coelho A, Soares M, Sousa B, Pinto D, Lopes C, Medeiros R, Scagliotti GV
Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature.
Oncologist. 2007 Feb;12(2):201-10.
Worldwide, approximately 1.3 billion individuals are current smokers, and smoking is the second major cause of death. Currently, lung cancer is the most common type of cancer in Europe, and the third in the U.S. Until now, cytotoxic chemotherapy has had a limited impact on survival in metastatic non-small cell lung cancer (NSCLC). The central role of epidermal growth factor (EGF) and its receptor (EGFR) in lung carcinogenesis is well recognized. Genetic polymorphisms are variants in individual genomes that may be responsible for different functional molecular roles and contribute to variability in drug pharmacokinetic and pharmacodynamic processes. Herein, we review the literature on EGF and EGFR functions and activities, particularly the current role of their functional polymorphisms as related to NSCLC. [Abstract/Link to Full Text]

Gridelli C, Maione P, Del Gaizo F, Colantuoni G, Guerriero C, Ferrara C, Nicolella D, Comunale D, De Vita A, Rossi A
Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer.
Oncologist. 2007 Feb;12(2):191-200.
Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC. [Abstract/Link to Full Text]

Markman M
New, expanded, and modified use of approved antineoplastic agents in ovarian cancer.
Oncologist. 2007 Feb;12(2):186-90.
Over the past several years, clinical research efforts in ovarian cancer employing a number of U.S. Food and Drug Administration (FDA)-approved antineoplastic agents have permitted the development of approaches that both improve the effectiveness and decrease the toxicities of systemic therapy of ovarian cancer. These initiatives, including prospective trials and retrospective examinations of large clinical experience, have involved agents previously approved by the FDA for use in ovarian cancer (e.g., cisplatin, paclitaxel, topotecan, and liposomal doxorubicin) and the development of new strategies for drugs approved for other malignant conditions (e.g., gemcitabine, docetaxel, etoposide, irinotecan, vinorelbine, and bevacizumab). It can be anticipated that future studies involving novel approved agents will further expand the oncologist's weapons against ovarian cancer. [Abstract/Link to Full Text]

Gee DW, Rattner DW
Management of gastroesophageal tumors.
Oncologist. 2007 Feb;12(2):175-85.
The incidence of adenocarcinomas of the gastroesophageal junction has increased in recent years. These tumors possess distinct pathophysiologic characteristics. Although the consensus is that an R0 resection (complete microscopic and macroscopic resection) is the goal when operating for curative intent, much controversy remains regarding other aspects of patient management. There is lack of consensus regarding the type of surgery to perform, the role and extent of lymphadenectomy, and the role of neoadjuvant therapy. Utilizing an evidence-based approach, this review article provides an overview of the management of gastroesophageal junction carcinomas with particular emphasis on current areas of controversy. [Abstract/Link to Full Text]

Mitchell IC, Nwariaku FE
Adrenal masses in the cancer patient: surveillance or excision.
Oncologist. 2007 Feb;12(2):168-74.
An increasing number of patients with a history of solid organ malignancy now undergo surveillance imaging as part of their follow-up or for evaluation of other conditions. This imaging has led to both greater identification of asymptomatic adrenal masses and subsequent confusion among clinicians regarding the evaluation and treatment. Although established algorithms exist for treating such "incidentalomas" in otherwise healthy patients, the most effective way to do so in patients with known prior or concurrent malignancies is unclear. In this review, we explore methods of biochemical testing in such patients and discuss the role of imaging techniques in their ability to differentiate benign versus malignant lesions. In this population, we examine the increasing use of biopsy and discuss current data on both surveillance and resection of lesions based on their identity. Finally, we propose an algorithm to aid the clinician in evaluating and treating these complex patients efficiently. [Abstract/Link to Full Text]

Byrne BJ, Gockerman JP
Salvage therapy in Hodgkin's lymphoma.
Oncologist. 2007 Feb;12(2):156-67.
Hodgkin's disease is a rare malignancy that affects approximately 7,500 patients per year in the U.S., leading to an estimated 1,400 deaths. The relapse rate for this disease varies from around 5% for early-stage disease to 35% for patients with advanced disease. Patients who relapse after chemotherapy have about a 20% cure rate with conventional salvage chemotherapy. Two randomized phase III studies have shown an improved failure-free survival rate with high-dose chemotherapy and autologous stem cell support compared with conventional chemotherapy in relapsed patients. They failed to show any improvement in overall survival. For patients who experience failure with autologous transplant, the options of single-agent chemotherapy with gemcitabine, vinblastine, or vinorelbine can be used for palliation. Standard myeloablative allogeneic bone marrow transplant has a high mortality rate in this population. Allogeneic transplant regimens with reduced intensity are currently being studied in clinical trials. Further studies on the use of monoclonal antibodies and radiolabeled antibodies need to be conducted to define their role in the treatment of Hodgkin's disease. [Abstract/Link to Full Text]

Schellens JH
Capecitabine.
Oncologist. 2007 Feb;12(2):152-5. [Abstract/Link to Full Text]

James CR, Quinn JE, Mullan PB, Johnston PG, Harkin DP
BRCA1, a potential predictive biomarker in the treatment of breast cancer.
Oncologist. 2007 Feb;12(2):142-50.
To date, estrogen receptor, progestogen receptor, and HER2/neu represent molecular biomarkers currently used in routine clinical practice to aid treatment decisions. Over the last few years, a large body of preclinical and retrospective clinical data has accumulated that suggests that BRCA1 mutation functions as a novel predictive marker of response to chemotherapy. This article reviews the role of BRCA1 as a predictive marker of chemotherapy response in breast cancer and examines the link between BRCA1 deficiency and the basal-like phenotype. Search strategy. Data for this article were identified through MEDLINE and PubMed searches for published reports using the terms BRCA1, breast cancer, basal-like, chemotherapy, prognosis, and predictive markers. In some cases, due to the restriction of space, readers are referred to review articles to allow further reading. Only articles published in English were included. [Abstract/Link to Full Text]

Zerhouni EA, Sharp PA, Leavitt M, Niederhuber JE
Investiture of John E. Niederhuber, M.D., director of National Cancer Institute.
Oncologist. 2007 Feb;12(2):136-41. [Abstract/Link to Full Text]

Sequist LV, Joshi VA, J�nne PA, Muzikansky A, Fidias P, Meyerson M, Haber DA, Kucherlapati R, Johnson BE, Lynch TJ
Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing.
Oncologist. 2007 Jan;12(1):90-8.
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response and prolonged survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). We began screening patients for somatic EGFR mutations by DNA sequencing as part of clinical care in 2004. We performed a retrospective cohort study of 278 patients with NSCLC referred for EGFR testing over a 10-month period. Tumor samples underwent direct DNA sequence analyses of EGFR exons 18 through 24. We determined the clinical characteristics and EGFR mutation status of the patients and analyzed their response to therapy and survival. EGFR somatic mutations were identified in 68 (24%) of patients. A minimal smoking history was the strongest clinical predictor of harboring a mutation. In multivariable analyses, each pack-year of smoking corresponded to a 5% decreased likelihood of having an EGFR mutation. Among 92 patients with unresectable disease undergoing subsequent systemic therapy, EGFR mutations were associated with an increased response rate to EGFR TKIs (p < .0001) but not chemotherapy. Overall survival was significantly prolonged in EGFR mutation-positive patients (p = .001), with a median survival of 3.1 years compared with 1.6 years in mutation-negative patients, after adjusting for age, gender, and stage at diagnosis. Integrating molecular profiling into clinical care is feasible in NSCLC patients and provides useful clinical information. [Abstract/Link to Full Text]

Carpenter JS, Storniolo AM, Johns S, Monahan PO, Azzouz F, Elam JL, Johnson CS, Shelton RC
Randomized, double-blind, placebo-controlled crossover trials of venlafaxine for hot flashes after breast cancer.
Oncologist. 2007 Jan;12(1):124-35.
BACKGROUND: Although venlafaxine reduces self-reported hot flashes, no data have established the drug's impact on physiologically documented hot flashes. Two randomized, double-blind, placebo-controlled crossover trials examined the efficacy of two doses of venlafaxine in relation to physiological and self-reported hot flashes and other outcomes, including negative affect, fatigue, sleep, and quality of life. METHODS: Sample: 57 breast cancer survivors in the low-dose study; 20 in the high-dose study. Setting: university cancer clinics in the Southeast and Midwest. Intervention: 37.5 mg of venlafaxine (low-dose study) or 75 mg of venlafaxine (high-dose study). Measures: hot flash frequency (physiological monitor, diary, and event marker), hot flash severity (diary), hot flash bother (diary), and questionnaires for hot flash impact on daily life, negative affect, fatigue, sleep, and quality of life. RESULTS: Subjective but not physiological hot flash measures showed placebo effects. Venlafaxine resulted in modest decreases in hot flashes, but only hot flash interference improved differentially at the higher dose. The timing of venlafaxine's effects on hot flashes varied by dose. Only women with a > or =50% decrease in physiological hot flashes experienced significant improvement in fatigue, sleep quality, and quality of life. Although side effects were mild, most patients discontinued venlafaxine long-term. CONCLUSIONS: Although venlafaxine resulted in modest and acute reductions in hot flashes with few side effects, it may not be tolerable to some patients long-term. At least 50% relief in physiological hot flashes may be needed for patients to demonstrate improvement in other outcomes, including decreased fatigue, improved sleep, and improved quality of life. [Abstract/Link to Full Text]

Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W
A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma.
Oncologist. 2007 Jan;12(1):114-23.
BACKGROUND: Despite a decreased incidence of AIDS-related Kaposi's sarcoma (KS) due to the advent of highly active antiretroviral therapy, approximately 15% of AIDS patients still develop AIDS-related KS. This study evaluated the clinical benefit, tumor response, and safety of pegylated liposomal doxorubicin for the treatment of AIDS-related KS. METHODS. This was a double-blind, multicenter study that randomized patients with AIDS-related KS to six cycles of pegylated liposomal doxorubicin (20 mg/m2; n = 60) or liposomal daunorubicin (40 mg/m2; n = 19) every 2 weeks. Clinical benefit was assessed using patient questionnaires and monitoring of KS-associated symptoms. Tumor responses were assessed using imaging techniques, direct measurement of skin lesions, and photographs, when possible. RESULTS. Clinical benefit was observed in 48/60 patients (80%) receiving pegylated liposomal doxorubicin and was maintained for a median of 62 days (range, 28-107 days). Clinical benefit was achieved by 12/19 patients (63.2%) receiving liposomal daunorubicin and was maintained for a median of 55 days (range, 28-84 +days). Clinical benefit correlated with tumor response. Tumor responses were achieved by 55.0% of patients receiving pegylated liposomal doxorubicin and 31.6% of patients receiving liposomal daunorubicin. Response rates were similar within each treatment group when only those patients without changes in antiretroviral therapy during treatment were considered. Adverse events associated with pegylated liposomal doxorubicin were neutropenia (30%), nausea (28.3%), and asthenia (16.7%). CONCLUSIONS. Pegylated liposomal doxorubicin is safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit, tumor response, or both. [Abstract/Link to Full Text]

Rock EP, Goodman V, Jiang JX, Mahjoob K, Verbois SL, Morse D, Dagher R, Justice R, Pazdur R
Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma.
Oncologist. 2007 Jan;12(1):107-13.
On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors. [Abstract/Link to Full Text]

Recent Articles in CA: A Cancer Journal for Clinicians

Holmes CE, Muss HB
Diagnosis and treatment of breast cancer in the elderly.
CA Cancer J Clin. 2003 Jul-Aug;53(4):227-44.
As the population of the United States ages, women over the age of 65 have become a prominent cohort in the breast cancer population, with approximately 50% of all new breast cancers occurring in women aged 65 years and older. Early studies in breast cancer often excluded women based on age or comorbidity, leaving physicians and patients with a growing number of diagnostic and treatment options, each of which often carry short-term morbidity risks for potential long-term gain. We review the current data available for diagnosis and treatment of elderly women with breast cancer in both the adjuvant and metastatic disease setting. In addition, the role of screening and new concepts in prevention are discussed with emphasis on the older patient. [Abstract/Link to Full Text]

O'Brien K, Cokkinides V, Jemal A, Cardinez CJ, Murray T, Samuels A, Ward E, Thun MJ
Cancer statistics for Hispanics, 2003.
CA Cancer J Clin. 2003 Jul-Aug;53(4):208-26.
In this article, the American Cancer Society (ACS) provides estimates on the number of new cancer cases and deaths, and compiles health statistics on the US Hispanic population. The compiled statistics include cancer incidence, mortality, and behaviors relevant to cancer using the most recent data on incidence from the National Cancer Institute's (NCI) Surveillance, Epidemiolgy, and End Results (SEER) Program, mortality data from the National Center for Health Statistics, and behavioral information from the Behavior Risk Factor Surveillance System (Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System [BRFSS], Youth Risk Behavior Surveillance System [YRBSS], and National Health Interview Survey [NHIS].) An estimated 67,400 new cases of cancer and 22,100 cancer deaths will occur among Hispanics in 2003. Hispanics have lower incidence and death rates from all cancers combined and from the four most common cancers (breast, prostate, lung and bronchus, and colon and rectum) than non-Hispanic whites. However, Hispanics have higher incidence and mortality rates from cancers of the stomach, liver, uterine cervix, and gallbladder, reflecting in part greater exposure to specific infectious agents and lower rates of screening for cervical cancer, as well as dietary patterns and possible genetic factors. Strategies for reducing cancer risk among Hispanics include further development of effective interventions to increase screening and physical activity, reductions in tobacco use and obesity, and the development and application of effective vaccines. [Abstract/Link to Full Text]

Huerta EE
Cancer statistics for Hispanics, 2003: good news, bad news, and the need for a health system paradigm change.
CA Cancer J Clin. 2003 Jul-Aug;53(4):205-7. [Abstract/Link to Full Text]

Excess weight linked to 90,000 US cancer deaths annually.
CA Cancer J Clin. 2003 Jul-Aug;53(4):203-4. [Abstract/Link to Full Text]

Medicare managed care patients more likely to use hospice.
CA Cancer J Clin. 2003 Jul-Aug;53(4):202-3. [Abstract/Link to Full Text]

Two studies find high-fiber diet lowers colon cancer risk.
CA Cancer J Clin. 2003 Jul-Aug;53(4):201-2. [Abstract/Link to Full Text]

Invasive lobular carcinoma incidence increasing.
CA Cancer J Clin. 2003 May-Jun;53(3):137. [Abstract/Link to Full Text]

Kattlove H, Winn RJ
Ongoing care of patients after primary treatment for their cancer.
CA Cancer J Clin. 2003 May-Jun;53(3):172-96.
Nearly nine million people living in the United States have had a diagnosis of cancer. As the population ages, this number will increase. Most of these people will need follow-up care to deal with problems related to their cancer. Depending on the cancer, they may or may not benefit from surveillance to detect recurrence. Most will be more likely than average to develop a second primary cancer. Some will be genetically susceptible to another type of cancer. Many will have complications from their treatment that need attention. Also, their treatment may have altered certain physiologic functions. Finally, many will have suffered psychosocial difficulties either as a result of their cancer or its treatment. This article deals with these issues for the most commonly encountered cancers. Its major goal is to alert physicians to be aware of and help them to deal with these issues. Clearly, such an ambitious goal can only be partly achieved in a single journal article. Hopefully, the references included will allow physicians to proceed further if they wish. [Abstract/Link to Full Text]

Finding breast cancer early.
CA Cancer J Clin. 2003 May-Jun;53(3):170-1. [Abstract/Link to Full Text]

Smith RA, Saslow D, Sawyer KA, Burke W, Costanza ME, Evans WP, Foster RS, Hendrick E, Eyre HJ, Sener S
American Cancer Society guidelines for breast cancer screening: update 2003.
CA Cancer J Clin. 2003 May-Jun;53(3):141-69.
In 2003, the American Cancer Society updated its guidelines for early detection of breast cancer based on recommendations from a formal review of evidence and a recent workshop. The new screening recommendations address screening mammography, physical examination, screening older women and women with comorbid conditions, screening women at high risk, and new screening technologies. [Abstract/Link to Full Text]

Garber JE
Breast cancer screening: a final analysis?
CA Cancer J Clin. 2003 May-Jun;53(3):138-40. [Abstract/Link to Full Text]

Oncologists disagree on impact of patient internet use.
CA Cancer J Clin. 2003 May-Jun;53(3):135-7. [Abstract/Link to Full Text]

Tobacco control as a lifetime process.
CA Cancer J Clin. 2003 May-Jun;53(3):134-5. [Abstract/Link to Full Text]

Patient pages. Important facts for parents who don't want their kids to smoke.
CA Cancer J Clin. 2003 Mar-Apr;53(2):124-5. [Abstract/Link to Full Text]

Sargent JD, DiFranza JR
Tobacco control for clinicians who treat adolescents.
CA Cancer J Clin. 2003 Mar-Apr;53(2):102-23.
Smoking remains the most common preventable cause of death in the developed world, and is rapidly becoming an important cause of death in the developing world. Nicotine is a powerfully addictive substance, and the tobacco industry spends billions annually promoting it in the United States. It is therefore important for clinicians to understand why people smoke, to address smoking in patients of all ages, and to lobby for health-preserving tobacco control policies at the community level. Children take up smoking in response to social influences: smoking by friends, parents, and family, and through exposure to smoking in media. Parents who smoke not only model the behavior, but also often make the product available by leaving cigarettes around the house. Media influences include the dollar 10 billion spent per year on tobacco marketing, but more importantly, the modeling of the behavior on screen by movie and television stars. Once children start smoking, many rapidly lose autonomy over the behavior. Youth can get hooked after smoking just a few cigarettes. The most effective community efforts for reducing tobacco use are: raising the price of tobacco; halting the sale of tobacco to minors; enforcing strict school tobacco policies; and making public places smoke free through local ordinances. Working with individuals, clinicians should support cessation in all smokers, including parents of children and adolescents. They should screen children for smoking risk factors beginning at age 10. They should teach parents to maintain smoke-free households, to set nonsmoking expectations early on, and to monitor adolescents for signs of smoking. Parents should limit exposure to adult media (e.g., R-rated movies) and use family television time to discuss the effect of seeing screen depictions of smoking on adolescent behavior. Adolescents who smoke should be assessed for signs of nicotine dependence and counseled about quitting. Clinicians are effective community voices; they should participate in efforts to raise tobacco taxes, limit the display of tobacco advertising, and make public places smoke free because of the adverse health effects of passive exposure to cigarette smoke. [Abstract/Link to Full Text]

Ford LG, Minasian LM, McCaskill-Stevens W, Pisano ED, Sullivan D, Smith RA
Prevention and early detection clinical trials: opportunities for primary care providers and their patients.
CA Cancer J Clin. 2003 Mar-Apr;53(2):82-101.
Enrollment into cancer prevention and early detection clinical trials represents a unique challenge compared with a diagnostic or treatment trial because it involves subjects without a diagnosis of cancer. This paper examines some of the barriers to participation in prevention and early detection trials and provides detailed information about two ongoing prevention and two ongoing early detection clinical trials open to enrollment as well as brief summaries of seven additional trials now open to enrollment. [Abstract/Link to Full Text]

Yates JI
Clinicians in community practice are major contributors to clinical trials in cancer prevention, early detection, and treatment.
CA Cancer J Clin. 2003 Mar-Apr;53(2):69-72. [Abstract/Link to Full Text]

Cohen GI
Clinical research by community oncologists.
CA Cancer J Clin. 2003 Mar-Apr;53(2):73-81.
Practicing and hospital-based community oncologists are increasingly recognized as sources for clinical research activity. Although surveys have documented patients' and physicians' willingness to consider participation in clinical research studies, accrual to clinical trials by adults in cancer research studies remains embarrassingly low. This may be due in part to a lack of knowledge about available studies by community oncologists, a lack of time or interest, or a lack of resources to support the cost of performing clinical trials. This article addresses these issues as an instructional module for community physicians interested in increasing their activity in clinical trials or improving their abilities to facilitate patient accrual to cancer research studies. [Abstract/Link to Full Text]

Levin B, Brooks D, Smith RA, Stone A
Emerging technologies in screening for colorectal cancer: CT colonography, immunochemical fecal occult blood tests, and stool screening using molecular markers.
CA Cancer J Clin. 2003 Jan-Feb;53(1):44-55.
The American Cancer Society's (ACS) Colorectal Cancer Advisory Group held a workshop on new technologies for the early detection of colorectal cancer and adenomatous polyps as part of a regular review of ACS guidelines for colorectal cancer screening. The Advisory Group formally reviewed CT colonography, immunochemical fecal occult blood tests (FOBT), and stool screening using molecular markers, and also addressed other technologies including capsule video endoscopy. With the exception of immunochemical stool testing, the ACS has determined that at this time there is insufficient evidence to recommend these technologies for routine colorectal cancer screening. Based on recommendations of the Advisory Group, only a minor modification has been made to the ACS's Recommendations for Screening and Surveillance of the Early Detection of Adenomatous Polyps and Colorectal Cancer. [Abstract/Link to Full Text]

Smith RA, Cokkinides V, Eyre HJ
American Cancer Society guidelines for the early detection of cancer, 2003.
CA Cancer J Clin. 2003 Jan-Feb;53(1):27-43.
Each January, the American Cancer Society (ACS) publishes a summary of existing recommendations for early cancer detection, including updates, and/or emerging issues that are relevant to screening for cancer. In 2002, the ACS assembled expert groups to update guidelines for cervical cancer screening and breast cancer screening, and to evaluate new technology for colorectal cancer screening. In November 2002, updated guidelines for cervical cancer screening were published in this journal, and breast cancer screening guidelines will be updated in 2003. In this issue, there is a report of a workshop held to review emerging technology for colorectal cancer screening that resulted in a modification of current previous recommendations for fecal occult blood tests, and revised recommendations for the "cancer-related check-up" in which clinical encounters provide case-finding and health-counseling opportunities. Finally, we provide an update of the most recent data pertaining to participation rates in cancer screening by age, gender, and ethnicity from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System (BRFSS). [Abstract/Link to Full Text]

Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ
Cancer statistics, 2003.
CA Cancer J Clin. 2003 Jan-Feb;53(1):5-26.
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 by using incidence data from the National Cancer Institute (NCI) and mortality data from the National Center for Health Statistics (NCHS). Incidence and death rates are age adjusted to the 2000 US standard population. In the year 2003, we estimate that 1,334,100 new cases of cancer will be diagnosed, and 556,500 people will die from cancer in the United States. Age-adjusted cancer death rates declined in both males and females in the 1990s, though the magnitude of decline is substantially higher in males than in females. In contrast, incidence rates continued to increase in females while stabilizing in males. African-American males showed the largest decline for mortality. However, African Americans still carry the highest burden of cancer with diagnosis of cancer at a later stage and poorer survival within each stage compared with Whites. In spite of the continued decline in cancer death rates in the most recent time period, the total number of recorded cancer deaths in the United States continues to increase slightly due to the aging and expanding population. [Abstract/Link to Full Text]

Simmonds MA
Cancer statistics, 2003: further decrease in mortality rate, increase in persons living with cancer.
CA Cancer J Clin. 2003 Jan-Feb;53(1):4. [Abstract/Link to Full Text]

Arceci R, Ettinger A, Forman E, Haase GM, Hammond GD, Hoffman R, Kupst MJ, Link MP, Lustig CP, Traynor DS
National action plan for childhood cancer: report of the national summit meetings on childhood cancer.
CA Cancer J Clin. 2002 Nov-Dec;52(6):377-9. [Abstract/Link to Full Text]

Patient pages. Early detection of cervical cancer.
CA Cancer J Clin. 2002 Nov-Dec;52(6):375-6. [Abstract/Link to Full Text]

Stone RM
The difficult problem of acute myeloid leukemia in the older adult.
CA Cancer J Clin. 2002 Nov-Dec;52(6):363-71.
Acute myeloid leukemia (AML) in older adults is a biologically and clinically distinct entity. Based on analysis of cytogenetic and molecular data, it is known that leukemic cells in older patients are intrinsically resistant to standard chemotherapy. Due to comorbid disease and impaired bone marrow stem cell reserve, older adults tolerate myelosuppressive chemotherapy poorly, with a treatment-related mortality rate of 25 percent. About 35 percent of adults under age 40 are cured, but the complete remission rate (likelihood of temporary disease eradication) is 45 percent in those over age 60, considerably lower than the 75% rate among younger patients, and the possibility of long-term disease free survival is 20 percent in those achieving remission or less than 10 percent overall. Standard allogeneic bone marrow transplantation is too dangerous to be considered as a means to eradicate minimal residual disease after remission is obtained and myelointensive chemotherapy is not a beneficial post-remission strategy in this age cohort. These disappointing results call for more effective and less toxic therapeutic options. Advances in our understanding of the pathophysiology of AML and promising early clinical data suggest that the era of truly targeted therapy in this difficult disease may soon be a reality. [Abstract/Link to Full Text]

Saslow D, Runowicz CD, Solomon D, Moscicki AB, Smith RA, Eyre HJ, Cohen C
American Cancer Society guideline for the early detection of cervical neoplasia and cancer.
CA Cancer J Clin. 2002 Nov-Dec;52(6):342-62.
An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical neoplasia and cancer, based on recommendations from a formal review and recent workshop, is presented. The new screening recommendations address when to begin screening, when screening may be discontinued, whether to screen women who have had a hysterectomy, appropriate screening intervals, and new screening technologies, including liquid-based cytology and HPV DNA testing. [Abstract/Link to Full Text]

Ghafoor A, Jemal A, Cokkinides V, Cardinez C, Murray T, Samuels A, Thun MJ
Cancer statistics for African Americans.
CA Cancer J Clin. 2002 Nov-Dec;52(6):326-41.
The American Cancer Society provides estimates on the number of new cancer cases and deaths, and compiles health statistics on African Americans in a biennial publication, Cancer Facts and Figures for African Americans. The compiled statistics include cancer incidence, mortality, survival, and lifestyle behaviors using the most recent data on incidence and survival from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program, mortality data from the National Center for Health Statistics (NCHS), and behavioral information from the Behavior Risk Factor Surveillance System (BRFSS), Youth Risk Behavior Surveillance System (YRBSS), and National Health Interview Survey (NHIS). It is estimated that 132,700 new cases of cancer and 63,100 deaths will occur among African Americans in the year 2003. Although African Americans have experienced higher incidence and mortality rates of cancer than whites for many years, incidence rates have declined by 2.7 percent per year in African-American males since 1992, while stabilizing in African-American females. During the same period, death rates declined by 2.1 percent and 0.4 percent per year among African-American males and females, respectively. The decrease in both incidence and death rates from cancer among African-American males was the largest of any racial or ethnic group. Nonetheless, African Americans still carry the highest cancer burden among US racial and ethnic groups. Most cancers detectable by screening are diagnosed at a later stage and survival rates are lower within each stage of disease in African Americans than in whites. The extent to which these disparities reflect unequal access to health care versus other factors is an active area of research. [Abstract/Link to Full Text]

Brawley OW
Some perspective on black-white cancer statistics.
CA Cancer J Clin. 2002 Nov-Dec;52(6):322-5. [Abstract/Link to Full Text]

Calle EE, Frumkin H, Henley SJ, Savitz DA, Thun MJ
Organochlorines and breast cancer risk.
CA Cancer J Clin. 2002 Sep-Oct;52(5):301-9.
Organochlorines are a diverse group of synthetic chemicals that include polychlorinated biphenyls (PCBs), dioxins, and organochlorine pesticides such as dichlorodiphenyl-trichloroethane (DDT), lindane, and hexachlorobenzene. Although use of DDT and PCBs has been banned in the United States since the 1970s, some organochlorine compounds have accumulated and persisted within the environment. As a result, measurable amounts can still be found in human tissue. Because some organochlorine compounds act as estrogen agonists or antagonists within in vitro and experimental animal systems, a possible association of breast cancer risk with organochlorine exposure has been hypothesized and investigated. Although a few studies support this hypothesis, the vast majority of epidemiological studies do not. While some of these compounds may have other adverse environmental or health effects, organochlorine exposure is not believed to be causally related to breast cancer. Women concerned about possible organochlorine exposure can be reassured that available evidence does not suggest an association between these chemicals and breast cancer. [Abstract/Link to Full Text]

Ganz PA
Breast cancer 2002: where do we stand?
CA Cancer J Clin. 2002 Sep-Oct;52(5):253-5. [Abstract/Link to Full Text]

Morrow M, Strom EA, Bassett LW, Dershaw DD, Fowble B, Giuliano A, Harris JR, O'Malley F, Schnitt SJ, Singletary SE, Winchester DP
Standard for breast conservation therapy in the management of invasive breast carcinoma.
CA Cancer J Clin. 2002 Sep-Oct;52(5):277-300.
Multidisciplinary guidelines for management of invasive breast carcinoma from the American College of Radiology, the American College of Surgeons, the College of American Pathology, and the Society of Surgical Oncology have been updated to reflect the continuing advances in the diagnosis and treatment of invasive breast cancer. The guidelines provide a framework for clinical decision-making for patients with invasive breast carcinoma based on review of relevant literature and include information on patient selection and evaluation, technical aspects of surgical treatment, techniques of irradiation, and follow-up care. [Abstract/Link to Full Text]

Morrow M, Strom EA, Bassett LW, Dershaw DD, Fowble B, Harris JR, O'Malley F, Schnitt SJ, Singletary SE, Winchester DP
Standard for the management of ductal carcinoma in situ of the breast (DCIS).
CA Cancer J Clin. 2002 Sep-Oct;52(5):256-76.
The multidisciplinary guidelines for management of ductal carcinoma in situ of the breast from the American College of Radiology, the American College of Surgeons, the College of American Pathology, and the Society of Surgical Oncology have been updated to take into account continuing advances in the diagnosis and treatment of this disease. The continued growth in mammographic evaluation and technology has resulted in an increase in the diagnosis of ductal carcinoma in situ of the breast (DCIS). The resulting guidelines provide a framework for clinical decision-making for patients with DCIS based on review of relevant literature, and includes information on patient selection and evaluation, technical aspects of surgical treatment, techniques of irradiation, and follow-up care. [Abstract/Link to Full Text]

Shelby RA, Taylor KL, Kerner JF, Coleman E, Blum D
The role of community-based and philanthropic organizations in meeting cancer patient and caregiver needs.
CA Cancer J Clin. 2002 Jul-Aug;52(4):229-46.
We examined information from community-based and philanthropic organizations to document the cancer-related services that are currently available, establish which services are still needed, and determine who utilizes these formal support networks. In Phase I, 32 of 41 eligible organizations participated in a survey conducted from December 1999 to March 2000. The most common mission focus among participating organizations was information/referral-centered. The most common services provided were referrals to information resources and provision of cancer-related information. Only two of the organizations in Phase I provided client demographic information and both indicated that client populations were predominantly white, female, and over age 40. Phase II of the study involved analyzing patient data from Cancer Care, Inc., a national service organizations for cancer patients. Between 1983 and 1997, there were 2,714 prostate cancer patients and 9,451 breast cancer patients included in the Cancer Care database. Their most commonly reported problems were related to personal adjustment to illness, financial, home care, and transportation needs. There were significant differences in problems reported depending upon age and disease status. In addition, the results of this study support the idea that those at highest risk for developing and dying of cancer are the least likely to utilize formal support networks. Further, a gap in service provision for assistance with practical needs (e.g., transportation, home care, child care, psychosocial support) was identified. Due to the increasing use of outpatient care for cancer patients, a greater demand for practical assistance can be expected in the future. The availability of practical services will need to be increased in order to effectively meet cancer patient needs. [Abstract/Link to Full Text]

Shfflett P, Gansler T, Baker F
Navigating the health service network: helping cancer survivors find what they need.
CA Cancer J Clin. 2002 Jul-Aug;52(4):190-4. [Abstract/Link to Full Text]

Barnes MN, Grizzle WE, Grubbs CJ, Partridge EE
Paradigms for primary prevention of ovarian carcinoma.
CA Cancer J Clin. 2002 Jul-Aug;52(4):216-25.
OBJECTIVE: To provide the clinician with current concepts regarding prevention of ovarian cancer. Specifically, in this review, we provide a rationale for chemoprevention of ovarian cancer, a description of promising chemopreventive agents, and an overview of surgical strategies used in the prevention of ovarian cancer. DATA SOURCES: A computerized search of articles published through December 2001 was performed using the MEDLINE database from the period of 1966 to present. Search terms utilized included ovarian neoplasms, primary prevention, chemoprevention, oral contraceptives, NSAIDs, retinoids, ovariectomy, and tubal sterilization. Additional sources were identified through cross-referencing. METHODS OF STUDY SELECTION: All identified references relevant to prevention of ovarian carcinoma were reviewed. TABULATION, INTEGRATION, AND RESULTS: Each reference was reviewed to determine the relevant contribution to the fundamental science of ovarian cancer prevention. Particular attention was paid to those studies that offered insight into the development of translational trials in ovarian cancer chemoprevention. CONCLUSIONS: Investigation into chemoprevention for ovarian cancer represents a vastly underdeveloped area of research. Continued research efforts toward identification of novel compounds will accelerate the progress of clinical trials in this neglected area of investigation. [Abstract/Link to Full Text]

Neville BW, Day TA
Oral cancer and precancerous lesions.
CA Cancer J Clin. 2002 Jul-Aug;52(4):195-215.
In the United States, cancers of the oral cavity and oropharynx represent approximately three percent of all malignancies in men and two percent of all malignancies in women. The American Cancer Society estimates that 28,900 new cases of oral cancer will be diagnosed in 2002, and nearly 7,400 people will die from this disease. Over 90 percent of these tumors are squamous cell carcinomas, which arise from the oral mucosal lining. In spite of the ready accessibility of the oral cavity to direct examination, these malignancies still are often not detected until a late stage, and the survival rate for oral cancer has remained essentially unchanged over the past three decades. The purpose of this article is to review the clinical features of oral cancer and premalignant oral lesions, with an emphasis on early detection. [Abstract/Link to Full Text]

Patient page. Early detection of prostate cancer.
CA Cancer J Clin. 2002 May-Jun;52(3):180. [Abstract/Link to Full Text]

Hellerstedt BA, Pienta KJ
The current state of hormonal therapy for prostate cancer.
CA Cancer J Clin. 2002 May-Jun;52(3):154-79.
Androgen deprivation therapy remains a mainstay of treatment for men with prostate cancer. New uses for hormonal therapy, including use in the adjuvant and neoadjuvant setting, are being evaluated. Prevention of the side effects of therapy has led to the development of alternative schedules and therapeutics. [Abstract/Link to Full Text]

Davis TC, Williams MV, Marin E, Parker RM, Glass J
Health literacy and cancer communication.
CA Cancer J Clin. 2002 May-Jun;52(3):134-49.
Health literacy is increasingly recognized as a critical factor affecting communication across the continuum of cancer care. We reviewed research on health literacy and examined its impact on cancer outcomes and communication. According to the National Adult Literacy Survey (NALS), considered the most accurate portrait of literacy in our society, about one in five American adults may lack the necessary literacy skills to function adequately in our society. As patients, such individuals are at a disadvantage in their capacity to obtain, process, and understand cancer information and services needed to make appropriate health care decisions. Patients with poor health literacy have a complex array of difficulties with written and oral communication that may limit their understanding of cancer screening and of symptoms of cancer, adversely affecting their stage at diagnosis. In addition, these barriers impair communication and discussion about risks and benefits of treatment options, and patient understanding of informed consent for routine procedures and clinical trials. More research is needed to identify successful methods for educating and communicating with patients who have limited health literacy. Based on our own experience, we offer practical communication aids that can help bridge the cancer communication gap. [Abstract/Link to Full Text]

Merriman B, Ades T, Seffrin JR
Health literacy in the information age: communicating cancer information to patients and families.
CA Cancer J Clin. 2002 May-Jun;52(3):130-3. [Abstract/Link to Full Text]

Byers T, Nestle M, McTiernan A, Doyle C, Currie-Williams A, Gansler T, Thun M
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. 2002 Mar-Apr;52(2):92-119.
The American Cancer Society (ACS) has set aggressive challenge goals for the nation to decrease cancer incidence and mortality--and to improve the quality of life of cancer survivors--by the year 2015. To address these critical goals, the ACS publishes the 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 five 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 American Cancer Society 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. Therefore, this committee presents one key recommendation for community action to accompany the four recommendations for individual choices for nutrition and physical activity to reduce cancer risk. This recommendation for community action underscores just how important community measures are to the support of healthy behaviors by means of increasing access to healthful food choices and opportunities to be physically active. The ACS guidelines are consistent with guidelines from the American Heart Association for the prevention of coronary heart disease as well as for general health promotion, as defined by the Department of Health and Human Services' 2000 Dietary Guidelines for Americans. [Abstract/Link to Full Text]

Inui A
Cancer anorexia-cachexia syndrome: current issues in research and management.
CA Cancer J Clin. 2002 Mar-Apr;52(2):72-91.
Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a six-month period. The two major options for pharmacological therapy have been either progestational agents, such as megestrol acetate, or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide--all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life. [Abstract/Link to Full Text]

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

Coppage L, Sroufe A, Robinson L
Imaging in oncology: chest mass.
Cancer Control. 2005 Apr;12(2):126, 137-9. [Abstract/Link to Full Text]

Dalton WS
The "total cancer care" concept: linking technology and health care.
Cancer Control. 2005 Apr;12(2):140-1. [Abstract/Link to Full Text]

Dapic V, Carvalho MA, Monteiro AN
Breast cancer susceptibility and the DNA damage response.
Cancer Control. 2005 Apr;12(2):127-36. [Abstract/Link to Full Text]

Butowski N, Chang SM
Small molecule and monoclonal antibody therapies in neurooncology.
Cancer Control. 2005 Apr;12(2):116-24.
BACKGROUND: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors. METHODS: We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years. RESULTS: Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing. CONCLUSIONS: The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed. [Abstract/Link to Full Text]

Hersh MR, Choi J, Garrett C, Clark R
Imaging gastrointestinal stromal tumors.
Cancer Control. 2005 Apr;12(2):111-5.
BACKGROUND: Because of the recent reclassification of mesenchymal tumors, which was based on a better understanding of the genetics and immunophenotype of gastrointestinal stromal tumors (GISTs), only a limited number of studies have described the radiologic appearance of GISTs. METHODS: This study reviews the imaging characteristics of GISTs, with an emphasis on differentiating benign and malignant tumors using positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI). We reviewed the data from 53 cases of GISTs treated at our institute. The imaging studies from these cases, which were recorded at our institute from January 1998 through June 2003, included PET, CT, and MRI. RESULTS: Of the 53 GIST cases, stomach and small bowel tumors accounted for 80% of the tumors. Malignant lesions were larger and more heterogeneous, had ulcerations, and were PET positive. Peritoneal and liver metastases were most common. CONCLUSIONS: PET, CT, and MRI appear to be useful in differentiating nonmetastasizing from malignant GISTs. [Abstract/Link to Full Text]

Alekshun T, Garrett C
Targeted therapies in the treatment of colorectal cancers.
Cancer Control. 2005 Apr;12(2):105-10.
BACKGROUND: In solid organ malignancies, no tumor type has seen a greater impact from the development of novel targeted therapies in 2004 than metastatic colorectal cancer. METHODS: We review the current progress to date with the use of monoclonal antibodies in colorectal cancer and look at newer therapies under investigation. RESULTS: Two monoclonal antibodies received Food and Drug Administration approval in early 2004, both for the indication of advanced, metastatic colorectal cancer. A large, randomized, placebo-controlled study demonstrated that the addition of a monoclonal antibody to vascular endothelial growth factor, bevacizumab, led to a statistically significant improvement in overall survival, with tolerable additional toxicity. Chimeric monoclonal antibody therapy directed at the epidermal growth factor receptor was associated with radiographic responses in a significant minority of patients with irinotecan-refractory colon cancer in a randomized phase II study of patients with irinotecan-refractory disease. CONCLUSIONS: These dramatic successes have led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research. [Abstract/Link to Full Text]

Chng WJ, Lau LG, Yusof N, Mow BM
Targeted therapy in multiple myeloma.
Cancer Control. 2005 Apr;12(2):91-104.
BACKGROUND: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. METHODS: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. RESULTS: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. CONCLUSIONS: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients. [Abstract/Link to Full Text]

Kuriakose P
Targeted therapy for hematologic malignancies.
Cancer Control. 2005 Apr;12(2):82-90.
BACKGROUND: The introduction of monoclonal antibodies, either as native molecules or conjugated to radioisotopes or other toxins, has led to new therapeutic options for patients with hematologic malignancies. In addition, the use of small molecules against specific cell surface receptors, enzymes, and proteins has become an important strategy in the treatment of such disorders. METHODS: The author reviewed the published clinical trials of monoclonal antibody and other targeted therapies in hematologic malignancies. RESULTS: Results from several trials demonstrate a therapeutic benefit for the use of monoclonal antibodies (either native or conjugated) and other targeted therapies, used alone or in combination with standard cytotoxic chemotherapy. CONCLUSIONS: Targeted therapy of hematologic malignancies seems to be an effective and less toxic approach to the treatment of such disorders. Nevertheless, additional studies are needed to determine where and when such management fits into a therapeutic regimen for any given disorder, whether upfront or as salvage therapy, alone or in combination with chemotherapy (concurrent or sequential). [Abstract/Link to Full Text]

Hobday TJ, Perez EA
Molecularly targeted therapies for breast cancer.
Cancer Control. 2005 Apr;12(2):73-81.
BACKGROUND: The management of patients with localized and advanced breast cancer continues to evolve. Chemotherapy, endocrine therapy, and trastuzumab are effective therapies but leave considerable room for improvement. As the cellular aberrations inherent to cancer cells in general and breast cancer cells specifically are better understood, therapies to target specific cellular pathways continue to be developed with the goal of expanding available effective therapy through better patient selection. METHODS: We conducted a computerized search of the medical literature as well as a manual search of selected meeting abstracts. RESULTS: Several targeted therapies are in phase III clinical trials testing their promise in the treatment of breast cancer. Many other agents are completing phase I and II testing. An overview of the most promising agents in clinical development is discussed herein. CONCLUSIONS: Targeted therapy for breast cancer is a reality at this time, and several new agents hold promise for expanding and refining the pool of patients likely to further benefit from this approach in the near future. [Abstract/Link to Full Text]

Garrett C
Targeted therapy: the fast pace of progress.
Cancer Control. 2005 Apr;12(2):71-2. [Abstract/Link to Full Text]

Ebeid W, Amin S, Abdelmegid A
Limb salvage management of pathologic fractures of primary malignant bone tumors.
Cancer Control. 2005 Jan-Feb;12(1):57-61.
BACKGROUND: Little is known about oncologic outcomes of patients with primary bone tumors complicated by a pathologic fracture and treated by limb salvage. METHODS: Our study included 17 men and 14 women aged 6 to 61 years (average age 17 years). All 31 patients had primary bone tumors complicated by a pathologic fracture. Diagnoses included osteosarcoma (17 patients), Ewing's sarcoma (10), malignant fibrous histiocytoma (3), and lymphoma (1). All received preoperative chemotherapy. The distal femur was affected in 13 patients, the proximal femur in 6, mid shaft femur in 4, the proximal humerus in 4, the proximal tibia in 3, and the fibula in 1. All patients underwent limb salvage and achieved a wide resection margin. RESULTS: The average follow-up period was 18 months (range 8 to 51 months). Two patients required amputation due to local recurrence. Six patients developed pulmonary metastases and eventually died. CONCLUSIONS: A pathologic fracture of primary bone tumor is not always a contraindication for limb salvage since the oncologic outcome appears acceptable. [Abstract/Link to Full Text]

D'Amato G, Steinert DM, McAuliffe JC, Trent JC
Update on the biology and therapy of gastrointestinal stromal tumors.
Cancer Control. 2005 Jan-Feb;12(1):44-56.
BACKGROUND: Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are an example of a disease with an effective, molecularly targeted therapy. METHODS: Published articles and author experience were used to comprehensively define the clinical features, biology, and state-of-the-art therapy of GISTs. RESULTS: GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal, the intestinal pacemaker cells. GISTs commonly have mutations in the kit gene, resulting in a gain-of-function mutation and ligand-independent constitutive activation of the KIT receptor tyrosine kinase. Successful tyrosine kinase inhibitors target the aberrant pathways that are critical for tumor cell viability. The development of imatinib mesylate (formerly STI 571) in the treatment of metastatic GISTs represents a therapeutic breakthrough. CONCLUSIONS: Progress in the clinical diagnosis has led to an increased recognition of this disease as a distinct clinical entity. Treatment of metastatic GIST with imatinib has led to unprecedented improvements in progression-free and overall survival. The use of imatinib in the preoperative and postoperative treatment of GISTs is an area of intense investigation. [Abstract/Link to Full Text]

Windham TC, Pisters PW
Retroperitoneal sarcomas.
Cancer Control. 2005 Jan-Feb;12(1):36-43.
BACKGROUND: The evaluation and treatment of retroperitoneal sarcomas are challenging because the tumors are relatively rare and frequently present with advanced disease in an anatomically complex location. METHODS: We reviewed the literature on experience in the management of retroperitoneal sarcomas, and we present our own experience in the treatment of these tumors. RESULTS: The identification of prognostic factors other than the adequacy of resection has been inconsistent. Due to a lack of associated symptoms, retroperitoneal sarcomas smaller than 5 cm are rare. Computed tomography is the most useful tool in the evaluation of retroperitoneal tumors. Surgery, radiation therapy, and chemotherapy are treatment options, but the most important factor in the treatment of primary tumors is complete surgical resection. The role of neoadjuvant and adjuvant therapies is not defined and should be considered within the context of clinical trials. CONCLUSIONS: Early referral of patients with retroperitoneal soft tissue tumors will help to ensure that they will receive the benefits of multidisciplinary evaluation and treatment of their disease and ready access to clinical trials. [Abstract/Link to Full Text]

DeLaney TF, Trofimov AV, Engelsman M, Suit HD
Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas.
Cancer Control. 2005 Jan-Feb;12(1):27-35.
BACKGROUND: For patients with sarcomas, radiotherapy can be used as neoadjuvant, adjuvant, or primary local therapy, depending on the site and type of sarcoma, the surgical approach, and the efficacy of chemotherapy. METHODS: The authors review the current status of advanced technology radiation therapy in the management of bone and soft tissue sarcoma. RESULTS: Advances in radiotherapy have resulted in improved treatment for bone and soft tissue sarcomas. Intensity-modulated radiation therapy (IMRT) uses modifications in the intensity of the photon-beam from a linear accelerator across the irradiated fields to enhance dose conformation in three dimensions. For proton-beam radiation therapy, the nuclei of hydrogen atoms are accelerated in cyclotrons or synchrotrons, extracted, and transported to treatment rooms where the proton beam undergoes a series of modifications that conform the dose in a particular patient to the tumor target. Brachytherapy and intraoperative radiation therapy have generally been used to treat microscopic residual disease in patients with sarcomas. These technologies deliver dose to tumor cells with irradiation of limited volumes of normal tissue. Patients who may benefit from technically advanced radiotherapy include those with skull base and spine/paraspinal sarcomas, Ewing's sarcoma, and retroperitoneal/extremity sarcomas. CONCLUSIONS: Advances in radiation therapy technology, particularly IMRT, proton-beam or other charged-particle radiation therapy, brachytherapy, and intraoperative radiation therapy, have led to improved treatment for patients with bone and soft tissue sarcomas. [Abstract/Link to Full Text]

Knapp EL, Kransdorf MJ, Letson GD
Diagnostic imaging update: soft tissue sarcomas.
Cancer Control. 2005 Jan-Feb;12(1):22-6.
BACKGROUND: No single imaging approach is ideal for every tumor. While radiography can be effective for diagnosis of specific tumors, additional imaging is often required. Soft tissue sarcomas require a multimodality approach. METHODS: The authors discuss the general imaging approaches for patients who present with soft tissue masses, the fundamental principles inherent to tumor imaging, and the specific applications of newer imaging modalities. RESULTS: Magnetic resonance imaging has emerged as the preferred technique for evaluating soft tissue tumors but is limited in demonstrating the pattern of soft tissue calcification. Computed tomography is the best modality for evaluating osseous architecture and for patients who cannot be evaluated with MRI. PET is helpful in metabolic imaging, and ultrasonography is useful in differentiating cystic from solid masses. Magnetic resonance angiography accurately reveals the arterial and venous supply of vascular tumors. CONCLUSIONS: Current imaging techniques provide numerous noninvasive methods to diagnose and stage suspected soft tissue sarcomas. [Abstract/Link to Full Text]

Mankin HJ, Hornicek FJ
Diagnosis, classification, and management of soft tissue sarcomas.
Cancer Control. 2005 Jan-Feb;12(1):5-21.
BACKGROUND: Soft tissue sarcomas are challenging to oncologists due to their unique character, the infrequency of their occurrence, and the difficulties in predicting outcomes. Advances in imaging, as well as improvements in surgical techniques and adjunctive treatment methods, have improved care for patients with these unusual disorders. METHODS: The various types of soft tissue tumors are defined, and the statistics for the Orthopaedic Oncology Group in relation to them are reviewed and compared with literature references. RESULTS: The overall survival rate for 1,220 tumors treated at our institute from June 1972 to June of 2001 was 72%, with a wide range. Patients with leiomyosarcomas, clear cell sarcomas, and malignant fibrous histiocytomas had a poorer survival rate, while those with fibrosarcomas, liposarcomas, and neurofibrosarcomas fared better. Outcome was affected by patient age, tumor anatomic site, tumor stage, and a history of recurrence. CONCLUSIONS: Competent imaging, predictive immunological and genetic studies, improved surgery, and newer methods of adjunctive and neoadjunctive treatment should result in improvements in outcomes for patients with these tumors. [Abstract/Link to Full Text]

Letson GD
Soft tissue sarcoma: status in 2005.
Cancer Control. 2005 Jan-Feb;12(1):2. [Abstract/Link to Full Text]

List A
Methyltransferase inhibitors: changing the treatment algorithm for myelodysplastic syndromes.
Cancer Control. 2004 Nov-Dec;11(6 Suppl):16-9. [Abstract/Link to Full Text]

Silverman LR
The role of methyltransferase inhibitors in the management of the myelodysplastic syndromes.
Cancer Control. 2004 Nov-Dec;11(6 Suppl):11-5. [Abstract/Link to Full Text]

Stone R
Treatment options for myelodysplastic syndromes.
Cancer Control. 2004 Nov-Dec;11(6 Suppl):7-10. [Abstract/Link to Full Text]

Gore S
Classification, treatment goals, and management principles for myelodysplastic syndromes.
Cancer Control. 2004 Nov-Dec;11(6 Suppl):3-6. [Abstract/Link to Full Text]

Hann DM, Baker F, Denniston MM, Winter K
Oncology professionals' views of complementary therapies: a survey of physicians, nurses, and social workers.
Cancer Control. 2004 Nov-Dec;11(6):404-10. [Abstract/Link to Full Text]

Roscoe LA, Egan KA, Schonwetter RS
Creating an academic-community provider partnership in hospice, palliative care, and end-of-life studies.
Cancer Control. 2004 Nov-Dec;11(6):397-403. [Abstract/Link to Full Text]

Woods VD, Montgomery SB, Belliard JC, Ramirez-Johnson J, Wilson CM
Culture, black men, and prostate cancer: what is reality?
Cancer Control. 2004 Nov-Dec;11(6):388-96.
BACKGROUND: The worldwide incidence of prostate cancer is higher among American black men than any other male group. In the United States, lack of participation in screening for prostate cancer by black men is influenced by several cultural factors, including knowledge, health beliefs, barriers, and relationships with primary healthcare providers. METHODS: We used the qualitative and paralleling descriptive quantitative findings of a mixed-method longitudinal study exploring prostate cancer screening behaviors among 277 black men. RESULTS: Five themes were identified as critical elements affecting men's screening for prostate cancer: lack of knowledge, communication, social support, quality of care, and sexuality. These themes were associated with a sense of disconnectedness by black men from the healthcare system and contributed to nonparticipation in prostate cancer early detection activities. CONCLUSIONS: Lack of discussion about the decision to screen for prostate cancer and general lack of culturally appropriate communication with healthcare providers has engendered distrust, created fear, fostered disconnect, and increased the likelihood of nonparticipation in prostate cancer screening among black men. [Abstract/Link to Full Text]

Sesterhenn IA, Davis CJ
Pathology of germ cell tumors of the testis.
Cancer Control. 2004 Nov-Dec;11(6):374-87.
BACKGROUND: An increasing incidence of testis tumors has been noted over the second half of the 20th century. Congenital malformation of the male genitalia, prenatal risk factors, nonspecific and specific exposures in adulthood, and male infertility have all been associated with the etiology of germ cell tumors. METHODS: The histologic classification, pathology, and current concepts of testicular germ cell tumors are reviewed. RESULTS: Germ cell tumors occur at all ages. The tumors are identified as pure form (those of one histologic type) and mixed form (more than one histologic type). Over half of germ cell tumors consist of more than one cell type, requiring appropriate sampling for the correct diagnosis and correlation with the serum tumor markers. Burned-out germ cell tumors may occur in patients with metastatic disease with no gross evidence of a testicular tumor. CONCLUSIONS: Appropriate management of testis tumors relies on accurate pathology and classification of these tumors. [Abstract/Link to Full Text]

Diaz M, Patterson SG
Management of androgen-independent prostate cancer.
Cancer Control. 2004 Nov-Dec;11(6):364-73.
BACKGROUND: Although androgen withdrawal can control prostate cancer for long periods in many patients, controversy exists regarding management when the tumor becomes androgen independent. Several options are now available. METHODS: A review of the pertinent literature of the last 20 years was conducted to provide guidance in defining and managing hormone-refractory prostate cancer. RESULTS: Stage D prostate cancer can be subclassified to correlate tumor biology with disease stage. Secondary hormone manipulations may induce responses in patients after failure of initial androgen suppression, and chemotherapy with docetaxel has prolonged survival in patients with androgen-independent prostate cancer (AIPC). The weight of evidence supports the maintenance of castrate levels of testosterone in metastatic AIPC. Bisphosphonates decrease skeletal complications. CONCLUSIONS: Secondary hormone therapy, chemotherapy, and bisphosphonate therapy may provide benefits for selected patients. Correlation of disease stage with biologic characteristics of the tumor and host facilitates proper choices of interventions. Docetaxel-based chemotherapy regimens should be considered for first-line treatment of patients with progressive metastatic AIPC. [Abstract/Link to Full Text]

Torres-Roca JF
Bladder preservation protocols in the treatment of muscle-invasive bladder cancer.
Cancer Control. 2004 Nov-Dec;11(6):358-63.
BACKGROUND: Over the last 3 decades, we have seen a paradigm shift in our approach to the treatment of malignancy. During that time, organ conservation protocols have become standard in the treatment of breast cancer, laryngeal cancer, esophageal cancer, anal cancer and soft tissue sarcomas. METHODS: Data from reports of bladder preservation protocols were reviewed to evaluate organ preservation approaches in muscle-invasive bladder cancer. RESULTS: These trials have shown equivalent disease control rates when compared to radical surgery, with the advantage of organ function preservation. In spite of this, organ preservation efforts in muscle-invasive bladder cancer have lagged behind this overall trend in clinical oncology. However, efforts by several investigators over the last 2 decades have shown that for a number of selected patients with muscle-invasive bladder cancer, bladder preservation is feasible without an apparent compromise of overall survival. CONCLUSIONS: Bladder preservation therapy with a trimodality approach for a carefully selected patient population is safe and effective. Formal randomized trials comparing radical cystectomy and trimodality bladder-sparing therapy are justified. [Abstract/Link to Full Text]

Hersh MR, Knapp EL, Choi J
Newer imaging modalities to assess tumor in the prostate.
Cancer Control. 2004 Nov-Dec;11(6):353-7.
BACKGROUND: Several advances in the imaging of prostate cancer have been made in recent years. Diagnostic staging has become increasingly complex and confusing as newer technologies have developed more rapidly than research has been able to confirm or refute the accuracy of these technologies. By the time research has been performed, the technology used for a study has often become outdated and newer and more sophisticated imaging has become available. METHODS: We reviewed the literature on local and nodal staging of prostate cancer, as well as the role of magnetic resonance imaging (MRI), magnetic resonance spectroscopic imaging (MRSI), dynamic contrast-enhanced MRI, positron emission tomography (PET), endorectal power Doppler, lymphotropic MRI contrast agents, and future possibilities such as diffusion MRI. This review is not systematic, but rather focused on these imaging modalities. RESULTS: Advances in MRI, ultrasound, and lymphotropic contrast agents have improved our ability to differentiate between T2 and T3 prostate tumors. PET imaging has proven less successful at staging prostate cancer. A literature review suggests patients with moderate risk of extracapsular extension benefit most from endorectal MRI evaluation. Spectroscopy, dynamic imaging, and lymphotropic contrast agents are expected to continue to improve sensitivity and specificity of staging of prostate cancer. Power Doppler evaluation with endorectal ultrasound has proved useful for evaluation during endorectal biopsy for identifying hypervascular tumors for directed biopsy. Diffusion-weighted MRI remains untested clinically and represents a future direction for research. CONCLUSIONS: Future studies using these new techniques are needed to demonstrate changes in outcomes in large patient populations. [Abstract/Link to Full Text]

Turbin RE, Pokorny K
Diagnosis and treatment of orbital optic nerve sheath meningioma.
Cancer Control. 2004 Sep-Oct;11(5):334-41.
BACKGROUND: Primary and secondary optic nerve sheath meningiomas (ONSMs) are neoplasms that account for a large proportion of optic nerve and orbital tumors. The diagnosis is not always straightforward and is based on the appropriate clinical findings and neuroimaging. Biopsy or surgical intervention may occasionally be necessary but is associated with significant morbidity. METHODS: Issues related to clinical signs and symptoms, diagnosis, natural history, and treatment strategies are reviewed based on a review of published literature. RESULTS: Diagnosis is usually based on radiographic and clinical findings. Biopsies are not obtained in most cases, thus adding further to the bias of possible misdiagnosis in all reported case series that do not have the benefit of histopathologic confirmation. Natural history typically shows inexorable progression in most cases, although long periods of stability are occasionally reported. Treatment options include observation, radiation alone, surgery alone, and combined radiation and surgery. The optimum timing of interventional therapy and radiation are evolving. CONCLUSIONS: After serial examination documents new decline in acuity and/or visual field, fractionated radiotherapy appears most likely to preserve visual function and is a valid treatment approach for primary orbital ONSM. Tumor enlargement, as determined by serial imaging, may also provide an indication to begin radiotherapy. [Abstract/Link to Full Text]

Karcioglu ZA, Hadjistilianou D, Rozans M, DeFrancesco S
Orbital rhabdomyosarcoma.
Cancer Control. 2004 Sep-Oct;11(5):328-33.
BACKGROUND: Although rhabdomyosarcoma (RMS) is a rare tumor among the entire group of mesenchymal malignancies, it is a relatively common lesion and significant challenge for the ocular oncologist in terms of its diagnosis and management. METHODS: A comprehensive literature search of articles published over the past 30 years in PubMed was conducted. RESULTS: Orbital RMS usually presents as a space-occupying lesion in the orbit during the first decade and may mimic other neoplastic or inflammatory masses. The tumor has predilection for the superior nasal quadrant of the orbit. The clinical manifestations depend on the location of the tumor within the orbit and its rate of growth. The common histopathologic types are embryonal and alveolar varieties. CT and MR imaging are important in the evaluation of this tumor. Particular attention should be placed on the bone invasion and extension of the tumor into the intracranial cavity and paranasal sinuses. Treatment usually consists of a combination of chemotherapy and radiation therapy following excisional biopsy. CONCLUSIONS: Survival of orbital RMS has improved due to advances in chemotherapy and radiotherapy. Posttreatment complications, including side effects of radiotherapy and secondary orbital malignancies, as well as visual dysfunction, occur more often and present new challenges due to improved long-term survival. [Abstract/Link to Full Text]

Shields CL, Shields JA
Diagnosis and management of retinoblastoma.
Cancer Control. 2004 Sep-Oct;11(5):317-27.
BACKGROUND: Retinoblastoma is a highly malignant tumor of the eye that manifests most often in the first 3 years of life. METHODS: Published articles were reviewed to evaluate the clinical features and current methods of diagnosis and to assess the trends in management. RESULTS: This malignancy leads to metastatic disease and death in 50% of children worldwide but in less than 5% of children in the United States and other developed nations with advanced medical care. Over the past decade, there has been a trend away from enucleation and external beam radiotherapy and toward chemoreduction followed by focal therapies. This is largely due to more effective chemotherapeutic regimens, improved focal treatment modalities, and the desire to avoid loss of the globe and/or exposure to radiotherapy. Chemoreduction and focal therapies are most successful for eyes with minimal to moderate retinoblastoma, with enucleation needed in less than 15% of cases. Eyes with very advanced retinoblastoma require enucleation in approximately 50% of cases. CONCLUSIONS: Progress in the clinical recognition and management of retinoblastoma has led to high survival rates. Improved methods of treatment using chemoreduction and focal treatments without the need for external beam radiotherapy allow preservation of the eye in some cases, often with visual function. [Abstract/Link to Full Text]

Recent Articles in Pathology Oncology Research

Kopper L, T�m�r J
Genomics of lung cancer may change diagnosis, prognosis and therapy.
Pathol Oncol Res. 2005;11(1):5-10.
Despite significant improvements in tumor management in general, the prognosis of lung cancer patients remains dismal. It is a hope that our increasing knowledge in molecular aspects of tumor development, growth and progression will open new targets for therapeutic interventions. In this review we discuss some of the more recent results of this field. This includes the susceptibility factors, an association between genetic changes in EGFR pathway and tyrosine kinase inhibitors, the role of gene hypermethylation and genetic profiling, as well as different molecular aspects of tumor progression. Available data all support that lung cancer is a group of diseases with not only distinct histological but with similarly different genetic characters. Accordingly, the diagnosis, prognosis and therapy must accommodate this heterogeneity. [Abstract/Link to Full Text]

Swiatoniowski G, Mazur G, Ha?o? A, Rozumek G, Dabrowska M, Zawisza R, Prudlak E
Malignant melanoma with gall bladder metastasis as a second neoplasm in the course of prostate cancer.
Pathol Oncol Res. 2004;10(4):243-5.
Malignant melanoma is a neoplasm with an often unpredictable course and metastases potentially affecting all organs of the human body. Metastases into the gall bladder are rare. The role of hormonal background in the development and progression of malignant melanoma has not been established. The authors present a case of a 63-year-old man who had initially undergone long-term hormone therapy for the treatment of prostate cancer, and later presented with melanoma metastatic to the gall bladder. [Abstract/Link to Full Text]

Bolat F, Kayaselcuk F, Erkan AN, Cagici CA, Bal N, Tuncer I
Epidermoid carcinoma arising in Warthin's tumor.
Pathol Oncol Res. 2004;10(4):240-2.
Warthin's tumor is a well-defined salivary gland neoplasm consisting of benign epithelial and lymphoid components. However, malignant transformation is extremely rare and the differential diagnosis of metastasis from an epidermoid carcinoma in Warthin's tumor is important. We present a case with epidermoid carcinoma arising in Warthin's tumor of parotid gland in a 48-year-old woman, and differential diagnosis is discussed. [Abstract/Link to Full Text]

Vargas-Gonzalez R, San Martin-Brieke W, Gil-Ordu�a C, Lara-Hernandez F
Desmoplastic fibroma-like tumor of maxillofacial region associated with tuberous sclerosis.
Pathol Oncol Res. 2004;10(4):237-9.
Desmoplastic fibroma is a rare primary tumor of bone that histologically and biologically mimics the extra-abdominal desmoid tumor of soft tissue. It usually presents in patients during the first three decades of life and often involves the mandible or long bones of the skeleton. Its clinical behavior is characterized by a locally aggressive, infiltrating, and destructing course, often with invasion of surrounding tissues but without metastasis. We present herein the clinicopathological features of a desmoplastic fibroma-like tumor involving the left maxillofacial region in a 14-year-old Hispanic boy with tuberous sclerosis. [Abstract/Link to Full Text]

Ulhaci N, Meteo?lu I, Kacar F, Ozba? S
Abscess of the spleen.
Pathol Oncol Res. 2004;10(4):234-6.
Abscess of the spleen is a very rare lesion. In this study, 4 cases of splenic abscess are presented and discussed along with the literature. The cases were between 16 and 55 years-old and two of them had hematologic malignancy. All of them had been operated on because of acute abdomen, and in two cases splenic rupture was present. Only in one of the cases was salmonellosis detected by microbiological methods. By histological examination, expansion and congestion in splenic sinusoids, and foci of abscess including wide areas of necrosis and inflammatory infiltration by neutrophils were seen in all cases. The most frequent cause of splenic abscess is septic embolism arising from bacterial endocarditis. There are also a few splenic abscess cases seen with malignancies. While splenic abscess is seen rarely, it has a high rate of mortality when it is diagnosed late. [Abstract/Link to Full Text]

Dekel Y, Rath-Wolfson L, Rudniki C, Koren R
Talc inhalation is a life-threatening condition.
Pathol Oncol Res. 2004;10(4):231-3.
A case of rapidly progressive disease and pulmonary hypertension due to chronic cosmetic talc inhalation is presented. Although an uncommon cause of pulmonary hypertension, talc, especially through intravenous administration, should be included in the etiology of parenchymal pulmonary hypertension. In our case talc inhalation was inadvertent, causing fulminant disease leading to the patient's death. To our knowledge, this is the first case of inadvertent talc inhalation causing death in adult patient. [Abstract/Link to Full Text]

Tarracciano L, Bouygue GR, Startatri R, Guerriero F, M R Bouygue C
A case of fulminant "talc pneumoconiosis": where is the smoking gun?
Pathol Oncol Res. 2005;11(3):184; author reply 185. [Abstract/Link to Full Text]

Sharifzadeh S, Owji SM, Pezeshki AM, Malek-Hoseini Z, Kumar PV, Ghayumi SM, Ghaderi A
Establishment and characterization of a human large cell lung cancer cell line with neuroendocrine differentiation.
Pathol Oncol Res. 2004;10(4):225-30.
Characterization of a human lung cancer cell line is reported. This cell line was established from a patient referred to Nemazi Hospital of Shiraz University of Medical Sciences with a diagnosis of poorly differentiated carcinoma. Sterile sample from peritoneal effusion was taken and immediately cultured in RPMI-1640 medium containing 20% FBS, at 37 degrees C with 5% CO2. This cell line has been in continuous culture for more than one year and has been named as Mehr-80. Several features of the cell line were investigated, including growth characteristics, electron microscopic features, cloning efficiency in soft agar, expression of various antigenic markers, chromosomal and DNA analysis. On the basis of morphological and immunohistochemical analysis of Mehr-80, it is possible to conclude that this cell line is characterized by features similar to those reported for large cell carcinoma with neuroendocrine differentiation (LCCND). This cell line will be a valuable in vitro tool for further studies on lung cancers. [Abstract/Link to Full Text]

Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C
Subependymal giant cell astrocytoma--a clinicopathological study of 23 cases with special emphasis on histogenesis.
Pathol Oncol Res. 2004;10(4):219-24.
Subependymal giant cell astrocytomas (SEGAs) are relatively rare tumors but occur commonly in the setting of the familial syndrome of tuberous sclerosis complex (TSC). In view of its varied morphology, i.e. resemblance to astrocytic and ganglion cells, its histogenesis remains controversial. We studied 23 cases of SEGA, 19 from our own institute and 4 from NIMHANS, Bangalore. These 19 cases of SEGAs were collected over a period of 23 years (1979 to 2001), and accounted for 0.16% of intracranial tumors and 0.51% of all gliomas reported at our center. The majority of patients presented with visual disturbances (19/23, 82.6%) in the form of decreased vision (60.8%) and blindness (21.7%), generalized tonic clonic seizures (43.4%) and focal motor seizures (4.37%). Age ranged from 4 to 37 years (mean 13.2 years) with male predominance (M:F 2.2:1), and the duration of symptoms varied from 1 month to 96 months (mean 17.2 months). Lateral ventricular involvement was the most common site (91.3%), followed by the third ventricle (8.6%). Nine patients (39.1%) had stigmata of tuberous sclerosis (6 at the time of diagnosis and 3 in the follow-up period). Two patients died due to surgical complications, while the rest were alive and well in the follow-up period ranging from 3 to 264 months (mean 37.1 months). Two patients experienced recurrences, one two years and another 22 years after surgery. Microscopic examination showed varied histology consisting of sweeping bundles of spindle cells, gemistocyte and ganglion-like cells with interspersed inflammatory cell component. The inflammatory cell component on special staining turned out to be an admixture of mast cells and T lymphocytes. Six cases showed areas of necrosis and/or mitosis, but were not indicative of aggressive nature of this tumor. Immunoreactivity for GFAP, NF, S-100, NSE and synaptophysin indicates that this is a hybrid tumor with glial and neuronal differentiation. None of the tumors was immunopositive for HMB-45. The significance of the presence of T lymphocytes and mast cells is not clear. It could be related to tumor immunology and may indicate a favorable prognosis. [Abstract/Link to Full Text]

Wu D, Qiao Y, Kristensen GB, Li S, Troen G, Holm R, Nesland JM, Suo Z
Prognostic significance of dysadherin expression in cervical squamous cell carcinoma.
Pathol Oncol Res. 2004;10(4):212-8.
The protein and mRNA expression of dysadherin was studied in a series of squamous cell cervical carcinomas, and their clinicopathological associations and prognostic value were explored. Immunohistochemistry was used to assess protein expression of dysadherin in 206 patients with squamous cell cervical carcinoma, FIGO stage Ia-IVb. Frozen tissues from 20 cases in which the tumors showed variable dysadherin protein expression were used for laser capture microdissection (LCM) and processed for RTPCR detection of dysadherin mRNA. Immunohistochemically, all the dysadherin-positive staining was membranous. Positive cell membranous dysadherinpositive staining was often observed at the edge of tumor nests, although strong immunoreactivity throughout whole tumor nests was also seen in some tumors. Basal cells of the normal cervical epithelia were positive for dysadherin while its expression in the squamous cell cervical carcinomas was variable. Among the 206 tumors, 23 (11.2%) were negative, 53 (25.7%) were scored 1+, 54 (26.2%) were scored 2+ and 76 (36.9%) were scored 3+. In the 20 tumors analyzed, mRNA expression of dysadherin basically corresponded to its protein expression. No significant correlation between expression of dysadherin and age, FIGO stage or lymph node status was observed. Higher level of dysadherin expression, however, was significantly associated with shorter overall survival (p=0.04). We conclude that there is dysadherin protein expression in basal and parabasal cells of normal cervical epithelia, and higher level of dysadherin protein expression in squamous cell cervical carcinoma is predictive of a shorter overall survival, indicating that dysadherin may be a valuable prognostic marker in cervical carcinoma. [Abstract/Link to Full Text]

Surowiak P, Paluchowski P, Wysocka T, Wojnar A, Zabel M
Steroid receptor status, proliferation and metallothionein expression in primary invasive ductal breast cancers.
Pathol Oncol Res. 2004;10(4):207-11.
The most important immunocytochemical prognostic and predictive factors in cases of breast cancer include estrogen receptor alpha (ER) and progesterone receptor (PgR). The present study aimed at examining the relationship between the manifestation intensity of proliferation markers (Ki-67 and nucleolar organizer regions--AgNORs) on one hand, and expression of ER and PgR on the other in a uniform group of invasive ductal breast cancers of G2 grade. Moreover, the study aimed at examining the relationship between the above mentioned markers and expression of metallothionein (MT). The studies were performed on samples of invasive ductal breast cancers of G2 grade, originating from 60 females. In paraffin sections originating from the studied cases immunocytochemical reactions were performed using monoclonal antibodies to ER, PgR, Ki-67 and MT, and silver staining was conducted to localize AgNORs. The obtained results were subjected to statistical analysis using Statistica software. Results indicate that manifestation of AgNORs does not correlate with any of the studied antigens (ER, PgR, Ki-67, MT) (p>0.05). Moreover, no relationship could be demonstrated between the intensity of MT expression and proliferation markers or steroid receptor status (p>0.05). A negative correlation was shown between the expression of ER and Ki-67 (p=0.0009). The most intense proliferative activity was demonstrated in cases of breast cancer showing PgR expression but no ER expression (p=0.015), while the lowest proliferative activity was detected in breast cancers with expression of both ER and PgR (p<0.05). [Abstract/Link to Full Text]

Kida A, Ohashi K, Kobayashii T, Sakai M, Yamashita T, Akiyama H, Kishida S, Sakamaki H
Incapacitating lower limb pain syndrome in cord blood stem cell transplant recipients with calcineurin inhibitor.
Pathol Oncol Res. 2004;10(4):204-6.
Calcineurin-inhibitor induced pain syndrome (CIPS) is a newly described entity with a characteristic feature of sudden onset of severe lower limb pain, and high levels of cyclosporine or tacrolimus may be involved in the pathogenesis. This syndrome is rarely seen in recipients of hematopoietic stem cell transplantation (HSCT) compared with other organ transplant recipients, however, heightened awareness of this complication after HSCT may be needed for hematologists, as misdiagnosis can result in catastrophic consequences. We report herein two cases of lower limb pain syndrome, with some clinical features resembling CIPS, occurring during the early phase of cord blood stem cell transplantation for hematological malignancy. [Abstract/Link to Full Text]

Gundy S, Babosa M, Baki M, Bodrogi I
Increased predisposition to cancer in brothers and offspring of testicular tumor patients.
Pathol Oncol Res. 2004;10(4):197-203.
Cancer susceptibility was examined in first-degree relatives of 293 testicular tumor patients (TTPs) and 586 age-matched healthy males. Significantly increased risk was found in the families of TTPs (OR: 1.4; CI: 1.08-1.79), however, except for testicular cancer of 7 brothers (OR: 11.7; CI: 1.42-256.5), and 6 various childhood tumors (bilateral Wilms' tumor, neuroblastoma, medulloblastoma, ALL, histiocytosis-X, testicular tumor) of 200 offspring (OR: 12.9; CI: 1.54-286.2), no association with other malignancies was observed. No differences were seen between the fertility of patients and controls when occupational or socio-economic status of the families was taken into account. However, the majority of the controls (85%) fathered the first child between 20-30 years of age, while only 61% of TTPs had the first child in the same age group. TTPs fathered more girls than boys (P=0.009), and the lower male - higher female ratio of index children was also identical, irrespective of the conception taking place before or after the father's treatment. Occupations did not, but smoking might have influenced cancer susceptibility of the patients. Aggregation of fraternal testicular tumors, and both dramatically increased cancer risk and altered sex ratio of the offspring indicate a remarkable role of hereditary factors in tumorigenesis and later consequences of a certain portion of testicular malignancies, which must be refined by molecular studies. [Abstract/Link to Full Text]

Sinkovics JG
Chondrosarcoma cell differentiation.
Pathol Oncol Res. 2004;10(3):174-87.
A mixed population of lymphocytes from a healthy donor co-existed with an established culture of allogeneic chondrosarcoma cells, during which time the tumor cells changed from malignantly transformed to benign fibroblast-like morphology; from multilayered to a monolayered growth pattern; lost their potency to grow in colonies in soft agar; and showed signs of senescence. A discussion of possible molecular mechanisms for this event is offered. If there are as yet undiscovered lymphokines that can induce reversal of the malignant geno/phenotype, the cognate gene(s) should be cloned for genetic engineering and for the mass production of the corresponding molecular mediators for clinical trials. [Abstract/Link to Full Text]

Brittig F, Weinkauf P, K�rchner H
Ideal cooling process for paraffin-embedded tissues.
Pathol Oncol Res. 2004;10(3):172-3.
Back in the seventies everybody was convinced that it was no longer necessary to cool paraffinembedded tissues, because of the new advances in the production of paraffin. The reason for this assumption was the addition of plastic polymers and dimethyl sulfoxide. The quality of tissue sectioning improved because of these additives. The daily routine in the histology laboratories shows that it is impossible to produce good quality cutting without cooling. Cooling the paraffin by means of cooling plates or ice dishes creates drastic improvement; the cutting quality improves and it is much easier. Both improvements speed up the process and save time for the technicians and the physician. Long-term study indicates that not only the temperature but also the methodology of cooling and the cooling rate are playing a decisive role in the cutting quality. [Abstract/Link to Full Text]

Kovacs J, Varga A, Bessenyei M, Gomba S
Renal cell cancer associated with sarcoid-like reaction.
Pathol Oncol Res. 2004;10(3):169-71.
An unusual granulomatous reaction within a conventional clear cell renal cancer in a 62 year-old woman is reported. Using immunohistochemical evaluation, cells of the granuloma were CD68 (Kp1), carboxypeptidase M and CD3 positive. No signs of sarcoidosis were found in other organs. According to the few publications that mention cancer associated sarcoid-like reaction, such lesions do not influence the prognosis. Our patient is still well for a 15 months follow-up. [Abstract/Link to Full Text]

Pires FR, da Cruz Perez DE, de Almeida OP, Kowalski LP
Estrogen receptor expression in salivary gland mucoepidermoid carcinoma and adenoid cystic carcinoma.
Pathol Oncol Res. 2004;10(3):166-8.
Estrogen receptor (ER) expression in salivary gland carcinomas is controversial, and most published studies considered no more than 10 cases. We analyzed ER expression by immunohistochemistry in 136 mucoepidermoid carcinomas and 72 adenoid cystic carcinomas. All cases were negative. These results do not support a role for estrogens in salivary gland mucoepidermoid carcinoma and adenoid cystic carcinoma. [Abstract/Link to Full Text]

Hegyi L, Hockings PD, Benson MG, Busza AL, Overend P, Grimsditch DC, Burton KJ, Lloyd H, Whelan GA, Skepper JN, Vidgeon-Hart MP, Carpenter AT, Reid DG, Suckling KE, Weissberg PL
Short term arterial remodelling in the aortae of cholesterol fed New Zealand white rabbits shown in vivo by high-resolution magnetic resonance imaging - implications for human pathology.
Pathol Oncol Res. 2004;10(3):159-65.
High-resolution, non-invasive imaging methods are required to monitor progression and regression of atherosclerotic plaques. We investigated the use of MRI to measure changes in plaque volume and vessel remodelling during progression and regression of atherosclerosis in New Zealand White rabbits. Atherosclerotic lesions were induced in the abdominal aorta by balloon injury and cholesterol feeding. MR images (2D) of the abdominal aorta were acquired with cardiac and respiratory gating using a fast spin echo sequence with and without fat-suppression. In an initial study on rabbits treated for 30 weeks we imaged the aortae with a spatial resolution of 250x250 micrometers with a slice thickness of 2 mm and achieved a close correlation between MRI-derived measurements and those made on perfusion pressure-fixed histological sections (r(1) = 0.83, slope p(1) < 0.01). We subsequently imaged 18 rabbits before and periodically during 12 weeks of cholesterol feeding (progression) followed by 12 weeks on normal diet (regression). Aortic wall (atherosclerotic lesion) volume increased significantly during progression and decreased during regression. In contrast, lumen volume increased during progression and did not change during regression. In conclusion, this study confirms that non-invasive, high-resolution MRI can be used to monitor progression and regression of atherosclerosis, each within 3 months and shows, for the first time in a short-term model, that positive remodelling occurs early during progression and persists through regression of atherosclerotic lesions. [Abstract/Link to Full Text]

Amirghofran Z, Monabati A, Khezri A, Malek-Hosseini Z
Apoptosis in transitional cell carcinoma of bladder and its relation to proliferation and expression of p53 and bcl-2.
Pathol Oncol Res. 2004;10(3):154-8.
Transitional cell carcinoma of bladder (TCC) is a relatively common cancer among men. Tumor progression is associated with expression or modulation of several gene products that control apoptosis and proliferation. Apoptosis is a negative growth regulatory mechanism in tumors. The aim of this study is to examine apoptosis and related regulatory molecular markers in a group of patients with TCC. Paraffinembedded tissues from 49 patients with TCC were examined for the expression of bcl-2, p53 and Ki-67 by immunohistochemistry. Apoptosis was detected by TUNEL method. Correlation between apoptotic index (AI), proliferation index (PI) and bcl-2 and p53 expression with each other and with pathological grade was determined. Apoptosis was observed in 28.1% of TCC cases. The mean AI of all cases was 13.7+/-24. No correlation was found between apoptosis and differentiation status of carcinoma. Bcl-2 expression was weakly detected in only one sample. P53 expression was detected in 26 of cases with mean staining index of 102+/-96. A significant correlation between p53 and Ki-67 staining indices was observed (r=0.521, p=0.001). Both p53 and Ki-67 expression showed a good association with the pathological grade (p=0.0001 and p=0.004, respectively). None of the markers showed significant correlation with AI and no correlation was found between the ratio of AI to PI and other parameters either. In conclusion, the frequency of apoptosis in TCC of bladder appears not to be associated with tumor grade, and with bcl-2, p53 and Ki-67 expression. [Abstract/Link to Full Text]

L�rincz T, T�m�r J, Szendr�i M
Alterations of microvascular density in bone metastases of adenocarcinomas.
Pathol Oncol Res. 2004;10(3):149-53.
Bone may provide an extremely fertile microenvironment for angiogenesis. Experimental investigations indicate angiogenesis as a major regulator of bone metastasis development. Vascularization and angiogenic potential is known for most of the primary tumor types, but no studies investigated angiogenesis in bone metastases of human cancers. We have evaluated microvessel density of bone metastases of various cancer types (all adenocarcinomas) and compared to their primary tumors in paraffin samples of 39 patients. Microvessel density was determined by using the hot spot method and the blood vessel marker, CD34. The most vascularized adenocarcinoma was found to be renal cell cancer followed by lung adenocarcinoma, while breast cancer was heterogenous in this respect. Two patterns of modulation of the angiogenic phenotype in the bone metastases emerged in this study, which seemed to be cancer type specific: decreased angiogenic potential characterizing 45% of renal cell cancers and breast cancers of high vascularity in their primary, and increased angiogenic potential characterizing 40% of lung adenocarcinomas and breast cancers of low vascularity in their primary lesion. Our data demonstrate that i., the vascularization of bone metastases is frequently altered compared to the primary tumors, ii., patterns are different in the case of various cancer types. The tumor-type specific alterations of the angiogenic phenotype of cancers, metastatic to the bone, can have a clinical significance when angiosuppressive therapies are considered. [Abstract/Link to Full Text]

M�hes G, Speich N, Bollmann M, Bollmann R
Chromosomal aberrations accumulate in polyploid cells of high-grade squamous intraepithelial lesions (HSIL).
Pathol Oncol Res. 2004;10(3):142-8.
Persistant infection with human papillomavirus (HPV) of the uterine cervix is related with cytological atypia (SIL), the oncogenic potential of which is unclear in a given time point of monitoring. HPV-induced genetic instability result in polyploidization as well as in low frequency random chromosome aberrations in squamous cells. In the present work we analyzed whether highly polyploid/aneuploid cells reflect genomic changes at the chromosomal level. 13 samples with the cytological diagnosis of HSIL were analyzed for HPV type and nuclear DNA content measured by laser scanning cytometry (LSC). Hyperdiploid cells with >5c and with >9c DNA content were further analyzed for numerical aberrations of the chromosomes 3 and 17 by fluorescence in situ hybridization (FISH) following repositioning. Cells with >5c DNA content were found more frequently than cells with >9c DNA content (5-98 and 1-44 cells, respectively). The FISH analysis demonstrated frequent polysomies, however, the rate of aneusomy (other than 2, 4, 8 or 16 chromosome copies) was significantly higher in cells with >9c DNA content than in cells with >5c DNA content or the normal diploid cells. The imbalance of chromosome 3 and 17 copy number was also increased in cells with >9c DNA content. Moreover, in three out of the 13 analyzed HSIL samples, recurrent abnormal chromosome 3/17 ratio was demonstrated in a significant part of the cells, indicating a common origin of these cells. Highly polyploid/aneuploid cells in HSIL accumulate cytogenetic aberrations detectable by FISH analysis. These cells may reflect early changes with tumorigenic potential in a very concentrated fashion. [Abstract/Link to Full Text]

Bruheim S, Bruland OS, Breistol K, Maelandsmo GM, Fodstad O
Human osteosarcoma xenografts and their sensitivity to chemotherapy.
Pathol Oncol Res. 2004;10(3):133-41.
Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still die due to their disease. Further improvements in the management of osteosarcoma may rely on a more individualised treatment strategy, as well as on the introduction of new drugs. To aid in the preclinical evaluation of new candidate substances against osteosarcoma, we have established 11 human osteosarcoma xenograft lines and characterised them with regard to response to five different reference drugs. Doxorubicin, cisplatin methotrexate, ifosfamide and lomustine were effective in 3/11, 3/11, 1/10, 5/11 and 4/11 of the xenografts, respectively. Five xenografts were resistant to all compounds tested. We also assessed the mRNA expression levels of the xenografts for the O(6)-Methylguanine DNA Methyltransferase (MGMT), DNA topoisomerase II- (Topo II)-alpha, Gluthathione-S-transferase (GST)-pi, Multidrug-resistance related protein (MRP) 1 and Multidrug-resistance (MDR) 1 genes. There was an inverse correlation between the transcript levels of GST-pi and doxorubicin growth inhibition (r=-0.66; p<0.05), and between the transcript levels of MGMT and the effect of lomustine (r=-0.72; p<0.01), whereas the expression of MRP1 and cisplatin growth inhibition was positively correlated (r=0.82; p<0.005). This panel of xenografts should constitute a good tool for pharmacological and molecular studies in osteosarcoma. [Abstract/Link to Full Text]

Kabukcuoglu F, Kabukcuoglu Y, Yilmaz B, Erdem Y, Evren I
Mazabraud's syndrome: intramuscular myxoma associated with fibrous dysplasia.
Pathol Oncol Res. 2004;10(2):121-3.
The association of fibrous dysplasia and intramuscular myxoma is a rare disease known as Mazabraud's syndrome. Both lesions tend to occur in the same anatomical region. The relationship between fibrous dysplasia and myxoma remains unclear, where an underlying localized error in tissue metabolism has been proposed to explain this occasional coexistence. Another example of this syndrome in a 52 year-old woman is reported. The patient presented with a soft tissue mass at the anteromedial mid part of the left thigh. After excision of the mass, three separate bone lesions were detected in her control MRI. The soft tissue mass was misdiagnosed as liposarcoma in another center, and the bone lesions were interpreted as metastasis. The hypocellularity and the indistinct vascular pattern of the lesion were consistent with myxoma. The Jam-Shidi needle biopsies of the osseous lesions were diagnosed as fibrous dysplasia. The recognition of this entity is important for appropriate management of the patient. Patients with soft tissue myxomas should be thoroughly examined for fibrous dysplasia. The greater risk of sarcomatous transformation in fibrous dysplasia with Mazabraud's syndrome should also be kept in mind. [Abstract/Link to Full Text]

Vermes G, Acs N, Szab� I, Langm�r Z, J�ray B, B�nhidy F
Simultaneous bilateral occurrence of a mixed mesodermal tumor and cystadenocarcinoma in the ovary.
Pathol Oncol Res. 2004;10(2):117-20.
The mixed mesodermal tumor is a very uncommon malignancy. The aggressiveness of this lesion is illustrated by extremely poor prospects for afflicted patients: postoperative survival is usually shorter than 24 months. According to the literature, malignant mixed tumor of the ovary is rather rare and its occurrence with other malignancy is exceptional. We report here a case of a 62-years old woman with serous cystadenocarcinoma in the right ovary and a heterologous malignant mixed mesodermal tumor in the left one. Both tumors expressed cytokeratins, while only the mesodermal tumor expressed S-100 and focal NSE. [Abstract/Link to Full Text]

Csisz�r A, Szentes T, Haraszti B, Bal�zs A, Petr�nyi GG, P�csik E
The pattern of cytokine gene expression in human colorectal carcinoma.
Pathol Oncol Res. 2004;10(2):109-16.
Systemic and local cytokine environment may modulate the immunogenicity of colorectal cancer cells, and affect anti-tumor immune functions of tumor-infiltrating lymphocytes. We therefore investigated cytokine mRNA expression patterns in tumors and peripheral blood mononuclear cells (PBMC) from patients with colorectal adenocarcinoma. IL-2, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), IL-4, IL-6, IL-8, IL-10 and IL-1 beta mRNAs in single cell suspension of freshly isolated colorectal cancer tissue were studied by RT-PCR. Frequencies of cytokine gene expression were compared to those in normal colonic mucosa from tumor patients. The frequencies of IL-2, IFN-gamma, IL-4 and IL-10 gene expression were also determined in peripheral blood mononuclear cells from patients with colorectal adenocarcinoma and compared to those of healthy individuals. Tumor samples were more frequently positive for IFN-gamma, IL-2, TNF-alpha and IL-10 gene expression than normal mucosa (p=0.0001, p=0.0118, p=0.001 and p<0.0001, respectively). Frequencies of IL-2 and TNF-alpha gene expressions were significantly higher in tumors with a diameter <5 cm, than in those with a diameter >5 cm. The genes for IL-6, IL-1 beta and IL-8 were commonly expressed in both tumor tissue and normal colonic mucosa. IFN-gamma transcripts were detected in more PBMC samples from patients with colorectal cancer than those from normal controls (p=0.0449). Thus, colorectal cancer tissue is characterized by a specific pattern of cytokine gene expression. It is likely that multiple interactions between pro- and anti-inflammatory cytokines regulate tumor growth and the functional activity of tumor-infiltrating lymphocytes. [Abstract/Link to Full Text]

Ghosh S, Maity P
Isolation and purification of vascular endothelial growth factor (VEGF) from ascitic fluid of ovarian cancer patients.
Pathol Oncol Res. 2004;10(2):104-8.
Vascular Endothelial Growth Factor (VEGF) or Vascular Permeability Factor (VPF) is an angiogenic cytokine expressed by many human and animal tumors. Because of the importance of VEGF in animal tumors, we purified VEGF/VPF from ascitic fluid of ovarian cancer patients with heparin sepharose column. The purified protein gave protein bands of 37 and 26 kD, respectively in 12% SDS PAGE. The specificity of the purified protein was determined with dot blot, trans-immunoblot and ELISA using polyclonal goat anti-VEGF antibody (Santa Cruz Biotechnology). The vasodilatatory effect of the purified protein was confirmed by a vascular permeability assay on mouse. A polyclonal mouse antibody was raised against the purified protein, which recognized the same protein by ELISA, transimmunoblot and dot-blot analysis. It has been also found that the raised polyclonal antibody in mouse- and the commercial VEGF polyclonal antibody (Santa Cruz Biotechnology) both inhibited in vitrocell proliferation of human MCF-7 cell line. This study shows for the first time an effort to purify VEGF from human source. [Abstract/Link to Full Text]

Szende B, Farid P, V�gso G, Perner F, Kopper L
Apoptosis and P53, Bcl-2 and Bax gene expression in parathyroid glands of patients with hyperparathyroidism.
Pathol Oncol Res. 2004;10(2):98-103.
Altogether 107 patients were operated on at the Department of Transplantation and Surgery of Semmelweis University in the past four years, for clinical symptoms of hyperparathyroidism. Clinical and laboratory data of the patients supported the diagnosis of primary or secondary hyperparathyroidism. Chronically impaired renal function was found in 52 cases. The removed parathyroid glands showed hyperplasia in 54, adenoma in 50 and carcinoma in 3 cases. The majority of parathyroid lesions in primary hyperparathyroidism were adenomas (41 cases) and in secondary hyperparathyroidism were hyperplasias (43 cases). The ratio of oxyphil to chief cells as well as occasional mitotic and apoptotic figures were determined. The oxyphil component was present in both hyperplastic and tumorous lesions. Apoptosis and mitosis were rarely seen in hyperplasias and adenomas (under 2%), whereas in carcinomas 3% of the tumor cells were apoptotic and 4% showed mitosis. Cytoplasmic p53 positivity could be observed in 3 of the adenomas and in 2 of the hyperplasias. The carcinomas, four adenomas and 3 hyperplasias showed nuclear p53 positivity. Bcl-2 and Bax were detected in the cytoplasm of the tumor cells in the majority of adenomas and in the cells of hyperplasias. Oxyphil cells were more frequently positive than chief cells or clear cells. Colocalization of Bcl-2 and Bax was found randomly in all types of lesions. The very low incidence of carcinoma, the low mitotic and apoptotic ratio in adenomas and hyperplasias suggest a potent antiproliferative defense mechanism in the parathyroid cell population. This may also be reflected in the cytoplasmic colocalization of various gene products which regulate cell death and cell proliferation. No significant differences in the p53, Bcl-2 and Bax spectrum were found between the primary and secondary (i.e. renal failure) parathyroid alterations. [Abstract/Link to Full Text]

Ozkara SK, Corakci A
Significantly decreased P27 expression in endometrial carcinoma compared to complex hyperplasia with atypia (correlation with p53 expression).
Pathol Oncol Res. 2004;10(2):89-97.
P27 expression was examined on paraffin-embedded specimens in proliferative, secretory, hyperplastic and neoplastic human endometrium by immunohistochemistry. The results of p27 immunoreactivity in endometrial carcinomas were compared with clinicopathological indicators as well as with p53 expression. Thirty-eight cases of endometrial carcinoma, 30 normal functional (15 proliferative, 15 secretory), 24 hyperplastic endometrium (12 without atypia, 12 with atypia) specimens were studied by using monoclonal p27 and p53 antibodies. The streptavidin-biotin-peroxidase detection system was used and the intensity and the distribution of immunoreactivity was evaluated semiquantitatively. p27 expression was present both in the proliferative and secretory phases; the expression being stronger in the secretory period. In complex hyperplasia with atypia, p27 expression was even higher and it was significantly reduced in the endometrial carcinoma group (p<0.05). No significant correlation was found between p27 expression and any of the clinicopathologic prognostic parameters (p>0.05). Nuclear p53 expression was detected in 13 (34.2%) patients with endometrial carcinoma and was higher in non-endometrioid carcinomas and in tumors with increasing FIGO grade (p<0.05). High expression of p53 was not found to be a significant prognostic indicator of survival (p>0.05). No p53 expression was detected in the endometria with proliferation, secretion or hyperplasia either simple without atypia or complex with atypia. Surprisingly, tumors with absent/low p27 expression showed absent/low p53 expression. Our data suggest that p27 is necessary to control the proliferation of endometrium and its loss of expression seems to play a role in some aspects of endometrial carcinogenesis. [Abstract/Link to Full Text]

Moldvay J, Jackel M, Bogos K, Solt�sz I, Ag�cs L, Kov�cs G, Schaff Z
The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas.
Pathol Oncol Res. 2004;10(2):85-8.
Thyroid transcription factor-1 (TTF-1) is a sensitive marker for pulmonary and thyroid adenocarcinomas. The aim of this work was to determine its usefulness in distinction between primary and metastatic lung adenocarcinomas. We have examined the expression of TTF-1 in 100 solitary pulmonary nodules. They included 50 stage I peripheral primary bronchial adenocarcinomas (30 men, 20 women, mean age: 60 years) and 50 metastatic pulmonary adenocarcinomas (21 men, 29 women, mean age: 57 years) of different origins, such as breast (13), colon (13), rectum (13), kidney (7), stomach (2), and thyroid gland (2). TTF-1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. In primary bronchial adenocarcinomas we found immunopositivity in 46/50 cases, among them 30 cases showed strong nuclear immunostaining. In four primary adenocarcinoma cases the observed immunopositivity was localized to the cytoplasm. Out of the metastatic adenocarcinomas all but the 2 thyroid cancers were negative. Both thyroid tumors showed strong immunopositivity. Our results confirm that TTF-1 immunohistochemistry is a very sensitive and highly specific method in the differential diagnosis of primary and metastatic lung adenocarcinomas and should be used in the everyday clinical practice. [Abstract/Link to Full Text]

Helal Tel-A, Alla AE, Laban MA, Fahmy RM
Immunophenotyping of tumor-infiltrating mononuclear cells in ovarian carcinoma.
Pathol Oncol Res. 2004;10(2):80-4.
Infiltrating mononuclear cells play an important role in many types of cancer. The aim of this work was to determine the immunologic characteristics of mononuclear cellular infiltrate in ovarian cancer as compared to benign ovarian tumors. Paraffin-embedded tissues obtained from 52 ovarian carcinomas and 21 benign ovarian neoplasms were examined immunohistochemically to demonstrate suppressor/cytotoxic T cells and macrophages by using CD8 and CD68 monoclonal antibodies, respectively. The mean percentage of CD8+ cells was much higher in the malignant than in the benign group (P=0.00009). Similarly, the mean level of CD68+ cells was significantly higher in carcinomas than in benign cases (P=0.006). There was a significant negative correlation between the percentage of CD8+ cells and CD68+ cells in the malignant group (P=0.000002). Conversely, no correlation could be obtained between the values of these two cell types in the benign lesions. In the malignant group, although the percentages of CD8+ cells and CD68+ cells were not related to tumor differentiation, they were significantly related to tumor type. CD8+ cells were significantly higher in the serous (P=0.02), and CD68+ cells were higher in the mucinous carcinomas (P=0.0005). CD8+ T cells and macrophages constitute a major component of the infiltrating mononuclear cells in ovarian carcinoma. Their frequency seems to be related to the tumor type rather than the degree of tumor differentiation. [Abstract/Link to Full Text]

Jin R, Huang J, Tan PH, Bay BH
Clinicopathological significance of metallothioneins in breast cancer.
Pathol Oncol Res. 2004;10(2):74-9.
Metallothioneins (MTs) are a family of metal binding proteins that play an important role in maintaining transition metal ion homoeostasis, redox balance in the cell and fundamental cellular processes such as proliferation and apoptosis. In humans, there are 4 groups of MT proteins which are encoded by 10 functional MT isoforms. In breast tissues, MT is primarily expressed in myoepithelial and malignant epithelial cells. Immunohistochemical studies have revealed that 26% to 100% of invasive ductal breast cancers express the MT protein. The MT-1F and MT-2A isoforms have been reported to be associated with higher histological grade in breast cancer, whereas higher MT-1E mRNA expression was found in estrogen receptor-negative tumors compared to their estrogen receptor-positive counterparts. A number of studies have shown that MT expression in breast cancer is associated with poorer prognosis. In addition, metallothionein expression may have a potential role in protecting the breast cancer cell from chemotherapeutic threats to survival. [Abstract/Link to Full Text]

Kopper L, Hajd� M
Tumor stem cells.
Pathol Oncol Res. 2004;10(2):69-73.
Stem cells possess two basic characteristics: they are able to renew themselves and to develop into different cell types. The link between normal stem cells and tumor cells could be examined in three aspects: what are the differences and similarities in the control of self-renewal capacity between stem cells and tumor cells; whether tumor cells arise from stem cells; do tumorous stem cells exist? Since tumor cells also exhibit self-renewal capacity, it seems plausible that their regulation is similar to that of the stem cells. The infinite self-renewal ability (immortalization) is assured by several, so far only partly known, mechanisms. One of these is telomerase activity, another important regulatory step for survival is the inhibition of apoptosis. Other signal transduction pathways in stem cell regulation may also play certain roles in carcinogenesis: e.g. Notch, Sonic hedgehog (SHH), and Wnt signals. Existence of tumor stem cells was suggested since it is simpler to retain the self-renewal capacity than to reactivate the immortality program in an already differentiated cell. Moreover, stem cells live much longer than the differentiated ones, and so they are exposed for a long period of time to impairments, collecting gene errors leading to the breakdown of the regulation. However, it is still an open question whether all cells in the tumor possess the capacity that produces this tissue or not, that is: are there tumor stem cells or there are not. If tumor stem cells exist, they would be the main target for therapy: only these must be killed since the other tumor cells possess limited proliferative capacity, therefore limited life span. The only problem is that during tumor progression stem-like cells can develop continuously and the identification but mainly the prevention of their formation is still a great challenge. [Abstract/Link to Full Text]