Primary "breast-like" cancer of the vulva: a case report and critical review of the literature.

Ectopic mammary gland tissue in the vulva is an uncommon clinical or pathologic finding. Such ectopic tissue can be the site of the same physiologic and pathologic processes found in the normal breast. However, the occurrence of adenocarcinoma is very rare, the first case being reported by Greene in 1935. We here report the 16th case of primary "breast-like" cancer arising in the vulva, together with a critical review of the literature, in order to highlight the dilemmas of a clinical approach to this neoplasm. Clear guidelines for diagnosis and therapy are still unavailable. The main diagnostic criteria suggested by the authors of previous reports are discussed together with our own findings. The therapeutic approach to this rare malignancy is also critically reviewed. In our opinion, when diagnosis of breast-like vulvar cancer is finally confirmed, treatment and follow-up should be the same as that would be chosen in a case of orthotopic breast neoplasm.

Methylation of the insulin-like growth factor binding protein-3 gene and prognosis of epithelial ovarian cancer.

Insulin-like growth factor binding protein-3 (IGFBP-3) is a member of the IGFBP family, which regulates the mitogenic and antiapoptotic effects of insulin-like growth factors. Hypermethylation of the IGFBP-3 promoter has been found to suppress its expression. To evaluate the role of IGFBP-3 in ovarian cancer progression, we examined the survival of 235 consecutively selected epithelial ovarian cancer patients in association with IGFBP-3 promoter methylation and IGFBP-3 expression in tumor tissue. IGFBP-3 promoter methylation was analyzed using methylation-specific polymerase chain reaction. Cytosol protein was extracted and measured using a bicinchoninic acid assay; IGFBP-3 was measured by enzyme linked immunosorbent assay. Promoter methylation of the IGFBP-3 gene was detected in 44% (104/235) of patients. IGFBP-3 promoter methylation was associated with disease progression and death after adjusting for clinical and pathologic variables. The association was more evident in patients with early-stage disease: RR = 2.87 (95% CI: 0.78-10.63) for disease progression and RR = 3.94 (95% CI: 0.91-15.78) for death. Tissue levels of IGFBP-3 did not differ by methylation status but were inversely associated with disease stage and residual tumor size. These results suggest that IGFBP-3 promoter methylation may be a useful prognostic marker for disease progression and death in early-stage ovarian cancer.

Glutathione S-transferase polymorphisms and ovarian cancer treatment and survival.

OBJECTIVE: Members of the glutathione S-transferase (GST) family have been shown to have functional polymorphisms that may affect drug metabolism and influence the effects of chemotherapy and survival from cancer. GSTM1, GSTT1, and GSTP1 genotypes were evaluated for their role in ovarian cancer treatment and survival. METHODS: DNA was extracted from tumor tissues of 215 patients diagnosed with primary epithelial ovarian cancer. GSTM1 and GSTT1 genotypes were determined by multiplex PCR; GSTP1 genotypes were assessed with PCR-RFLP. Associations between GST polymorphisms and risk of ovarian cancer progression or death were analyzed using Cox proportional hazards regression; subgroups of patients receiving different chemotherapeutics were also evaluated. RESULTS: GST polymorphisms were not found to be associated with patient or tumor characteristics or response to treatment. However, GSTM1 null patients were less likely to have disease progression (HR: 0.65, 95% CI: 0.43-0.99) or to die (HR: 0.68, 95% CI: 0.45-1.03) compared to patients with GSTM1. Patients with GSTM1 null and GSTP1 ile/val or val/val (reduced function) had a further reduction in risk of disease progression compared to patients with GSTM1 or GSTP1 ile/ile (HR: 0.42, 95% CI: 0.24-0.75). A similar association was also suggested for overall survival (HR: 0.61, 95% CI: 0.36-1.05). Subgroup analyses indicated that the effects of GST on survival were more pronounced among patients treated with specific chemotherapeutics. CONCLUSION: These findings support the idea that reduced GST function may improve ovarian cancer survival after post-operative chemotherapy; evaluation of GST functional polymorphisms may help to predict ovarian cancer prognosis.

Clinical and pharmacokinetic phase II study of pegylated liposomal doxorubicin and vinorelbine in heavily pretreated recurrent ovarian carcinoma.

BACKGROUND: This multicenter phase II study evaluated feasibility, clinical efficacy, toxicity and pharmacokinetics of the combination of pegylated liposomal doxorubicin (PLD) and vinorelbine (VNR) in patients with platinum-paclitaxel pretreated recurrent ovarian cancer. PATIENTS AND METHODS: All patients received prior treatment with platinum and paclitaxel. Thirty-two heavily pretreated (median number of chemotherapy regimens two, range one to six) ovarian cancer patients received treatment with PLD 30 mg/m(2) and VNR 30 mg/m(2) every three weeks for six cycles. Ten patients entered the pharmacokinetic study, five receiving the PLD-VNR and five the VNR-PLD sequence. RESULTS: In 30 patients evaluated for response and toxicity, the overall response rate was 37% and 10% of patients achieved stable disease. Median time to progression and overall survival were 5.5 months (range 1-10) and 9 months (range 2-16), respectively. Toxicity was generally mild and reversible. VNR AUC(tot) and plasma levels were considerably higher in the PLD-VNR sequence. CONCLUSIONS: The PLD-VNR regimen exhibits significant activity in heavily pretreated patients, is well tolerated and is associated with encouraging survival. Preliminary pharmacokinetic results suggest the PLD-VNR sequence for further clinical applications. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.

Methylation of tumor suppressor gene p16 and prognosis of epithelial ovarian cancer.

OBJECTIVE: Methylation of p16 promoter was evaluated in ovarian cancer to determine the role of p16 methylation in ovarian cancer prognosis. METHODS: Two hundred and forty-nine patients with primary epithelial ovarian cancer were selected for the study; these patients were followed for a median of 31 months. Genomic DNA extracted from fresh frozen tumor tissues were treated with sodium bisulfite and were analyzed for p16 methylation using methylation-specific PCR (MSP). Cox regression survival analysis was performed to examine the associations of p16 methylation with progression-free and overall survivals. RESULTS: Of the 249 patients, 100 (40%) were tested positive for p16 promoter methylation. The status of p16 methylation did not change significantly with patient age, disease stage, histological grade, residual tumor size, and debulking results, although p16 methylation seemed to occur more often in patients with advanced diseases or aggressive tumors. Compared to those without p16 methylation, patients with p16 methylation had significantly higher risk for disease progression (P = 0.01). The relative risk for progression was 1.69 (95% CI: 1.12-2.54), and the association remained statistically significant (RR = 1.54, 95% CI: 1.01-2.34) after adjusting for clinical and pathological variables. The risk for death was also higher in methylation positive patients than in methylation negative patients (RR = 1.33, 95% CI: 0.88-2.00), but the difference was not statistically significant. CONCLUSION: The study suggests that promoter methylation in the p16 gene is associated with ovarian cancer progression, and evaluation of p16 methylation may have values in predicting ovarian cancer prognosis.

[Biologic therapy and epithelial ovarian cancer]. / La terapia biologica nel tumore epiteliale dell'ovaio.

The identification of new molecular prognostic and predictive factors for ovarian cancer may contribute in deciding individual therapeutic strategies; on the other hand, there has been growing interest in new biologic therapies to correct molecular or genic lesions of neoplastic cells (genic therapy), or to activate the specific immune response (immunological therapy). Chemotherapy collateral toxic effects, as myelotoxicity, should be reduced through transfection of genes that modulate drug resistance in stem cells. The data at present available suggest then the potential role of these new treatments, are more specific and less toxic than current therapies; however, other biological-molecular studies are required to obtain the clinical applications of the results: Aim of this study is to provide a review of the most interesting data in ovarian cancer biologic therapy.

Oral squamous carcinoma in a patient with cervix cancer: use of human papillomavirus analysis to differentiate synchronous versus metastatic tumor.

BACKGROUND: Cervical cancer usually spreads by direct infiltration and disseminates by lymphatic and hematogenous pathways. The common sites of distant metastases are the lungs, liver, and bones. Other rare metastatic sites have been previously described including only one case of oral cavity metastasis. CASE: We present here the second case of a patient with apparent oral cavity metastasis from cervical cancer. By cloning specific human papilloma virus (HPV) genomic regions, the two lesions showed HPV genomic sequences from different viruses (18 and 33, for the uterine cervix and the oral cavity, respectively), thus indicating the oral lesion as a synchronous second primary tumor. CONCLUSION: The use of molecular markers to distinguish between a secondary and a primary lesion is recommendable in cervical cancer, particularly when reporting rare site metastases.

Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker.

Human kallikrein 6 protein is a newly discovered human kallikrein. We determined the amount of human kallikrein 6 in extracts of 182 ovarian tumours and correlated specific activity (ng hK6 mg(-1) total protein) with clinicopathological variables documented at the time of surgical excision and with outcome (progression free survival, overall survival) monitored over a median interval of 62 months. Thirty per cent of the tumours were positive for human kallikrein 6 (>35 ng hK6 mg(-1) total protein). Human kallikrein 6-specific immunohistochemical staining of four ovarian tissues that included benign, borderline and malignant lesions indicated a cytoplasmic location of human kallikrein 6 in tumour cells of epithelial origin, although the intensity of staining was variable. Tumour human kallikrein 6 (ng hK6 mg(-1) total protein) was higher in late stage disease, serous histotype, residual tumour >1 cm and suboptimal debulking (>1 cm) (P<0.05). Univariate analysis revealed that patients with tumour human kallikrein 6 positive specific activity were more likely to suffer progressive disease and to die (hazard ratio 1.71 (P=0.015) and 1.88 (P=0.022), respectively). Survival curves demonstrated the same (P=0.013 and 0.019, respectively). Multivariate analysis revealed that human kallikrein 6 positivity was retained as an independent prognostic variable in several subgroups of patients, namely those with (low) grade I and II tumours (hazard ratio progression free survival 4.3 (P=0.027) and overall survival 4.1 (P=0.023)) and those with optimal debulking (hazard ratio progression free survival 3.8 (P=0.019) and overall survival 5.6 (P=0.011)). We conclude that tumour kallikrein 6 protein levels have utility as an independent adverse prognostic marker in a subgroup of ovarian cancer patients with otherwise apparently good prognosis.

[Expression and prognostic significance in epithelial ovarian cancer]. / Espressione e significato prognostico nel carcinoma ovarico epiteliale.

BACKGROUND: Insulin-like growth factor binding protein-3 (IGFBP-3) is a glycoprotein with specific binding affinity to peptide hormones insulin-like growth factors (IGFs) which are potent mitogens for a variety of cells. IGFBP-3 can inhibit the activities of IGFs by interfering with the interaction between IGFs and their receptor IGF-IR. Epithelial ovarian cancer (EOC) tissues express IGFBP-3, IGFs and IGF-IR. Moreover, high levels of IGF-I and IGF-IR have been shown in epithelial ovarian cancer, and IGF-I stimulates the growth of ovarian cancer. METHODS: We measured IGFBP-3 levels in ovarian cancer tissues of 147 consecutive patients and we examined its association with clinical and pathological features of the disease and patient survival. The average age of the patients in the study was 55 years and the median follow-up time was 37 months. IGFBP-3 levels were measured in the tissue extracts by a commercial ELISA kit and non-parametric statistics and the Cox regression survival analysis were used to determine the associations of IGFBP-3 with clinical and pathologic variables as well as with patient survival. RESULTS: High IGFBP-3 levels resulted significantly associated with some of the favorable prognostic features of the disease, including early clinical stage (p=0.048), small size of residual tumor (p=0.007), and optimal debulking result (p=0.007). High IGFBP-3 was also associated with a significantly reduced risk for disease progression (RR=0.52, p=0.034) and we showed an inverse dose-dependent relationship between IGFBP-3 and disease progression-free survival (p=0.033). However, the association with disease progression-free survival was no longer statistically significant in a multivariate analysis. An association between IGFBP-3 and overall survival was not shown. CONCLUSIONS: This study suggest that IGFBP-3 may play a role in the progression of epithelial ovarian cancer.

[Growth factors in epithelial ovarian cancer]. / Fattori di crescita e carcinoma epiteliale ovarico.

The aim of this study was to provide an up-to-date review of the knowledge on the role of the main growth factors involved in the onset and progression of epithelial ovarian cancer (Transforming Growth Factor a-TGFa, Trans-forming Growth Factor-TGFb, Epidermal Growth Factor-EGF, Insulin-Like Growth Factor-IGF, Vascular Endothelial Growth Factor-VEGF). Relevant articles published between 1991 and 2001 were identified using the Medline database. Publications identified by the search were reviewed and critically evaluated for their relevance to growth factors role in ovarian cancer. This review may be useful for clinicians wishing to study the biological mechanisms involved in epithelial ovarian neoplasms, in order to evaluate the possible value of Growth Factors as prognostic or predictive markers which could lead to novel therapeutic regimens, fitting individual needs based on single biological variations.

Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker.

Many members of the human kallikrein gene family were found to be differentially expressed in various malignancies and some are useful cancer diagnostic/prognostic markers. KLK9 is a newly discovered human kallikrein gene that is expressed in several tissues including thymus, testis, spinal cord, salivary gland, ovary, and skin. Like other kallikreins, the KLK9 gene was found to be regulated by steroid hormones in cancer cell lines. Our purpose is to examine whether quantitative analysis of KLK9 expression has prognostic value in ovarian cancer. We studied the expression of KLK9 by quantitative reverse transcription-PCR in 168 consecutive ovarian tumors of different stages, grades, and histological types, and correlated the expression with clinicopathological parameters, response to chemotherapy, and patients' survival. We found that KLK9 expression was significantly higher in patients with early disease stages (I or II; P = 0.044) and in patients with optimal debulking (P = 0.019). Kaplan-Meier survival curves demonstrated that patients with KLK9-positive tumors have substantially longer progression-free and overall survival (P < 0.001 and P = 0.016, respectively). When the Cox proportional hazard regression analysis was applied to subgroups of patients, KLK9 expression was found to be a significant predictor of progression-free survival in the subgroup of patients with low-grade tumors [hazard ratio (HR), 0.13; P = 0.0015], early stage (HR, 0.099; P = 0.031); and those with optimal debulking (HR, 0.26; P = 0.012). After adjusting for other known prognostic variables, KLK9 retained its independent prognostic value in all of these subgroups of patients. A negative correlation was found between the expression levels of CA125 and KLK9 (rs, 0.350; P = 0.002). Our results indicate that KLK9 is under steroid hormone regulation in ovarian and breast cancer cell lines. Immmunohistochemically, human kallikrein protein (hK9) was localized in the cytoplasm, but not in the nuclei, of the epithelial cells of ovarian cancer tissues. We conclude that KLK9 is a potential new independent favorable prognostic marker for early stage, low-grade, optimally debulked ovarian cancer patients.

Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma.

PURPOSE: Human kallikrein 10 (hK10; also known as the normal epithelial cell-specific 1 gene and protein) is a secreted serine protease, which belongs to the human kallikrein family. It has been reported that hK10 is down-regulated in breast and prostate cancer cell lines and that it may function as a tumor suppressor. Recently, we developed a highly sensitive and specific immunoassay for hK10 and found that this protein is abundantly expressed in ovarian tissue. In this study, we measured quantitatively hK10 levels in ovarian cancer cytosolic extracts and evaluated the prognostic value of this biomarker in ovarian cancer. EXPERIMENTAL DESIGN: Specimens from eight normal ovarian tissues, eight ovarian tissues with benign disease, and 182 ovarian tumors were investigated. RESULTS: hK10 concentration in ovarian tumor cytosols ranged from 0 to 84 ng/mg of total protein, with a median of 2.6. This median was highly elevated in comparison with normal and benign ovarian tissues (P < 0.001). A cutoff of 1.35 ng/mg was selected to categorize tumors as hK10 high and hK10 low. With chi(2) test and Fisher's exact test, high concentration hK10 was found to be associated with advanced disease stage, serous histological type, suboptimal debulking, and large residual tumor (>1 cm; all P < 0.05). hK10 status was additionally correlated with clinical outcome, including progression-free (PFS) and overall survival (OS) using the Cox model. In univariate analysis, we found that patients with hK10 high tumors were more likely to die and relapse, in comparison with patients with hK10 low tumors (hazards ratios for PFS and OS were 1.93 and 2.42, respectively; P < 0.05). Although this correlation disappeared after the entire patient population was subjected to multivariate analysis, it remained significant in the subgroup of patients with stage III/IV ovarian cancer (hazards ratios for PFS and OS were 1.98 and 2.12, respectively; P < 0.05). CONCLUSIONS: Our results indicate that hK10 is a new, independent, unfavorable prognostic marker, especially for late-stage ovarian cancer.

Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients.

PURPOSE: Kallikrein gene 4 (KLK4, also known as prostase/KLK-L1), located on chromosome 19q13.4, is one of the newly discovered members of the human KLK-like gene family. This gene is up-regulated by androgens in the LNCaP prostatic carcinoma cell line and by androgens and progestins in the BT-474 breast cancer cell line. On the basis of its apparent association with hormonally regulated tissues, we have undertaken to examine the prognostic value of KLK4 expression in 147 malignant ovarian tissues. EXPERIMENTAL DESIGN: Tumors were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK4 was amplified by PCR using gene-specific primers, and its identity was verified by sequencing. Ovarian tissues were then classified as KLK4-positive or -negative, based on ethidium bromide visualization of the PCR product on agarose gels. RESULTS: KLK4 was found to be expressed in 69 (55%) of 147 of ovarian cancer samples. We found a strong positive association between KLK4 expression and tumor grade (P = 0.02) and clinical stage (P < 0.001). Univariate survival analysis revealed that patients with ovarian tumors positive for KLK4 expression had an increased risk for relapse and death (P = 0.003 and 0.001, respectively). Whereas knowledge of KLK4 status did not significantly increase the prognostic power of the multivariate models, additional analyses did determine that KLK4 was an independent unfavorable prognostic factor in patients with grade 1 and 2 tumors. CONCLUSIONS: Our findings indicate that KLK4 expression is associated with more aggressive forms of ovarian cancer.

The human KLK8 (neuropsin/ovasin) gene: identification of two novel splice variants and its prognostic value in ovarian cancer.

UNLABELLED: KLK8 (neuropsin/ovasin) is a new member of the human kallikrein gene family, which consists of enzymes with serine protease enzymatic activity. Recent reports have implicated KLK8 in ovarian cancer. KLK8 may have potential clinical value for disease diagnosis or prognosis and it may also be a useful therapeutic target. PURPOSE: We undertook this study to evaluate the prognostic value of KLK8 in ovarian carcinoma by examining its expression in ovarian tumors. EXPERIMENTAL DESIGN: The KLK8 gene was analyzed by reverse transcription-PCR and direct sequencing in several human normal tissues. Subsequently, its expression was studied in a set of ovarian tumors, and statistical analysis was performed. RESULTS: We have identified two novel mRNA splice variants of the KLK8 gene, which are abundantly expressed in many tissues. These new variants were named KLK8 type 3 and type 4. Study of the expression of the KLK8 gene and its spliced variants in ovarian tumors indicated that the new variants were expressed very frequently and that full-length KLK8 expression is an independent and favorable prognostic marker for ovarian cancer. Patients with higher KLK8 expression in the tumor have lower grade disease, lower residual tumor left after surgery, live longer, and relapse less frequently. In multivariate analysis, higher KLK8 expression was significantly associated with longer disease-free survival. CONCLUSIONS: These results suggest that KLK8 is a novel, favorable prognostic marker in ovarian cancer. Because KLK8 encodes for a predicted secreted protein, its detection in serum may aid in ovarian cancer diagnosis.

IGFBP-3 in epithelial ovarian carcinoma and its association with clinico-pathological features and patient survival.

Insulin-like growth factor binding protein-3 (IGFBP-3) regulates the mitogenic and anti-apoptotic actions of insulin-like growth factors (IGFs). To study the role of IGFBP-3 in ovarian cancer progression, we measured IGFBP-3 concentrations in tumour tissues from 147 patients with epithelial ovarian carcinoma and examined its associations with clinicopathological features of disease and patient survival. The average age of the patients was 54.6 years (range 25-88 years) and the median follow-up time was 37 months. IGFBP-3 levels were measured with a commercial immunoassay kit. Low IGFBP-3 levels were significantly associated with unfavourable prognostic features of the disease, including advanced stage (P=0.048), large size of residual tumour (P=0.007), and suboptimal debulking outcome (P=0.007). Low IGFBP-3 levels were also associated with a significantly increased risk for disease progression (RR=1.92; 95% confidence interval (CI) 1.05-3.45; P=0.034), but the association was not sustained when other clinical and pathological variables were adjusted for in the analysis. No significant associations were observed between the IGFBP-3 level and patients' overall survival and response to chemotherapy. Findings of the study indicate that IGFBP-3 may play a role in the progression of epithelial ovarian cancer, but that it has no independent value in predicting either disease prognosis or the response of patients to chemotherapy.

Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer.

Kallikrein gene 5 (KLK5, also known as KLK-L2), located on chromosome 19q13.4, is one of the newly identified members of the kallikrein gene family, which is a subgroup of the serine protease enzyme family. In normal human tissues, KLK5 is highly expressed in skin, mammary gland and testis. Preliminary RT-PCR analysis has indicated that KLK5 is expressed in a subset of ovarian tumours. We have thus hypothesized that KLK5 may be a new prognostic indicator in ovarian cancer. We have examined the mRNA expression of KLK5 in 142 malignant ovarian tissues. Tumours were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK5 was amplified by PCR using gene specific primers, and the identity of the PCR product was verified by sequencing. Ovarian tissues were then classified as KLK5 positive or negative, based on ethidium bromide staining of the PCR product on agarose gels. KLK5 was found to be highly expressed in 58/142 (41%) of ovarian cancer samples while its level of expression was very low in normal ovarian tissues. We found a strong positive relation between KLK5 expression and tumour grade (P = 0.006) and disease stage (P = 0.027). Univariate survival analysis revealed that patients with ovarian tumours positive for KLK5 expression had an increased risk for relapse and death (P = 0.018 and 0.022, respectively). In multivariate analysis, KLK5 expression showed independent prognostic value only in the subset of tumours with lower grade disease (grades I and II). We conclude that KLK5 expression is associated with more aggressive forms of epithelial ovarian carcinoma and has indepdent prognostic value in low grade tumours.

Evidence for a dose-response effect between p53 (but not p21WAF1/Cip1) protein concentrations, survival, and responsiveness in patients with epithelial ovarian cancer treated with platinum-based chemotherapy.

The prognostic values of p53 and of its downstream mediator p21WAF1/Cip1 in patients receiving adjuvant chemotherapy for epithelial ovarian cancer have not been clearly established. Tumor extracts from a series of 120 patients treated postsurgically with cisplatin or carboplatin alone or together with other chemotherapeutics for primary ovarian carcinoma were assayed both for p53 protein by an immunofluorometric assay developed by us and for p21 protein by a commercially available immunoassay. Relative risks (RRs) for cancer relapse and death after 24 months of follow-up were determined by multivariate Cox regression analysis. Disease-free (DFS) and overall survival (OS) probabilities were also examined by the Kaplan-Meier method and log-rank tests. All other procedures were similarly nonparametric and based on two-sided tests of significance. Concentrations of p53 were elevated in patients with advanced stage disease (P = 0.02) or poorly differentiated (P = 0.03), suboptimally debulked tumors (P = 0.02), as well as in patients who failed to respond to chemotherapy (P = 0.03), as assessed by computed tomography scanning, serum CA125 determination, and second-look laparotomy. Statistically significant associations between concentrations of p53 and p21 were not found, nor were relationships demonstrated between concentrations of p21 and other clinicopathological variables or treatment response. Univariate analysis showed that p53 concentrations above the median indicated significantly higher risks for relapse (P = 0.04) and death (P < 0.01) and showed trends for increasing risks for relapse (P = 0.04) and death (P < 0.01) when p53 was considered as a four-level categorical variable. Multivariate analyses adjusted for age, stage, grade, and residual tumor size confirmed these observations (RR = 1.50; P = 0.05 for DFS and RR = 1.92; P = 0.03 for OS) for median-dichotomized p53, but the trends were of borderline significance (P = 0.09 for DFS and P = 0.07 for OS). In contrast, p21 positivity was not a significant predictor of favorable outcome in univariate survival analysis, and use of a three-level variable combining positivity or negativity status for both p53 and p21 did not yield greater separation of patients into risk groups (P = 0.07 for DFS and P = 0.06 for OS) than the use of p53 alone. Assessment of p53 expression may be an independent indicator of poor prognosis in ovarian cancer patients treated with adjuvant chemotherapy. The prognostic value of p21 expression, however, could not be demonstrated in our series of ovarian cancer patients.

[Evaluation of Ron and Met proto-oncogene expression in epithelial ovarian tumors]. / Valutazione dell'espressione dei proto-oncogeni Ron e Met nei tumori epiteliali ovarici.

BACKGROUND: Epithelial ovarian cancer is the most lethal gynecologic neoplasia. Up to date, little is known about its biology, and this makes even more difficult the definition of new therapies and the finding of early diagnostic methods. In this study, the expression of two oncogenes, Ron and Met, whose role in cancer progression has already been shown, and the possible clinical implication of their presence in the neoplastic tissue have been evaluated. METHODS: Forty-eight ovarian cancer specimens, 5 borderline lesions, 4 benign ovarian tumors and 2 normal ovaries were analyzed; from frozen tissue, Rna was extracted and cDna obtained by a RT-PCR (Retrotranscriptase-Polymerase Chain Reaction). Finally, the cDna was assayed for the presence of the Ron and the Met gene by another PCR. The results were correlated with clinicopathological parameters, and patient survival. RESULTS: Ron expression was shown in 56% of malignant lesions, and in 60% of borderline ones, while Met expression was detected in 54 and 60%, respectively. No statistically significant correlation was found between Ron and Met expression and clinicopathological features, such as histotype, grading, staging, residual tumor after debulking surgery, and response to chemotherapy, while a strong correlation (p = 0.001) was observed between overexpression of one of the oncogenes and the concomitant expression of the other. CONCLUSIONS: Even if residual tumor after debulking surgery was the most relevant prognostic factor, this study showed new data about the concomitant expression of Ron and Met oncogenes, which may suggest their cooperative role in ovarian cancer progression.

[Expression and prognostic value of the drug resistance markers P-gp, Mrp1, Mrp2, and Lrp in ovarian carcinoma]. / Espressione e significato prognostico dei markers di chemioresistenza P-gp, Mrp1, Mrp2 e Lrp nei carcinomi ovarici.

BACKGROUND: Intrinsic and/or acquired chemoresistance is the major obstacle to overcome in the treatment of patients with ovarian carcinoma. The aim of the present study was to investigate the prognostic value of drug resistance associated proteins P-glycoprotein (P-gp), multidrug resistance related protein (Mrp1), canalicular multispecific organic anion trans-porter (c-MOAT or Mrp2) and lung resistance protein (Lrp) in ovarian carcinoma. METHODS: Expression of P-gp, Mrp1, Mrp2 and Lrp was determined by immunohistochemistry of frozen tissue sections of 115 ovarian carcinoma patients and associated to clinico-pathological factors, response to chemotherapy and (progression free) survival. RESULTS: Expression of P-gp was observed in 20 out of 115 (17%), Mrp1 in 51 out of 115 (44%), Mrp2 in 19 out of 115 (16%) and Lrp in 85 out 115 (74%) tumors. Expression of Mrp1 was related to Mrp2 (p < 0.0001) and P-gp (p < 0.001) expression, while Lrp expression was more frequently observed in patients with stage I/II versus stage III/IV tumors (p < 0.01), grade I/II versus III tumors (p < 0.05) and residual tumor < 2 cm versus > 2 cm after laparotomy (p < 0.05). Lower stage (p < 0.001), small residual tumor after first laparotomy (p < 0.001) and lower differentiation grade (p < 0.05) were related to longer (progression free) survival. P-gp, Mrp1, Mrp2, and Lrp expression was neither related to response to first line chemotherapy (59 evaluable patients) nor to (progression free) survival (all patients). On multivariate analysis only stage and residual tumor after first laparotomy were independent prognostic factors for (progression free) survival. CONCLUSIONS: In ovarian carcinoma Mrp1 expression is associated with Mrp2 and P-gp expression, while Lrp expression is associated with favorable clinicopathological characteristics. Assessment of P-gp, Mrp1, Mrp2 or Lrp does not allow prediction of response to chemotherapy or (progression free) survival in ovarian carcinoma.

[Chemoresistance in ovarian cancer. State of the art and future prospects]. / La chemioresistenza nel carcinoma dell'ovaio. Stato dell'arte e prospettive future.

Aim of this study was to provide a review of the basic mechanisms of drug resistance in ovarian cancer and novel strategies to modulate drug resistance. Relevant articles published through August 1999 were identified using the Medline data base. Publications identified by the search were reviewed and evaluated critically for their relevance to drug resistance in ovarian cancer. Ovarian cancer patients have high response rates to initial chemotherapy after cytoreductive surgery. However, most will develop resistance to chemotherapy during the course of their treatment. There are multiple mechanisms resulting in drug resistance. Strategies to modulate drug resistance include dose intensity, various pharmacologic agents, and gene therapy.