VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Clinical significance of hepatitis B surface antigen in cord blood of hepatitis B e-antigen-negative chronic hepatitis B virus-infected mothers.

Vertical transmission of hepatitis B virus (HBV) infection during the perinatal period is the major cause of HBV transmission. The aim of our study was to evaluate the serological and virological profiles of HBV infection in cord blood samples obtained from HBeAg-negative chronic HBV-infected women, at delivery, and to investigate their relationship with the clinical outcome (possible transmission of HBV) in neonates receiving the currently approved passive-active immunoprophylaxis schedule. Sixteen women (32%) exhibited HBsAg positivity in the cord blood but HBV-DNA has not been detected in any of the 50 cord blood samples evaluated. We conclude that HBsAg can be transferred through the placental barrier, as with other proteins, in about one third of HBeAg-negative chronic HBV-infected pregnant women, irrespective of the maternal viral load, the mode of delivery or the placenta HBV pathology. The clinical impact of this phenomenon on the intrauterine-transplacental or perinatal transmission of HBV infection and/or passive-active immunoprophylaxis failure does not seem to be important.

Prognostic factors in patients treated with taxane-based chemotherapy for recurrent or metastatic endometrial cancer: proposal for a new prognostic model.

OBJECTIVE: Taxane-based chemotherapy has been recently introduced as an effective therapeutic option in recurrent or metastatic endometrial carcinoma (RMEC). The aim of the study was to determine the prognostic factors in RMEC after taxane-based chemotherapy. METHODS: One hundred ten patients who received paclitaxel-containing regimen for RMEC were retrospectively evaluated. Potential prognostic factors for overall survival were identified with the Kaplan-Meier method in univariate and the Cox regression model in multivariate analysis. RESULTS: Performance status (PS) and relapse within the field of previous external radiation were independent prognostic factors for overall survival (p=0.007 and p=0.026 respectively). Non-endometriod histology was associated with a shorter median survival compared to endometriod adenocarcinoma (14.46 vs. 17.57 months, p=0.093), but histology was not an independent prognostic factor (HR=1.43, 95% CI: 0.82-2.48, p=0.21). Stratification according to PS and relapse within the irradiation field identified three risk groups with distinctly different prognosis (median survival 27.36, 16.71, and 11.33 months for the group of favorable, intermediate, and unfavorable prognosis respectively, p<0.001). Within the favorable prognosis group, 34% of patients had a probability of 5-year survival. CONCLUSION: PS at diagnosis and relapse within the irradiated area may constitute a valid prognostic model in RMEC patients who receive taxane-based chemotherapy and are able to identify long-term survivors.

Correlation of NK T-like CD3+CD56+ cells and CD4+CD25+(hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: Association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy.

BACKGROUND: Several cytokines have been associated with immune regulation and prognosis in ovarian cancer. CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are involved in the immune response against the tumor. We have investigated the association of cytokines in the ascites from patients with ovarian cancer with these populations, the platinum resistance and the prognosis of these patients. PATIENTS AND METHODS: Ascites from 64 patients with ovarian cancer was analysed. Forty-two patients were studied at diagnosis (FIGO stage III in 40 cases) and were treated with cytoreductive surgery and platinum-based chemotherapy. Ascites from 9 patients with cirrhosis was used as control. Vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), interleukin-10 (IL10) and interleukin-12 (IL12) in ascites and serum were measured by enzyme-linked immunosorbent assay (ELISA), while lymphocytic populations were studied with three-colour flow cytometry. RESULTS: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho=-0.316, p=0.012), while a similar correlation was observed between TNFalpha ascites levels and CD4+CD25+(hi) cells (rho=-0.332, p=0.041). Among patients receiving first-line chemotherapy, VEGF levels <1900 pg/ml and TNFalpha levels >35 pg/ml were associated with platinum sensitivity (p=0.021 and p=0.028, respectively) and improved progression-free survival (PFS) (p=0.007 and p=0.045, respectively). Low VEGF levels were also associated with improved overall survival (p=0.026). CONCLUSION: VEGF and TNFalpha ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to their association with immunologically important populations, namely the NK T-like CD3+CD56+ cells and the Tregs CD4+CD25+(hi) cells.

Adjuvant chemotherapy with paclitaxel and carboplatin in non-endometrioid carcinoma of the uterus.

PURPOSE OF INVESTIGATION: Uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) represent more aggressive tumors than the more common endometroid cancers, exhibiting a propensity for distant metastasis. The aim of this study was to investigate the activity and safety of paclitaxel/carboplatin chemotherapy as the only adjuvant treatment in patients with surgically resected UPSC and UCCC. METHODS: Fifteen patients with Stage IB-IV UPSC or UCCC were treated with a mean of six courses of paclitaxel 175 mg/m3 plus carboplatin AUC 5 at three-week intervals, three to six weeks after undergoing surgery with curative intent. No patient had residual disease after surgery and none underwent pre- or post-chemotherapy irradiation. RESULTS: With a median follow-up of 29.4 months, six patients (40%) relapsed and two (13%) died of disease. Mean time to recurrence was 16.9 months. Recurrence rate per Stage was 17% for Stage IB/C, 57% for Stage IIIA/C and 50% for Stage IV. Projected 5-year overall survival and progression-free survival was 79.7% and 55.7%, respectively. All relapses were abdominopelvic whereas in one case pelvic recurrence was accompanied by lung metastasis. The most frequent grade 3-4 toxicity was neutropenia. CONCLUSION: Chemotherapy with paclitaxel plus carboplatin is feasible and possibly prevents distant metastasis when used as adjuvant in UPSC and UCCC.

Late relapse of epithelial ovarian cancer: a single institution experience.

PURPOSE OF INVESTIGATION: Late relapses are infrequent in ovarian cancer. We present the characteristics and outcome of patients who relapsed at least five years after first-line chemotherapy. METHODS: Six cases were retrieved from 203 patients treated from 1994 to 1998. RESULTS: Time to recurrence ranged from five to nine years. The initial stage was I or II in all cases, while histology was: endometrioid (4 cases), clear cell (1 case) and unspecified adenocarcinoma (1 case). Only two of five assessable patients responded to chemotherapy. Compared to earlier relapses, late relapses were characterized by earlier stages (p < 0.001), non serous histology (p = 0.010) and absence of symptoms (0% vs 46.5%, p = 0.025) at baseline. Five of 16 relapses (31%) among patients with Stage I or II were late relapses. CONCLUSION: Late relapses of ovarian cancer occur in early stages, where they are relatively frequent, while the chemosensitivity of the disease may be less than expected.

Malignant rhabdoid tumor of the clitoris in an elderly patient: report of a case.

Malignant rhabdoid tumors of the vulva are rare neoplasms which most of the time show aggressive behavior and a dismal prognosis. We report a case of malignant rhabdoid tumor of the clitoris occurring in an elderly patient. Due to the similarities that these neoplasms show with other low-differentiated tumors, immunohistochemical and ultrastructural assessment should always be conducted so that accurate diagnosis is achieved. Individualized extensive surgical treatment might decrease relapsing disease.

Prognostic evaluation of tumour type and other histopathological characteristics in advanced epithelial ovarian cancer, treated with surgery and paclitaxel/carboplatin chemotherapy: cell type is the most useful prognostic factor.

AIM: Ovarian carcinomas have been classified into types I and II according to the hypothesised mode of carcinogenesis and molecular characteristics. The prognostic significance of this classification has not been studied. PATIENTS AND METHODS: Five hundred and sixty-eight patients with histologically confirmed, ovarian, fallopian tube or peritoneal carcinomas, international federation of gynecology and obstetrics (FIGO) stages IIC-IV, treated with paclitaxel/platinum following cytoreductive surgery, were included in this analysis. Type I included low-grade serous, mucinous, endometrioid and clear-cell and type II high-grade serous, unspecified adenocarcinomas and undifferentiated carcinomas. RESULTS: Median overall survival (OS) was 49 months for type I versus 45 for type II (p=0.576). In contrast to type II, there was considerable prognostic heterogeneity among the subtypes included in type I. Cox regression analysis showed that cell-type classification: low-grade serous, mucinous, endometrioid, clear-cell, type II (high-grade serous, unspecified adenocarcinomas, undifferentiated carcinoma) was an independent predictor of survival (respective median OS 121 versus 15 versus 64 versus 29 versus 45 months, p=0.003). On the contrary, histopathological subtype or tumour type (I versus II) did not offer additional prognostic information. CONCLUSION: The proposed model of ovarian tumourigenesis does not reflect tumour behaviour in advanced disease. Tumour-cell type is the most relevant histopathological prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel.

The impact of age in the outcome of patients with advanced or recurrent cervical cancer after platinum-based chemotherapy.

OBJECTIVES: Cervical cancer is a disease of middle-aged and elderly but still there are young women diagnosed with advanced disease that is incurable with local treatment and is treated with platinum-based combination chemotherapy. It is unknown whether these young patients have a poorer outcome compared to older patients or whether elderly patients have inferior outcome than younger patients when treated with combination chemotherapy. METHODS: We compared the outcome between young (<35), elderly (>70) and middle-aged (35-70) women who were treated with platinum-based combination chemotherapy for advanced, recurrent or persistent disease. RESULTS: Two hundred and eighteen patients were included in our database. The baseline clinical and disease characteristics were not different between age groups but anemia and thrombocytosis were more frequent in younger patients. Median survival for all patients was 13.4 (95%CI 11-15.8) months while survival of patients<35 years of age was 9 months (95% CI 5.8-12), of patients older than 70 was 10 months (95% CI 6.9-13) of patients 35 to 70 years of age was 14.5 months (95% CI 11-18) (p=0.004). Multiple factors were significant for survival in univariate analysis but only weight loss, pain score and relapse inside an irradiated filed were significant predictors of outcome in multivariate analysis. CONCLUSIONS: Very young (<35) and elderly (>70) patients have a worse prognosis after treatment with combination chemotherapy for advanced or recurrent cervical cancer. Nevertheless, this difference is not significant when adjusted for other prognostic factors.

Significant differences of lymphocytes isolated from ascites of patients with ovarian cancer compared to blood and tumor lymphocytes. Association of CD3+CD56+ cells with platinum resistance.

OBJECTIVES: Tumor infiltrating lymphocytes (TILs) and T regulatory cells (Tregs) have been associated with prognosis in ovarian cancer, but their prognostic significance in ascites has not been studied. We performed a prospective study of T lymphocytes isolated from ascites from patients with ovarian carcinoma and we compared them with the respective populations in blood and tumors. METHODS: Mononuclear cells from ascites (n=71) and blood were isolated by Ficoll, while tumor lymphocytes (n=20) were obtained upon mechanical dissociation. Phenotypic analysis was performed with flow cytometry. Ascites from 10 patients with cirrhosis was used as control. RESULTS: Tregs containing CD4(+)CD25(+) cells, NK-T containing CD3(+)CD56(+) cells and CD69 and HLADR expression of CD4 and CD8 lymphocytes were significantly increased in tumor ascites compared to blood and control ascites. A selective accumulation of these populations in the ascites of cancer patients, was suggested by the significantly higher ascites/blood (A/B) ratios in cancer patients but not controls. Cancer cell content in ascites was correlated with CD4(+)CD25(+), CD4(+)CD69(+), CD4(+)HLADR(+) and CD8(+)CD69(+) cells. There was no correlation of lymphocyte populations between ascites and samples from peritoneal metastases. Higher tumor grade was associated with increased A/B CD4(+)CD25(+) ratio and reduced CD3(+)CD56(+) cells, while platinum resistance was associated with reduced A/B CD3(+)CD56(+) ratio. CONCLUSIONS: There are significant differences of CD3(+)CD56(+) and CD25(+)CD4(+) lymphocytes and increase in lymphocyte activation between blood, ascites and peritoneal metastases from patients with ovarian cancer. The selective accumulation of CD3(+)CD56(+) population in ascites may be a predictive factor for platinum resistance.

Conservative management of cervical intraepithelial neoplasia (CIN(2-3)) in pregnant women.

The management of cervical intraepithelial neoplasia (CIN(2-3)) diagnosed during pregnancy was the subject of this study. Two hundred and eight pregnant women with an abnormal cytology were assessed in our unit over a 10-year period. The age of the patients ranged from 20 to 45 (mean 28) years. Seventy-eight of these women were histologically proven to have CIN(2-3). All patients were followed up every 8-10 weeks by cytology and colposcopy during pregnancy and reassessed 8-12 weeks postpartum. The disease persisted in 30 cases (38.4%), whereas in the remaining 48 cases it regressed to CIN(1). No case of invasive disease developed during the follow-up period in these pregnant patients. Conservative management of CIN(2-3) during pregnancy is acceptable, but close follow-up and colposcopic expertise are necessary.

Paclitaxel, cisplatin, and epirubicin first-line chemotherapy in stage III and IV ovarian carcinoma: long-term results of a phase II study.

BACKGROUND: The combination of paclitaxel with cisplatin or carboplatin has become the preferred chemotherapy regimen in the treatment of epithelial ovarian carcinoma. Anthracyclines also have activity in this disease. We conducted a Phase II study by using the combination of paclitaxel, cisplatin, and epirubicin for the treatment of advanced ovarian carcinoma. METHODS: Forty consecutive patients with optimally (n = 7) or suboptimally (n = 33) debulked advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV) were treated with paclitaxel, 135 mg/m(2), as a 3-hour intravenous infusion, cisplatin 75 mg/m(2) intravenously (i.v.), and epirubicin 50 mg/m(2) i.v. every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was administered at a dose of 5 microg/kg/day on Days 5-9. RESULTS: Among 28 patients with measurable disease, 24 (86%%) achieved an objective response including 19 complete and 5 partial responses. Among 18 patients who underwent reassessment laparotomy, pathologic complete response was confirmed in 9 patients. At a minimum follow-up of 40 months, the median overall survival had not been reached whereas the median time to progression for all patients was 18.7 months. The median remission duration for women with measurable disease who responded to treatment was 14 months. The treatment was well tolerated without toxic deaths; the most common toxicity was Grade 3/4 neutropenia that occurred in 30% of patients. Significant neuropathy (Grade 2 or higher) developed in only 8% of patients. CONCLUSIONS: The combination of paclitaxel, cisplatin, and epirubicin is a well tolerated outpatient regimen with significant activity in the treatment of advanced epithelial ovarian carcinoma.

A phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of metastatic carcinoma of the uterine cervix.

BACKGROUND: Patients with metastatic carcinoma of the uterine cervix have limited survival. Thus, new chemotherapeutic agents and combinations are needed to improve patient outcome. METHODS: Twenty-seven patients with Stage IV primary or recurrent carcinoma of the uterine cervix were assigned to chemotherapy treatment at 4-week intervals with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The treatment was comprised of methotrexate, 30 mg/m2 administered intravenously (i.v.) on Days 1, 15, and 22; vinblastine, 3 mg/m2 i.v. on Days 2, 15, and 22; doxorubicin, 30 mg/m2 i.v. on Day 2; and cisplatin, 70 mg/m2 i.v. on Day 2. Granulocyte-colony stimulating factor (G-CSF) was given subcutaneously on Days 6-10 at a dose of 5 micrograms/kg. RESULTS: After a median of 4 cycles (a maximum of 6 in responders), the authors observed objective responses in 14 patients (52%), including 3 complete responses (11%) and 11 partial responses (41%). Median overall survival was 11 months (range, 4-15+ months), and median progression free survival of the responders was 8 months (range, 6-15+ months). Toxicity was acceptable and included neutropenia, alopecia, vomiting, and stomatitis. CONCLUSIONS: MVAC is an active regimen in the treatment of patients with advanced or recurrent carcinoma of the uterine cervix. It produced responses in one-half of the patients in this study, and it can be administered on an outpatient basis. The addition of G-CSF appears to reduce hematologic toxicity.

Ifosfamide and paclitaxel salvage chemotherapy for advanced epithelial ovarian cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of the combination of ifosfamide (1.5 g/m2 i.v. on days 1, 2, 3) and paclitaxel (135 mg/m2 i.v. over 3 hours on day 3) with G-CSF (5 micrograms/kg/d subcutaneously, days 7-11) administered every 3 weeks on an outpatient basis in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Thirty-five consecutive patients were treated, 12 of whom had previously received two regimens. Twelve of the 35 were defined as platinum-resistant and 23 as potentially platinum-sensitive. RESULTS: Fifteen patients (43%; 95% CI: 26%-61%) achieved objective responses, five of them complete and ten partial. Objective responses occurred in 17% of the platinum-resistant patients and in 57% of those with potentially platinum-sensitive disease. The median duration of response was seven months and the median overall survival 11 months. The treatment was well tolerated and only 15% of the patients developed grade 3 or 4 neutropenia. With the exception of alopecia there were no other grade 3 or 4 toxicities. CONCLUSIONS: The combination of ifosfamide and paclitaxel was well tolerated and showed activity in patients with ovarian cancer who had previously undergone platinum-based chemotherapy.

Ifosfamide, paclitaxel and cisplatin first-line chemotherapy in advanced, suboptimally debulked epithelial ovarian cancer.

BACKGROUND: The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS: Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m(2), as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m(2) intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m(2) intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 microg/kg/day on Days 7-11. RESULTS: Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION: The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens.