Clinical and pathological features of breast cancer associated with the pathological complete response to anthracycline-based neoadjuvant chemotherapy.

OBJECTIVE: Patients with breast cancer with a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a better prognosis than patients with residual disease. The aim of the current study was to identify predictors of pCR. METHODS: This retrospective study included 388 patients treated with anthracycline-based NAC. Clinicopathological parameters were compared between the patients with and without pCR in breast and axilla. RESULTS: Treatment consisted of FAC/FEC in 230 patients (59%), TAC in 39 (10%) patients and AC followed by docetaxel in 119 (31%). In all, 36 (9.3%) patients had pCR. In univariate analysis, age, tumor size, lymph node involvement, tumor grade (p = 0.077, n = 265), ER and HER-2 status (n = 213), lymphovascular invasion (LVI), type of chemotherapy and taxane-containing chemotherapy were associated with pCR. In multivariate analysis, ER negativity (p = 0.003), the absence of LVI (p = 0.009) and taxane-containing NAC (p = 0.026) were found to be significant indicators of pCR. Median follow-up time was 69 months. Progression-free survival was significantly improved in patients achieving pCR (p = 0.001). CONCLUSIONS: pCR is associated with a better outcome regardless of clinical and pathological parameters in breast cancer patients who receive NAC. The probability of pCR was higher in ER-negative, LVI-negative tumors and in patients treated with sequential taxane-containing chemotherapy.

Identification of patients who may benefit from the prophylactic cranial radiotherapy among breast cancer patients with brain metastasis.

BACKGROUND: To identify the candidates for prophylactic cranial radiotherapy (PCI) among the patients with early and advanced-stage breast cancer. METHODS: The demographic, pathologic and clinical features and survival results of 182 brain metastatic breast cancer patients treated with cranial radiotherapy were examined. RESULTS: Early stage patients who progressed with isolated brain metastasis had longer survival (13 months vs. 4 months P = 0.006). Lobular/mixed type histology (P = 0.033), high nuclear (P = 0.046) and high histological grade (P = 0.034) were the prognostic factors for isolated brain metastases. The most significant factor for the time to brain metastasis was the number of involved of lymph nodes (P = 0.004). In 60% of 148 patients with metastatic breast cancer, a progression with isolated brain metastasis was developed while the systemic disease was under control. Isolated brain metastasis progression was related to the presence of the hepatic metastasis at the first relapse (P = 0.001) and with ErbB-2 overexpression (P = 0.034). The time to the brain metastasis from the first extracerabral metastasis was associated with the high nuclear grade (P = 0.040) and with chemoresistance (P = 0.037). The median survival time after the brain metastases in chemosensitive patients was longer than in chemoresistant patients (8 months vs. 3 months P = 0.044). In chemoresistant patients (P = 0.0028) and/or in triple negative patients (P = 0.05) the development of the brain metastasis was early and the survival after brain metastasis was short. DISCUSSIONS: Since there is a tendency to early brain metastasis in early stage patients with high-grade, lobular/mixed type histology tumors and with a high number of involved lymph nodes, the value of PCI can be explored in these patients by a well designed prospective trial. Advanced stage chemosensitive patients with ErbB-2 over-expression and/or with hepatic metastasis at their first relapse may be candidates for PCI. There is no place for PCI in chemoresistant and triple-negative breast cancer patients.

Factors related to recurrence after pathological complete response to postoperative chemotherapy in patients with epithelial ovarian cancer.

AIMS AND BACKGROUND: It has been appreciated for some time that the lack of detection of ovarian cancer at clinical and pathological (second-look laparotomy) evaluation is not synonymous with cure. The goal of this study was to define clinical risk factors for recurrence after complete pathological response to postoperative chemotherapy in patients with epithelial ovarian cancer. METHODS: Fifty-seven patients who met the inclusion criteria of our study were evaluated. The characteristics (age, menopausal status, histological subtype, tumor grade, presence of ascites at diagnosis, type of omentectomy, FIGO stage, and residual tumor volume after primary surgery) of patients with and those without tumor recurrence were compared. RESULTS: The median follow-up was 52 months (range, 15-142 months). The overall survival rates of the patients were 100%, 96%, and 87% at 1, 3 and 5 years, respectively. At the time of the study analysis, 21 of 57 (37%) patients had recurrent disease. The median time to recurrence was 16 months. Recurrences were most frequent in the pelvis and abdominal cavity (38%). Age, menopausal status, stage at diagnosis, and residual tumor volume after initial surgery were significantly related to the risk of recurrence in univariate analysis (P = 0.039, 0.038, 0.004, and 0.000, respectively). Residual tumor volume after initial surgery was found to be the only significant independent prognostic factor (P = 0.049, HR: 0.16, 95% CI: 0.02-0.99). CONCLUSION: We believe it is necessary to conduct randomized studies on this issue because insight into predictors of recurrence after pathological complete response to postoperative chemotherapy could be used to select patients for trials of consolidation therapy.

Serum levels of apoptosis biomarkers, survivin and TNF-alpha in nonsmall cell lung cancer.

CONTEXT: This study was conducted to investigate the prognostic role and the effects of chemotherapy on serum apoptosis biomarkers consisting of survivin and tumor necrosis factor alpha (TNF-alpha) in patients with advanced stage nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Fifty-seven patients with newly diagnosed NSCLC were enrolled into study. Performance status was 0 or 1 in 47 patients and 2 in 10 patients. Thirty-two of them were no or less than 10% weight loss. Patients were treated with platinum-based chemotherapy. Serum levels of TNF-alpha and survivin were determined by enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: While serum survivin levels in patients were not significantly different from controls (p=0.321), serum TNF-alpha levels in patients were found significantly higher than in controls (p=0.029). We found that serum TNF-alpha levels were increased (p<0.001), whereas serum levels of survivin (p=0.025) were decreased by the chemotherapy effects. The changes of the TNF-alpha and survivin serum levels due to chemotherapy effect showed a significant negative correlation (r=-0.36 p=0.007). The increase of serum TNF-alpha levels was independent from chemotherapy response; however, the reduction of serum survivin levels was found only significant in the chemoresponsive group (p=0.039). While older age, weight loss and performance status yielded prognostic value, neither TNF-alpha nor survivin levels proved to be significant for survival. CONCLUSION: Our findings suggest that the reduction in the serum survivin levels of advanced NSCLC patients after chemotherapy can be used as a predictor of response to the chemotherapy but not that of survival.

Lower level of MAPK expression is associated with anthracycline resistance and decreased survival in patients with hormone receptor negative breast cancer.

INTRODUCTION: Hormone receptor negative breast cancer is encountered in about 30% of all patients with breast cancer and is considered as a prognostically unfavorable subset. The aim of this study is to evaluate the prognostic impact of various molecular markers in patients with receptor negative breast cancer. METHODS: Tumor specimens from 140 patients with receptor negative (ER, PR) breast cancer were analyzed for MAPK, Her-2/neu, EGFR and PI3K expression by immunohistochemistry. The prognostic significance of these molecular factors, in addition to various prognostic variables were determined with respect to disease-free and overall survival. RESULTS: Nineteen (13.6%), 45 (32.1%), 16 (11.4%) and 47 (33.5%) patients had positive staining for EGFR, PI3K, Her-2/neu and MAPK, respectively. Twenty-three patients with positive MAPK (16.4%) had a high level of expression (score 4-7) and 24 (17.1%) had a low score (1-3). A lower percentage of MAPK expression was significantly associated with a poorer OS (p = 0.03) and a tendency for shorter DFS (p = 0.08) among those who were positive for MAPK. Anthracycline resistance remained the only independent significant variable for OS by Cox regression analysis (p = 0.001, HR:26.1). In patients with recurrent disease, median survival after initial relapse was 16.8 months. MAPK was determined as the only prognostic factor for this endpoint. Patients with higher level of MAPK staining showed significantly shorter survival following initial recurrence (p = 0.04). CONCLUSION: MAPK expression is a significant prognostic factor for non-metastatic patients with hormone receptor breast cancer. A lower level of staining is shown to be associated with with antracycline resistance and oveall survival, whereas a higher expression level is correlated with shorter survival following initial relapse, suggesting possible role of different molecular mechanisms pertaining to tumor progression once recurrence occurs. Further translational research is required to elucidate molecular mechanisms of the cross-talk between intracellular signaling and molecular pathways leading to drug resistance in patients with receptor negative breast cancer.

Leptomeningeal dissemination of ovarian carcinoma through a ventriculoperitoneal shunt.

BACKGROUND: Dissemination of ovarian cancer occurs mainly within the peritoneal cavity and central nervous system involvement (CNS) is encountered rarely. This report describes an unusual case with iatrogenic leptomeningeal metastasis from ovarian carcinoma. CASE: 36 year-old lady diagnosed with ovarian carcinoma develops neurologic symptoms 10 months following primary treatment. Medical history reveals a venticuloperitoneal shunt placement 16 years ago for non-communicating hydrocephalus. She undergoes surgery for obstruction of the VP catheter and pathologic evaluation reveals metastatic carcinoma consistent with the primary diagnosis. With subsequent systemic chemotherapy, the patient remains alive for 2 years. CONCLUSION: This report describes a unique patient with ovarian cancer, who developed iatrogenic leptomeningeal involvement of the lateral ventricule through an indwelling ventriculoperitoneal shunt.

Ovarian carcinosarcomas: clinicopathological prognostic factors and evaluation of chemotherapy regimens containing platinum.

OBJECTIVE: To evaluate the clinicopathological prognostic factors and outcome of chemotherapy in ovarian carcinosarcomas. METHODS: We reviewed the records of 26 patients treated from 1990 to 2006 at the Oncology Institute of Istanbul University. Clinical data including demographics, stage, surgery, chemotherapy, and survival were collected from patients' charts. RESULTS: All patients underwent initial debulking surgery. Optimal debulking was achieved in 21 (81%) patients. The most striking clinicopathological finding was the high incidence of hemorrhagic ascites (n: 6) which was observed in 60% of the patients with ascites (n: 10). The overall median survival of the patients was 26 months. Residual disease was associated with a decreased overall survival, P=0.04. Median survival (50 months vs 9.7 months, P=0.042) of the patients with early stage disease were longer than the patients with advanced stage. Twenty-two patients received platinum-based combination chemotherapy. There was a trend for increased median survival in the patients who were treated with carboplatin/paclitaxel combination (P=0.066). Although the numbers were insufficient for statistical evaluation, the patients treated with ifosfamide combinations had improved survival (36 months vs 26 months). However, when the patients treated with ifosfamide and carboplatin/paclitaxel combinations were combined, survival was statistically improved compared to the other regimens (36 months vs 9.7 months, P=0.04). Chemotherapy regimens containing doxorubicin or cyclophosphamide were not encouraging. Stage (P=0.02) and adjuvant platinum-based chemotherapy containing either paclitaxel or ifosfamide (P=0.024) remained predictive of outcome in the multivariate analysis. CONCLUSIONS: Hemorrhagic ascites can be used in the initial differential diagnosis of ovarian carcinosarcomas. Stage, optimal debulking and type of adjuvant therapy were statistically significant prognostic predictors of ovarian carcinosarcomas. We advise that patients with ovarian carcinosarcomas should be treated by optimal cytoreduction followed by adjuvant platinum/taxan or platinum/ifosfamide combinations.

Temozolomide in combination with fotemustine in patients with metastatic melanoma.

PURPOSE: Temozolomide and fotemustine are both active drugs for treating metastatic melanoma. The present study was designed to assess the efficacy and safety of combination therapy with temozolomide + fotemustine in patients with metastatic melanoma. METHODS: Forty patients (median age 50.5 and 22 males) with pathologically confirmed, unresectable, AJCO stage IV melanoma were enrolled into the study. The primary endpoints were tumor response and safety. Patients received oral temozolomide 125 mg/m(2) on days 1-7 and intravenous fotemustine 80 mg/m(2) on day 3 every 3 weeks. RESULTS: Fourteen (35%) patients achieved an objective response, including 3 (7.5%) complete and 11 (27.5%) partial responses. Median overall survival time was 6.7 months and 6-month survival rate was 57.4%. Myelosupression, particularly thrombocytopenia, was the primary toxicity. CONCLUSION: The regimen, temozolomide combined with fotemustine, is an active and moderately safe first-line chemotherapy regimen with acceptable and easily manageable toxicities in patients with metastatic melanoma.

Effect of maximum-tolerated doses and low-dose metronomic chemotherapy on serum vascular endothelial growth factor and thrombospondin-1 levels in patients with advanced nonsmall cell lung cancer.

BACKGROUND: Angiogenesis is regulated by a balance of both angiogenic inducers and inhibitors. This study was designed to evaluate the effect of both maximum-tolerated doses (MTD) and low-dose metronomic chemotherapy (LDM) on serum vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP1) and VEGFR1 concentrations in patients with advanced nonsmall cell lung cancer. PATIENTS AND METHODS: Forty consecutive patients with advanced stage nonsmall cell lung cancer were included in this prospective study. Twenty patients received MTD chemotherapy including 75 mg/m2 of cisplatin and 75 mg/m2 of docetaxel on day 1. The LDM treatment consisted of cisplatin 25 mg/m2 and docetaxel 25 mg/m2 were given to other 20 patients on weeks 1, 2 and 3. Serum levels were prospectively measured in serum by ELISA at four times; before chemotherapy and at 1, 2 and 3 weeks following initiation of chemotherapy. RESULTS: The major finding in this study that MTD chemotherapy but not LDM chemotherapy resulted in significant changes in VEGFR1 and TSP1 serum levels. Due to the effect of LDM chemotherapy, we showed no statistically significant change in patients for all serum VEGF, TSP1 and VEGFR1 levels. Similarly, serum VEGF levels did not also change under MTD chemotherapy. The MTD chemotherapy induced significant and long-lasting increase of TSP1 levels and decrease of VEGFR1 levels that persisted for at least 3 weeks after the chemotherapy initiation. No significant correlations were found between serum VEGF and TSP1 levels in cancer patients treated with both LDM and MTD chemotherapy. The circulating angiogenic balance (TSP1/VEGF) is decreased in cancer patients (P=0.039). CONCLUSIONS: The continuous/metronomic chemotherapy may not achieve a more pronounced antiangiogenic effect than MTD-scheduling chemotherapy. Future studies involving a larger number of patients are needed to confirm the present findings.

Ovarian carcinoma with simultaneous breast and rectum metastases.

BACKGROUND: Metastatic involvement of the breast and the rectum from ovarian carcinoma are very rare events. CASE REPORT: We report a case of ovarian carcinoma with metastasis to the breast and rectum simultaneously, 6 years after initial diagnosis. RESULTS: Morphologic and immunohistochemical findings from pathologic samples of all involved sites confirmed the ovarian origin, which spared the patient unnecessary breast and rectal surgery. To our knowledge, this is the first case of ovarian carcinoma with simultaneous metastases to the breast and rectum reported to date. CONCLUSION: Accurate differential diagnosis from primary breast and rectal carcinoma is very important because the prognosis and treatment differ significantly.

Circulating levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-3 (MMP-3), and BCL-2 in malignant melanoma.

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis that stimulates proliferation, migration, and metastasis of melanoma. In literature, all studies concerning influences of matrix metalloproteinases (MMPs) and antiapoptotic proteins on VEGF-induced angiogenesis in melanoma patients have been performed in tissue scale in melanoma. The objective of this study was to determine the value of circulating serum VEGF and its possible mechanisms of angiogenesis by circulating VEGF, MMP-3, and Bcl-2 in patients with melanoma. Fifty-one patients with cutaneous melanoma pathologically verified at different stages, and eighteen healthy controls were investigated. Serum VEGF, MMP-3, and Bcl-2 levels were quantitatively analyzed by ELISA. The serum VEGF (P = 0.034) and Bcl-2 (P = 0.005) levels were significantly higher in patients with melanoma than in the control group. However, there was no significant difference in the serum MMP-3 level between melanoma patients and controls (P = 0.51). The serum levels of VEGF were significantly influenced only by Breslow thickness (P = 0.045) and mitosis (0.039) and were not positively correlated with the stage of the disease. Among serum parameters, a significant relationship was found only between serum levels of VEGF and MMP-3 (r = 0.32, P = 0.023). In conclusion, our study demonstrates increased concentrations of VEGF and Bcl-2, but not MMP-3, in serum of melanoma patients regardless of the stage of the disease. VEGF may be a potential endothelial cell growth and survival factor. The mechanism of VEGF regulation of angiogenesis may be in part due to enhanced proliferation and survival of endothelial cells by differential expression of antiapoptotic genes and in part by activation of MMPs.

Effect of zoledronic acid on serum angiogenic factors in patients with bone metastases.

In this study we have investigated changes in circulating angiogenic factors after a single zoledronic acid intravenous infusion. Thirty consecutive patients who had histologically confirmed breast (n=20) and lung cancer (n=10) associated with confirmation of bone metastases were included in the study. Serum was also available from 10 healthy volunteers. Four mg of Zoledronic acid (Zometa, Novartis) was administered as a 15-min infusion in 100-ml normal saline on an outpatient basis. Venous blood for assessment of serum parameters was drawn just before the beginning of drug infusion and again at 7 and 28 days after the zoledronic acid infusion. Serum levels of VEGF and bFGF were assayed with ELISA kits. Serum VEGF and bFGF levels were not significantly different from healthy control groups (P>0.05). However, we found that serum VEGF levels in lung cancer patients were significantly higher than in patients with breast cancer and controls (P=0.009, and P=0.022, respectively). We found no significant correlation between serum VEGF and bFGF levels. No statistically significant changes were seen following infusion of zoledronic acid in patients with bone metastases for both serum VEGF and bFGF levels (P>0.05). Unlike previous studies, zoledronic acid did not appear to exert an angiogenic activity as there was no reduction of VEGF and bFGF circulating levels after zoledronic acid infusion.

Serum levels of intercellular adhesion molecule ICAM-1 and E-selectin in advanced stage non-small cell lung cancer.

Cell adhesion is a basic count in inter- and intra-cellular communication and plays an important role in tumor progression. This study was conducted to investigate the serum levels of intercellular adhesion molecule (ICAM-1) and E-selectin in patients with advanced stage non-small cell lung cancer (NSCLC) and the relationships with known prognostic parameters and therapy. These serum factors were measured of 57 NSCLC patients pathologically verified before and after chemotherapy in comparison with 24 healthy controls by using ELISA method. Serum levels of ICAM-1 were increased significantly in NSCLC patients compared with the healthy controls (P = 0.006). However, serum E-selectin levels were not significantly different from healthy control groups (0.643). No statistically significant relationships were found between investigated all serum parameters and various characteristics of patients, and the diseases such as stage and tumor burden. Likewise, we also found no correlation between serum ICAM-1 and E-selectin (P = 0.78). We found that serum ICAM-1 levels were decreased owing to the chemotherapy effect, independently from chemotherapy response. However, serum E-selectin levels were not changed by the chemotherapy effect. The median survival of all patients was 11.9 months and 1-year survival rate was 47.6%. We found that patients performance status (P = 0.013), age (P = 0.015), and weight loss (P = 0.007) were prognostic factors for survival. Serum E-selectin levels showed a trend (P = 0.08) related to worse prognosis, however serum ICAM-1 levels were determined as ineffective on survival (P = 0.11). Multivariate analysis revealed that only weight loss (P = 0.005) and E-selectin levels (P = 0.002) remained as an independent prognostic factor for survival in patients with advanced NSCLC. In conclusion, our data suggest that higher serum ICAM-1 can be useful for diagnosis while E-selectin levels have prognostic significance and could be a potential prognostic factor in NSCLC patients.

Prognostic and predictive value of vascular endothelial growth factor and its soluble receptors, VEGFR-1 and VEGFR-2 levels in the sera of small cell lung cancer patients.

OBJECTIVES: Small cell lung cancer (SCLC) has a rapid growth rate and is characterized by early metastases. Tumor growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Whether surveillance of pre- and post-treatment serum VEGF and especially its receptors VEGF-1 and VEGF-2 levels in SCLC patients have impact on clinical outcome is unknown. METHODS: From February 2001 to January 2003, 39 consecutive patients with histological proven SCLC were enrolled into the study. Pre-treatment (n: 39) and post-treatment (n: 25) samples of the same patients were collected at the time of their response evaluation. The levels of VEGF and its receptors VEGFR-1 and VEGFR-2 were measured in the serum by quantitative sandwich enzyme immunoassay technique. RESULTS: The median pre-treatment serum VEGF, VEGFR-1, and VEGFR-2 levels which were significantly higher than the normal controls were 1,200 pg/ml (range, 1,414.3 +/- 956.2 pg/ml), 85 pg/ml (range, 97.8 +/- 70.7 pg/ml), and 11,550 pg/ml (range, 14,481 +/- 6,267 pg/ml), respectively. We detected a poor but positive correlation between VEGF and VEGFR-2 (r: 0.46, p: 0.003). Pre-treatment low serum VEGF (<728.5 pg/ml) value (p: 0.02) and good response to treatment (p: 0.008) were found as good prognostic factors by multivariate analysis. CONCLUSIONS: Low serum VEGF concentration is a significant and independent prognostic factor in SCLC patients. Surveillance of VEGF and its receptors to predict chemotherapy response is not useful. Whether the levels of serum VEGF and its receptors VEGFR-1 and VEGFR-2 have value in detecting treatment modalities of SCLC need further studies.

Addition of topotecan to standard cisplatin/etoposide combination in patients with extended stage small cell lung carcinoma.

BACKGROUND: Topotecan is an active agent for the management of untreated and recurrent extensive-disease small cell lung cancer (ED-SCLC). This study was designed to evaluate the efficacy and safety of a triplet combination with topotecan added to the standard PE regimen in previously untreated patients with ED-SCLC. MATERIALS AND METHODS: Twenty-one patients (median age 55 years, and 18 male) with chemotherapy-naive ED-SCLC were enrolled into the study. PET treatment consisted of etoposide 80mg/m(2), cisplatin 20mg/m(2) and topotecan 0.75mg/m(2) and all were given intravenously on days 1 to 3 for every 3 weeks. RESULTS: Leucopoenia and/or neutropenia and to a lesser extent thrombocytopenia were the main dose-limiting toxicities. Severe leucopenia/neutropenia were observed in 14 (67%)/12 (57%) patients, and only two (10%) developed febrile neutropenia. Severe thrombocytopenia was observed in 6 (29%) patients and one patient died due to orbital and cerebral haemorrhage. Dose reductions were required in 13 (62%) patients, delays in 8 (38%) patients and early treatment discontinuation in 3 (14%) patients. The overall response rate was 52.6% (95% CI: 28, 9-75.6) with 2 (10.5%) complete and 8 (42.1%) partial responses. The overall median survival time was 6.6 months (range 0.5-16.5 months) and the 6-month overall survival was 65.3%+/-11.7. The overall median survival time of responders was 9.7 months compared to 5.7 months in non-responders (p=0.026). CONCLUSION: Topotecan combined with PE regimen with this schedule and dosage does not seem to provide any benefit in terms of response and survival in ED-SCLC patients and does not deserve further studies.

Serum IL-8 and IL-12 levels in breast cancer.

Interleukins (ILs) are known to play a fundamental role in cancer. We investigated the serum levels of IL-8 and IL-12, in breast cancer patients, and their relationship with the prognostic parameters and therapy. Forty eight patients with pathologically verified breast carcinoma and 21 healthy controls were enrolled into the study. Serum samples were obtained at baseline and after two cycles of chemotherapy. Serum IL-8 and IL-12 levels were determined using enzyme-linked immunosorbent assay (ELISA). There was no significant difference in the baseline serum IL-8 and IL-12 levels between breast cancer patients and healthy controls (p = 0.365 and p = 0.871, respectively), no significant correlation between the prognostic parameters and the serum IL-8, IL-12 levels. However, in the subgroup consisting of metastatic breast cancer patients, baseline serum IL-8 levels were significantly higher compared with non-metastatic disease (p = 0.047). Anthracycline-based chemotherapy and the addition of taxane did not change the levels of both serum IL-8 and IL-12. Serum IL-8 level may be useful in determining metastatic breast cancer. Larger studies are needed to confirm this finding.

The efficacy of tamoxifen in patients with advanced epithelial ovarian cancer.

BACKGROUND: Activity of tamoxifen as a salvage therapy in patients with advanced epithelial ovarian cancer was evaluated by a number of studies. In this study, we evaluated efficacy of tamoxifen in our patients with platinum-resistant epithelial ovarian carcinoma. PATIENTS AND METHODS: A retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer. RESULTS: Twenty-nine eligible patients were included to the study. There were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease. All patients were progressed after initiation of tamoxifen. Median progression-free survival was 4 mo (95% CI: 2.98-5.02). Disease progression of 19 (65%) patients were shown within the first 6 mo after initiation of tamoxifen. Progression-free survival was between 6 and 12 mo for 7 (24%) patients and > or =12 mo for 3 (10%) patients. The median survival after initiation of tamoxifen was 15 mo (95% CI: 7.2-22.8). No toxicity attributable to tamoxifen was seen in any of the patients. The only independent prognostic factor that had a significant predictive value for progression- free survival was the response to tamoxifen treatment (p = 0.043, hazard ratio: 0.12, 95% CI: 0.01-0.94). CONCLUSION: Considering minimal side effects and ability to cause objective responses, there is a place for tamoxifen in treatment of patients with platinum-resistant ovarian cancer. A phase III trial is required to con- firm the value of the drug in patients presenting these clinical settings.

Circulating serum levels of angiogenic factors and vascular endothelial growth factor receptors 1 and 2 in melanoma patients.

Angiogenesis is essential for tumor progression and metastasis; however, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. In this study, we analyzed the circulating serum levels of potent angiogenic factors, including vascular endothelial growth factor (VEGF), angiogenin, transforming growth factor-beta1 and VEGF receptors, VEGFR1 and VEGFR2, in human melanoma patients. One hundred and fourteen patients with histopathologically verified cutaneous melanoma at different stages and 30 healthy controls were investigated. Serum levels of angiogenic factors and VEGF receptors were quantitatively analyzed by solid-phase enzyme-linked immunosorbent assay. The age of the patients (61 men and 53 women) ranged from 18 to 80 years; median age was 51 years. Serum transforming growth factor-beta1 (P < 0.001), VEGF (P = 0.006) and VEGFR1 (P = 0.007) levels were significantly higher in patients with melanoma than in the control group. No significant differences, however, exist in the serum angiogenin and VEGFR2 levels between melanoma patients and the controls. The positive correlations of elevated serum levels of transforming growth factor-beta1, VEGF and VEGFR1 with advanced stages of disease were found. Significant relationship was found only between serum levels of VEGF and VEGFR2. Elevated serum transforming growth factor-beta1 (P < 0.001) and VEGF levels (P = 0.0012) were found to be poor prognostic factors. Serum level of angiogenin and VEGF receptors, however, had no effect on survival. Our data suggest that the angiogenic serum factors, including VEGF, transforming growth factor-beta1 and VEGFR1, but not angiogenin and VEGFR2 were increased in melanoma patients, especially associated with advanced disease stages. The mechanism of VEGF regulation of angiogenesis may in part be due to enhanced proliferation of VEGFRs, especially VEGFR1.

Intermediate dose interferon alpha in adjuvant treatment for high-risk melanoma: a single institution's experience.

Interferon is widely used as the most effective agent in the adjuvant therapy of patients with melanoma. However, little is known about the effect of intermediate dose interferon (IDI) in adjuvant therapy. We conducted this study to determine whether intermediate doses of interferon-alpha 2 could be beneficial for these patients. A series of 84 melanoma patients with high-risk relapse potential (stage II-III) after excisional biopsy were enrolled for adjuvant therapy with IDIs, either IFN-alpha 2a, 9 MU or IFN alpha 2b, 10 MU per day, subcutaneously, for 1 yr consisted of an induction period (5 d/wk for 4 wk) followed by 48 wk of same dose administered three times per week. The median follow-up was 25.9 mo with range 4-90.4 mo. Thirty-three (39%) patients had progressed; 18 (55%) of them while on treatment. The median (range) time of the failure occurrence was 9.1 mo (1.7-47.3 mo). Distribution of failure site was identical and the majority of the recurrences were found as single metastasis. For distant metastasis-free interval, mean (+/- SE) value was 28.8+/-3.6 mo; 1- and 2-yr survival rates were 87.8+/-5.7% and 61.6+/-9.3%, respectively. Twenty-two deaths were observed. Five-year survival rates of progression-free survival and overall survival were 50% and 60%, respectively. Generally, the treatment was found well-tolerated; drug-induced dose reduction or treatment discontinuation due to toxicity was minimal. Severe toxicity was rare. In conclusion, the small number of patients and the short follow-up does not permit any conclusion. However, the preliminary data seem to show that treatment with IDI was usually well tolerated with low toxicity of the patients during the adjuvant therapy.

The value of serum bcl-2 levels in advanced epithelial ovarian cancer.

The present study was conducted to investigate the value of serum bcl-2 levels in advanced epithelial ovarian cancer patients. Twenty-two patients with advanced ovarian carcinoma pathologically verified were investigated. Serum samples were obtained on the first admission before the chemotherapeutic treatment were given. Serum bcl-2 protein was determined by using ELISA. The baseline serum bcl-2 levels were significantly higher in patients with ovarian cancer than in the control group (p < 0.001). The sensitivity and specificity of serum bcl-2 were determined as 100% and 78%, respectively. None of the prognostic parameters analyzed such as age of patient, stage of disease, serum CA-125, albumin, hemoglobin, LDH, and response to chemotherapy was significantly correlated with bcl-2 serum concentrations. No prognostic value of serum bcl- 2 was determined. In conclusion, the results of the present study suggest that decreased apoptosis occurred due to the effect of serum bcl-2 elevation in advanced ovarian cancer patients. Also, serum bcl-2 level was a diagnostic but not a prognostic value in ovarian cancer. However, much researches still continues in this field, and exciting new knowledge will ultimately emerge.