Piotr Sobiczewski

Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients

BackgroundSurvivin is an inhibitor of apoptosis and a regulator of mitotic progression. TP53 protein is a negative transcriptional regulator of survivin. The aim of our study was to evaluate the clinical significance of survivin expression in advanced stages ovarian cancer with respect to the TP53 status.MethodsSurvivin and TP53 expression was evaluated immunohistochemically in 435 archival samples of ovarian carcinomas (244 patients were treated with platinum/cyclophosphamide-PC/PAC; 191-with taxane-platinum (TP) agents). Univariate and multivariate statistical analyses were performed in patients groups divided according to the administered chemotherapeutic regimen, and in subgroups with and without TP53 accumulation (TP53+ and TP53-, respectively).ResultsNuclear and cytoplasmic survivin expression was observed in 92% and 74% of the carcinomas, respectively. In patients treated with TP, high nuclear survivin expression decreased the risk of disease recurrence and death, and increased the probability of high platinum sensitivity (p < 0.01), but only in the TP53(+) group, and not in the TP53(-) group.ConclusionsIt appears that TP53 status determines the clinical importance of nuclear survivin expression in taxane-platinum treated ovarian cancer patients.

The evaluation of intra‐ and postoperative complications related to debulking surgery with bowel resection in patients with FIGO stage III–IV ovarian cancer

The surgical treatment of advanced ovarian cancer is based on the maximal debulking with widening the operation range to the infiltrated organs. The aims are as follows: (1) the assessment of the quantity and quality of intra- and postoperative complications in patients with advanced ovarian cancer in which partial bowel resection was performed and (2) the evaluation of intra- and postoperative complications related to surgery with bowel resection and anastomosis, compared to Hartmanns procedure. The analysis of debulking procedures with intestinal resection and postoperative period in 39 ovarian cancer patients, FIGO stage III–IV, was performed. During 39 operations, the most frequent type of resection was the sigmoidectomy or proctosigmoidectomy (29 patients). In the remaining patients, left- and right-side hemicolectomy or partial enterectomy was done. Twenty-four anastomosis and 15 Hartmanns procedures were performed. There were no differences between surgery with anastomosis and Hartmanns procedure in aspect of quantity of complications, blood loss, and the time of surgery. There were no statistically significant differences in overall survival and progression-free survival in both groups. We conclude that the percentage of complications related to debulking surgery with intestinal resection in advanced ovarian cancer patients might be accepted. The quantity of complications related to surgery with anastomosis and to Hartmanns procedure is similar. If possible, the surgery with anastomosis should be performed.

Results of chemotherapy for pulmonary metastases of carcinoma of the cervix in patients after primary surgical and radiotherapeutic management.

The purpose of this study was to evaluate the results of chemotherapy of pulmonary metastases from invasive carcinoma of the cervix, which were detected after a disease-free period after initial treatment with surgery or radiotherapy. Fifty patients with radiologically proven pulmonary metastases were treated with chemotherapy. All patients received a platinum-5-fluorouracil (PF) program: cisplatin 75 mg/m2 and 5-fluorouracil 800 mg/m2 every 4 weeks. The overall 1- and 3-year survival after PF chemotherapy was 62% and 17.6%, respectively. The progression-free survival at 1 and 3 years was 36.7% and 14.3%, respectively. There were 6 (12%) complete responses and 17 (34%) partial responses. Hematologic tolerance was acceptable. Third degree and fourth degree leukopenia was diagnosed in four (8%) and six (12%) patients, respectively. Three individuals had third degree thrombocytopenia. In the multivariate analysis, the following prognostic factors were associated with poor survival: time to recurrence after primary treatment (P= 0.002), number of lung metastases (P= 0.016), and progression during chemotherapy (P= 0.001). We conclude that PF regimen is a safe and reasonably effective chemotherapy in the management of patients with pulmonary metastases after primary treatment for invasive carcinoma of the cervix who do not qualify for surgical metastasectomy.

The Evaluation of Risk Factors Associated With Relapse and Recurrence of Borderline Ovarian Tumors With Long-Term Follow-up.

Objective The goal was to analyze the risk factors of relapse and to compare the type of recurrence in patients with borderline tumors treated and followed up in Oncologic Center in Warsaw. Materials and Methods This is a retrospective–prospective cohort study of 307 patients with confirmed borderline ovarian tumors treated in the Maria Sklodowska-Curie Memorial Cancer Center in Warsaw between 1994 and 2010. Univariate and multivariate analysis as well as Kaplan–Meier estimates were used to explore the impact of different covariates on progression-free survival. The analysis included the following potential prognostic factors: age, CA 125 value, stage according to classification of the International Federation of Gynecology and Obstetrics (FIGO), methods and radicality of operation, staging, tumor capsule rupture, histopathology, implants, ascites, and microinvasion. The analysis of relapses was also performed. Results Univariate analysis showed the negative impact of 2 factors on progression-free survival: FIGO II/III (implants) (P = 0.011) and ascites (P = 0.027). The multivariate analyses showed the detrimental effect of FIGO Ic (HR, 2.63; 95% confidence interval [CI], 1.12–6.17, P = 0.027), FIGO II or III (implants) (HR, 3.67; 95% CI, 1.56–8.61, P = 0.003), and incomplete staging (HR, 3.63; 95% CI, 1.09–12.07, P = 0.035), but not ascites (P > 0.1). Relapse occurred in 32 (10%) patients: in 22 patients as borderline and in 10 patients as invasive tumor. Seven (70%) patients with invasive relapse died of disease. All patients with borderline relapses were successfully managed by second surgery, which in 80% was again conservative. Conclusions Relapses in borderline ovarian tumor are uncommon, in 10% of patients. Invasive relapses are rare, only in 3% of patients, but often with fatal course irrespective of the treatment applied. The most important clinical risk factors of relapse are implants (FIGO II/III), FIGO Ic, and incomplete staging and this patients as well as patients with ascites should be closely followed. Relapses of borderline histology are easily detected and successfully managed by surgery.

Clinical value of human epididymis protein 4 and the Risk of Ovarian Malignancy Algorithm in differentiating borderline pelvic tumors from epithelial ovarian cancer in early stages.

OBJECTIVE The clinical value of human epididymis protein 4 (HE4) and the possibility of its use in the differential diagnosis in patients with benign, borderline and epithelial ovarian cancer in early International Federation of Gynaecology and Obstetrics (FIGO) stages. STUDY DESIGN The study group consisted of 205 women, including 60 with ovarian cancer, 18 with borderline tumors, 77 with benign lesions and 50 healthy subjects. In all the patients, before the treatment and in control groups, we determined CA 125 and HE4 in serum by electrochemiluminescence on the basis of the COBAS e601 system. For comparison of two independent groups, we used the U Mann-Whitney test. The analysis of the diagnostic power of the assessed parameters has been determined using the MedCalc statistical program. The probability of disease free survival (DFS) was evaluated using the log-rank test and Cox regression model. RESULTS Concentrations of HE4, CA 125 and Risk of Ovarian Malignancy Algorithm (ROMA) value were significantly higher in early ovarian cancer than in patients with benign (P<0.0001) and borderline tumors (P<0.002), the receiver operating characteristics (ROC) curves, demonstrated the highest diagnostic sensitivity for the ROMA score, as well post (AUC=0.817) as pre-menopausal (AUC=0.806). HE4 concentrations (P<0.021) and the value of the ROMA score (P<0.004) were significantly higher in patients with relapse than in patients in remission. There was no connection between concentrations of the studied tumor markers and DFS. CONCLUSIONS Determination of HE4 serum concentrations has a significant clinical value, especially in patients with benign lesions and elevated CA 125 levels. The combined assessment of HE4, CA 125 and the ROMA algorithm is helpful in differentiating benign tumors and borderline pelvic tumors from epithelial ovarian cancer in early FIGO stages. Determination of HE4, CA 125 and ROMA algorithm is not helpful in differentiating patients with borderline from benign lesions.

Comparison of cytogenetic changes between primary and relapsed patients with borderline tumors of the ovary

The aim of this work was to compare cytogenetic changes in primary and relapsed borderline tumors of the ovary. We analyzed 11 tumors (6 primary and 5 relapsed) by conventional GTG banding analysis and fluorescence in situ hybridization. The tumors studied were clinical stages I and III. Genomic imbalances were detected in both investigated groups. In the primary tumors group, only simple chromosome changes were detected. There were gains of chromosome 12, 7, and 8. The presence of additional copies of chromosomes 12 and 7 was independent of histologic subtype, whereas trisomy 8 appeared only in serous tumors. In the group of relapsed borderline tumors, besides trisomies 7 and 12, the structural aberrations of chromosomes 1, 6q, 7q, and 10q were revealed. Gains of tested oncogenes (CCND1 and MYC) have been demonstrated in both groups of investigated tumors. Gains of CCNC1 and MYC genes could be of prognostic value in borderline tumors, but this assumption requires further research.

Prognosis of patients with BRCA1-associated ovarian carcinomas depends on TP53 accumulation status in tumor cells

OBJECTIVE TP53 mutation is the most frequent molecular event in BRCA1-associated ovarian carcinomas. TP53 status may be a confounding factor in the evaluation of clinical importance of other proteins. We aimed to evaluate the clinical significance of BRCA1 mutations with respect to the TP53 accumulation status in 159 high-grade ovarian carcinomas. METHODS Statistical analyses were done with the Kaplan-Meier method, log-rank test, the Coxs and logistic regression models for all patients, and in subgroups with and without TP53 accumulation (TP53+ and TP53-, respectively). RESULTS Forty of 159 ovarian carcinomas (25.2%) were diagnosed in patients with BRCA1 germline mutations; 102 tumors (64.2%) were TP53+ and 57 (37.8%) were TP53-. Among patients with TP53+ carcinomas, BRCA1 carriers had increased odds of recurrence compared with sporadic cases (HR 2.25, P=0.003; median disease-free survival time 7.7 vs. 18.4months, respectively). In the smaller TP53- subgroup, BRCA1 mutation reduced the risk of death by 46% (HR 0.54, P=0.099, median overall survival time 42.7 vs. 28.1months), but beyond the border of significance. When the TP53 status was not taken into account, BRCA1 mutations did not show any significance, however, there was a trend toward increased odds of complete remission for women with BRCA1 mutations compared to non-carriers (OR 2.47, P=0.064). Taxane-platinum therapy showed advantage over the platinum-cyclophosphamide one in the entire group of patients and in the TP53+ subgroup. CONCLUSIONS Our results suggest that the TP53 accumulation status determines the prognosis of BRCA1 mutation carriers with high-grade ovarian carcinomas.

No evidence that genetic variation in the myeloid-derived suppressor cell pathway influences ovarian cancer survival

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.

Borderline ovarian tumors – diagnosis, treatment and follow-up

Tumors of borderline malignancy account for approximately 20% of all ovarian tumors. Their diagnostic criteria mainly include: the absence of...