Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data.

OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.

Immunohistochemical expression of heparanases 1 and 2 in benign tissue and in invasive neoplasia of the endometrium: a case-control study.

OBJECTIVES: Our purpose was to compare the expression of heparanase isoforms, in normal and in neoplastic endometrium. In a pioneering way, we sought to evaluate the expression of heparanase 1 (HPSE1) and heparanase 2 (HPSE2) in glandular and in stromal tissues. METHODS: This is a case-control study, conducted retrospectively in a public hospital, using paraffin blocks of endometrial tissue from patients admitted from 2002 to 2011 with and without endometrial cancer, with regard to the immunohistochemical expression of HPSE1 and HPSE2. The paraffin blocks were used for tissue microarray analysis and immunohistochemistry study in glandular and stromal tissues. RESULTS: In the study period, 195 participants were enrolled, 75 with and 120 without cancer. There was no significant difference between them regarding HPSE1 expression, both in gland and in stromal tissues. Heparanase 1 expression in the glandular tissue was more frequent among those with high-grade carcinoma, compared with patients with carcinoma type I. The difference in the expression of HPSE2 was significant between groups: it was less frequent in the controls than in the patients with cancer in the glandular tissue. In the stromal tissue, HPSE2 expression was significantly higher in the controls than in the patients with cancer and different when patients of the secretory endometrium subgroup were compared with those with hypotrophic, proliferative endometriums or with architectural disorders. No significant difference was found in the heparanase expressions in patients with cancer according to prognosis factors. CONCLUSIONS: Heparanase 1 is more intensely expressed in the glandular tissue of high-grade compared with type I carcinomas. Heparanase 2 is more intensely expressed in the glandular tissue of cancer than in nonneoplastic endometrium, whereas the HPSE2 expression in the stromal tissue is higher in the nonneoplastic controls compared with the group of patients with cancer mainly in the secretory endometrium. This suggests that HPSE2 might be stimulated by progesterone, with a possible antineoplastic role, antagonist to HPSE1, to be further investigated.

Expression of CK7 and CDKN2 in Cervical Intraepithelial Neoplasia and Correlation with Clinical Outcome.

AIM: To evaluate cyclin-dependent kinase inhibitor 2A (CDKN2A) and cytokeratin 7 (CK7) expression in cervical intraepithelial neoplasia (CIN) formalin-fixed samples. MATERIALS AND METHODS: Staining with antibody clones G175-405 for CDKN2A and OV-TL 12/30 for CK7 were evaluated and the detection of protein expressions were compared in 147 patients with CIN. RESULTS: Clinical follow-up of patients with CIN1 and CIN2 showed that most patients had a favorable outcome. Single CDKN2A or CK7 expression and their combined expression had a greater sensitivity and negative predictive value in CIN1, corresponding to the non-development of the disease. The positive predictive value of CDKN2A was greater than that of CK7. Combined expression of CDKN2A and CK7 showed that the sensitivity, specificity, positive predictive values, and negative predictive values had their maximum index in the CIN1 group. Analysis of combined expression of CDKN2A and CK7 showed that 85.7% of patients presented unfavorable clinical outcomes, with positive expression for both markers identified in CIN2. CONCLUSION: Combined expression of CK7 and CDKN2A was associated with a better diagnosis of CIN, and negative expression in CIN1/2 groups had a greater negative predictive value for patient clinical outcome.