Low P16INK4A Expression Associated with High Expression of Cancer Stem Cell Markers Predicts Poor Prognosis in Cervical Cancer after Radiotherapy.

Previous studies have suggested that cancer stem cells (CSCs) resisted radiotherapy and chemotherapy. P16INK4A is a biomarker for cervical carcinogenesis and reduces proliferation of stem cells. We aimed to investigate the expression and clinical significance of cyclin-dependent kinase inhibitor 2A (P16INK4A), sex determining region Y-box 2 (SOX2), and Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) in cervical cancer treated with radiotherapy and cervical cell line models. The expressions of P16INK4A, SOX2, and ALDH1A1 were performed by immunohistochemical staining of tumor samples from 139 cervical cancer patients with International Federation of Gynecology and Obstetrics stages Ib to IV. The staining showed high expression in 100, 107, and 13 patients with P16INK4A (>80%), SOX2 (≥10%), and ALDH1A1 (50%), respectively. The high-P16INK4A group had a higher five-year overall survival (OS) rate and disease-free survival (DFS) than the low-P16INK4A group (OS: 62.0% and 35.2%, p = 0.016; DFS: 60.0% and 31.2%, p = 0.002). The low-P16INK4A/high-SOX2 and low-P16INK4A/high-ALDH1A1 groups had a worse five-year OS and DFS rate than the high-P16INK4A/low-SOX2 and high-P16INK4A/low-ALDH1A1 groups, respectively. Depletion of P16INK4A promoted chemoresistance and radioresistance of cervical cancer cells increased the expression of SOX2 and ALDH1A1 and exhibited higher self-renewal ability. These results suggest that lower P16INK4A expression associated with higher CSC markers predicts poor prognostic outcomes and is a promising target in patients with cervical cancer.

Prognostic role of excision repair cross complementing-1 and topoisomerase-1 expression in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecologic cancer worldwide and chemoresistance is one of the major causes of treatment failure. We investigated whether ERCC1, TAU, TOPO2A, TOPO1, P53, and C-MYC expression could be used as predictors for treatment outcomes. MATERIALS AND METHODS: Immunohistochemical staining was used to examine the expression of these biomarkers in resected tumor specimens from 38 patients treated in our institute. Clinicopathological data including demographics, staging, histological type, treatment response, expression of the biomarkers, and patient outcomes were analyzed. RESULTS: The median follow-up period was 47.5 months (range, 10-135 months) and the median overall survival was 56.0 months. Patients who did not have expression of ERCC1, and those who had expression of TOPO1 had significantly better overall survival. Cox regression analysis also confirmed that these two biomarkers were significant independent factors predicting survival (ERCC1, hazard ratio 5.51, 95% confidence interval: 2.02-14.00, p = 0.001; TOPO1, hazard ratio 0.22, 95% confidence interval: 0.06-0.77, p = 0.017). CONCLUSION: We concluded that poor overall survival was significantly associated with positive ERCC1 and negative TOPO1 expression. The results might be the consequence of chemoresistance to platinum and camptothecins, both of which are commonly used regimens in the treatment of epithelial ovarian cancer.

The use of weekly topotecan in the treatment of heavily pretreated recurrent epithelial ovarian and primary peritoneal cancer: the Kaohsiung Chang Gung experience.

OBJECTIVE: We attempted to investigate the safety and efficacy of alternative weekly topotecan dosing in a heavily pretreated Taiwanese population with recurrent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC). MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with recurrent EOC and PPC who had been treated with weekly topotecan between November 2008 and May 2012. Topotecan was given at a dose of 2.75-4 mg/m(2) via a 30-minute intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity occurred. RESULTS: Thirty-two patients were identified and 24 (75%) of them had received at least two previous regimens of chemotherapy; the median number of treatment courses was seven. The main toxicities (Grades 3 and 4) were anemia in seven (21.9%), neutropenia in six (18.8%), and thrombocytopenia in two patients (6.2%). No deaths were attributable to the therapy. Overall, seven patients (21.9%) showed a partial response (PR), while seven patients (21.9%) with stable disease (SD) were observed. Furthermore, we found a favorable response and toxicity profile in patients who received the lowest dose intensity (2.75 mg/m(2)). The median progression-free survival (PFS) and overall survival (OS) were 3 months [95% confidence interval (CI) 2.7-3.2] and 20 months (95% CI 11.1-28.9), respectively. CONCLUSION: Topotecan administered as a weekly dosage (2.75-4 mg/m(2)) seems to be a tolerable regimen with modest activity in a Taiwanese population. Although the lower dose schedule showed a higher response with a better toxicity profile, further studies with more cases are needed to confirm this finding.

Pure-type clear cell carcinoma of the ovary as a distinct histological type and improved survival in patients treated with paclitaxel-platinum-based chemotherapy in pure-type advanced disease.

OBJECTIVE: The aim was to compare survival in pure and mixed-type advanced clear cell ovarian carcinoma and to determine the benefits among patients with pure advanced clear cell ovarian carcinoma treated in paclitaxel-platinum-based chemotherapy in comparison with those treated in conventional platinum-based chemotherapy after primary surgery. METHODS: Between 1994 and 2001, 31 women with stage III and IV pure clear cell ovarian carcinoma and nine patients with stage III and IV mixed-type clear cell carcinoma were identified from the tumor registry of six institutions. All patients underwent cytoreductive surgery followed by conventional platinum-based chemotherapy or paclitaxel and platinum-based chemotherapy. RESULTS: The median survival of women with pure clear cell carcinoma was 11 months, compared to 48+ months for those with mixed-type clear cell carcinoma (P = 0.003). Overall, for women with pure clear cell carcinoma, 35% had clinically complete responses to chemotherapy. For women with pure clear cell carcinoma treated with paclitaxel-platinum-based chemotherapy, the median survival was significantly longer than for those treated with conventional platinum-based chemotherapy (16.26 vs. 10.75 months, P = 0.045; with optimal cytoreduction, 40.95 vs. 9.02 months, P = 0.028). Univariate analysis showed paclitaxel-platinum-based treatment was the only favorable prognostic factor for women with advanced pure clear cell ovarian carcinoma (P = 0.05). CONCLUSIONS: Patients with advanced pure clear cell ovarian carcinoma have poorer prognoses than those with the mixed type. Paclitaxel-platinum-based chemotherapy improved survival among our patients with advanced pure clear cell carcinoma, especially for those with optimal cytoreduction.