Multiple lines of chemotherapy for patients with high-grade ovarian cancer: Predictors for response and effect on survival.

Guidelines for the treatment of tubo-ovarian cancer patients beyond third line are lacking. We aimed to evaluate the effect of response in each line on patient's outcome as well as identify variables that predict response for additional line of chemotherapy. A cohort study was performed including all patients with advanced high-grade ovarian cancer. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Odds ratios and hazard ratios were calculated using multilevel, mixed-effects logistic regression and Cox regression, adjusting for repeated measures within individual patients. Two-hundred thirty-eight patients were included and underwent up to 10 lines of chemotherapy. The median progression-free survival was 15.6 and overall survival (OS) was 55.6 months. Response rates dropped with each additional line and by line 5, most patients (61%) became refractory and only 16% had any type of response (complete 4% or partial 12%). By line 2, whether a patient had partial disease (PR), stable disease (SD) or progressive disease (PD) did not have an effect on the OS. From line 2, whether a patient had PR, SD or PD did not have an effect on chemotherapy-free interval. Number of previous lines and time from previous line were the only variables that significantly correlated with both outcome of patients and response to the next line. In conclusion, time interval from the previous line of chemotherapy is the major clinical factor that predicts beneficial effect of another line of treatment in patients with ovarian cancer.

Substantial Toxic Effect of Water-Pipe Smoking on the Early Stage of Embryonic Development.

Background: Water-pipe smoking (WPS) is the most widespread tobacco use in the Middle-East, and is rapidly spreading globally. Smoke from WP contains most of the compounds present in cigarette smoke, although in different proportions. WPS is associated with the risk of several human diseases; however, its impact on the early stage of normal development has not been investigated yet. Thus, in this investigation, we assess the effect of WPS on the embryo at the early stage of development. Methods: Chicken embryos at 3 days of incubations were used in this study. Meanwhile, we explored the outcome of WPS on angiogenesis using the chorioallantoic membrane (CAM) of the chicken embryos. Finally, quantitative real-time polymerase chain reaction was used to study the regulation of some key control genes of cell proliferation, apoptosis, and migration. Results: Our data reveal that WPS inhibits angiogenesis of the CAM and in embryos in comparison with their matched controls; in addition, WPS-exposed embryos show slight reduction in their sizes. We also noted that around 80% of WPS-exposed embryos die before 10 days of incubation. More significantly, WPS induces upregulations of BCL-2, Caspase-8, ATF-3, INHIB-A, and Cadherin 6 genes, which are important key regulators of cell apoptosis, proliferation, and migration. Conclusion: Our data reveal, for the first time, that WPS has very toxic effects during the early stage of embryogenesis. Thus, we believe that further studies are required to elucidate the pathogenic effect of WPS on human health especially on the embryo at the early stage of its development. Implications: This investigation addresses an important gap on the outcome of WPS during the early stage of embryogenesis. Data of this study point out that WPS can have a very toxic effect on the embryo at this stage. Additionally, results from this report display for the first time that WPS can damage normal angiogenesis of the embryo thus provoking a significant number of embryonic death. Moreover, this study reveals that this effect can occur via the deregulation of several genes related to cell apoptosis, proliferation, and migration.

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors.

BACKGROUND: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. METHODS: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay. RESULTS: Cells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor. CONCLUSION: Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.

Clinical outcome of neoadjuvant chemotherapy for advanced ovarian cancer.

OBJECTIVE: To evaluate clinical outcome in patients selected to receive neoadjuvant chemotherapy (NACT) compared to primary debulking surgery (PDS). METHODS: Retrospective study including all consecutive patients diagnosed and treated for advanced (stages III-IV) ovarian cancers between the years 2003-2015. RESULTS: 263 women were included in the study, of these, 127 patients were selected to receive NACT and 136 were treated with PDS followed by adjuvant chemotherapy. PDS was associated with longer OS in stage IIIc disease (median OS: 60.2 vs. 48.8months; p-value 0.039) compared with NACT. Patients achieved higher rates of complete cytoreduction in the NACT group compared to the PDS group (65.9% vs. 40.2%; p=0.001). Patients attaining complete cytoreduction after PDS had the best survival, (median OS 106months) followed by those with complete cytoreduction after NACT (median OS 71months), followed by those with residual disease after PDS (median OS 55months). Patients with residual disease following interval debulking after NACT had the worst outcome (median OS 36months). Platinum sensitivity following first line and second line chemotherapy was similar whether patients received neoadjuvant chemotherapy or not. CONCLUSION: PDS was associated with improved outcome. NACT appears to improve survival outcome in patients that would have had residual disease after PDS, and attain complete cytoreduction at the time of interval cytoreduction. This treatment option can be used in selected patients that are not candidates for complete cytoreduction at PDS.