Safety and Efficacy of Apixaban vs Enoxaparin for Preventing Postoperative Venous Thromboembolism in Women Undergoing Surgery for Gynecologic Malignant Neoplasm: A Randomized Clinical Trial.

Importance: Current guidelines recommend a 28-day course of enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The high cost of this medication and the low adherence rates observed in prior studies provide an opportunity to benefit patients by demonstrating the safety of a more cost-effective, easier to use thromboprophylactic. Objective: To investigate the safety and efficacy of an oral treatment alternative for thromboprophylaxis in postoperative patients with gynecologic cancer. Design, Setting, and Participants: This was a patient-based, multicenter, open-label, blinded, end point, randomized clinical trial conducted May 2015 to March 2019 in outpatient and inpatient gynecologic oncology settings. Women undergoing surgery for suspected or confirmed gynecologic cancer were approached for recruitment. The trial compared rates of major bleeding and clinically relevant nonmajor bleeding events during a 90-day follow-up period in patients taking apixaban or enoxaparin for postoperative thromboprophylaxis using a modified intent-to-treat analysis. Data analysis was performed from October to December 2019. Interventions: Women were randomized to 28 days of apixaban (2.5 mg orally twice daily) or enoxaparin (40 mg subcutaneously daily). Main Outcomes and Measures: The primary outcome was major bleeding and clinically relevant nonmajor bleeding events. Secondary outcomes included incidence of venous thromboembolic events, adverse events, medication adherence, participant quality of life, and medication satisfaction. Results: Of 500 women recruited for the study, 400 were enrolled and randomized (median age, 58.0 years; range, 18.0-89.0 years); 204 received apixaban and 196 received enoxaparin. Treatment groups did not differ in terms of race/ethnicity, cancer stage, or surgery modality (open vs robotic). There were no statistically significant differences between the apixaban and enoxaparin groups in terms of rates of major bleeding events (1 patient [0.5%] vs 1 patient [0.5%]; odds ratio [OR], 1.04; 95% CI, 0.07-16.76; P > .99), clinically relevant nonmajor bleeding events (12 patients [5.4%] vs 19 patients [9.7%]; OR, 1.88; 95% CI, 0.87-4.1; P = .11), venous thromboembolic events (2 patients [1.0%] vs 3 patients [1.5%]; OR, 1.57; 95% CI, 0.26-9.50; P = .68), adverse events, medication adherence, or quality of life between the groups. Participant satisfaction was significantly greater in the apixaban group with regard to ease of taking the medication (186 patients [98.9%] vs 110 patients [58.8%]; OR, 0.06; 95% CI, 0.01-0.25; P < .001) and pain associated with taking the medication (4 patients [2.1%] vs 92 patients [49.2%]; OR, 9.20; 95% CI, 2.67-31.82; P < .001). Conclusions and Relevance: These findings suggest that oral apixaban is a potentially safe, less painful, and easier-to-take alternative to subcutaneous enoxaparin for thromboprophylaxis after surgery for gynecologic cancer. The efficacy of apixaban to prevent venous thromboembolic events is hypothesized as being equivalent. Trial Registration: ClinicalTrials.gov Identifier: NCT02366871.

Ovarian Tumor Cell Expression of Claudin-4 Reduces Apoptotic Response to Paclitaxel.

A significant factor contributing to poor survival rates for patients with ovarian cancer is the insensitivity of tumors to standard-of-care chemotherapy. In this study, we investigated the effect of claudin-4 expression on ovarian tumor cell apoptotic response to cisplatin and paclitaxel. We manipulated claudin-4 gene expression by silencing expression [short hairpin RNA (shRNA)] in cells with endogenously expressed claudin-4 or overexpressing claudin-4 in cells that natively do not express claudin-4. In addition, we inhibited claudin-4 activity with a claudin mimic peptide (CMP). We monitored apoptotic response by caspase-3 and Annexin V binding. We examined proliferation rate by counting the cell number over time as well as measuring the number of mitotic cells. Proximity ligation assays, immunoprecipitation (IP), and immunofluorescence were performed to examine interactions of claudin-4. Western blot analysis of tubulin in cell fractions was used to determine the changes in tubulin polymerization with changes in claudin-4 expression. Results show that claudin-4 expression reduced epithelial ovarian cancer (EOC) cell apoptotic response to paclitaxel. EOCs without claudin-4 proliferated more slowly with enhanced mitotic arrest compared with the cells expressing claudin-4. Furthermore, our results indicate that claudin-4 interacts with tubulin, having a profound effect on the structure and polymerization of the microtubule network. In conclusion, we demonstrate that claudin-4 reduces the ovarian tumor cell response to microtubule-targeting paclitaxel and disrupting claudin-4 with CMP can restore apoptotic response. IMPLICATIONS: These results suggest that claudin-4 expression may provide a biomarker for paclitaxel response and can be a target for new therapeutic strategies to improve response.

Bevacizumab induced hypertension in gynecologic cancer: Does it resolve after completion of therapy?

Hypertension (HTN) induced by bevacizumab is a side effect that is often thought to resolve after treatment. However, there are currently no reports on rates of resolution. We assess the incidence and timing of the resolution of bevacizumab induced HTN. We evaluated all patients treated with bevacizumab for gynecologic malignancies at a single institution from 2012 through 2014. HTN was retrospectively diagnosed and staged by CTCAE v4.0 criteria. Resolution of HTN was defined as ≥ 2 values return to baseline blood pressure and/or discontinuation/decrease of blood pressure medications. We identified 104 patients; 35 were excluded due to receiving bevacizumab at time of analysis. Grade 2 or higher induced HTN was identified in 34/69 (49.3%) patients, of which 26/69 (37.7%) had grade 2 HTN and 8/69 (11.6%) had grade 3/4 HTN. Onset of HTN occurred at a median of 67 (14-791) days. Resolution of HTN occurred in 28/34 (82.4%) patients with a median time to resolution of 87 (3-236) days. BMI, history of HTN, blood pressure medications, prior bevacizumab treatment, number of bevacizumab cycles, CA-125 and albumin at initiation of treatment were not independent risk factors associated with developing HTN in multivariate analysis. Median PFS for those with HTN was 12.5 (1.9-45.8) months vs 11.0 (2.1-44.7) for those without (p = 0.17). Hypertension induced by bevacizumab resolved in 82% of patients in a median of 87 days. There were no identifiable risk factors associated with induced HTN and HTN was not a biomarker for improved prognosis in our cohort.

Resection and Advancement Flap Closure of a Combined Vascular Malformation of the Mons Pubis.

BACKGROUND: Vascular malformations are congenital abnormalities that do not spontaneously regress and may require surgical resection for treatment. CASE: A healthy 23-year-old woman presented with a painless, slowly enlarging mass of the mons pubis. Ultrasonography and magnetic resonance imaging demonstrated a cystic mass with minimal Doppler flow. The final pathology showed a combined lymphatic-venous vascular malformation. A meshed advancement flap was used to close the skin after surgical resection. These flaps create a lattice of small cutaneous defects that heal rapidly by secondary intention and optimize wound healing. CONCLUSION: Lower genital tract vascular malformations are rare but often become symptomatic in adolescents or young women. Larger lesions may warrant surgical resection. Flap closures may aid in proper wound healing.