Nikki L. Neubauer

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer

Objective To determine the efficacy, progression-free survival (PFS) and overall survival (OS) for the combination of intravenous bevacizumab and oral cyclophosphamide in heavily pretreated patients with recurrent ovarian carcinoma. Methods A retrospective review was performed for all patients with recurrent ovarian carcinoma treated with intravenous bevacizumab 10 mg/kg every 14 days and oral cyclophosphamide 50 mg daily between January 2006 and December 2010. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors criteria and/or CA-125 levels. Results Sixty-six eligible patients were identified. Median age was 53 years. Fifty-five patients (83%) had undergone optimal cytoreduction. All patients were primarily or secondarily platinum resistant at the time of administration of bevacizumab and cyclophosphamide. The median number of prior chemotherapy treatments was 6.5 (range, 3 to 16). Eight patients (12.1%) had side effects which required discontinuation of bevacizumab and cyclophosphamide. There was one bowel perforation (1.5%). Overall response rate was 42.4%, including, complete response in 7 patients (10.6%), and partial response in 21 patients (31.8%), while 15 patients (22.7%) had stable disease and 23 patients (34.8%) had disease progression. Median PFS for responders was 5 months (range, 2 to 14 months). Median OS from initiation of bevacizumab and cyclophosphamide was 20 months (range, 2 to 56 months) for responders and 9 months (range, 2 to 51 months) for non-responders (p=0.004). Conclusion Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with recurrent ovarian carcinoma. This combination significantly improved PFS and OS in responders. Response rates were similar and favorable to the rates reported for similar patients receiving other commonly used second-line chemotherapeutic agents.

Progesterone Receptor-B Induction of BIRC3 Protects Endometrial Cancer Cells from AP1-59-Mediated Apoptosis

Progesterone is a growth inhibitory hormone in the endometrium. While progestins can be used for the treatment of well-differentiated endometrial cancers, resistance to progestin therapy occurs for reasons that remain unclear. We have previously demonstrated that progesterone receptors (PR) A and B differentially regulate apoptosis in response to overexpression of the forkhead transcription factor, FOXO1. In this study, we further examined the PR-isoform-dependent cellular response to the AKT pathway. Treatment of PRA and PRB-expressing Ishikawa cells (PRA14, PRB23), with an AKT inhibitor API-59CJ-OMe (API-59) promoted apoptosis in the presence and absence of the ligand, R5020 preferentially in PRA14 cells. Upon PR knockdown using small interfering RNA, an increase in apoptosis was observed in PRB23 cells treated with API-59 with or without R5020 while there was no influence in PRA14 cells. Using an apoptosis-focused real-time PCR array, genes regulated by API-59 and R5020 were identified both common and unique to PRA14 and PRB23 cells. BIRC3 was identified as the only gene regulated by R5020 which occurred only in PRB cells. Knockdown of BIRC3 in PRB23 cells promoted a decrease in cell viability in response to API-59 + R5020. Furthermore, the important role of inhibitors of apoptosis (IAPs) in the PRB23 cells to promote cell survival was demonstrated using an antagonist to IAPs, a second mitochondria-derived activator of caspase (Smac also known as DIABLO) mimetic. Treatment of PRB23 cells with Smac mimetic increased apoptosis in response to API-59 + R5020. In summary, our findings indicate a mechanism by which PRB can promote cell survival in the setting of high AKT activity in endometrial cancer cells.

The Role of Lymphadenectomy in Surgical Staging of Endometrial Cancer

Surgical staging, including lymph node sampling, for endometrial cancer was adopted by the International Federation of Gynecology and Obstetrics (FIGO) in 1988 based on reports demonstrating diagnostic and therapeutic advantages. This review focuses on the incidence of lymph node metastasis, risk factors for lymph node involvement, the effect of lymph node metastasis on prognosis, the therapeutic effect and diagnostic usefulness of lymphadenectomy, risks of lymph node dissection, and future directions in surgical staging of endometrial cancer. Surgical staging identifies most patients with extrauterine disease as well as uterine risk factors for recurrence, thereby allowing for a more informed approach to postoperative adjuvant therapy. Lymphadenectomy as a part of surgical staging is not required in patients assessed intraoperatively to be at low risk for lymph node metastasis (<2 cm grade 1 tumors with superficial myometrial invasion), however, a systematic lymph node dissection should be performed in most other patients with endometrial cancer. In the future, molecular markers may be useful to predict preoperatively tumor aggressiveness and lymph node metastasis. It is hoped that an approach of surgical staging with selective lymph node dissection will improve survival and spare patients additional surgical complications or unnecessary postoperative exposure to radiation and/or chemotherapy.

A comparison of 2 methods of vaginal cuff closure during robotic hysterectomy

To compare 2 methods of vaginal cuff closure with regard to safety, ease of use, and postoperative outcome.

Management of adenocarcinoma in situ of the uterine cervix: a comparison of loop electrosurgical excision procedure and cold knife conization.

Objective This study aimed to compare loop electrosurgical excision procedure (LEEP) with cold knife conization (CKC) as therapeutic management procedures for women with adenocarcinoma in situ (ACIS) of the cervix. Methods We conducted a retrospective chart review of all patients who underwent a conization procedure with a preoperative or postoperative diagnosis of ACIS of the cervix from 1997 to 2011. Data gathered included demographics, risk factors, pretreatment Pap test and colposcopic biopsy results, conization pathology including presence of invasive cancer and margin status, subsequent need for reconization or hysterectomy, and follow-up. Outcome measures, such as diagnosis of invasive cancer, margin status, and recurrence of ACIS or development of invasive cancer, were compared between LEEP and CKC. Results Of 115 conization procedures performed, 61 were LEEP (31 diagnostic and 30 therapeutic) and 54 were CKC (6 diagnostic and 48 therapeutic). Patients who underwent CKC were more often nulliparous, on oral contraceptive pills, and smoking cigarettes than patients who underwent LEEP. For the 78 patients who underwent conization procedures with therapeutic intent, there were no differences in the rates of positive margins (20% vs 17%), invasive cancer (3.3% vs 4.2%), recurrence of ACIS (6.7% vs 8.3%), or subsequent development of invasive adenocarcinoma (0 vs 2.0%) between LEEP and CKC, respectively. Conclusions In our study, LEEP was as good as CKC for the treatment of ACIS of the cervix, achieving the same rates of negative margins, diagnosis of invasive cancer, and recurrence of ACIS or invasive cancer. The benefits of LEEP versus CKC include the ability to perform the procedure in an outpatient clinic under local anesthesia with less morbidity. Patients treated for ACIS of the cervix by a conization procedure need careful, regular follow-up given the risk of recurrent ACIS or invasive cancer.

A Comparison of Survival and Recurrence Outcomes in Patients With Endometrial Cancer Undergoing Robotic Versus Open Surgery

OBJECTIVE To compare recurrence and survival outcomes in women who underwent either robotic or open surgical procedures to treat endometrial cancer. DESIGN A retrospective chart review (Canadian Tack Force classification II-2). SETTING A single academic institution. PATIENTS A total of 936 patients who underwent surgical staging for endometrial cancer between 2001 and 2013. INTERVENTION Through retrospective chart review, data were collected on patient characteristics, surgical procedures, intraoperative and postoperative complications, histopathology, adjuvant therapies, and recurrence and survival outcomes. Estimated 3-year progression-free survival and 5-year overall survival were calculated using Kaplan-Meier curves. MAIN RESULTS Of the 936 patients who underwent endometrial cancer surgery, 350 had robotic-assisted surgery and 586 had laparotomy. Both groups were comparable in terms of age, race, body mass index, and comorbid conditions. The laparotomy group had significantly more patients with grade 2-3 tumors, nonendometrioid histology, and stage III-IV disease. In a multivariate analysis, operative type was not an independent prognostic factor for intraoperative complications, but robotic surgery was associated with decreased postoperative complications and readmission rate. Median duration of follow-up was 30 months in the robotic cohort and 42 months in the laparotomy cohort. Estimated 3-year progression-free survival was 90.87% for the robotic group and 78.30% for the laparotomy group, and estimated 5-year overall survival was 89.14%for the robotic group and 79.47% for the laparotomy group. In a multivariate analysis, including stage, grade, histology, operative type, and adjuvant therapy, operative type was not an independent prognostic factor for recurrence or overall survival. CONCLUSION Compared with laparotomy, robotic staging for endometrial cancer is associated with less postoperative morbidity without compromising short-term recurrence rates or survival outcomes.

Fatal gestational trophoblastic neoplasia: An analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978.

OBJECTIVE To determine clinical factors that contributed to death from gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. METHODS Nineteen women who died of GTN from 1979-2012 were retrospectively identified and compared to 45 women previously reported on who died of GTN from 1962-1978. Clinical factors analyzed included demographics, pretreatment human chorionic gonadotropin (hCG) level, duration of disease, antecedent pregnancy, number and sites of metastases, FIGO stage and score, treatment, and cause of death. RESULTS Death from GTN occurred in 19 (4%) of 483 patients treated from 1979-2012 compared to 45 (11%) of 396 patients treated from 1962-1978 (P<0.001). Pretreatment hCG level >100,000 mIU/mL, time from pregnancy event to treatment >4 months, nonmolar antecedent pregnancy and use of surgery to control metastatic disease were similar between the two treatment eras. Patients in the recent series were more likely to have presented with FIGO IV disease or brain metastasis, been initially treated with multiagent chemotherapy, and received treatment before referral to our center compared to the earlier series. The most common causes of death from 1979-2012 and 1962-1978 were hemorrhage from one or more metastatic sites (11% vs. 42%), respiratory failure (37% vs. 31%), and multiorgan failure due to widespread chemoresistant disease (42% vs. 8%), respectively. CONCLUSIONS Our overall survival rate in patients with gestational trophoblastic neoplasia improved from 89% in 1962-1978 to 96% in 1979-2012. More patients treated between 1979-2012 died from widespread chemoresistant disease rather than hemorrhagic complications.

Abstract 1196: Progesterone via the PRB receptor attenuates AKT inhibitor mediated apoptosis in endometrioid endometrial cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Mutations in the PTEN gene are the most common genetic defects in endometrioid endometrial carcinoma and seen in more than 50% of tumors. PTEN, a tumor suppressor gene, negatively regulates PI3K/Akt-driven cell growth and survival. Previously, we have shown that levels of the forkhead protein, FOX01, a direct target of AKT, were significantly lower in endometrial carcinoma and overexpression of this gene in endometrial cancer cell lines resulted in decreased cell proliferation and increased apoptosis. Interestingly, the function of FOX01 in this context was determined by the progesterone receptor isoform that was expressed, strongly implicating the regulatory role of the progesterone receptor predictably at the transcription level. In this study, we aimed to look at the effects of an AKT inhibitor (APi59) on endometrial cancer cells and the influence of PRA or PRB on its efficacy. The cell viability assay revealed a decrease in the number of viable PRA and PRB cells treated with APi59 for 48 hours, while the progestin, R5020, alone did not affect cell viability. In addition, more cell death was observed in the PRA cells compared to the PRB cells. APi59 treatment promoted apoptosis, as measured by cleaved PARP levels, in both PRA and PRB cells, with increased apoptosis in PRA cells compared to the PRB cells. R5020 treatment alone did not cause apoptosis as compared to control. In order to further investigate the increased levels of apoptosis in the PRA cells, a real time PCR array focused on genes associated with apoptosis was used to identify potential genes involved in this differential response. The most highly upregulated gene specifically expressed in PRB cells in response to R5020 was BIRC3 (ciap2). BIRC3 was upregulated 13-fold with R5020 treatment in PRB cells where its expression in PRA cells was unaffected. Given that BIRC3 is a member of the inhibitor of apoptosis genes (IAP), we hypothesized that the increased expression of BIRC3 in PRB cells attenuated APi59-mediated apoptosis. Thus, PR was silenced using transient transfection of siRNA specific to PR and cells were treated with APi59 and R5020. Upon PR silencing, there was an increase in apoptosis as measured by cleaved PARP in APi59 treated cells along with a concomitant decrease in BIRC3 protein. To determine if the attenuation in apoptosis through BIRC3 occurred with other cytotoxic agents, PRB cells were treated with 10nm paclitaxel and R5020. Again, apoptosis in response to paclitaxel was attenuated, as shown by lower cleaved PARP levels when R5020 was added. In conclusion, not only can the AKT inhibitor, APi59, promote apoptosis in endometrial cancer cells, but liganded PRB can blunt the apoptotic response through increased expression of BIRC3, an inhibitor of apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1196.