Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial.

OBJECTIVE: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). METHODS: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. RESULTS: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). CONCLUSIONS: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

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.

Risk of venous thromboembolism in abdominal versus minimally invasive hysterectomy for benign conditions.

OBJECTIVE: We sought to describe the incidence of venous thromboembolism (VTE) following hysterectomy for benign conditions and to estimate if VTE incidence differs for abdominal and minimally invasive hysterectomy. STUDY DESIGN: Data for patients who underwent hysterectomy for benign conditions from 2010 through 2012 were abstracted from the American College of Surgeons National Surgical Quality Improvement Program database. Cases of VTE were compared to those without VTE. Minimally invasive hysterectomy was defined as both vaginal and laparoscopic hysterectomy. Pearson χ2 test, Student t test, and binary logistic regression were used for analysis. RESULTS: A total of 44,167 patients underwent hysterectomy; 12,733 (28.8%) underwent open hysterectomy, 22,559 (51.1%) underwent laparoscopic hysterectomy, and 8875 (20.1%) underwent vaginal hysterectomy. The incidence of VTE for open hysterectomy was higher (0.6%, 81/12,733) than minimally invasive hysterectomy (0.2% 73/31,434, P<.001). Open surgery (P<.001), body mass index (P=.006), race (P<.001), diabetes (P=.037), preoperative functional status (P<.001), American Society of Anesthesiologists class (P<.001), total operative time (P<.001), and time from surgery to discharge (P<.001) were each associated with VTE. Age, hypertension, current smoking, pack-year history, and year operation was performed were not associated with VTE. Using binary logistic regression, open surgery (P<.001), operative time (P<.001), and length of stay (P<.001) remained associated with VTE. The odds ratio for VTE after open hysterectomy compared with minimally invasive hysterectomy was 2.45 (95% confidence interval, 1.77-3.40). CONCLUSION: In this large quality database, a minimally invasive approach to hysterectomy was independently associated with a decreased incidence of VTE when compared with open hysterectomy.

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.

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.

Brain metastasis in gestational trophoblastic neoplasia: an update.

OBJECTIVE: To update the treatment of brain metastases in gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center, comparing treatment and outcomes from 1995-2009 with those from 1962-1994. STUDY DESIGN: Thirty-seven patients with GTN who had brain metastases at presentation (25, 68%) or who developed brain metastases during treatment (12, 32%) were treated with chemotherapy and brain irradiation at the Brewer Center between 1962 and 2009 (26 prior to 1995 and 11 since 1995). Patients underwent whole brain irradiation (2400-4000 cGy in 200-300 cGy fractions prior to 1995, and 2400-3000 cGy in 200 cGy fractions since 1995) +/- radiosurgery. RESULTS: Of 11 patients with GTN treated for brain metastases since 1995, 7 (64%) are alive, and 4 died. Six (55%) of the 11 patients treated after 1995 were diagnosed with brain metastases during treatment, 3 (50%) of whom were cured, compared to 6 (23%) of the 26 patients treated before 1995, only 1 (17%) of whom was cured. CONCLUSION: The overall survival for all 37 patients with GTN who had brain metastases from 1962-2009 was 51% (19/37): 46% (12/26) before 1995 and 64% (7/11) after 1995. Survival was significantly influenced by symptoms at presentation: 100% (8/8) for asymptomatic patients versus 41% (7/17) for symptomatic patients (p=0.0005). No patient who died had uncontrolled brain metastases. In our experience, therefore, brain metastases in GTN are curable with a combination of systemic multiagent chemotherapy and whole brain irradiation.

Stage I, grade 3 endometrioid adenocarcinoma of the endometrium: an analysis of clinical outcomes and patterns of recurrence.

OBJECTIVE: To study patterns of recurrence and survival outcomes in patients with surgical stage I, grade 3 endometrioid adenocarcinoma of the endometrium (EA) treated with various treatment modalities. METHODS: A retrospective multi-institutional study of surgical stage I, grade 3 EA patients diagnosed between 1988 and 2006 was performed. Demographic, clinicopathologic, treatment and outcome data were collected. After surgery, patients were treated with either observation or radiotherapy (vaginal brachytherapy, whole pelvic or both). RESULTS: One hundred seventy-six patients were collected with a median age of 68 years. Twenty-six (15%) were stage IA, 96 (54%) IB and 54 (31%) IC. Sixty-one patients (35%) had lymphovascular space invasion (LVSI) and a mean of 18.9 lymph nodes (LNs) was removed. Seventy-eight patients (44%) were observed while 98 (56%) were treated with radiotherapy, the majority (n=51) receiving brachytherapy. After a median follow-up of 58 months, 20 recurrences (11%) were noted. Ninety percent of recurrences occurred in Stage IB/IC patients. The median time to recurrence was 22.5 months (5-74.5) and 80% of recurrences were extra-pelvic. There was no significant difference in recurrence based upon treatment modality or LVSI. Majority of recurrences were not salvaged as 75% (12/16) died of their disease with a median time of recurrence to death of 8 months. CONCLUSIONS: Patients with stage IB/IC, grade 3 endometrioid adenocarcinoma have a significant risk for extra-pelvic recurrence. Most patients will not be salvaged and will succumb to their disease, suggesting that current loco-regional adjuvant treatment strategies are not optimal and evaluation of more systemic therapies is warranted.

The role of lymphadenectomy in the management of preoperative grade 1 endometrial carcinoma.

OBJECTIVE: We sought to assess the accuracy of a preoperative grade 1 designation and role of lymphadenectomy in women with preoperative grade 1 endometrial cancer. METHODS: A retrospective analysis of patients diagnosed with preoperative grade 1 endometrial cancer from 1970 to 2006 was conducted. Inclusion criteria were preoperative grade 1 disease and hysterectomy with or without surgical staging. RESULTS: 581 patients who underwent surgery for preoperative grade 1 cancer were identified. Lymphadenectomy was performed in 46%. Pelvic and aortic node metastases were identified in 5.4% and 3.2% patients who underwent lymphadenectomy. 9.7% were upgraded intraoperatively and 25% were upgraded on final pathology with 22% having grade 2 and 3% grade 3 disease. 22.5% with grade 1 disease intraoperatively were upgraded on final pathology, with 21.1% having grade 2 and 1.4% grade 3 disease. 9% had advanced stage disease. 20% of patients with disease limited to the uterus had adverse features including high risk histologic variants, grade 3 disease, myometrial invasion >1/2, and/or cervical involvement. After adjusting for risk factors there was no significant difference in OS (HR 1.00, p=0.992) or PFS (HR 0.96, p=0.815) between the patients who did or did not undergo surgical staging. CONCLUSION: A substantial number of patients with grade 1 endometrial cancer based on preoperative and intraoperative assessments have higher grade disease on final pathology. Although lymphadenectomy does not affect survival in this group it may identify patients with advanced disease and assist in tailoring adjuvant therapy for those with adverse risk factors.

Can we screen for pelvic organ prolapse without a physical examination in epidemiologic studies?

OBJECTIVE: Large population-based epidemiologic studies of pelvic organ prolapse are rare. One barrier is the need for physical examination in order to confirm disease status. The objectives of this study were to develop a simple screening question for pelvic organ prolapse (POP) and to evaluate its test characteristics in high and low prevalence populations. STUDY DESIGN: Data from 100 women enrolled in the validation study of the Pelvic Floor Distress Inventory (PFDI) were used to identify the question or questions that most accurately identified women with advanced pelvic organ prolapse. After identifying an accurate and reliable screening question from this original group, its test characteristics were evaluated prospectively in 2 additional distinct populations: a group of 120 women presenting to a tertiary care urogynecology clinic (High prior probability of POP) and 448 women presenting to a nurse practitioner for annual gynecologic examination (Low prior probability of POP). Subjects in these 2 groups each completed the screening question and underwent a POPQ examination by a blinded examiner. RESULTS: A single question was identified from the original study population that most accurately and reliably identified those women with POP "Do you usually have a bulge or something falling out that you can see or feel in your vaginal area?" An affirmative answer to this question was 96% sensitive (95%CI 92-100) and 79% specific (95%CI 77-92) for prolapse beyond the hymen. The 1-week test-retest reliability was good (kappa .84). The prevalence of POP in this group was 29%. No other single question or group of questions had better test characteristics. When prospectively evaluated in the second High probability population (prevalence 39%), similar test characteristics were noted: sensitivity 85% (95%CI 71-93), specificity 86% (95%CI 75-92). However, when evaluated in the Low prior probability group (POP prevalence 3.8%) the specificity improved to 99% (95%CI 98-99), while the sensitivity decreased dramatically to 35% (95%CI 15-61). CONCLUSION: Screening for POP without a physical examination is subject to spectrum bias. Spectrum bias occurs when a diagnostic test performs differently in different groups of patients. In groups with a high prior probability of POP, a simple screening question can accurately screen for advanced POP without a physical exam. However, in groups with a low prior probability of POP such as might be seen in a population-based epidemiologic study, this question has poor sensitivity.

Minimally invasive surgery in gynecologic oncology.

Minimally invasive surgery has been utilized in the field of obstetrics and gynecology as far back as the 1940s when culdoscopy was first introduced as a visualization tool. Gynecologists then began to employ minimally invasive surgery for adhesiolysis and obtaining biopsies but then expanded its use to include procedures such as tubal sterilization (Clyman (1963), L. E. Smale and M. L. Smale (1973), Thompson and Wheeless (1971), Peterson and Behrman (1971)). With advances in instrumentation, the first laparoscopic hysterectomy was successfully performed in 1989 by Reich et al. At the same time, minimally invasive surgery in gynecologic oncology was being developed alongside its benign counterpart. In the 1975s, Rosenoff et al. reported using peritoneoscopy for pretreatment evaluation in ovarian cancer, and Spinelli et al. reported on using laparoscopy for the staging of ovarian cancer. In 1993, Nichols used operative laparoscopy to perform pelvic lymphadenectomy in cervical cancer patients. The initial goals of minimally invasive surgery, not dissimilar to those of modern medicine, were to decrease the morbidity and mortality associated with surgery and therefore improve patient outcomes and patient satisfaction. This review will summarize the history and use of minimally invasive surgery in gynecologic oncology and also highlight new minimally invasive surgical approaches currently in development.

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

OBJECTIVE: To compare 2 methods of vaginal cuff closure with regard to safety, ease of use, and postoperative outcome. METHODS: All patients undergoing robotic-assisted total hysterectomy by a gynecologic oncologist from July 1, 2010, to July 1, 2011, at Northwestern Memorial Prentice Women's Hospital were included in a retrospective analysis. Providers used either 2-0 monofilament synthetic absorbable suture to close the vaginal cuff in a running fashion, secured with an absorbable suture clip at the angles and then knotted in the middle, or 2-0 absorbable unidirectional barbed suture with a welded-loop closure in a running fashion. RESULTS: A total of 134 patients underwent robotic-assisted total hysterectomy. The 2-0 tied monofilament closure was used in 58 patients, and the 2-0 barbed knotless closure was used in 76 patients. There were no instances of vaginal cuff dehiscence or vaginal cuff cellulitis. Rates of vaginal spotting and bleeding were comparable between the groups (12.0% spotting in the monofilament suture group vs 13.0% spotting in the barbed suture group). All vaginal cuff bleeding resolved on its own without significant intervention. CONCLUSION: The use of either a 2-0 welded-loop unidirectional barbed suture or a 2-0 monofilament absorbable suture to close the vaginal cuff is safe and well tolerated.

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.

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.

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.