Alberto A. Mendivil

Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy

OBJECTIVES Obesity and diabetes are strong risk factors that drive the development of type I endometrial cancers. Recent epidemiological evidence suggests that metformin may lower cancer risk and reduce rates of cancer deaths among diabetic patients. In order to better understand metformins anti-tumorigenic potential, our goal was to assess the effect of metformin on proliferation and expression of key targets of metformin cell signaling in endometrial cancer cell lines. METHODS The endometrial cancer cell lines, ECC-1 and Ishikawa, were used. Cell proliferation was assessed after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3 activity. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin. RESULTS Metformin potently inhibited growth in a dose-dependent manner in both cell lines (IC(50) of 1 mM). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, within 24 h of exposure. In parallel, treatment with metformin decreased phosphorylation of S6 protein, a key target of the mTOR pathway. CONCLUSIONS We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines. This effect is partially mediated through AMPK activation and subsequent inhibition of the mTOR pathway. This work should provide the scientific foundation for future investigation of metformin as a strategy for endometrial cancer prevention and treatment.

What is the optimal minimally invasive surgical procedure for endometrial cancer staging in the obese and morbidly obese woman

OBJECTIVE Thirty-three percent of U.S. women are either obese or morbidly obese. This is associated with an increased risk of death from all causes and is also associated with an increased risk of endometrial carcinoma. We sought to compare minimally invasive surgical techniques for staging the obese and morbidly obese woman with endometrial cancer. MATERIALS AND METHODS Consecutive robotic endometrial cancer staging procedures were collected from 2005-2007 and were compared to consecutive laparoscopic cases (2000-2004). Demographics including age, weight, body mass index (BMI), operative time, estimated blood loss, lymph node retrieval, hospital stay and complications were collected and compared. RESULTS During the study period, there were 36 obese and 13 morbidly obese women who underwent surgery with the DaVinci robotic system and 25 obese and 7 morbidly obese women who underwent traditional laparoscopy. For both the obese and morbidly obese patient, robotic surgery was associated with shorter operative time (p=0.0004), less blood loss (p<0.0001), increased lymph node retrieval (p=0.004) and shorter hospital stay (p=0.0119). CONCLUSIONS Robotic surgery is a useful minimally invasive tool for the comprehensive surgical staging of the obese and morbidly obese woman with endometrial cancer. As this patient population is at increased risk of death from all causes, including post-operative complications, all efforts should be made to improve their outcomes and minimally invasive surgery provides a useful platform by which this can occur.

Survival outcomes for women undergoing type III robotic radical hysterectomy for cervical cancer: A 3-year experience ☆

OBJECTIVES.: To assess progression-free (PFS) and overall survival (OS) for women with cervical cancer who underwent type III robotic radical hysterectomy (RRH). METHODS.: A retrospective analysis of women who underwent RRH from 2005 to 2008 was performed. The data analyzed included patient demographics, histology, clinical stage, surgical margins, lymph node and disease status. Comparison was made to a group of historical open radical hysterectomies. Survival statistics were analyzed using the Kaplan-Meier method. RESULTS.: Seventy-one women underwent attempted RRH during the study period. Eight were excluded from analysis, 4 for non-cervical primary and 4 cases aborted due to extent of disease. Squamous was the most common histology (62%) followed by adenocarcinoma (32%). Median patient age was 43 years. There was one intraoperative complication (asystole after induction) and two postoperative complications (ICU admission to rule out myocardial infarction and reoperation for cuff dehiscence). Of the patients who underwent RRH, 32% received whole-pelvis radiation with chemo sensitization. The median follow-up was 12.2 months (range 0.2-36.3 months). Kaplan-Meier survival analysis demonstrated 94% PFS and OS at 36 months due to the recurrence and death of one patient. Compared with a historical cohort at our institution, there was no statistically significant difference in PFS (P=0.27) or OS (P=0.47). CONCLUSIONS.: RRH is safe and feasible and has been shown to be associated with improved operative measures. This study shows that at 3 years, RRH appears to have PFS and OS equivalent to that of traditional laparotomy. Longer follow-up is needed, but early data are supportive of at least equivalent oncologic outcomes compared with other surgical modalities.

Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes.

BACKGROUND Understanding the etiology, presentation, evaluation, and management of selected non-endometrioid endometrial adenocarcinomas of the uterine corpus is needed to define optimal treatment regimens. METHODS The pathology and treatment of selected non-endometrioid endometrial adenocarcinomas of the uterus are reviewed and summarized. RESULTS The most common non-endometrioid histology is papillary serous (10%), followed by clear cell (2% to 4%), mucinous (0.6% to 5%), and squamous cell (0.1% to 0.5%). Some non-endometrioid endometrial carcinomas behave more aggressively than the endometrioid cancers such that even women with clinical stage I disease often have extrauterine metastasis at the time of surgical evaluation. Therefore, when technically and medically feasible, comprehensive surgical staging is helpful for women with non-endometrioid endometrial cancer histology. Comprehensive surgical staging includes hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cytological evaluation of the abdominal cavity. While whole abdominal radiotherapy has a limited role in early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC), there may be a role for postoperative chemotherapy and volume-directed radiotherapy in both early-stage UPSC and CC. In the setting of optimally debulked advanced-stage disease, a combination of radiation and chemotherapy may be indicated. In the setting of recurrent disease or in women with residual disease after surgery, a platinum-based regimen or enrollment in a clinical trial is recommended. CONCLUSIONS UPSC and CC are managed similarly since sufficient data to separate treatment recommendations are lacking. Because both histologies are associated with a high rate of recurrence, adjuvant therapy is recommended even in women with early-stage disease. The remaining cell types should be treated similar to endometrioid or other low-grade histologies.

Perioperative Outcomes of Robotically Assisted Hysterectomy for Benign Cases With Complex Pathology

OBJECTIVE: To report on the perioperative outcomes after robotically assisted total hysterectomy for benign indications in a large patient population with predominantly complex pathology. METHODS: One hundred fifty-two patients underwent robotic hysterectomy for noncancer indications from May 2005 to May 2008. A systematic chart review of consecutive robotic cases was conducted based on preoperative and perioperative characteristics of each patient. Each case was evaluated for its complexity based on preoperative diagnosis, prior pelvic or abdominal surgery, patient’s body mass index, and uterine weight. RESULTS: The overall operative time was 122.9 minutes, estimated blood loss was 79.0 mL, and there were three (2.1%) intraoperative complications, with no perioperative blood transfusions or conversions. There were five (3.5%) patients with postoperative complications, and length of hospital stay was 1.0 days on average. Of the characteristics indicating complexity, only uterine weight greater than 250 g resulted in significantly increased operative times, attributable to increased morcellation time. CONCLUSION: Robotically assisted total hysterectomy for benign indications in patients with complex pathology is feasible, with low morbidity and a short hospital stay. This study suggests that robotic assistance facilitates the use of a minimally invasive approach in high-risk patient populations. LEVEL OF EVIDENCE: III

Emergence of robotic assisted surgery in gynecologic oncology: American perspective

OBJECTIVES To discuss the emergence of robotic surgery in gynecologic oncology and describe the growth of robotic surgery in a university medical center and a community based practice. METHODS In addition to the historical evolution of the robotic assisted surgery medicine, a survey of robotic cases was performed on two robotic programs since the inception of the programs. A review of the current literature on the use of the da Vinci robot in gynecologic oncology was also performed. RESULTS The robotic surgery programs at UNC Hospital and Florida Hospital are growing steadily since the inception of the programs in 2005 and 2006, respectively. Since 2005 there have also been numerous publications detailing the effectiveness, safety, and efficiency of the robot. CONCLUSIONS Robotic surgery is gaining acceptance and is rapidly growing as evidenced by an increased number of publications on the topic; these publications demonstrate the safety, efficacy, and improved outcomes compared to open surgery and conventional laparoscopy.

Survival rate comparisons amongst cervical cancer patients treated with an open, robotic-assisted or laparoscopic radical hysterectomy: A five year experience.

BACKGROUND The purpose of this retrospective study was to assess the 5-year survival outcomes of cervical cancer patients who underwent an, open radical hysterectomy (ORH), robotic-assisted radical hysterectomy (RRH) or laparoscopic radical hysterectomy (LRH) for the treatment of their disease. METHOD We conducted a review of all cervical cancer patients who were managed with an ORH, RRH or LRH. RESULT Forty-nine patients were treated with LRH, 58 were managed via RRH and 39 patients underwent an ORH. The LRH (1.78 h) patients had a significantly shorter operative duration than the RRH (2.88 h) and ORH (2.39 h) subjects (p < 0.001). Blood loss was the highest in the ORH (475 cc) group (RRH = 207 cc and LRH = 312 cc) (P < 0.001). Moreover, the ORH (5.04 days) patients had a significantly longer hospital stay than the LRH (2.95 days) and RRH (2.50 day) subjects (P < 0.001). Kaplan-Meier survival analysis revealed a progression free survival (PFS) rate of 84.6% for the ORH group, 89.8% for the LRH group and 89.7% for the RRH patients (P = 0.271) at 60 months; overall survival was 92.3% for the ORH group, 95.9% for the LRH group and 96.6% for the RRH patients (P = 0.80). CONCLUSION The results from this study suggest that, irrespective of operative approach, patients who underwent a radical hysterectomy for early stage cervical cancer attained similar 5-year disease free and overall survival outcomes.

Same-Day Discharge in Clinical Stage I Endometrial Cancer Patients Treated with Total Laparoscopic Hysterectomy, Bilateral Salpingo-Oophorectomy and Bilateral Pelvic Lymphadenectomy

Objectives: The purpose of this retrospective study was to evaluate the capacity for same-day discharge in clinical stage I endometrial cancer (EC) patients treated with total laparoscopic hysterectomy (TLH), bilateral salpingo-oophorectomy (BSO) and bilateral pelvic lymph node dissection (BPLND). Methods: We retrospectively reviewed the charts of stage I EC patients who were treated with TLH, BSO and BPLND and discharged on the same day. The intra- and postoperative clinical variables (e.g., age, complications, surgery time, patient hospital stay) were evaluated in an attempt to discern which factors may predispose a patient to same-day discharge. Results: Twenty-one patients were successfully discharged on the same day of surgery. Mean operative time was 1.48 h and length of hospital stay was 6.35 h. There were no intraoperative complications or hospital readmissions. Conclusions: We present a single, institutional experience solely assessing the capacity for same-day discharge in clinical stage I EC patients treated with TLH, BSO and BPLND. Since the postoperative complication rate was minimal with no hospital readmissions, we suggest that particularly selected stage I EC patients are amenable to outpatient management.

Increased incidence of severe gastrointestinal events with first-line paclitaxel, carboplatin, and vorinostat chemotherapy for advanced-stage epithelial ovarian, primary peritoneal, and fallopian tube cancer.

Objectives We sought to assess the response rate and toxicity of paclitaxel, carboplatin, andvorinostat primary induction therapy for the treatment of advanced-stage ovarian carcinoma. Methods Patients were treated with 6 cycles of weekly paclitaxel (80 mg/m2), carboplatin (6 times area under the curve), and vorinostat (200 mg) every 28 days according to an institutional review board–approved protocol. The subjects were eligible for response evaluation; in patients who achieved stable disease or better following the conclusion of primary induction chemotherapy, they were subsequently treated with a planned 12 cycles of paclitaxel (135 mg/m2) and vorinostat (400 mg) maintenance chemotherapy every 28 days. Results Eighteen patients received a combined 90 cycles (median, 6 cycles; range, 1–6 cycles) of primary induction chemotherapy. Of the 18 subjects, 7 demonstrated a complete response, and 2 subjects exhibited a partial response (a total response rate of 50.0%). Eight patients also received a combined total of 50 cycles (median, 5 cycles; range, 1–12 cycles) of consolidation therapy. Grade 3/4 neutropenia and thrombocytopenia were observed in 9 (56.3%) and 2 (12.5%) patients. One patient (6.3%) developed grade 3 anemia, and another (6.3%) manifested a grade 3 neuropathy. Remarkably, we observed a significant gastrointestinal event (eg, bowel anastomotic perforation) in 3 patients, which effectuated the study’s closure. Conclusions Because the current study was prematurely terminated, we cannot derive a conclusive assessment regarding the efficacy of this treatment. Nevertheless, the high incidence of severe gastrointestinal toxicity warrants further consideration when using vorinostat in the adjuvant setting for patients who have undergone a bowel resection as part of their initial tumor debulking.

Sequential chemotherapy and radiotherapy as sandwich therapy for the treatment of high risk endometrial cancer

Objective The purpose of this retrospective study was to assess the tolerability and efficacy of sequential chemotherapy and radiotherapy for the treatment of high risk endometrial cancer. Methods We conducted a retrospective study of previously untreated high risk endometrial cancer patients who received sequential chemotherapy and radiotherapy in accordance with the sandwich approach from June 2008 until June 2011. High risk endometrial cancer patients underwent complete surgical staging followed by adjuvant therapy encompassing sequential chemotherapy, radiation therapy and consolidation chemotherapy. Results The study analysis comprised 32 endometrial cancer patients. All subjects were treated with carboplatin and paclitaxel chemotherapy; currently, 186 cycles have been administered and 94% of patients have completed the planned number of cycles. Grade 3 neutropenia developed in 1 (3.1%) patient; there was no incidence of grade 4 neutropenia. Moreover, we observed grade 3 anemia in four (12.5%) patients and grade 4 anemia in one (3.1%) patient. One (3.1%) patient developed grade 3 thrombocytopenia; grade 4 thrombocytopenia was not observed. Five patients exhibited progressive disease, three of whom have since expired; mean progression free survival and follow-up were 17.4 months and 18.9 months, respectively. Conclusion The preliminary results from our study suggest that the sandwich approach to treating high risk endometrial cancer patients is feasible. Hematologic toxicity was well tolerated and non-hematologic toxicity was mild and easily managed. Further study of this novel regimen in a larger patient population with extended follow-up is necessary.