V. Kolev

microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition.

Ovarian cancer is a leading cause of cancer deaths among women. Effective targets to treat advanced epithelial ovarian cancer (EOC) and biomarkers to predict treatment response are still lacking because of the complexity of pathways involved in ovarian cancer progression. Here we show that miR-181a promotes TGF-β-mediated epithelial-to-mesenchymal transition via repression of its functional target, Smad7. miR-181a and phosphorylated Smad2 are enriched in recurrent compared with matched-primary ovarian tumours and their expression is associated with shorter time to recurrence and poor outcome in patients with EOC. Furthermore, ectopic expression of miR-181a results in increased cellular survival, migration, invasion, drug resistance and in vivo tumour burden and dissemination. In contrast, miR-181a inhibition via decoy vector suppression and Smad7 re-expression results in significant reversion of these phenotypes. Combined, our findings highlight an unappreciated role for miR-181a, Smad7, and the TGF-β signalling pathway in high-grade serous ovarian cancer.

The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas.

OBJECTIVE To assess the morbidity and mortality associated with extensive upper abdominal surgery (EUAS) performed during primary cytoreduction for advanced ovarian carcinoma. METHODS We identified all patients who underwent EUAS during primary cytoreduction for advanced ovarian, tubal, or peritoneal cancer at our institution from 1/01 to 12/06. Major grade 3-5 complications were those that led to invasive radiologic intervention, re-operation, unplanned ICU admission, chronic disability, or death within 30 days of surgery. RESULTS There were 141 eligible patients, with a median age of 60 years (range, 38-82). The majority of patients had stage IIIC disease, 103 (73%); serous histology, 131 (93%); and ascites, 118 (84%). There were 229 EUAS procedures performed-diaphragm peritonectomy, 101 (72%); splenectomy, 45 (32%); full-thickness diaphragm resection, 19 (14%); partial hepatectomy, 18 (13%); distal pancreatectomy, 17 (12%); cholecystectomy, 15 (11%); and resection of porta hepatis tumor, 14 (10%). Cytoreductive outcomes were: no gross residual, 42 (30%); residual ≤ 1cm, 85 (60%); and residual >1cm, 14 (10%). Grade 3-5 complications occurred in 31 (22%) patients, including 2 mortalities (1.4%). In 21/31 (68%), the complication was successfully managed with percutaneous drainage of infected or non-infected collections. Overall median survival for all patients was 57 months. CONCLUSIONS Rates of major morbidity and mortality following EUAS for primary cytoreduction were 22% and 1.4%, respectively. Approximately two-thirds of complications were readily managed by percutaneous drainage of collections. With an overall median survival of 57 months in a cohort of patients with a large tumor burden, this rate of morbidity and mortality appears acceptable.

Nomogram for predicting 5-year disease-specific mortality after primary surgery for epithelial ovarian cancer

OBJECTIVE To develop a nomogram based on established prognostic factors to predict the probability of 5-year disease-specific mortality after primary surgery for patients with all stages of epithelial ovarian cancer (EOC) and compare the predictive accuracy with the currently used International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS Using a prospectively kept database, we identified all patients with EOC who had their primary surgery at our institution between January 1996 and December 2004. Disease-specific mortality was estimated using the Kaplan-Meier method. Twenty-eight clinical and pathologic factors were analyzed. Significant factors on univariate analysis were included in the Cox proportional hazards regression model, which identified factors utilized in the nomogram. The concordance index (CI) was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. RESULTS A total of 478 patients with EOC were included. The most predictive nomogram was constructed using seven variables: age, FIGO stage, residual disease status, preoperative albumin level, histology, family history suggestive of hereditary breast/ovarian cancer (HBOC) syndrome, and American Society of Anesthesiologists (ASA) status. This nomogram was internally validated using bootstrapping and shown to have excellent calibration with a bootstrap-corrected CI of 0.714. The CI for FIGO staging alone was significantly less at 0.62 (P=0.002). CONCLUSION We have developed an all-stage nomogram to predict 5-year disease-specific mortality after primary surgery for epithelial ovarian cancer. This tool is more accurate than FIGO staging and should be useful for patient counseling, clinical trial eligibility, postoperative management, and follow-up.

Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens?

OBJECTIVE Laparoscopically assisted vaginal hysterectomy (LAVH), which usually involves the use of an intrauterine manipulator for optimal surgical control, has been shown to be as effective and safe as conventional total abdominal hysterectomy (TAH) for the staging of endometrial carcinoma. The purpose of this study was to determine whether the use of an intrauterine manipulator was associated with an increase in the pathologic reporting of lymphovascular space invasion (LVSI), which is an important determinant in choosing adjuvant therapy. We hypothesized that intracavitary manipulation and an increase of the intrauterine pressure could cause pseudolymphovascular invasion. STUDY DESIGN We performed a retrospective chart review of endometrial cancer patients treated at our institution from January 1996 through January 2006. Records were reviewed for patients age, preoperative diagnosis, procedure type, final surgical staging, and final pathology report. Using the 2009 International Federation of Gynecology and Obstetrics staging, we included all patients having stage IA or IB endometrioid-type endometrial cancer who had undergone either a TAH or LAVH with or without pelvic and paraaortic lymph node dissection. The χ2 and Fisher exact tests were used to measure the association between risk of positive lymphovascular invasion and surgical groups. RESULTS Of 568 women identified as having endometrioid-type endometrial cancer, 486 (85.6%) met criteria for stage IA-IB endometrioid histology, grade 1, 2, or 3. LVSI was reported in 553/568 cases, with LVSI positivity in 16.9% (n = 96/568). The mean ages of the LAVH and TAH groups were significantly different (59.4 vs 62.4 years, respectively, P = .0050). Also, mean estimated blood loss and uterine weight significantly varied between TAH and LAVH groups (P = .0001 and .008, respectively). For stage IA, 17/220 (7.7%) who had been treated with LAVH had positive LVSI compared with 20/199 (10.1%) of patients receiving TAH (P = .73). For stage IB, 11/25 (44.0%) of patients treated with LAVH had positive LVSI compared with 10/31 (32.3%) of patients receiving TAH (P = .53). The stage I cancer patients were further subdivided into histological grades 1, 2, and 3, and LVSI was not significantly different between TAH and LAVH groups per grade of cancer. We found no differences between TAH and LAVH in early-stage endometrial cancer (stage IA and IB), with respect to the presence of positive peritoneal washings. CONCLUSION In early-stage endometrial cancer (stage IA and IB), there were no differences between TAH and LAVH in the final pathologic report of LVSI. The use of an intrauterine manipulator for LAVH was not associated with an increased detection of LVSI.

Survey of Current Practice Patterns in the Treatment of Early-Stage Endometrial Cancer.

Objectives Our aim was to assess current surgical practices and use of adjuvant therapy in the treatment of FIGO (International Federation of Gynecology and Obstetrics) stage I endometrioid endometrial cancer. Methods A 19-question survey was developed and sent to all Society of Gynecologic Oncologist members by e-mail. Data were collected anonymously using Internet-based survey software. Respondents were asked questions regarding preoperative evaluation, surgical approach, lymph node dissection (LND), and adjuvant therapy. Results A total of 1399 surveys were distributed, 320 (23%) members completed the survey. Ninety-seven percent of respondents were gynecologic oncologists or fellows, and 87% treat 30 or more endometrial cancer patients yearly. Respondents were more likely to order preoperative tests such as computed tomography abdomen/pelvis and CA-125 for biopsy-proven grade 3 disease versus grade 1 (82% vs 29%). Robot-assisted laparoscopy was the preferred surgical approach (66%), followed by conventional laparoscopy (21%). Twenty-six percent of respondents perform LND in all cases. Forty-eight percent describe their LND as complete, to the level of the inferior mesenteric artery. Adjuvant therapy was recommended more often with increasing myometrial invasion, tumor grade, and lymphovascular space invasion. Vaginal brachytherapy was the most commonly recommended adjuvant therapy for stage IA. For stage IB, grade 3, positive lymphovascular space invasion disease, respondents were more likely to combine vaginal brachytherapy with external beam radiotherapy and/or chemotherapy. Older patients were more likely to have adjuvant therapy in earlier stages of disease than younger patients. Conclusions Our findings demonstrate that respondents are individualizing care based on preoperative, intraoperative, and pathologic findings. As expected, adjuvant treatment is recommended for patients with higher stage and grade disease. Robot-assisted hysterectomy and chemotherapy are now commonly used in the management of this disease. We anticipate that new trends will continue to emerge as results from additional studies become available.

Case of maternal and infantile choriocarcinoma following normal pregnancy

► 33 years old woman diagnosed with choriocarcinoma after delivery, her newborn son with the same diagnosis. ► Case of transplasental dissemination of choriacarcinoma. ► Advanced disease both in the mother and the infant.

Primary pulmonary carcinoid tumor with metastasis to endometrial polyp.

INTRODUCTION A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patients known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp.

Detection of endometrial precancer by a targeted gynecologic cancer liquid biopsy.

Endometrial cancer is the most common gynecologic malignancy in industrialized countries, and both its incidence and its associated mortality are increasing. The “liquid biopsy” is becoming an important transformative precision oncology tool, but barriers intrinsic to blood sampling have limited its use in early cancer detection. We hypothesized that using a more targeted sample for analysis—namely, a uterine lavage—should provide a more sensitive and specific diagnostic test for endometrial cancer. Using a custom 12-gene endometrial cancer panel, molecular analysis of uterine lavage fluid from an asymptomatic 67-yr-old female without histopathologic evidence of premalignant lesions or cancer in her uterine tissue revealed two oncogenic PTEN mutations. Ten months later, the patient returned with postmenopausal bleeding and a single microscopic focus of endometrial cancer. DNA isolated and sequenced from laser-capture microdissected tumor tissue revealed the same two PTEN mutations. These mutations were unlikely to occur by chance alone (P < 3 × 10−7). This illustrative case provides the first demonstration that future, tumor-specific mutations can be identified in an asymptomatic individual without clinical or pathologic evidence of cancer by using already established sequencing technologies but targeted sampling methods. This finding provides the basis for new opportunities in early cancer screening, detection, and prevention.

Clinical Outcomes of Type II Endometrial Cancer in Open Versus Minimally Invasive Staging Surgery.

Demographic data, surgical parameters and histopathology details were analyzed. Intervention: We performed da Vinci robot-assisted radical hysterectomy. The learning curve was evaluated using the cumulative summation (CUSUM) technique. Measurements and Main Results: The mean operating time (273.9 88.5 min) of phase I was significantly longer than phase II (222.0 51.4min) (p = 0.032) and phase III (218.2 50.6 min) (p = 0.015). Significant differences were found among the 3 groups which the number of pelvic autonomic nerve preservation and para-aortic lymph node resection, (p \ 0.005). There were no significant differences between the three groups with respect to lymph node yield and identifying positive lymph nodes, and pathologic outcome. Time to resume voiding function did differ between the three groups, (p \ 0.005). The learning period of da Vinci robotic surgical system for radical hysterectomy to reach a turning point was calculated to be 30 cases. Conclusion: An extended learning period can be required for da Vinci robotic surgical system for radical hysterectomy, during which pathologic outcome of radical hysterectomy may not be adversely affected. As for the surgeons with abundant experiences of laparoscopic surgery for cervical cancer surgery, after about 30 resections, they can overcome the learning curve and master da Vinci robotic surgical system for radical hysterectomy in cervical cancer.

Abstract B47: microRNA-181a plays a critical role in ovarian cancer progression through the regulation of epithelial-mesenchymal transition

Ovarian cancer is the most lethal gynecological cancer primarily due to advanced stage of disease at diagnosis. Effective therapeutic targets and prognostic biomarkers are still lacking due to insufficient knowledge of the pathways that regulate ovarian cancer progression. Here, we identify miR-181a as a mediator of disease dissemination through the induction of EMT and direct activation of the TGF-β signaling pathway via repression of its functional target, Smad7. High expression of miR-181a and phospho-Smad2 were associated with poor patient outcome and were enriched in recurrent compared to matched-primary tumors. Ectopic expression of miR-181a resulted in increased cellular survival, migration, drug resistance, and in vivo tumor burden, and dissemination. Conversely, targeting this miRNA using a decoy vector resulted in significant decreases in cell survival, migration, and MET in ovarian cancer cell lines. Combined, our findings identify miR-181a as a novel modulator of ovarian cancer dissemination through the induction of EMT and highlight its role as a potential biomarker and therapeutic target for aggressive late-stage ovarian cancer. Citation Format: Aditya Parikh, Christine Lee, Peronne Joseph, Sergio Marchini, Alessia Baccarini, Valentin Kolev, Chiara Romualdi, Robert Fruscio, Hardik Shah, Wang Feng, Gavriel Mullokandov, David Fishman, Maurizio D9Incalci, Jamal Rahaman, Tamara Kalir, Raymond Redline, Brian D. Brown, Goutham Narla, Analisa DiFeo. microRNA-181a plays a critical role in ovarian cancer progression through the regulation of epithelial-mesenchymal transition. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B47.