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Objectives: The most widely used approach for the clinical management of women with high-grade serous ovarian cancer (HGSOC) is surgery, followed by platinum and taxane based chemotherapy. The degree of macroscopic disease remaining at the conclusion of surgery is a key prognostic factor determining progression free and overall survival. We sought to develop a non-invasive test to assist surgeons to determine the likelihood of achieving complete surgical resection. This knowledge could be used to plan surgical approaches for optimal clinical management., Methods: We profiled 170 serum microRNAs (miRNAs) using the Serum/Plasma Focus miRNA PCR panel containing locked nucleic acid (LNA) primers (Exiqon) in women with HGSOC (N=56) and age-matched healthy volunteers (N=30). Additionally, we measured serum CA-125 levels in the same samples. The HGSOC cohort was further classified based on the degree of macroscopic disease at the conclusion of surgery. Stepwise logistic regression was used to identify predictive markers., Results: We identified a combination of miR-375 and CA-125 as the strongest discriminator of healthy versus HGSOC serum, with an area under the curve (AUC) of 0.956. The inclusion of miR-210 increased the AUC to 0.984; however, miR-210 was affected by hemolysis. The combination of miR-34a-5p and CA-125 was the strongest predictor of completeness of surgical resection with an AUC of 0.818., Conclusion: A molecular test incorporating circulating miRNA to predict completeness of surgical resection for women with HGSOC has the potential to contribute to planning for optimal patient management, ultimately improving patient outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under-recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) "leiomyomas" and 1 of 44 (2.3%) "leiomyosarcomas" were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for "leiomyoma" from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC.

Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access Array™ System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA; EGAS00001002200). Herein, we present analyses of this dataset using HaplotypeCaller and MuTect2 through the Broad Institute's Genome Analysis Toolkit (GATK). We anticipate that this TP53 mutation dataset will be useful to researchers developing and testing new software to accurately determine high and low frequency variant alleles in heterogeneous aneuploid tumor tissue. Furthermore, the analysis pipeline we present provides a valuable framework for determining somatic variants more broadly in tumor tissue.

Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

The tumour suppressor p53 is mutated in cancer, including over 96% of high-grade serous ovarian cancer (HGSOC). Mutations cause loss of wild-type p53 function due to either gain of abnormal function of mutant p53 (mutp53), or absent to low mutp53. Massively parallel sequencing (MPS) enables increased accuracy of detection of somatic variants in heterogeneous tumours. We used MPS and immunohistochemistry (IHC) to characterise HGSOCs for TP53 mutation and p53 expression. TP53 mutation was identified in 94% (68/72) of HGSOCs, 62% of which were missense. Missense mutations demonstrated high p53 by IHC, as did 35% (9/26) of non-missense mutations. Low p53 was seen by IHC in 62% of HGSOC associated with non-missense mutations. Most wild-type TP53 tumours (75%, 6/8) displayed intermediate p53 levels. The overall sensitivity of detecting a TP53 mutation based on classification as 'Low', 'Intermediate' or 'High' for p53 IHC was 99%, with a specificity of 75%. We suggest p53 IHC can be used as a surrogate marker of TP53 mutation in HGSOC; however, this will result in misclassification of a proportion of TP53 wild-type and mutant tumours. Therapeutic targeting of mutp53 will require knowledge of both TP53 mutations and mutp53 expression.

► We describe a case of uterus didelphys with synchronous endometrial cancers. ► Unfavorable post-operative disturbance of the vaginal vault topography was present. ► Hence the Institut Gustave-Roussy "moulage" IVBT technique was utilised. ► This customised technique achieved excellent mould-to-mucosa conformance.

Objective: To define the learning curve for robotic hysterectomy and pelvic-aortic lymphadenectomy for endometrial carcinoma., Methods: Patient demographics and segmental operative times on all patients at one institution who underwent robotic comprehensive surgical staging (hysterectomy, pelvic and aortic lymphadenectomy) for endometrial cancer were prospectively collected. Patients were arranged in order based on surgery date and outcomes were compared between quartiles (cases 1-20, 21-40, 41-60, and 61-79). Proficiency was defined as the point at which the slope of the curve becomes less steep for operative times. Efficiency was defined as the point at which the slope is zero. ANOVA or Fisher's exact test was used to compare the procedure times. Locally weighted regression generated smoothed lines that represent operative time over the sequence of the operations., Results: 79 patients were comprehensively staged robotically. While age, the percentage of patients with >/=2 co-morbidities, number of patients with previous laparotomy, EBL, LOS and lymph node counts do not differ between groups, the first 20 patients had a lower BMI compared to the next 20 (27 vs. 34 kg/m(2), P=0.009). Operative times decreased from the first 20 cases to next 20, but was not significantly changed over the next three quartiles. Each component of the procedure has a separate learning curve., Conclusions: Proficiency for robotic hysterectomy with pelvic-aortic lymphadenectomy for endometrial cancer is achieved after 20 cases; however, the number of procedures to gain efficiency varies for each portion of the case and continues to improve over time.

Objective: To report the learning curve and outcomes after our first 105 patients underwent robotic hysterectomy and pelvic-aortic lymphadenectomy for the comprehensive staging of endometrial cancer., Methods: We prospectively collected patient demographics, operative times, complications, pathologic results, and length of stay on all patients who underwent robotic hysterectomy pelvic-aortic lymphadenectomy for clinical stage I or occult stage II endometrial carcinoma., Results: One hundred five patients at The Ohio State University between March 2006 and April 2008 underwent exploration with the intent of robotic hysterectomy pelvic-aortic lymphadenectomy. Ninety-two (87.6%) were completed robotically and 13 (12.4%) were converted. The probability of conversion was 15% (95% confidence interval [CI] 8.4-25.7), 24% (95% CI 12.4-39.9), 35% (95% CI 15.9-59.6), and 48% (95% CI 19.1-77.8) for a body mass index of 40, 45, 50, and 55 kg/m(2), respectively. The median body mass index was 34 kg/m(2) (range 19-58). In patients who underwent a robotic hysterectomy pelvic-aortic lymphadenectomy (n=79, 75%) or a robotic hysterectomy-pelvic lymphadenectomy (n=6, 5.7%), the average operating time from skin opening to closure was 242 minutes (+/-50 minutes). The median estimated blood loss was 99 mL (+/-83 mL). The median number of lymph nodes recovered was 29 (range 9-56), 21 (range 5-40) pelvic nodes and 9 (range 2-21) aortic nodes. The median length of stay was 1 night. After analysis of the data, we determined approximately 20 cases are needed to gain proficiency., Conclusion: Early experience demonstrates that robotic hysterectomy pelvic-aortic lymphadenectomy for endometrial cancer is feasible, with approximately 20 procedures needed to gain proficiency., Level of Evidence: III.

Limited data exist regarding description and technical aspects of operating room (OR) set-up, port placement, and instrument selection for robotic gynecologic oncology procedures. The objective of this manuscript and video is to show the established protocol steps at our institution for setting up a robotic hysterectomy and comprehensive lymphadenectomy (dVH-LND) for endometrial cancer. OR preparation of the robotic system prior to patient entry and set-up is demonstrated. The patient is placed in low-lithotomy on an OR table that includes a beanbag and a gel pad that is taped securely for additional stabilization. The arms/shoulders are padded to decrease injury risk and the chest is padded with foam to protect the patient from robotic arm movements. The patient is prepped widely from mid-nipple line to beyond the mid-axillary line and draped. Vaginal instrumentation includes an end-to-end anstomosis (EEA) sizer and pneumo-occluder. Port preferences, placement, and instrument selections are also demonstrated. Using a four-arm robotic system, the camera port is placed midline, approximately 20-27 cm above the pubic symphysis. Robotic ports (RP) for arms #2 and #3 are placed 8-12 cm left lateral to and 15-30° down from the camera port at approximately the level of the umbilicus. A 12 mm laparoscopic assistant port and RP#1 are placed 8-12 cm right lateral to the umbilicus and in the same position as RP#3 and #2, respectively. An additional 5 mm port is placed beneath the costal margin. This method requires only a single docking and one instrument exchange. The bedside assistant stands on the right and is essential for exposure, manipulating the uterus, passage of suture, and troubleshooting potential problems. In addition, port closure technique and methods to remove a large uterus are discussed. We have successfully completed over 70 dVH-LND for endometrial cancer using this protocol. Establishing a systematic routine for OR set-up and port placement in robotic surgery for gynecologic oncology is important for patient safety and allows for efficient use of OR time.

Autopsy studies have demonstrated a very high incidence of positive retroperitoneal lymph nodes in patients with advanced ovarian cancer, but the clinical management of these nodes has only recently been investigated. Several institutional studies had suggested an advantage to systematic removal of pelvic and paraaortic nodes in patients whose tumor was optimally cytoreduced in the peritoneal cavity. However, the only randomized prospective study revealed a 7-month benefit in progression-free survival for patients having systematic lymphadenectomy, but no benefit in terms of overall survival. Unless a future randomized trial shows evidence to the contrary, removal of clinically normal nodes should not be considered part of the standard care for patients with advanced ovarian cancer. Bulky nodes should be removed as part of the surgical aim of removing all macroscopic residual disease.

Eighty-two patients with adenocarcinoma in situ of the cervix managed at Royal Prince Alfred Hospital were reviewed and data were collected on those treated by cold knife cone biopsy (n= 38) and laser cone biopsy (n= 44). No differences were found in patient age, cytologic or referral history, or outcomes. Having laser excision did not compromise margin status or subsequent management. Invasive disease was found in 24 patients, 16 of whom were managed conservatively with good outcome. Twelve of these were in the laser cone group. In those patients from both groups managed conservatively, there was only one recurrence, squamous preinvasive disease after 8 years. Laser cone biopsy is as effective as cold knife cone biopsy with no compromise of outcome for these patients.

The effect of a gynecological oncology fellow on obstetrics and gynecology resident education and training is uncertain. The objective is to assess the effect of gynecological oncology fellows on the surgical training of residents in obstetrics and gynecology. Fourth year residents in obstetrics and gynecology in the United States were identified and stratified as to the presence or absence of an oncology fellowship program. Demographics, surgical volume, procedures performed, and self-assessment of surgical proficiency were collected. Responses were compared between residency programs with and without fellowships. Responses were received from 40% of programs. Residents at programs without a fellowship more frequently operated with attendings than did residents at programs with fellows, 91% vs 77%, P= 0.016, and more frequently were responsible for complicated cases, 39% vs 22%, P < 0.0001. Over 90% of residents in both groups reported surgical training as positive and valuable; both groups reported a similar perceived lack of proficiency in radical hysterectomy and lymphadenectomy. Attitudes toward the fellows were generally positive; however, competition for cancer cases was reported by over 66% of residents from programs with fellows. While fellows are often thought of as a detracting factor to residency training, they do not appear to affect the perception of the quality of resident surgical training.

Patients with clinical palpable involved groin lymph nodes and squamous cell cancer of the vulva are frequently treated by a full inguinal-femoral lymph node dissection followed by adjuvant radiotherapy to the groins and pelvis. Theoretically, less radical surgery for the groin such as nodal debulking, where only the macroscopically involved nodes are resected, allowing radiotherapy to treat any remaining microscopic disease may potentially decrease morbidity without compromising survival The objective of this retrospective study was to compare the groin recurrence rate and survival (disease specific and overall survival) of patients with clinically involved groin nodes and squamous cell carcinoma of the vulva treated either by a full inguino-femoral lymphadenectomy or by a nodal debulking followed by radiotherapy. Forty patients from three separate databases who met these criteria were identified. Patients were treated either by a full inguino-femoral lymphadenectomy or by a debulking of the clinically involved inguinal lymph nodes. All patients received adjuvant radiotherapy to the groins. In these two groups, there was no difference in groin recurrence rate expressed as groin recurrence-free survival (P= 0.247). In a univariate analysis, both overall and disease-free survival were better in the group of patients treated by nodal debulking. However, in a multivariate analysis, other variables such as extracapsular growth were independent predictors for survival while the method of surgical dissection for the groin had no independent significant impact on survival.

Objective: To determine the ability of patients to be treated with biweekly bevacizumab and weekly taxane chemotherapy in women with advanced, refractory ovarian cancer., Methods: Ten patients with advanced, recurrent, and refractory ovarian cancer who were treated with biweekly bevacizumab (10 mg/kg) and weekly taxane (paclitaxel or docetaxel) chemotherapy days 1, 8, 15, and 22 every 28 days were identified retrospectively. All patients were followed with serial CA125 measurements prior to each cycle of therapy; cross-sectional imaging was not used to follow response to therapy. Toxicities were assessed prior to each cycle of treatment., Results: Of the 10 patients treated with weekly taxane and biweekly bevacizumab therapy, all 9 that were evaluable had a decrease in CA125. Five patients have had an increase in CA125 after therapy after a median of three cycles (range 1-4), while 3 patients experienced normalization of CA125 and another with continued improvement in CA125. All symptomatic patients experienced rapid palliation of pain, nausea, and ascites. Side effects have been mild, with no grade 3 or 4 toxicities noted. No treatment delays or discontinuations have been necessary., Conclusion: Treatment of advanced, recurrent, refractory epithelial ovarian cancer with bevacizumab and weekly taxane chemotherapy leads to significant, albeit temporary, improvement in the cancer-related symptoms in women treated on this regimen, and short-term exposure to these agents is not associated with significant toxicity. Thus, continued investigation of bevacizumab with weekly scheduling of cytotoxic chemotherapy is imperative.

A case of epithelioid trophoblastic tumour (ETT), occurring in a fallopian tube of a 39-year-old woman, is reported. The patient presented with a positive pregnancy test, but continued to have 'periods'. A palpable right adnexal mass was noted that was confirmed on ultrasound. The mass was removed together with the uterus, omentum and associated ovary. Careful examination of the uterus revealed no evidence of either an antecedent tumour or intra-uterine pregnancy. Histologically, the tubal mass displayed sheets and islands of large, relatively uniform, mitotically active polyhedral cells, with surrounding necrosis. The immunoprofile of the tumour was atypical in that alpha-inhibin and epidermal growth factor were weakly positive, but other results were consistent with the diagnosis of ETT. The patient received a foreshortened course of standard EMACO (etoposide, actinomycin-D, methotrexate, vincristine, and cyclophosphamide) combination chemotherapy for high-risk gestational trophoblastic disease. Serum beta-hCG fell from a pre-operative level of 52 000 U/mL to non-pregnant levels within two courses and she remains well and disease-free 12 months post-diagnosis.

Objective: The National Health and Medical Research Council (NHMRC) recommends a report of 'inconclusive possible high grade epithelial abnormality', but many laboratories only report 'inconclusive' with reference to any possible high grade disease elsewhere in the report. This study was performed to determine possible reasons for cytological difficulties resulting in this category of report and to determine the rate of significant disease within this category., Design: Retrospective record review. Clinical details were extracted without patient-identifying data., Setting: Gynaecological Oncology Department, King George V/Royal Prince Alfred Hospital., Population: Two hundred patients referred with the cytological abnormality., Materials and Methods: An adequate colposcopic diagram documenting size, distribution and grade of lesion was required. All patients had colposcopy with management according to colposcopic and histological results as appropriate to their disease., Outcome Measures: Colposcopic features, topography and size of any lesion, histological results, treatments performed and subsequent review of untreated patients., Results: Colposcopy found high-grade lesions in 43% and carcinoma in 1%. Histopathology found 49% and 4% respectively. Treatment was performed in 124 patients. Inflammation was found in 27%, a small lesion in 43% and endocervical disease in 21%., Conclusions: The high rate of endocervical disease, inflammation and small lesions may explain the cytological difficulties leading to an 'inconclusive' result. The authors believe that the term 'inconclusive' alone does not adequately convey the high level of risk faced by these patients.

The aim of this study was to retrospectively analyze the clinical and pathologic data of a series of patients presenting to our unit with uterine malignant mixed Müllerian tumors (MMMT) to attempt to identify prognostic factors and relate them to survival. Thirty-seven patients diagnosed with MMMT of the uterus from 1988 through 2000 were identified from the gynecological tumor registry. Data was abstracted and analyzed. The effect of a variety of clinical, histopathologic, and surgical variables on recurrence and survival were analyzed by univariate and multivariate analyses. Patients tended to be postmenopausal, overweight, hypertensive, and presented with abnormal bleeding. Preoperatively 28 (76%) were thought to have clinical stage I-II disease. Nine (32%) were upstaged based on surgical data. Five (56%) of these patients were found to have gross extrauterine disease and four (44%) were found subsequently to have microscopic extrauterine disease. Twenty (54%) patients underwent lymph node dissection and positive nodes were found in seven (35%) patients. Nine patients underwent omentectomy and disease was found in three (33%). Peritoneal washings were positive in three of 16 patients (19%). At the completion of primary surgery, 27 (75%) patients had no residual disease. Twelve (44%) of these patients had recurrence of disease. Median disease-free interval prior to first recurrence was 15 months. Median overall survival was 30 months. Log-rank analysis performed on multiple variables, including stage, age, residual disease, and depth of myometrial invasion showed a statistically significant association with overall survival probability. Only stage remained a significant independent variable predictive of overall survival (P = 0.034). We found that stage was an independent prognostic factor for overall survival in patients with uterine MMMT. Age, depth of myometrial invasion, and residual tumor were significant prognostic factors on univariate analysis. These factors may be a guide in order to select a group of high risk patients that may benefit from adjuvant therapy.

Background: While most patients with advanced ovarian cancer can achieve prolonged remission with surgery and chemotherapy, eventually most will recur. Commonly bowel obstruction will complicate their recurrence, usually heralding the terminal phase of their disease. Standard management of bowel obstruction has involved surgical intervention after a period of conservative medical management. Unfortunately, many patients submitted for surgery do not derive benefit from such an approach, spending the majority of their remaining life in the hospital or recovering from the surgery., Cases: Two cases of patients with large bowel obstruction resulting from advanced and recurrent ovarian cancer are presented. In the first case, a rectal stent was decided upon as the appropriate management as she was failing first-line therapy, with little likelihood of recovering from a laparotomy. In the second case a large recurrent infected tumor mass had already been debulked, but was continuing to cause obstructive symptoms. In both cases immediate relief of their gastrointestinal symptoms was achieved., Conclusions: In patients with large bowel obstruction secondary to extrinsic compression, useful palliation can be achieved with a colonoscopically placed endoluminal stent.