Low BRCA1 and BRCA2 Germline Mutation Rates in a French-Canadian Population with a Diagnosis of Epithelial Tubo-Ovarian Carcinoma.

OBJECTIVE: Universal genetic testing has become increasingly important in the management of epithelial tubo-ovarian and peritoneal carcinoma. Worldwide, reported incidences of deleterious BRCA mutations vary between 12% and 15%. We sought to evaluate the incidence in our population, given its specific genetic background (French-Canadian ancestry). METHOD: Mainstream genetic testing was implemented in our service in May 2017 and offered to all patients with epithelial tubo-ovarian or peritoneal carcinomas, except mucinous and borderline tumours. Data were prospectively collected in a database and retrospectively analyzed. RESULTS: We tested 222 patients in our centre, of whom 183 (82.4%) had high-grade serous carcinoma (HGSC). Overall, 139 patients had no identified mutation (62.6%). Deleterious BRCA1 and BRCA2 mutations were found in 12 patients (5.4%): 6 had BRCA1, and 6 BRCA2 mutations; 11 of these patients had HGSC. Other non-BRCA mutations (ATM, RAD51C, RAD51D, BRIP1, CDH1, MRE11, MSH6, MUTYH, PALB2, and PMS2) were observed in an additional 20 patients (9.0%), of whom 18 had HGSC. A total of 63 different variants of unknown significance (VUS) were found, of which 4 were in the BRCA1 and BRCA2 genes. Deleterious mutations were not identified in clear cell carcinomas, and only 1 was found in low-grade serous carcinoma. CONCLUSION: In our French-Canadian population, the incidence of deleterious germline BRCA mutations was surprisingly low at 5.4%-less than half that reported in the literature. This may affect patient response to poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy. Mainstream genetic testing was successfully implemented in our service and facilitated access to genetic testing in our patient population.

Endometrial carcinoma molecular subtype correlates with the presence of lymph node metastases.

BACKGROUND: The role of lymph node assessment/dissection (LND) in endometrial cancer (EC) has been debated for decades, with significant practice variation between centers. Molecular classification of EC provides prognostic information and can be accurately performed on preoperative endometrial biopsies. We assessed the association between molecular subtype and lymph node metastases (LNM) in order to determine if this tool could be used to stratify surgical decision making. METHODS: All EC patients undergoing primary staging surgery with planned complete pelvic +/- para-aortic LND from a single institution in the 2015 calendar year were identified, with clinicopathological and outcome data assessed in the context of retrospectively assigned molecular classification. RESULTS: 172 patients were included. Molecular classification of the total cohort showed 21 POLEmut (12.2%), 47 MMRd (27.3%), 74 NSMP (43.1%), and 30 p53abn (17.4%) ECs. Complete pelvic +/- para-aortic LND was performed in 171 of 172 patients, and LNM were found in 31/171 (18.1%). This included macrometastases (19/31), micrometastases (5/31), and isolated tumour cells (ITCs) (7/31). LNM were pelvic only in 83.9%, and pelvic plus para-aortic in 16.1%. There were no isolated para-aortic LNM. Molecular subtype was significantly associated with LNM (p = 0.004). There was a strong association between the presence of LNM and p53abn EC (nodal involvement in 44.8% of cases), with LNM detected in 14.2% of POLEmut, 14.9% of MMRd, and 10.8% of NSMP EC. On multivariate analysis, molecular subtype and preoperative CA 125 > 25 were significantly associated with LNM (p = 0.021 and p = 0.022 respectively) but preoperative grade and histotype were not (p = 0.24). CONCLUSION: EC molecular subtype is significantly associated with the presence of LNM. As molecular classification can be obtained on preoperative diagnostic specimens, this information can be used to guide surgical treatment planning and may reduce the cost and morbidity of unnecessary lymph node staging in EC care.

Five-Year Experience in the Surgical Treatment of Endometrial Cancer: Comparing Laparotomy with Robotic and Minimally Invasive Hysterectomy.

OBJECTIVES: To compare surgical and oncological outcomes in the treatment of endometrial cancer between laparotomy and minimally invasive surgery. The secondary objective was to determine which MIS approach was the most beneficial. METHODS: This was a single-centre retrospective review of all endometrial cancer surgeries performed between November 1, 2012 and October 31, 2017 in a gynaecologic oncology unit of a university hospital. Descriptive statistics were used to compare histopathologic results and oncological outcomes, and Kaplan-Meier estimates were used to compare survival. RESULTS: A total of 735 cases were reviewed. The majority of patients (77%) underwent either laparotomy (35%) or robotic-assisted hysterectomy (42%); the remaining patients underwent total laparoscopic hysterectomy (12%) or a laparoscopic-assisted vaginal hysterectomy (8.7%). There was a statistically significant overall survival benefit (P = 0.02), a shorter hospital stay (P < 0.0001), and fewer early surgical complications (<30 d; P = 0.0002), as well as a survival benefit in elderly patients (>70 y) in the robotic-assisted hysterectomy group (P = 0.043) than the laparotomy group. Operating time was shorter in the laparotomy group (P < 0.0001). Recurrence rates in stage 1 low-risk disease were similar between groups. CONCLUSION: Minimally invasive surgical approaches, particularly robotic surgery, do not compromise oncologic outcomes, especially for early-stage low-risk disease. In addition, these approaches are associated with fewer early surgical complications and shorter hospital stay, with significantly more same-day discharges. Overall survival and survival in a subgroup of elderly patients were significantly better in the robotic-assisted hysterectomy group.

An in-home rehabilitation program for the treatment of urinary incontinence symptoms in endometrial cancer survivors: a single-case experimental design study.

INTRODUCTION AND HYPOTHESIS: There is a high prevalence of urinary incontinence among endometrial cancer survivors. They are also known to present with pelvic floor muscle alterations. Evidence on the effects of conservative interventions for the management of UI is scarce. This study aims at verifying the effects of an in-home rehabilitation program, including the use of a mobile technology, to reduce UI severity in endometrial cancer survivors. METHODS: This study used a single-case experimental design with replications. Primary outcome for UI severity was the pad test, and secondary outcomes were the ICIQ-UI SF questionnaire and 3-day bladder diary. Pelvic floor muscle function was assessed using 2D-transperineal ultrasound and intravaginal dynamometry. Adherence was documented using mobile technology and an exercise log. Visual and non-parametric analyses of longitudinal data were conducted. RESULTS: Results show a reduction in UI severity for 87.5% of participants, with a significant relative treatment effect of moderate size (RTE: 0.30). Significant small relative treatment effects were found for the quick contraction and endurance dynamometric tests. CONCLUSION: This study provides new evidence that endometrial cancer survivors can improve the severity of their UI following an in-home rehabilitation program, including the use of a mobile technology. This mode of delivery has the potential to address a gap in access to pelvic floor physiotherapy services for survivors of EC living in rural and remote communities.

High-grade endometrial carcinoma limited to the endometrium or a polyp: is adjuvant treatment necessary?

OBJECTIVE: High-grade endometrial carcinoma limited to the endometrium or a polyp is a rare clinical entity. Currently there is no consensus on standard treatment. Thus, the goal of this study was to evaluate the clinical outcomes of patients with type II endometrial carcinoma without myometrial infiltration or limited to a polyp. METHODS: We retrospectively identified type II endometrial carcinoma (FIGO endometrioid grade 3, serous, clear cell, mixed and carcinosarcoma) with spread limited to the endometrium or a polyp from April 2013 to November 2017. Medical records were reviewed for the following information: age at diagnosis, patient characteristics, type of surgery, histology, stage according to FIGO 2009 classification, adjuvant treatments, and site of recurrence. Descriptive statistics and the Kaplan-Meier estimate were used for analysis. RESULTS: A total of 25 patients with a type II stage IA adenocarcinoma were included. All were surgically staged with total hysterectomy, salpingo-oophorectomy, and lymph nodes assessment. The median age at diagnosis was 69 years. All patients had either disease limited to the endometrium (60%) or a polyp (40%). Only four patients had lymphovascular space invasion (16%). The median follow-up was 44 (range 2-67) months. Six patients (24%) received vault brachytherapy only and all others received no adjuvant treatment after surgery (n=19, 76%). Three patients (12%) experienced recurrences at 15, 21, and 55 months after surgery. Following systemic treatment all are alive and disease-free. The 3-year progression-free survival and overall survival were 91% and 100%, respectively. CONCLUSION: Expectant management with surveillance alone following surgery appears to be safe for patients with high-grade endometrial carcinoma limited to a polyp or the endometrium without myometrial invasion.

A Collaborative Model to Implement Flexible, Accessible and Efficient Oncogenetic Services for Hereditary Breast and Ovarian Cancer: The C-MOnGene Study.

Medical genetic services are facing an unprecedented demand for counseling and testing for hereditary breast and ovarian cancer (HBOC) in a context of limited resources. To help resolve this issue, a collaborative oncogenetic model was recently developed and implemented at the CHU de Québec-Université Laval; Quebec; Canada. Here, we present the protocol of the C-MOnGene (Collaborative Model in OncoGenetics) study, funded to examine the context in which the model was implemented and document the lessons that can be learned to optimize the delivery of oncogenetic services. Within three years of implementation, the model allowed researchers to double the annual number of patients seen in genetic counseling. The average number of days between genetic counseling and disclosure of test results significantly decreased. Group counseling sessions improved participants' understanding of breast cancer risk and increased knowledge of breast cancer and genetics and a large majority of them reported to be overwhelmingly satisfied with the process. These quality and performance indicators suggest this oncogenetic model offers a flexible, patient-centered and efficient genetic counseling and testing for HBOC. By identifying the critical facilitating factors and barriers, our study will provide an evidence base for organizations interested in transitioning to an oncogenetic model integrated into oncology care; including teams that are not specialized but are trained in genetics.

Directive clinique no 408 : Prise en charge des maladies gestationnelles trophoblastiques.

OBJECTIF: Cette directive passe en revue l'évaluation clinique et la prise en charge des maladies gestationnelles trophoblastiques, notamment les traitements chirurgicaux et médicamenteux des tumeurs bénignes, prémalignes et malignes. L'objectif de la présente directive clinique est d'aider les fournisseurs de soins de santé à rapidement diagnostiquer les maladies gestationnelles trophoblastiques, à normaliser les traitements et le suivi et à assurer des soins spécialisés précoces aux patientes dont l'atteinte est maligne ou métastatique. PROFESSIONNELS CONCERNéS: Gynécologues généralistes, obstétriciens, médecins de famille, sages-femmes, urgentologues, anesthésistes, radiologistes, anatomopathologistes, infirmières autorisées, infirmières praticiennes, résidents, gynécologues-oncologues, oncologues médicaux, radio-oncologues, chirurgiens, omnipraticiens en oncologie, infirmières en oncologie, pharmaciens, auxiliaires médicaux et autres professionnels de la santé qui traitent des patientes atteintes d'une maladie gestationnelle trophoblastique. La présente directive vise également à fournir des renseignements aux parties intéressées qui prodiguent des soins de suivi à ces patientes après le traitement. POPULATION CIBLE: Femmes en âge de procréer atteintes d'une maladie gestationnelle trophoblastique. OPTIONS: Les femmes ayant reçu un diagnostic de maladie gestationnelle trophoblastique doivent être orientées vers un gynécologue afin qu'il réalise une évaluation initiale, envisage une intervention chirurgicale primaire (évacuation ou hystérectomie) et effectue un suivi. Il y a lieu d'orienter les femmes ayant reçu un diagnostic de tumeur trophoblastique gestationnelle vers un gynécologue-oncologue afin qu'il effectue la stadification tumorale, établisse le score de risque et envisage l'intervention chirurgicale primaire ou un traitement systémique (mono- ou polychimiothérapie) et la nécessité d'éventuels traitements supplémentaires. Il est recommandé de discuter de chaque cas de néoplasie gestationnelle trophoblastique lors d'une réunion multidisciplinaire de cas oncologiques et de l'inscrire dans une base de données centralisée (régionale et/ou nationale). DONNéES PROBANTES: Des recherches ont été effectuées au moyen des bases de données Embase et MEDLINE, du Cochrane Central Register of Controlled Trials et de la Cochrane Database of Systematic Reviews afin de trouver les études publiées depuis 2002 utilisant un ou plusieurs des mots clés suivants : trophoblastic neoplasms, choriocarcinoma, trophoblastic tumor, placental site, gestational trophoblastic disease, hydatidiform mole, drug therapy, surgical therapy, radiotherapy, cure, complications, recurrence, survival, prognosis, pregnancy outcome, disease outcome, treatment outcome et remission. La recherche initiale a été effectuée en avril 2017; une mise à jour a été faite en mai 2019. Les données probantes pertinentes ont été sélectionnées aux fins d'inclusion selon l'ordre suivant : méta-analyses, revues systématiques, directives cliniques, essais cliniques randomisés, études de cohortes prospectives, études observationnelles, revues non systématiques, études de séries de cas et rapports. D'autres articles pertinents ont été trouvés en recoupant les revues répertoriées. Le nombre total d'études relevées était de 673, dont 79 études sont citées dans la présente revue. MéTHODES DE VALIDATION: Le contenu et les recommandations ont été rédigés et acceptés par les auteurs. La direction et le conseil d'administration de la Société de gynéco-oncologie du Canada ont passé en revue le contenu de la version préliminaire et ont soumis des commentaires à prendre en considération. Le conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version définitive aux fins de publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation). Consulter les tableaux dans l'annexe en ligne pour connaître les critères de notation et d'interprétation des recommandations. BéNéFICES, RISQUES, COûTS: Les présentes recommandations aideront les médecins à diagnostiquer rapidement les maladies gestationnelles trophoblastiques et à orienter de façon urgente les patientes ayant reçu un diagnostic de maladie gestationnelle trophoblastique en gynécologie oncologique pour une prise en charge spécialisée. Le traitement des néoplasies gestationnelles trophoblastiques en centre spécialisé combiné à l'utilisation de bases de données centralisées permet de recueillir et de comparer des données sur les résultats thérapeutiques des patientes atteintes de ces tumeurs rares et d'optimiser les soins aux patientes. DÉCLARATIONS SOMMAIRES (CLASSEMENT GRADE ENTRE PARENTHèSES): RECOMMANDATIONS (CLASSEMENT GRADE ENTRE PARENTHèSES).

Guideline No. 408: Management of Gestational Trophoblastic Diseases.

OBJECTIVE: This guideline reviews the clinical evaluation and management of gestational trophoblastic diseases, including surgical and medical management of benign, premalignant, and malignant entities. The objective of this guideline is to assist health care providers in promptly diagnosing gestational trophoblastic diseases, to standardize treatment and follow-up, and to ensure early specialized care of patients with malignant or metastatic disease. INTENDED USERS: General gynaecologists, obstetricians, family physicians, midwives, emergency department physicians, anaesthesiologists, radiologists, pathologists, registered nurses, nurse practitioners, residents, gynaecologic oncologists, medical oncologists, radiation oncologists, surgeons, general practitioners in oncology, oncology nurses, pharmacists, physician assistants, and other health care providers who treat patients with gestational trophoblastic diseases. This guideline is also intended to provide information for interested parties who provide follow-up care for these patients following treatment. TARGET POPULATION: Women of reproductive age with gestational trophoblastic diseases. OPTIONS: Women diagnosed with a gestational trophoblastic disease should be referred to a gynaecologist for initial evaluation and consideration for primary surgery (uterine evacuation or hysterectomy) and follow-up. Women diagnosed with gestational trophoblastic neoplasia should be referred to a gynaecologic oncologist for staging, risk scoring, and consideration for primary surgery or systemic therapy (single- or multi-agent chemotherapy) with the potential need for additional therapies. All cases of gestational trophoblastic neoplasia should be discussed at a multidisciplinary cancer case conference and registered in a centralized (regional and/or national) database. EVIDENCE: Relevant studies from 2002 onwards were searched in Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, and Cochrane Systematic Reviews using the following terms, either alone or in combination: trophoblastic neoplasms, choriocarcinoma, trophoblastic tumor, placental site, gestational trophoblastic disease, hydatidiform mole, drug therapy, surgical therapy, radiotherapy, cure, complications, recurrence, survival, prognosis, pregnancy outcome, disease outcome, treatment outcome, and remission. The initial search was performed in April 2017 and updated in May 2019. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 673, with 79 studies cited in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of Directors of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of Directors for the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework. See the online appendix tables for key to grading and interpretation of recommendations. BENEFITS: These guidelines will assist physicians in promptly diagnosing gestational trophoblastic diseases and urgently referring patients diagnosed with gestational trophoblastic neoplasia to gynaecologic oncology for specialized management. Treating gestational trophoblastic neoplasia in specialized centres with the use of centralized databases allows for capturing and comparing data on treatment outcomes of patients with these rare tumours and for optimizing patient care. SUMMARY STATEMENTS (GRADE RATINGS IN PARENTHESES): RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as "BRCAness". Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. METHODS: We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. RESULTS: The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%-60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. CONCLUSION: The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.

Guideline No. 403: Initial Investigation and Management of Adnexal Masses.

OBJECTIVES: To aid primary care physicians, emergency medicine physicians, and gynaecologists in the initial investigation of adnexal masses, defined as lumps that appear near the uterus or in or around ovaries, fallopian tubes, or surrounding connective tissue, and to outline recommendations for identifying women who would benefit from a referral to a gynaecologic oncologist for further management. INTENDED USERS: Gynaecologists, obstetricians, family physicians, general surgeons, emergency medicine specialists, radiologists, sonographers, nurses, medical learners, residents, and fellows. TARGET POPULATION: Adult women 18 years of age and older presenting for the evaluation of an adnexal mass. OPTIONS: Women with adnexal masses should be assessed for personal risk factors, history, and physical findings. Initial evaluation should also include imaging and laboratory testing to triage women for management of their care either by a gynaecologic oncologist or as per SOGC guideline no. 404 on the initial investigation and management of benign ovarian masses. EVIDENCE: A search of PubMed, Cochrane Wiley, and the Cochrane systematic reviews was conducted in January 2018 for English-language materials involving human subjects published since 2000 using three sets of terms: (i) ovarian cancer, ovarian carcinoma, adnexal disease, ovarian neoplasm, adnexal mass, fallopian tube disease, fallopian tube neoplasm, ovarian cyst, and ovarian tumour; (ii) the above terms in combination with predict neoplasm staging, follow-up, and staging; and (iii) the above two sets of terms in combination with ultrasound, tumour marker, CA 125, CEA, CA19-9, HE4, multivariable-index-assay, risk-of-ovarian-malignancy-algorithm, risk-of-malignancy-index, diagnostic imaging, CT, MRI, and PET. Relevant evidence was selected for inclusion in descending order of quality of evidence as follows: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional articles were identified through cross-referencing the identified reviews. The total number of studies identified was 2350, with 59 being included in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration. The Board of Directors of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework (Table A1 of Online Appendix A). See Table A2 of Online Appendix A for the interpretation of strong and weak recommendations. The summary of findings is available upon request. BENEFITS, HARMS, COSTS: Adnexal masses are common, and guidelines on how to triage them and manage the care of patients presenting with adnexal masses will continue to guide the practice of primary care providers and gynaecologists. Ovarian cancer outcomes are improved when initial surgery is performed by a gynaecologic oncologist, likely as a result of complete surgical staging and optimal cytoreduction. Given these superior outcomes, guidelines to assist in the triage of adnexal masses and the referral and management of the care of patients with an adnexal mass are critical. SUMMARY STATEMENTS (GRADE RATINGS IN PARENTHESES): RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).

Guideline No. 403: initial investigation and management of adnexal masses

To aid primary care physicians, emergency medicine physicians, and gynaecologists in the initial investigation of adnexal masses, defined as lumps that appear near the uterus or in or around ovaries, fallopian tubes, or surrounding connective tissue, and to outline recommendations for identifying women who would benefit from a referral to a gynaecologic oncologist for further management.

Simple vaginal trachelectomy in women with early-stage low-risk cervical cancer who wish to preserve fertility: the new standard of care?

OBJECTIVE: There is a trend toward less radical surgery in women with small-volume disease who wish to preserve fertility. The objective of our study was to evaluate the oncologic and obstetrical outcome of simple vaginal trachelectomy and lymph node assessment in patients with low-risk early-stage cervical cancer (<2 cm). METHODS: From May 2007 to January 2020, 50 patients underwent a simple vaginal trachelectomy/conization with laparoscopic sentinel lymph node mapping±complete pelvic node dissection. Patients underwent loop electrocautery excision (LEEP), cone/cervical biopsies, or simple trachelectomy. A preoperative pelvic MRI with gadolinium contrast was systematically performed in all cases. The size of the lesion was established by review of the LEEP, cone or trachelectomy specimen, MRI, and clinical examination. Data was collected prospectively in a computerized database. Descriptive statistics and the Kaplan-Meier estimate were used for analysis. RESULTS: The median age was 29 years (range: 21-44) and 35 (70%) patients were nulliparous. As per FIGO 2009 classification, 11 patients had stage IA1 with lymphovascular space invasion (LVSI), 13 patients had stage IA2, and 26 patients had stage IB1. Twenty-six patients had squamous histology, 20 patients adenocarcinoma, and four patients other histologies. On final pathology, lymph nodes were negative in 46 patients (92%), three patients had isolated tumor cells, and one patient had micrometastasis. Thirty patients (60%) had either no residual disease in the trachelectomy specimen (22) or residual dysplasia only (eight). With a median follow-up of 76 months (range: 1-140), only one local recurrence occurred which was treated initially with chemoradiation. She recurred again locally and underwent a pelvic exenteration: the patient progressed again and died of disease. The 5-year progression-free survival and overall survival was 97.9% and 97.6%, respectively. There were 40 pregnancies: five (12.5%) ended in the first trimester, one (2.5%) in the second trimester, and three (7.5%) were late preterm: all the others (30 or 75%) delivered >36 weeks and one pregnancy is ongoing. CONCLUSION: Simple trachelectomy/conization and lymph node assessment is an oncologically safe fertility-preserving surgery in well-selected patients with low-risk early-stage cervical cancer (<2 cm). Obstetrical outcomes are comparable to the general population.

Guideline No. 390-Classification and Management of Endometrial Hyperplasia.

OBJECTIVE: The aim of this guideline is to aid primary care physicians and gynaecologists in the initial evaluation of women with suspected endometrial hyperplasia, to recommend the use of the 2014 World Health Organization classification for endometrial hyperplasia by all health care providers, and to guide the optimal treatment of women diagnosed with endometrial hyperplasia. INTENDED USERS: Physicians, including gynaecologists, obstetricians, family physicians, general surgeons, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; medical trainees, including medical students, residents, and fellows; and all other health care providers. TARGET POPULATION: Adult women (18 years and older) presenting with suspected or confirmed endometrial hyperplasia. OPTIONS: The discussion relates to the medical therapy as well as surgical treatment options for women with and without atypical endometrial hyperplasia. EVIDENCE: For this guideline, relevant studies were searched in PubMed, Cochrane Wiley, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials, human subjects, and published since 2000: (endometrial hyperplasia, endometrial intraepithelial neoplasia, endometrial sampling, endometrial curettage, diagnosis) AND (treatment, progestin therapy, surgery, LNG-IUS, aromatase inhibitors, metformin ), AND (obesity). The search was performed in April 2018. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 2152, and 82 studies were included in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework. The interpretation of strong and weak recommendations was also included. The Summary of Findings is available upon request. BENEFITS, HARMS, AND/OR COSTS: It is expected that this guideline will benefit women with endometrial hyperplasia. This should guide patient informed consent before both medical and surgical management of this condition. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SUMMARY STATEMENTS: RECOMMENDATIONS.

Effectiveness of an Enhanced Recovery After Surgery Program in Gynaecology Oncologic Surgery: A Single-Centre Prospective Cohort Study.

OBJECTIVE: This study sought to evaluate whether the partial implementation of an Early Recovery After Surgery (ERAS) program lowers length of hospital stay (LOS) without compromising postoperative outcome. METHODS: A single-centre prospective cohort study was conducted in a tertiary gynaecologic oncology department, by comparing standard perioperative care with a partially implemented ERAS protocol. Data on postoperative evolution were gathered for patients who underwent laparotomy for suspected or confirmed endometrial, adnexal, or cervical neoplasia between July 1, 2015 and June 30, 2017 at the Hôtel-Dieu de Québec. RESULTS: A total of 390 cases were identified; 140 patients followed the ERAS protocol, and 250 patients received standard perioperative care. The median LOS in hours was significantly reduced for patients in the ERAS group (65.5 hours [interquartile range 59.8, 71.0] vs. 69.0 hours [interquartile range 64.3, 81.0], P < 0.001). There was no difference in complication rates, neither grade 1 (3% vs. 7%, P = 0.155) nor grades 2 to 4 (7% vs. 5%, P = 0.577), or in readmission rates (0.7% vs. 1.2%, P > 0.99). CONCLUSION: Even a partially implemented ERAS program can significantly affect LOS without compromising patient care.

No 370 - Prise en charge du cancer spinocellulaire de la vulve.

OBJECTIF: Cette directive clinique porte sur l'évaluation clinique et la prise en charge du cancer spinocellulaire (CSC) de la vulve, plus particulièrement sur son diagnostic, sa prise en charge primaire au moyen de la chirurgie, de la radiothérapie ou de la chimiothérapie et la nécessité d'une chimiothérapie et/ou d'une radiothérapie adjuvante. Cette directive clinique ne traite pas des autres diagnostics pathologiques de cancer de la vulve. UTILISATEURS CIBLES: La première partie de ce document, qui comprend les recommandations 1 à 3, s'adresse aux gynécologues, aux obstétriciens, aux médecins de famille, aux infirmières autorisées, aux infirmières praticiennes, aux résidents et aux fournisseurs de soins généralistes; elle est axée sur la présentation et le diagnostic de la maladie, et fournit des renseignements à jour sur les chirurgies effectuées par les professionnels surspécialisés. La partie sur la prise en charge chirurgicale et le traitement des cancers avancés de la vulve s'adresse aux gynécologues oncologues, aux radio-oncologues et aux oncologues médicaux appelés à traiter les patientes aux besoins complexes. Cette directive clinique a pour but de renseigner les intervenants qui pourraient suivre ces patientes après leur traitement. POPULATION CIBLE: Femmes adultes (18 ans et plus) présentant un CSC de la vulve. Les femmes atteintes d'un cancer préinvasif ne sont pas visées par cette directive clinique. OPTIONS: Les femmes ayant reçu un diagnostic de CSC de la vulve devraient être dirigées vers un gynécologue oncologue, qui effectuera une évaluation initiale et déterminera si une chirurgie primaire, une évaluation des ganglions lymphatiques inguinaux et une radiothérapie ou une chimiothérapie adjuvante sont nécessaires. Ces femmes devraient également faire l'objet d'une discussion tenue dans le cadre d'une conférence de cas multidisciplinaire. La radiothérapie et la chimiothérapie primaires peuvent être envisagées chez les femmes qui pourraient avoir besoin d'une exentération ou d'une chirurgie radicale, comme une résection abdomino-périnéale. ÉVIDENCE: Des études pertinentes rédigées en anglais ont été repérées dans PubMed, Medline, et la Cochrane Database of Systematic Reviews à l'aide des termes suivants, seuls ou combinés : « vulva ¼, « vulvar cancer ¼, « inguinofemoral lymph node dissection ¼, « sentinel nodes ¼, « systemic chemotherapy ¼, « radiotherapy ¼, « neoadjuvant ¼, « adjuvant ¼, « primary ¼, « exenteration ¼, « survival ¼, « follow up ¼. La recherche initiale a été menée en septembre 2016, et une dernière recherche a été effectuée en mai 2017. Dans l'ordre, les données probantes pertinentes pour la sélection ont été tirées de méta-analyses, de revues systématiques, de directives cliniques, d'essais cliniques randomisés, d'études de cohortes prospectives, d'études observationnelles, de revues non systématiques, d'études de série de cas et de rapports. D'autres articles pertinents ont été ciblés au moyen d'une vérification des références des revues de la littérature retenues. Au total, 286 études ont été repérées, et 78 ont été retenues pour la présente directive. VALEURS: Le contenu et les recommandations ont été rédigés et acceptés par les auteurs principaux. La direction et le conseil de la Société de gynéco-oncologie du Canada ont examiné le contenu et soumis des commentaires, puis le Conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version finale avant publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interprétation des recommandations fortes et faibles est décrite dans le tableau 2. Le résumé des conclusions peut être fourni sur demande. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique vise à guider les médecins vers une utilisation appropriée de l'évaluation du ganglion sentinelle inguinal en cas de CSC de la vulve. Le comité encourage également la centralisation du traitement des cancers de la vulve dans des centres de traitement spécialisés. MIS-à-JOUR: Une revue des données probantes sera menée cinq ans après la publication de la présente directive clinique afin de déterminer si une mise à jour complète ou partielle s'impose. Cependant, si de nouvelles données probantes importantes sont publiées avant la fin du cycle de cinq ans, le processus pourrait être accéléré afin que certaines recommandations soient mises à jour rapidement. COMMANDITAIRES: Cette directive Clinique a été développée avec les ressources de la Société de gynécologie oncologique du Canada et de la Société des obstétriciens et gynécologues du Canada. DéCLARATIONS SOMMAIRES: RECOMMENDATIONS.

No. 370-Management of Squamous Cell Cancer of the Vulva.

OBJECTIVE: This guideline reviews the clinical evaluation and management of squamous cell cancer (SCC) of the vulva with respect to diagnosis, primary surgical, radiation, or chemotherapy management and need for adjuvant treatment with chemotherapy and/or radiation therapy. Other vulvar cancer pathologic diagnoses are not included in the guideline. INTENDED USERS: The first part of this document which includes recommendations 1 through 3 is for general gynaecologists, obstetricians, family doctors, registered nurses, nurse practitioners, residents, and health care providers with a focus on the presentation, diagnosis, and updated information about surgical procedures performed by subspecialists. The surgical management and treatment of advanced vulvar cancer are intended for gynaecologic oncologists, radiation oncologists, and medical oncologists who treat these complex patients. This guideline is intended to provide information for interested parties who may follow these patients once treatment is complete. TARGET POPULATION: Adult women (18 years and older) with SCC of the vulva. Excluded from these guidelines are women with preinvasive disease. OPTIONS: Women diagnosed with SCC of the vulva should be referred to a gynaecologic oncologist for initial evaluation, consideration for primary surgery and inguinal lymph node assessment, and potentially adjuvant radiation and/or chemotherapy. All cases of vulvar cancer should have access to discussion at a multidisciplinary cancer case conference. Women who would otherwise require radical surgery such as abdominal-perineal resection or exenterative procedures may be considered for primary treatment with radiation and/or chemotherapy. EVIDENCE: For this guideline, relevant studies were searched in PubMed, Medline, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials: vulva, vulvar cancer, inguinofemoral lymph node dissection, sentinel nodes, systemic chemotherapy, radiotherapy, neoadjuvant, adjuvant, primary, exenteration, survival, follow up. The initial search was performed in September 2016 with a final literature search in May 2017. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 286, and 78 studies were included in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework (Table 1). The interpretation of strong and weak recommendations is described in Table 2. The Summary of Findings is available upon request. BENEFITS, HARMS, AND/OR COSTS: These guidelines are to encourage physicians in the appropriate use of sentinel inguinal lymph node assessment for SCC of the vulva. The committee also promotes the centralization of treatment of vulvar cancer in specialized treatment centres. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Gynecologic Oncology of Canada and the Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: RECOMMENDATIONS.

Tips and tricks to improve sentinel lymph node mapping with Indocyanin green in endometrial cancer.

OBJECTIVE: To determine the validity of sentinel lymph node (SLN) biopsy with ICG in endometrial cancer and to evaluate the factors associated with poor mapping or false negative. METHODS: We reviewed all patients who underwent primary surgery for endometrial carcinoma with SLN mapping using ICG followed by pelvic lymphadenectomy from February 2014 to December 2015. SLNs were ultrastaged on final pathology. Patients' demographics, surgical approach and histopathological factors were prospectively collected. Detection rate, sensitivity and negative predictive value (NPV) were calculated and univariate analysis was performed to evaluate factors associated with failed bilateral detection of SLNs. RESULTS: A total of 119 patients were included. The overall and bilateral detection rates were 93% and 74%. Sensitivity and NPV were 100% in patients with bilateral detection; 95% and 99% respectively in cases with at least unilateral detection. Advanced FIGO stage (III or IV) was the only factor related to failed bilateral detection (p = 0.01). In 14 hemi-pelvis, the specimen labelled as SLN did not contain nodal tissue on final pathology (only lymphatic channels), which represented 37% of the "failed detection" cases. One false negative occurred in a patient with an ipsilateral clinically suspicious enlarged lymph node. CONCLUSION: ICG is an excellent tracer for SLN mapping in endometrial cancer. Advanced FIGO stage correlated with failed bilateral detection (p = 0.01). Suspicious lymph nodes should be removed regardless of the mapping. Care should be taken to ensure that SLN specimen actually contains nodal tissue and not only swollen lymphatic channels, as this represents a significant cause of failed SLN mapping.

The utility of sentinel lymph node mapping in the management of endometrial atypical hyperplasia.

OBJECTIVES: To determine the risk of endometrial cancer (EC) and lymph node involvement in patients with a preoperative diagnosis of "AH-only" versus "AH - cannot rule out carcinoma" and to study the value of SLN mapping. METHODS: We reviewed all patients with a preoperative diagnosis of atypical hyperplasia, who underwent primary surgery with SLN mapping followed by pelvic lymphadenectomy. Sensitivity and negative predictive value (NPV) of SLN and rates of endometrial cancer were calculated. RESULTS: Overall, 64/120 (53.3%) patients were found to have EC on final pathology: 58 stage IA, 3 IB, and 3 IIIC1. In patients with preoperative diagnosis of "AH", 44.3% (31/70) had EC on final pathology compared to 66% (33/50) in patients with "AH - cannot rule out cancer" (p=0.02). Overall, 3.3% of the patients (4/120) had lymph node involvement. In patients with EC with a pre-operative diagnosis of "AH", none had lymph node metastasis (0/31), compared to 12.1% (4/33) in patients with "AH - cannot rule out cancer" (p=0.06). Elevated preoperative CA125 levels (>25U/mL) were statistically associated with the risk of lymph node metastasis on final pathology (p=0.024). Unilateral and bilateral SLN detection occurred in 93.7% and 78.1% respectively. In patients with EC and bilateral SLN mapping, sensitivity and NPV were respectively 66.6% and 97.9%. There was one false negative (ITCs in non-SLN). CONCLUSION: Our data indicate that the risk of lymph node involvement in patients with a preoperative diagnosis of "AH-only" is null. Lymph node assessment could be omitted in those patients. Conversely this risk is significant in patients with "AH - cannot rule out cancer". SLN mapping could be a valuable staging procedure in these patients.

Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFß1-independent manner.

The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. We have previously identified the hydrogen peroxide-inducible clone-5 (Hic-5) gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. Hic-5 is a focal adhesion scaffold protein and has been primarily studied for its role as a key mediator of TGF-ß-induced epithelial-to-mesenchymal transition (EMT) in epithelial cells of both normal and malignant origin; however, its role in EOC has been never investigated. Here we demonstrate that Hic-5 is overexpressed in advanced EOC, and that Hic-5 is upregulated upon TGFß1 treatment in the EOC cell line with epithelial morphology (A2780s), associated with EMT induction. However, ectopic expression of Hic-5 in A2780s cells induces EMT independently of TGFß1, accompanied with enhancement of cellular proliferation rate and migratory/invasive capacity and increased resistance to chemotherapeutic drugs. Moreover, Hic-5 knockdown in the EOC cells with mesenchymal morphology (SKOV3) was accompanied by induction of mesenchymal-to-epithelial transition (MET), followed by a reduction of their proliferative, migratory/invasive capacity, and increased drugs sensitivity in vitro, as well as enhanced tumor cell colonization and metastatic growth in vivo. The modulation of Hic-5 expression in EOC cells resulted in altered regulation of numerous EMT-related canonical pathways and was indicative for a possible role of Hic-5 in controlling EMT through a RhoA/ROCK mediated mechanism. To our knowledge, this is the first report examining the role of Hic-5 in EOC, and its role in maintaining the mesenchymal phenotype of EOC cells independently of exogenous TGFß1 treatment.