DIONYSUS: a database of protein-carbohydrate interfaces.

Protein-carbohydrate interactions govern a wide variety of biological processes and play an essential role in the development of different diseases. Here, we present DIONYSUS, the first database of protein-carbohydrate interfaces annotated according to structural, chemical and functional properties of both proteins and carbohydrates. We provide exhaustive information on the nature of interactions, binding site composition, biological function and specific additional information retrieved from existing databases. The user can easily search the database using protein sequence and structure information or by carbohydrate binding site properties. Moreover, for a given interaction site, the user can perform its comparison with a representative subset of non-covalent protein-carbohydrate interactions to retrieve information on its potential function or specificity. Therefore, DIONYSUS is a source of valuable information both for a deeper understanding of general protein-carbohydrate interaction patterns, for annotation of the previously unannotated proteins and for such applications as carbohydrate-based drug design. DIONYSUS is freely available at www.dsimb.inserm.fr/DIONYSUS/.

Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer.

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Outcomes of minimal residual disease at upfront debulking surgery compared with complete cytoreduction after neoadjuvant chemotherapy.

OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

Impact of pattern of recurrence on post-relapse survival according to surgical timing in patients with advanced ovarian cancer.

OBJECTIVE: Our study aimed to evaluate the association between timing of cytoreductive surgery and pattern of presentation of the first recurrence in patients with advanced ovarian cancer. We also aimed to assess the impact of the pattern of recurrence on post-relapse overall survival according to surgical timing. METHODS: This retrospective multicenter study evaluated patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV ovarian cancer. Patients had undergone either primary debulking surgery, early interval debulking surgery after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery after 6 cycles, with minimal or no residual disease, between January 2008 and December 2015. Survival analyses were conducted using the Log-rank test and the Cox model. Cumulative incidences of the different patterns of recurrence were estimated using a competing risks methodology. RESULTS: A total of 549 patients were included: 175 (31.9%) patients had primary, 224 (40.8%) early interval, and 150 (27.3%) delayed debulking surgery. The cumulative incidence of peritoneal recurrences at 2 years was higher with increasing neoadjuvant cycles (24.4%, 30.9% and 39.2%; p=0.019). For pleural or pulmonary recurrences, it was higher after early interval surgery (9.9%, 13.0% and 4.1%; p=0.022). Median post-relapse overall survival was 33.5 months (95% confidence interval (CI) (24.3 to 44.2)), 26.8 months (95% CI (22.8 to 32.6)), and 24.5 months (95% CI (18.6 to 29.4)) for primary, early interval, and delayed debulking surgery groups, respectively (p=0.025). The pattern of recurrence in a lymph node (hazard ratio (HR) 0.42, 95% CI (0.27 to 0.64)), delayed surgery (HR 1.53, 95% CI (1.11 to 2.13)) and time to first recurrence (HR 0.95, 95% CI (0.93 to 0.96)) were associated with post-relapse overall survival. For primary and early interval surgery, lymph node recurrences were associated with significantly longer post-relapse overall survival. CONCLUSIONS: The pattern of first recurrence was associated with timing of surgery, with peritoneal recurrences being more frequent with the increasing number of cycles of neoadjuvant chemotherapy. Lymph node recurrences were associated with better prognosis, having higher post-relapse overall survival. This improved prognosis of lymphatic recurrences was not observed in patients who underwent delayed surgery.

Management of patients with advanced epithelial ovarian cancer: a European survey.

BACKGROUND: The aim of this study was to assess current European practices in the management of patients with advanced epithelial ovarian cancer in 2021. METHODS: A 58-question electronic survey was distributed anonymously to the members of six European learned societies. Initial diagnostic workup and staging, pathological data, surgical data, treatments and follow-up strategies were assessed. RESULTS: A total of 171 participants from 17 European countries responded to emailed surveys. Most participants were experienced practitioners (superior than 15 years of experience) specializing in gynecology-obstetrics (29.8%), surgical oncology (25.1%), and oncogynecology (21.6%). According to most (64.8%) participants, less than 50% of patients were eligible for primary debulking surgery. Variations in the rate of primary debulking surgery depending on the country of origin of the practitioners were observed in this study. The LION study criteria were applied in 70.4% of cases during PDS and 27.1% after chemotherapy. In cases of BRCA1-2 mutations, olaparib was given by 75.0-84.8% of respondents, whereas niraparib was given in cases of BRCA wild-type diseases. CONCLUSIONS: This study sheds light on current practices and attitudes regarding the management of patients with advanced epithelial ovarian cancer in Europe in 2021.

The effect of major postoperative complications on recurrence and long-term survival after cytoreductive surgery for ovarian cancer.

OBJECTIVE: To assess the impact on survival of major postoperative complications and to identify the factors associated with these complications in patients with advanced ovarian cancer after cytoreductive surgery. METHODS: We designed a retrospective multicenter study collecting data from patients with IIIC-IV FIGO Stage ovarian cancer who had undergone either primary debulking surgery (PDS), early interval debulking surgery (IDS) after 3-4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery (DDS) after 6 cycles, with minimal or no residual disease, from January 2008 to December 2015. Univariable and multivariable analyses were conducted to identify factors associated with major surgical complications (≥Grade 3). We assessed disease-free survival (DFS) and overall survival (OS) rates according to the occurrence of major postoperative complications. RESULTS: 549 women were included. The overall rate of major surgical complications was 22.4%. Patients who underwent PDS had a higher rate of major complications (28.6%) than patients who underwent either early IDS (23.2%) or DDS (14.0%). Multivariable analysis revealed that extensive peritonectomy and surgical timing were associated with the occurrence of major complications. Median DFS and OS were 16.9 months (95%CI = [13.7-18.4]) and 48.0 months (95%CI = [37.2-73.1]) for the group of patients with major complications, and 20.1 months (95%CI = [18.6-22.4]) and 56.7 months (95%CI = [51.2-70.4]) for the group without major complications. Multivariable analysis revealed that major surgical complications were significantly associated with DFS, but not with OS. CONCLUSIONS: Patients who experienced major surgical complications had reduced DFS, compared with patients without major morbidity. Extensive peritonectomy and surgical timing were predictive factors of postoperative morbidity.

Uterine sarcomas and rare uterine mesenchymal tumors with malignant potential. Diagnostic guidelines of the French Sarcoma Group and the Rare Gynecological Tumors Group.

The landscape of uterine sarcomas is becoming increasingly complex with the description of new entities associated with recurrent molecular alterations. Uterine sarcomas, as well as soft tissue sarcomas, can be distinguished into complex genomic sarcomas and simple genomic sarcomas. Leiomyosarcoma and pleomorphic type undifferentiated uterine sarcoma belong to the first group. Low-grade and high-grade endometrial stromal sarcomas, NTRK, COL1A1::PDGFB, ALK, RET, ROS1 associated sarcomas, and SMARCA4 deficient uterine sarcoma belong to the second group. Leiomyosarcoma is the most common uterine sarcoma followed by endometrial stromal sarcomas. Three different histologic subtypes of leiomyosarcomas are recognized with distinct diagnostic criteria and different clinical outcomes, the myxoid and epithelioid leiomyosarcomas being even more aggressive than the fusiform type. The distinction between low-grade and high-grade endometrial stromal sarcoma is based first on morphology and immunohistochemistry. The detection of fusion transcripts helps in the diagnosis. Definitely recognized as a separate entity, uterine PEComa is a rare tumor whose diagnostic criteria are being recently defined. Uterine PEComa has a specific algorithm stratifying the tumors into uncertain malignant potential and malignant tumors. Embryonal rhabdomyosarcomas of the uterine cervix are not restricted to children but can also be observed in adult women and are almost always DICER1 mutated, unlike embryonal rhabdomyosarcoma of the vagina which are DICER1wild-type, and adenosarcoma which can be DICER1 mutated but with less frequency. As sarcomas associated with fusion transcripts involving the NTRK, ALK, COL1A1::PDGFB genes can benefit from targeted therapy, systematic detection are now relevant especially for patients with high risk of relapse or in recurrent setting. The integration of molecular data with dedicated expert pathology review for histology and clinical data allows better identification of uterine sarcomas in order to better treat them.

Survival impact of histological response to neoadjuvant chemotherapy according to number of cycles in patients with advanced ovarian cancer.

OBJECTIVE: We sought to evaluate the impact of chemotherapy response score according to the number of cycles of neoadjuvant chemotherapy, on disease-free survival and overall survival, in patients with advanced epithelial ovarian cancer ineligible for primary debulking surgery. METHODS: This multicenter retrospective study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent 3-4 or 6 cycles of a platinum and taxane-based neoadjuvant chemotherapy, followed by complete cytoreduction surgery (CC-0) or cytoreduction to minimal residual disease (CC-1), between January 2008 and December 2015, in four institutions. Disease-free survival and overall survival were assessed according to the histological response to chemotherapy defined by the validated chemotherapy response score. RESULTS: A total of 365 patients were included: 219 (60.0%) received 3-4 cycles of neoadjuvant chemotherapy, and 146 (40.0%) had 6 cycles of neoadjuvant chemotherapy before cytoreductive surgery. There were no significant differences in early relapses, disease-free survival, and overall survival according to the number of neoadjuvant chemotherapy cycles. However, regardless of the number cycles of neoadjuvant chemotherapy, persistent extensive histological disease (chemotherapy response score 1-2) was significantly associated with a higher peritoneal cancer index, minimal residual disease (CC-1), and early relapses. Median disease-free survival in patients with complete or near-complete response (score 3) was 28.3 months (95% CI 21.6 to 36.8), whereas it was 16.3 months in patients with chemotherapy response score 1-2 (95% CI 14.7 to 18.0, p<0.001). CONCLUSION: In our cohort, the number of neoadjuvant chemotherapy cycles was not associated with disease-free survival or overall survival. Chemotherapy response score 3 improved oncological outcome regardless of the number of neoadjuvant chemotherapy cycles.

Neoadjuvant chemotherapy in advanced-stage ovarian cancer - state of the art.

Ovarian cancer represents the fifth cause of cancer death among women, carrying one of the worst prognoses among gynaecological malignancies. The need to achieve no residual disease after surgery in order to optimize prognosis of advanced-stage ovarian cancer introduced the idea of neoadjuvant chemotherapy. The present review aims to summarize current state-of-the-art evidence regarding the efficacy and safety of neoadjuvant chemotherapy as well as novel insights regarding the usage of modern therapeutic regimens in the context of neoadjuvant chemotherapy. The last decade has been characterized by the breakthrough scientific evidence that neoadjuvant chemotherapy followed by interval debulking surgery for advanced-stage ovarian cancer may be comparable to primary debulking surgery. Neoadjuvant chemotherapy followed by interval debulking surgery is an acceptable - if not preferable - therapeutic approach in advanced-staged ovarian cancer patients because it is associated with higher optimal debulking surgery, fewer complications, and non-inferior survival outcomes. The addition of bevacizumab to chemotherapy contributes significantly to survival outcomes without causing side effects that outbalance the benefits. Patients with recurrent high-grade serous ovarian cancer and a germline or breast cancer mutation should be offered maintenance olaparib after a response to platinum-based chemotherapy. Finally, the role of hyperthermic intraperitoneal chemotherapy in the context of neoadjuvant chemotherapy remains unjustified.

BIOPSAR study: ultrasound-guided pre-operative biopsy to assess histology of sarcoma-suspicious uterine tumors: a new study protocol.

BACKGROUND: The pre-operative differential diagnosis between a uterine leiomyoma and a sarcoma can be a challenge. Available diagnostic tools have difficulty distinguishing between the two pathologies. PRIMARY OBJECTIVE: Τo evaluate the possibility of a pre-operative pathological diagnosis of atypical uterine muscle tumors by vaginal ultrasound-guided biopsy (VUGB). STUDY HYPOTHESIS: Diagnostic performance of ultrasound-guided biopsy will be capable of differentiating a leiomyoma from a sarcoma with a sensitivity of >90%. TRIAL DESIGN: A prospective multi-center interventional study will be performed at 10 tertiary French centers. Vaginal ultrasound Doppler examination and pelvic magnetic resonance imaging will be performed before surgery. VUGB will then be performed by a specialist radiologist. The biopsy will be obtained by performing transvaginal ultrasound under local anesthesia with lidocaine using a 16G needle. At least 4-5 specimens will be obtained in order to provide a histopathological diagnosis. All patients included in the study will be operated by laparotomy. All patients included in the study will be followed up for the subsequent 3 years according to their pathological results. MAJOR INCLUSION/EXCLUSION CRITERIA: All patients >35 years old diagnosed with a suspicious uterine tumor will be included. PRIMARY ENDPOINT: Sensitivity of VUGB on pathological diagnosis. SAMPLE SIZE: Considering a sensitivity of 90% (H0) as acceptable and a sensitivity of 95% (H1) as excellent, a sample size of 250 evaluable patients will be necessary to achieve 80% statistical power with a 5% type 1 statistical error. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual will be completed in December 2024 with results presented in December 2029. TRIAL REGISTRATION: Institutional Review Board (Ethic Committee of Paris Ile de France 6) no 2018-A02343-52.

PatchSearch: a web server for off-target protein identification.

The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target. The PatchSearch web server provides an automated workflow that allows users to identify structurally conserved binding sites at the protein surfaces in a set of user-supplied protein structures. Thus, this web server may help to detect potential off-target protein. It takes as input a protein complexed with a ligand and identifies within user-defined or predefined collections of protein structures, those having a binding site compatible with this ligand in terms of geometry and physicochemical properties. It is based on a non-sequential local alignment of the patch over the entire protein surface. Then the PatchSearch web server proposes a ligand binding mode for the potential off-target, as well as an estimated affinity calculated by the Vinardo scoring function. This novel tool is able to efficiently detects potential interactions of ligands with distant off-target proteins. Furthermore, by facilitating the discovery of unexpected off-targets, PatchSearch could contribute to the repurposing of existing drugs. The server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/PatchSearch.

A multivariate analysis of the prognostic impact of tumor burden, surgical timing and complexity after complete cytoreduction for advanced ovarian cancer.

OBJECTIVE: To assess the survival benefit of primary debulking surgery (PDS) compared to interval debulking surgery (IDS) after complete cytoreduction (CC-0) or cytoreduction to minimal residual disease (CC-1) in advanced ovarian cancer. Secondary objective was to evaluate the effect of tumor load and surgical complexity on patients' survival. METHODS: A retrospective multicentric study was designed, including patients with IIIC-IV FIGO stage ovarian cancer who underwent PDS or IDS with CC-0 or CC-1 from January 2008 to December 2015 in four high-volume institutions. Patients were classified in three groups: PDS, IDS after 3-4 cycles of neoadjuvant chemotherapy (NACT), and IDS after 6 cycles. Disease-free survival (DFS) and overall survival (OS) were estimated. Univariable and multivariable analyses were conducted. RESULTS: We included 549 patients, 175 (31.9%) underwent PDS, 224 (40.8%) had IDS after 3-4 cycles of NACT, and 150 (27.3%) underwent IDS after 6 cycles. Median DFS in PDS, IDS at 3-4 cycles and IDS at 6 cycles were 23.0 months (95%CI = [20.0-29.3]), 18.0 months (95%CI = [15.9-20.0]) and 17.1 months (95%CI = [15.0-20.9]), respectively; p < .001. Median OS were 84.0 months (95%CI = [68.3-111.0]), 50.7 months (95%CI = [44.6-59.5]) and 47.5 months (95%CI = [39.3-52.9]), respectively; p < .001. In multivariable analysis, high peritoneal cancer index score and NACT were negatively associated to DFS and OS. Surgical complexity and CC-1 were negatively associated to DFS. CONCLUSION: PDS offered a survival gain of almost three years compared to IDS in patients with minimal or no residual disease after surgery. PDS should remain the standard of care for advanced ovarian cancer.

Fertility and prognosis of borderline ovarian tumor after conservative management: Results of the multicentric OPTIBOT study by the GINECO & TMRG group.

OBJECTIVES: Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network. METHODS: All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth. RESULTS: Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility. CONCLUSION: Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.

Frozen section examination of sentinel lymph nodes can be used as a decisional tool in the surgical management of early cervical cancer.

INTRODUCTION: Sentinel lymph node (SLN) detection has been shown to be accurate in detecting lymph node involvement in early-stage cervical cancer. The objective of this study was to evaluate the accuracy of frozen section examination in the assessment of SLN status, with the aim of adequately driving the intra-operative decision. METHODS: We designed a retrospective study including patients from two comprehensive cancer centers between January 2001 and December 2018 with early-stage cervical cancer (IA1-IB2 according to International Federation of Gynecology and Obstetrics (FIGO) 2018) undergoing SLN dissection. The SLN procedure was performed using a cervical injection with technetium-99m combined with blue dye or indocyanine green in most cases. RESULTS: A total of 176 patients fulfilled inclusion criteria. Bilateral mapping was detected in 153 (86.7%) of them. Nineteen of these patients (12.4%) had SLN involvement: 13 with macrometastases, three with micrometastases and three with isolated tumor cells (ITC). Macrometastatic disease was missed on frozen section in 3/13 FIGO 2018 stage IIIC patients. The three patients with ITC were also missed by frozen section examination.Considering only macrometastases as lymph node involvement, frozen section sensitivity was 76.9% (95% CI 49.7 to 91.8) and negative predictive value (NPV) was 97.9% (95% CI 94.0 to 99.3) in patients with bilateral detection. Including micrometastases, sensitivity was 81.2% (95% CI 57.0 to 93.4) and NPV remained at 97.9% (95% CI 93.9 to 99.3). CONCLUSIONS: With a prevalence of final-stage IIIC in patients with pre-operative early-stage cervical cancer of the order of 10% in this series, the NPV of frozen section examination of SLN is very high, with an inferior limit of the CI superior to 94%. Diagnostic accuracy remains acceptable even if micrometastases are considered. The impact of missed ITC has not been established. Frozen section examination can be incorporated in the intra-operative decision algorithm.

Comparison of postoperative complications and quality of life between patients undergoing continent versus non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.

BACKGROUND: Pelvic exenteration and its reconstructive techniques have been associated with high postoperative morbidity and a negative impact on patient quality of life. The aim of our study was to compare postoperative complications and quality of life in patients undergoing continent compared with non-continent urinary diversion after pelvic exenteration for gynecologic malignancies. METHODS: We designed a multicenter study of patients from 10 centers who underwent an anterior or total pelvic exenteration with urinary reconstruction for histologically confirmed persistent or recurrent gynecologic malignancy after previous treatment with radiotherapy. From January 2005 to September 2008, we included patients retrospectively, and from September 2008 to May 2009, patients were included prospectively which allowed collection of quality of life data. Demographic, surgical, and follow-up data were analyzed. Postoperative complications were classified according to the Clavien-Dindo classification. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 (V.3.0) and EORTC-QLQ-OV28 quality of life questionnaires. We compared patients who underwent a continent urinary diversion with those who underwent a non-continent reconstruction. RESULTS: We included 148 patients, 92 retrospectively and 56 prospectively. Among them, 77.4% had recurrent disease and 22.6% persistent disease after the primary treatment. In 70 patients, a urinary continent diversion was performed, and 78 patients underwent a non-continent diversion. Median age of the continent and incontinent groups was 53.5 (range 33-78) years and 57 (26-79) years, respectively. There were no significant differences between the continent and non-continent groups in median length of hospitalization (28.5 vs 26 days, P=0.19), postoperative grade III-IV complications (42.9% vs 42.3%, P=0.95), complications needing surgical (27.9% vs 34.6%, P=0.39) or radiological (14.7% vs 12.8%, P=0.74) intervention, and complication type (digestive (23.2% vs 16.7%, P=0.32) and urinary (15.9% vs 16.7%, P=0.91)). There were no significant differences between the groups in global health, global quality of life, and body image perception scores 1 year after surgery. CONCLUSION: Continent and incontinent urinary reconstructions are equivalent in terms of postoperative complications and quality of life scores.

Combined pelvic and para-aortic is superior to only pelvic lymphadenectomy in intermediate and high-risk endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis is a principal prognostic factor for the treatment of endometrial cancer. Added value of para-aortic lymphadenectomy to only pelvic lymphadenectomy for intermediate/high-risk endometrial cancer patients remains controversial. OBJECTIVE: A systematic review and meta-analysis was performed to assess the impact of combined pelvic and para-aortic lymph node dissection (PPALND) compared to only pelvic lymph node dissection (PLND) on survival outcomes of intermediate and/or high-risk patients. STUDY DESIGN: The systematic review and meta-analysis adhered to the PRISMA guidelines for meta-analyses of interventional studies. Pubmed, Scopus, EMBASE and Cochrane were searched up to April 20, 2018. Included studies were those comparing high-risk endometrial cancer patients that had performed pelvic and para-aortic lymph node dissection (PPALND) vs. only pelvic lymph node dissection (PLND) apart from standard procedure (total hysterectomy with bilateral salpingo-oophorectomy, TAHBSO). Primary outcomes of the study were overall survival and disease-free survival rates. Methodological quality of the included studies was assessed using the ROBINS-I tool. Overall quality of the evidence for the primary and secondary outcomes was evaluated as per GRADE guideline using the GRADE pro GD tool. RESULTS: There were 13 studies identified with 7349 patients included. All studies were retrospective observational as no RCTs or prospective studies adhering to inclusion criteria were retrieved. Combined pelvic and para-aortic lymphadenectomy was associated with 46% decreased risk for death (HR 0.54, 95% CI 0.35-0.83, I2 = 62.1%) and 49% decreased risk for recurrence (HR 0.51, 95% CI 0.28-0.93). It was also associated with increased 5-year OS rate (RR 1.13, 95% CI 1.04-0.24, I2 = 57.3%) and increased 5-year DFS rate (RR 1.23, 95% CI 1.14-1.31, I2 = 85.5) compared with only pelvic lymphadenectomy. CONCLUSION: Combined pelvic and para-aortic lymphadenectomy is associated with improved survival outcomes compared with only pelvic lymphadenectomy in women with intermediate/high-risk endometrial cancers. Further prospective studies should be performed.

GREB1-CTNNB1 fusion transcript detected by RNA-sequencing in a uterine tumor resembling ovarian sex cord tumor (UTROSCT): A novel CTNNB1 rearrangement.

Mutations of CTNNB1 have been implicated in tumorigenesis in many organs. However, tumors harboring a CTNNB1 translocation are extremely rare and this translocation has never been reported in a uterine mesenchymal neoplasm. We report a novel translocation t(2;3)(p25;p22) involving the GREB1 (intron 8) and CTNNB1 (exon 3) in a uterine tumor resembling ovarian sex cord tumor (UTROSCT), which exhibited extrauterine metastasis. The translocation detected by RNA-sequencing was validated by RT-PCR, and resulted in nuclear expression of ß-catenin. Juxtapositioning with GREB1, which is overexpressed in response to estrogens, resulted in overexpression of a truncated and hypophosphorylated nuclear ß-catenin in the primary and recurrent tumors. This accumulation of nuclear ß-catenin results in a constitutive activation of the Wnt/ß-catenin signaling pathway with a major oncogenic effect. The CTNNB1 gene fusion, promoted by an estrogen-responsive gene (GREB1), could be a potential driver of tumorigenesis in this case and a therapeutic target with adapted inhibitors. RT-PCR and immunohistochemistry performed on 11 additional UTROSCTs showed no CTNNB1 fusion transcript or nuclear ß-catenin immunoreactivity.

Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.