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Purpose: There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here., Methods: In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design)., Results: Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3)., Conclusions: Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed., Competing Interests: Declaration of Competing Interest No conflicts of interest to dissclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Using a transcriptional approach on tissue samples, we sought to identify predictive biomarkers of post molar malignant transformation, and of choriocarcinoma chemosensitivity to mono- (methotrexate or actinomycin D) or polychemotherapy [EMA(Etoposide, Methotrexate, Actinomycin D)-CO(Cyclophosphamide, Vincristine) and EMA-EP(Etoposide, Cisplatine)] regimens., Methods: We studied the expression of a 760-gene panel (PanCancer Pathway) related to oncogenesis and immune tolerance in tissue samples of complete hydatidiform moles and gestational choriocarcinoma., Results: We did not identify any differentially expressed gene between moles with post molar malignant transformation in choriocarcinoma (n = 14) and moles with remission (n = 20). In monochemoresistant choriocarcinoma (n = 34), four genes (HLA-G, COL27A1, IL1R2 and GLI3) had a significantly reduced expression and one (THEM4) had an increased expression [FDR (false discovery rate) adjusted p-value ≤ 0.05] when compared to monochemosensitive choriocarcinoma (n = 9). The proportion of trophoblast cells and the intensity of immunohistochemical HLA-G expression were reduced in monochemoresistant choriocarcinoma (p < 0.05). In polychemoresistant choriocarcinoma (n = 20) we did not identify differentially expressed genes with an FDR adjusted p-value ≤ 0.05 when compared to polychemosensitive choriocarcinoma (n = 15). Gene pathway analysis revealed a predicted activation of IFN ᵞ in monochemoresistant choriocarcinoma and inhibited IL2 and TNF in polychemoresistant choriocarcinoma. The main biological functions predicted to be altered in chemoresistant choriocarcinoma were related to immunological homeostasis and leukopoiesis., Conclusion: HLA-G is a strong candidate gene to predict choriocarcinoma resistance to monochemotherapy and that further studies are required to implement its routine quantification in the decision process for the management of gestational choriocarcinoma., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Gastric-type endocervical carcinoma is a rare entity of carcinoma of the cervix. In contrast to the intestinal type, the gastric type is not related to Human Papilloma Virus (HPV) infection and has been reported to be much more aggressive than the usual type. Oncogenic pathways involved in this poor-prognosis phenotype are largely unexplored., Methods: We compared activation of the main signaling pathways involved in cancer progression between the intestinal- (n = 5), gastric- (n = 6) and usual-type (n = 6) adenocarcinomas of the cervix using a targeted transcriptomic approach (expression of 770 genes) on FFPE samples., Results: We identified a gene-expression signature composed of 11 genes that allows the classification of these endocervical carcinoma as three distinct molecular entities. There were similarities between mucinous endocervical carcinomas (gastric and intestinal types) despite difference in pathogenesis related to HPV infection. Among HPV-related endocervical carcinoma, the intestinal type could be molecularly distinguished from the usual type by high expression of EIF2AK3 and low expression of PPFIBP2 genes, supporting its classification as a distinct entity. Overexpression of TAL1 and S1PR1 genes were characteristic of the gastric type. The usual type was characterized by high expression of occludin and VAV3 genes. Tight junction disruptions might play an essential role in the metastatic potential of mucinous endocervical carcinoma with concomitant loss of OCLN and claudin 4 proteins. An overexpression of NTRK1 transcript was observed in mucinous endocervical carcinomas when compared to the usual type., Conclusions: This transcriptomic study identified a signature that supports the classification of endocervical carcinomas as three distinct entities: usual-, intestinal- and gastric-type. It also points out to disruption of tight junctions as a potential mechanism of metastatic dissemination of these rare tumors., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT., Methods: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS)., Results: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively)., Conclusions: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking., Objectives: To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients., Study Design: Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy., Results: First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8-90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5-6 (exact OR 8.961, 95%CI 1.60-64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78-138.13) were associated with the risk of requiring salvage chemotherapy., Conclusion: Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: We report the long-term results of the SENTI-ENDO study evaluating the impact of sentinel lymph node (SLN) biopsy on management and survival in patients with early stages of endometrial cancer (EC)., Methods: Patients with FIGO stage I-II EC underwent pelvic SLN biopsy after cervical dual injection (technetium and patent blue) and systematic pelvic node dissection. This study is a secondary endpoint reporting the long-term recurrence free survival (RFS) and the impact of the SLN procedure on adjuvant therapies., Results: The median follow-up was 50 months (range: 3-77 months). Eighteen of the 125 patients (14.4%) experienced a recurrence. The 50-month recurrence-free survival (RFS) was 84.7% with no difference between patients with and without detected SLN (p = 0.09). Among patients with detected SLN (111), no difference in RFS was observed between those with and without positive SLN (p = 0.5). In the whole population, adjuvant therapy was performed in low-, intermediate- and high-risk groups in 31 of 64 patients (48.4%), 28 of 37 patients (75.7%) and 14 of 17 patients (82.3%), respectively (p = 0.0001). For the 111 patients with detected SLN, EBRT was performed in 27 of the 89 with negative SLN and in 11 of the 14 with positive SLN (p = 0.001). Chemotherapy was performed more frequently in patients with positive SLN (6/12, 50%) than in patients with negative SLN (7/56, 12.5%) (p = 0.009)., Conclusions: Our results support the impact of SLN biopsy on surgical management and indications for adjuvant therapies. Further studies are required to assess the clinical impact of the SLN biopsy in early stage EC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The risk of gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) is well known. However, the risk of GTN after normalisation of hCG in HM is poorly reported. The aim of this study was to evaluate the risk of GTN after normalisation of hCG according to HM types., Methods: This prospective cohort study carried out between 2000 and 2010 used the database of the French Trophoblastic Disease Centre (FTDC). A total of 2008 registered patients with ascertained types of HM were analysed. Cases of GTN occurring after normalisation of hCG were analysed., Results: A GTN developed in 239 out of 1980 HMs (12.1%) and 6 out of these 239 post-molar GTN (2.5%) were diagnosed after normalisation of hCG. The risk of GTN after normalisation of hCG was 0.34% (6/1747) following a HM, 0% (0/593) after a partial HM (PHM), 0.36% (4/1122) after a complete HM (CHM), and 9.5% (2/21) after a multiple pregnancy with HM., Conclusions: The risk of post-molar GTN justifies hCG monitoring in all women with HM. However, after normalisation of hCG, monitoring of PHM can be stopped safely while it should be maintained for CHM and more importantly for multiple pregnancies with HM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical and histological pitfalls in the diagnosis of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT), two rare types of gestational trophoblastic neoplasia (GTN)., Methods: This retrospective, observational, study was carried out in the French Trophoblastic Disease Reference Centre, Lyon, between 2000 and 2011. Due to the many similarities in the diagnosis, treatment and prognosis of PSTT and ETT, these two types of tumour were investigated together. Twenty-two patients with PSTT or ETT were analysed., Results: The clinical presentation of these two types of tumour was irregular vaginal bleeding (55%) or amenorrhoea (27%), with a median plasma hCG level of 205IU/L. Seven of the 22 patients (32%) were initially misdiagnosed as an ectopic pregnancy. Median age at presentation was 35-years, with a median interval of 12months between the antecedent pregnancy and diagnosis of PSTT or ETT. The initial histological diagnosis was incorrect in 7/18 (39%) patients; there was a major disagreement with the referral pathologist in five of these seven patients (28%)., Conclusions: PSTT and ETT are the most difficult types of GTN to diagnose clinically and histologically. An incorrect diagnosis can lead to significant therapeutic deviations from the recommended first-line treatment, namely hysterectomy. Clinical and histological expertise is essential to avoid the pitfalls in the diagnosis of PSTT and ETT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Gestational trophoblastic diseases (GTD), a group of rare placenta disorders, have a varying potential for invasion, either local, or remote under the form of metastases, and are definitely cured by chemotherapy in 85 to 99% of cases. Single-agent methotrexate is the usual primary treatment for women with low-risk trophoblastic tumors (TT), yet various regimens are currently used worldwide. We reviewed these regimens and the available evidence for evaluating their respective efficacy and tolerance., Methods: We performed an exhaustive literature search and applied the French agency for evaluation in healthcare (HAS) methodology for critical appraisal and level of evidence. We summarised the protocols used in the selected studies and their respective results regarding efficacy and toxicity., Results: We selected 18 original studies on the efficacy and tolerance of methotrexate used alone or in association with folinic acid for the treatment of nonmetastatic or low-risk metastatic trophoblastic tumors. Among these 18 studies, 15 were retrospective series, 3 were prospective series without any control group, and none were controlled clinical trial. We identified four main chemotherapy regimens and two very different strategies for repeating the treatment courses. It was not possible to perform a meta-analysis due to the lack of controlled clinical trials. Because all studies were observational with no control group and methods were heterogeneous for scoring women, setting criteria for starting therapy, defining remission, and collecting information on adverse events, we found no objective element allowing recommending one protocol rather than another., Conclusion: Objective comparison should be addressed in the scope of comparative trials organised at the national or even international level. However their feasibility is highly problematic for rare diseases such as GTD. International collaborative works should be encouraged to reduce practice variations and allow a better comparability between strategies.

Background: Invasive carcinoma of the cervix above stage IA1 is usually treated by radical hysterectomy and/or radiotherapy, leading to definitive sterility., Case Report: We report the case of a young patient with stage IB1 carcinoma of the cervix treated in June 1995 by radical trachelectomy (according to the technique described by Dargent) and adjuvant brachy + teletherapy. A hormonal replacement of "menopause" was prescribed. One year later, she became pregnant and at 27 weeks gestation gave birth to a healthy child by cesarean section., Conclusion: Radical trachelectomy is one of the most recent therapeutic steps forward in the treatment of early stage invasive cervical carcinoma, which can surely be treated in some cases preserving child-bearing potential., (Copyright 1999 Academic Press.)