Pierre-Adrien Bolze

Comparison of survival outcomes between laparoscopic and abdominal radical hysterectomy for early-stage cervical cancer: A French multicentric study

A recent randomized controlled trial has reconsidered the use of laparoscopy for treating patients with early-stage cervical cancer with radical hysterectomy (RH). We aimed to evaluate if surgical approach had an impact on surgical and oncological outcomes in these patients in a French setting. Data of 1706 patients with cervical cancer treated between 1996 and 2017 were extracted from maintained databases of 9 French University hospitals. Patients, with FIGO stage IA2 to IIB tumors, treated by radical hysterectomy were selected for further analysis. A propensity score matching was used with a ratio of 2:1 in favor of laparoscopic approach was used. The Kaplan Meier method was used to estimate the survival distribution. 34 patients treated with laparotomy were matched with 61 patients treated by minimally invasive surgery (MIS). There was no difference regarding overall survival (91 % vs 81 %, p > 0.05) or disease-free survival (82 % vs 78 %, p > 0.05). There was no difference regarding surgical outcomes with no excess of postoperative complication in patients with MIS. Hospital stay was significantly longer in patients operated on laparotomy. In our study, there was no evidence of a difference in survival between minimally invasive surgery and laparotomy in patients treated with radical hysterectomy for early-stage cervical cancer.

Comparison of retroperitoneal and transperitoneal surgical routes in laparoscopic nodal staging for locally advanced cervical cancers (FIGO IB3-IVA)

This study compares morbidity and mortality associated with retroperitoneal and transperitoneal para-aortic lymphadenectomy (PAAL) for pretherapeutic nodal staging of locally advanced cervical cancers (FIGO IB3-IVA). Pre-, per- and postoperative data of patients treated for locally advanced stage cervical cancer between 1999 and 2018 in 12 French referral centers (FRANCOGYN Study Group) were retrospectively collected. The study was conducted using a sample of 448 patients, of whom 223 (49,8%) underwent retroperitoneal (group 1) and 225 (50,2%) had transperitoneal PAAL (group 2). No differences were noted concerning clinical and histological characteristics between the two groups. Among these 448 patients, 23 (5,1%) had an intraoperative complication (9 (2,0%) in group 1 and 14 (3,1%) in group 2, p = 0.28) and 47 (10,5%) had a postoperative complication (22 (4,9%) in group 1 and 25 (5,6%) in group 2, p = 0.44), only one of which required revision surgery but the patient died. The length of hospital stay was significantly shorter in group 1 than in group 2 (3.97 versus 4.88 days, p < 0.001). There was no significant difference in mortality between the two groups; 34 of 223 patients in group 1 (15.3%) and 40 of 225 patients in group 2 (15.6%) died (HR = 0.968, 95% CI [0.591-1.585]). There was no significant difference in recurrence-free or overall survival between the two groups. Retroperitoneal PAAL appears as a valuable and safety surgical route for nodal staging in locally advanced cervical cancer compared with standard transperitoneal PAAL.

Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.

FcγR3A polymorphism influences natural killer cell activation and response to anti-PD-L1 (avelumab) in gestational trophoblastic neoplasia

Low-risk gestational trophoblastic neoplasia are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line monochemotherapy or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity mediated by FcγR3A-expressing natural killer cells. This translational study aimed at testing whether antibody-dependent cell-mediated cytotoxicity is involved in avelumab efficacy on gestational trophoblastic neoplasia and if FcγR3A affinity polymorphism could help predicting the response to avelumab in gestational trophoblastic neoplasia. The expression of PD-L1 by the tumor and the phenotype of natural killer cells infiltrating gestational trophoblastic neoplasia were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human natural killer cells in the presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of natural killer cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were re-analyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab. We confirmed that FcγR3A+ natural killer cells infiltrated PD-L1-expressing gestational trophoblastic neoplasia. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced natural killer cell activation, which promoted the destruction of JEG-3 cells. Natural killer cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of antibody-dependent cell-mediated cytotoxicity, we demonstrated that high-affinity FcγR3A polymorphism on natural killer cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high-affinity FcγR3A polymorphism had better clinical response to avelumab. Our work demonstrates that antibody-dependent cell-mediated cytotoxicity contributes to the therapeutic effect of avelumab in gestational trophoblastic neoplasia and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant gestational trophoblastic neoplasia who are most likely to respond to avelumab.

Impact of age on tumor size in vulvar cancer: A multicenter study by the Francogyn group

Vulvar cancer is a rare pathology affecting mainly elderly women. This study aims to evaluate the impact of age on tumor size in vulvar cancer. This was a multicenter retrospective observational study carried out between January 1, 1998, and December 31, 2020, in patients operated on for vulvar cancer. Univariate analysis was performed according to patients' age ≥ or <65 years. Factors associated with tumor size found to be significant according to age were then included in a multiple linear regression model. Of the 382 patients included, there were 133 patients aged <65 years and 249 ≥ 65 years. Radical total vulvectomy surgeries were more frequently performed in women ≥65 years (n = 72 (28.9 %) versus n = 20 (15 %); p = 0.004). The median histological tumor size and interquartile range was 20 mm [13-29] in the <65 years and 30 mm [15-42] in patients ≥65 years (p = 0.001). Multiple linear regression showed that age ≥65 years had a regression coefficient of 7.15 95 % CI [2.32; 11.99] (p = 0.004), constituting a risk factor for larger histological tumour size. Patients aged ≥65 years old had a higher early complication rate (n = 150 (62 %) versus n = 56 (42.7 %), p = 0.001). They also had a greater risk of recurrence (HR = 1.89 (95%CI (1.24-2.89)), p = 0.003) with a worse overall survival (HR = 5.64 (95%CI (1.70-18.68)), p = 0.005). Age is a risk factor for larger tumor size, leading to more radical surgery and a greater risk of complications in already fragile patients, with a greater risk of recurrence and an impact on overall survival.

Chemotherapy is not needed when complete evacuation of gestational choriocarcinoma leads to hCG normalization

The standard treatment for gestational choriocarcinoma is chemotherapy. To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy. A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization. Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases. This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients.

Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors

To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.