Initial experience with vNOTES hysterectomy for benign conditions in a French university hospital.

Background: Natural orifice transluminal endoscopic surgery by the vaginal route (vNOTES) is a new approach to performing hysterectomy. Clinical outcomes must be evaluated in centres that have started performing this technique. Objectives: To compare operative outcomes between vNOTES hysterectomy and laparoscopic hysterectomy during the introduction of the vNOTES approach in a teaching hospital. Material and Methods: A retrospective study was conducted from November 2019 to May 2021 at a French academic hospital in Marseille. The included patients underwent total hysterectomy for benign indications by vNOTES or conventional laparoscopy. Main outcome measures: Operative time, uterus weight, intraoperative complications, and postoperative complications according to the Clavien-Dindo classification. Results: Eighty-six patients underwent hysterectomy according to the selected criteria: 36 procedures were performed by vNOTES and 50 by laparoscopy. The mean operative time was shorter in the vNOTES group than in the laparoscopy group [116 min versus 149 min; p=0.003]. The mean uterus weight was not different between the vNOTES group and the laparoscopy group (238g versus 281g; p=0.572). Laparo-conversion occurred in one case in the vNOTES group (2.7%) and three cases in the laparoscopy group (3.4%). One Grade III postoperative complication occurred in the laparoscopy group, and no severe complication occurred in the vNOTES group. Conclusion: Operative outcomes of the vNOTES hysterectomy were favourable and support good feasibility without additional morbidity compared to laparoscopy. What is new?: During the introduction period of the vNOTES hysterectomy technique in a teaching hospital, reassuring operative outcomes and a low rate of complications were observed.

Ecdysteroid metabolism in mammals: The fate of ingested 20-hydroxyecdysone in mice and rats.

Phytoecdysteroids are molecules derived from sterol metabolism and found in many plants. They display a wide array of pharmacological effects on mammals (e.g. anabolic, anti-diabetic). Although these effects have been long established, the molecular targets involved remain to be identified. Like endogenous steroid hormones and bile acids, which are biochemically related, ingested or injected phytoecdysteroids undergo a set of reactions in mammals leading to the formation of numerous metabolites, only some of which have been so far identified, and it is presently unknown whether they represent active metabolites or inactivation products. In the large intestine, ecdysteroids undergo efficient 14-dehydroxylation. Other changes (reductions, epimerization, side-chain cleavage) are also observed, but whether these occur in the liver and/or large intestine is not known. The purpose of this study was to investigate the pharmacokinetics of 20-hydroxyecdysone (20E), the most common phytoecdysteroid, when administered to mice and rats, using, when required, tritium-labelled molecules to permit metabolic tracking. Bioavailability, the distribution of radioactivity and the kinetics of formation of metabolites were followed for 24-48 hours after ingestion and qualitative and quantitative analyses of circulating and excreted compounds were performed. In mice, the digestive tract always contains the majority of the ingested 20E. Within 30 min after ingestion, 20E reaches the large intestine, where microorganisms firstly remove the 14-hydroxyl group and reduce the 6-one. Then a very complex set of metabolites (not all of which have yet been identified) appears, which correspond to poststerone derivatives formed in the liver. We have observed that these compounds (like bile acids) undergo an entero-hepatic cycle, involving glucuronide conjugation in the liver and subsequent deconjugation in the intestine. Despite the very short half-life of ecdysteroids in mammals, this entero-hepatic cycle helps to maintain their plasma levels at values which, albeit low (≤0.2 µM), would be sufficient to evoke several pharmacological effects. Similar 20E metabolites were observed in mice and rats; they include in particular 14-deoxy-20E, poststerone and 14-deoxypoststerone and their diverse reduction products; the major products of this metabolism have been unambiguously identified. The major sites of metabolism of exogenous ecdysteroids in mammals are the large intestine and the liver. The entero-hepatic cycle contributes to the metabolism and to maintaining a low, but pharmacologically significant, concentration of ecdysteroids in the blood for ca. 24 h after ingestion. These data, together with parallel in vitro experiments provide a basis for the identification of 20E metabolite(s) possibly involved in the physiological effects associated with ecdysteroids in mammals.

Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

[Feasibility of outpatient laparoscopic sacrocolpopexy surgery: A pilot study]. / Étude pilote de faisabilité de la promontofixation cœlioscopique en ambulatoire.

OBJECTIVE: To evaluate the feasibility of outpatient laparoscopic sacrocolpopexy surgery. METHODS: A prospective analysis was carried out in one center from May 2014 to July 2015. The main outcome was the success of day care, meaning no hospitalization, consultation to a doctor or emergency during the first 48h following the surgery. Patients requiring laparoscopic sacrocolpopexy with eligibility for day care were included. The patients were not included if they didn't match to the administrative or medical criteria of ambulatory, or if they refused ambulatory surgery. The postoperative consultation was 1 month after surgery, the satisfaction was assessed by phone call two months after surgery. RESULTS: We included 14 patients during the study. One patient stayed the night (7.1%). The median operative time of the surgery was 95minutes (70-168minutes), no complication occurred. Ten patients of 13 (76.9%) were very satisfied or satisfied of day care. CONCLUSION: With 71% of satisfaction and only one patient who stayed the night, outpatient laparoscopic sacrocolpopexy surgery seems to be feasible. LEVEL OF EVIDENCE: 4.

[Feasability and morbidity of apical and anterior mesh repair, a multicenter cohort study]. / Suspension utérovaginale prothétique par fixation obturatrice et sacrospinofixation bilatérale, étude multicentrique.

OBJECTIVE: To assess safety anatomic results, satisfaction patient and to report short-term results of a new surgical approach for a combined treatment of pelvic organ prolapse (POP) of anterior and medium compartments. MATERIAL AND METHODS: A longitudinal case series of 83 consecutive patients operated between January 2012 and April 2014 in four tertiary centers by 8 surgeons. Potential complications have been reported. The satisfaction of patients was conducted at 6 weeks post-procedure. The anatomical evaluation was conducted at 6 weeks and 6 months post-procedure. Anatomic success was defined as prolapse stage<1 (POPQ) for both anterior and apical compartment. RESULTS: Mean age was 69.2±8.6 years. There were two intraoperative complications: a bladder injury and an ureteral injury. Postoperative complications were 14/83 (16.8%) transient urinary retentions. Seventy-three patients out of 83 (87.9%) were available for anatomic evaluation at 6 months. Anatomical success at 6 months for both anterior and apical compartments was 68/73 (93.1%). Patient satisfaction rate at 6 months was 79/83 (95.1%). Four subjects/73 (5.5%) experienced mesh exposure treated conservatively. CONCLUSION: In the current series, uterovaginal suspension anterior using a mesh Nuvia® was associated with correct anatomical results and a good satisfaction of patients. This technique seems reproducible and associated with few complications. Prospective, comparative and long-term data are required to confirm these results. LEVEL OF EVIDENCE: 4.

[Indications for methotrexate in gynecology outside the first-line treatment of ectopic tubal pregnancies]. / Indications du méthotrexate en gynécologie en dehors du traitement de première intention des grossesses extra-utérines tubaires.

The objective of this work is to discuss the indications for methotrexate in gynecology outside the first-line treatment of tubal ectopic pregnancy. In tubal ectopic pregnancy, the prophylactic use of systemic methotrexate can be discussed when performing laparoscopic salpingotomy. In case of failure of salpingotomy, administration seems justified especially if it avoids re-intervention. The combination of methotrexate with other therapies such as mifepristone, potassium chloride or gefitinib is not recommended in the treatment of ectopic pregnancy. For non-tubal ectopic pregnancy, the intramuscular or local administration of methotrexate is an acceptable treatment for uncomplicated interstitial pregnancies. For uncomplicated cervical or cesarean scar pregnancies, the local administration of methotrexate should be considered as a first-line treatment. For ovarian pregnancies, methotrexate should not be a first-line treatment, surgical treatment remains the standard. Asymptomatic women presenting with a pregnancy of unknown location and plateauing serum hCG concentration<2000 UI/L can be managed expectantly: it is recommended to take an additional quantitative hCG serum level after 48 hours. Thus, methotrexate is not recommended in the first intention. Other gynecological indications were discussed: methotrexate is not recommended in the management of first-trimester miscarriages or in the management of placenta accreta.

[Evidence-based evaluation and expertise of methotrexate off label use in gynaecology and obstetrics: work of the CNGOF]. / États des lieux et expertise de l'usage hors AMM du méthotrexate en gynécologie-obstétrique: travail du CNGOF.

In the absence of contraindication, methotrexate by intramuscular unique injection of 1mg/kg or 50mg/m(2) is the medical treatment recommended for tubal ectopic pregnancy (EP; LE1). It can be renewed once, at the same dose, according to hCG rates decrease. The pretherapeutic biological assessment contains blood cells numeration, renal and hepatic function. Methotrexate therapy constitutes an alternative conservative treatment to laparoscopic salpingotomy for non-complicated tubal EP (LE1) with hCG level <5000 UI/L (LE2). When the rates of hCG are <1000 UI and or presented a spontaneous decreasing kinetics, the simple prospect (LE2) is preferred. It is recommended to use intramuscular methotrexate in case of surgical conservative treatment failure or more prematurely if the follow-up is not possible (LE3). Except in particular cases there is no indication to use methotrexate in local injection under sonographic control in usual tubal EP (LE2). The use of in situ injection methotrexate is an option to handle the cervical, interstitial or on caesareans scar pregnancies (LE2). In front of a persistent undetermined location pregnancy, after more than 10 days of survey, in an asymptomatic woman and/or at rate of hCG >2000 UI/L, the systematic treatment by methotrexate is an option. The methotrexate is not indicated for first trimester termination of pregnancy or miscarriage neither in placentas accreta nor in association with other treatments such myfegine or potassium.

[Influencing factors on surgical duration of ovarian cystectomy by single-port access]. / Facteurs influençant la durée opératoire de la kystectomie ovarienne par accès endoscopique unique.

OBJECTIVES: To evaluate the factors influencing the operative duration of ovarian cystectomy by single-port access (SPA). MATERIALS AND METHODS: Observational monocentric study from June 2010 to September 2012. Inclusive patients were patients with an indication of ovarian cystectomy may be done by laparoscopy. The procedures were performed by the SPA system LESS®. Factors evaluated were BMI of the patient, histological nature and size of the cyst. RESULTS: We performed 54 cystectomy in 49 patients. SPA surgery was successfully completed in 53 patients. The median operative time was statistically longer for endometriotic cysts than dermoid cysts or serous-mucinous cysts (P=0.003). Cases exceeding 60minutes were significantly higher in the endometriosis group (P=0.005). There wasn't correlation found between the BMI of the patient and operative time (P=0.5). The operating time wasn't increased according to the size of the cyst (P=0.9). CONCLUSION: Endometriotic cysts nature appears to be the only limiting factor of cystectomy by SPA. Further studies are needed to evaluate the factors that may limit the SPA actions.

[Comparative study of patients with placenta accreta with or without a history of cesarean section]. / Étude comparative des patientes présentant un placenta accreta avec ou sans antécédent de césarienne.

OBJECTIVE: To evaluate characteristics of placenta accreta (PA) in patients without previous cesarean section. MATERIAL AND METHODS: Retrospective cohort study from December 1993 to April 2010 in two departments of obstetrics in university hospitals, Marseille, France. Comparison of clinical characteristics, circumstances of diagnosis, maternal morbidity and treatment was performed between PA diagnosed in patients with (n=63) and without prior cesarean section (n=35). RESULTS: In group of patients without previous caesarean section, rate of placenta praevia, and antenatal diagnosis were lower (16/35 [46 %] vs. 44/63 [70 %], [P: 0.02]) and (4/35 [11 %] vs. 28/63 [44 %], [P<0.001]) and rate of pregnancies obtained by IVF was higher (5/35 [15 %] vs. 2/63 [3 %], [P=0.05]). In this group, no hysterectomy was performed but risk of uterus necrosis following embolization was increased (3/35 [8.6 %] patients vs. 0/63 patients [P: 0.02]). CONCLUSIONS: Patients without previous caesarean section have specific characteristics in terms of risk factor and of management.

[Interest of robot-assisted laparoscopy in the initial surgical training: Resident survey]. / Place du robot dans la formation chirurgicale initiale : enquête auprès des internes.

OBJECTIVE: This survey evaluated if residents felt a benefit to their participation in robot-assisted procedures and highlights the interest of robot in the initial surgical training. PATIENTS AND METHODS: A questionnaire was submitted to 33 residents participating as assistants in robot-assisted surgical procedures in our department and to seven residents of the Chapel Hill hospital, North Carolina, USA. Items rated their experience with the robot, their feeling during the surgical procedures and whether they thought they improved their technical skills. RESULTS: The majority of French residents felt passive during the procedures (97%) or bored (75%); most of them found an immediate interest to learn anatomy (72.7%) and surgical procedures (66.7%). Then, a minority of them reported an improvement of their knowledge in anatomy (39.4%), in surgical procedures (24.2%), and conventional laparoscopy (9.1%). Most of French residents are not willing to repeat the experience as an assistant (81.8%), whereas they showed great interest in practicing robot-assisted surgery later. The oldest residents benefited more than younger in learning anatomy and surgical procedures. US resident' ratings concerning the contribution of the robot in their training were generally more positive. They were all convinced they made progress in anatomy, as in surgical techniques and they all wanted to repeat such procedures. DISCUSSION AND CONCLUSION: This work demonstrates the pedagogical value of using the robot for teaching surgical procedures and anatomy. It also suggests the establishment of training programs dedicated to the learning of robot-assisted surgery in gynaecology, in parallel with training in conventional laparoscopy.

[An unexpected aetiology of massive haemoperitoneum during pregnancy]. / Une cause inattendue d'hémopéritoine en cours de grossesse.

We report the case of a 28-year-old woman who was diagnosed with massive hémoperitoneum while being 28 weeks pregnant. This para one woman had no previous history of endometriosis. During emergency caesarean section, she was diagnosed with superficial uterine rupture due to the spontaneous tearing of a sigmoid colon endometriotic lesion that was adherent to the posterior wall of the uterus. Endometriotic lesion is an exceptional aetiology of spontaneous hemoperitoneum during pregnancy and is usually due to the rupture of uterine vessel. To our knowledge, spontaneous rupture of a colon lesion adherent to the posterior surface of the uterus has not yet been reported.