[Pregnancy after intrauterine insemination following hysterosalpingo-foam-sonography or hysterosalpingography]. / Grossesse par insémination intra-utérine après hystérosalpingo-foam-sonographie ou hystérosalpingographie.

OBJECTIVE: To compare clinical pregnancy rates following intrauterine insemination performed after hysterosalpingography (HSG) or hysterosalpingo-foam-sonography (HyFoSy). MATERIAL AND METHODS: This is a retrospective study including 242 intrauterine insemination (IUI) performed between 2015 and 2020 at the fertility center of the Reunion Island. Among these inseminations, 121 with previous HSG and 121 with previous HyFoSy were matched. The main outcome of interest was clinical pregnancy rate. Secondary outcomes were birth rate and time to pregnancy after tubal patency test. RESULTS: The pregnancy rate after insemination was 9.9% for the HSG group and 11.6% for the HyFoSy group, with no statistically significant difference between the groups (P=0.66). The live birth rate was similar in the two groups (7.4% for HSG and 10.7% for HyFoSy; P=0.37). Over half (57.1%) of the pregnancies occurred within 6 months after HyFoSy, whereas only 8.3% after HSG. CONCLUSION: IUI results are not influenced by HyFoSy compared to HSG with regard to the pregnancy rates. Use of HyFoSy in infertility assessment allows global evaluation and more rapid adapted management. This approach could optimize management of patients undergoing IUI.

Understanding barriers and motivations to papillomavirus vaccination in a middle school in Reunion Island.

BACKGROUND: In Reunion Island, papillomavirus (HPV) vaccination coverage is low. A study encouraging vaccination in middle school showed low rate of participation. The main objective of the study was to understand barriers and motivations to HPV vaccination in populations yet sensitized to its benefits. METHODS: The study focused on population around the intervention school where a health promotion program was conducted during school year 2020-2021. Semi-structured face-to-face interviews among children, children's parents, school staff, general practitioners (GP) and association members were conducted. A qualitative study was adopted using a grounded theory approach to obtain an in-depth understanding of issues pertaining to HPV vaccination. FINDINGS: A total of 19 school staff members, 20 parents of middle school children, 39 children, 5 GPs and 3 association members were interviewed in May 2021. Anti-vaccination attitudes included: fear of serious adverse effects (such as fertility) due to poor knowledge, fear of encouraging sexuality among teenagers, mistrust towards scientists and the pharmaceutical industry and the negative impact from social networks. However, we found that the influence of the school, GP's and 'story-telling' study testimonials were crucial to invert the balance and motivate children's vaccination. INTERPRETATION: Reproductive adverse events related to the HPV vaccine may be strongly perceived amongst our population, either regarding fertility or negative fetal effects; though Reunion island has 5% of pregnancies among teenagers. It is crucial to lift this taboo related to sexuality and encourage dialogue between children and their close social network. This better understanding of barriers and motivations will help us increase the impact of school-based HPV vaccination, which will be introduced in September 2023 in whole France.

Factors associated with non-visualisation of tubal patency during Hysterosalpingo-Foam-Sonography.

OBJECTIVE: Investigate potential factors associated with non-visualisation of tubal patency during Hysterosalpingo-Foam-Sonography (HyFoSy). STUDY DESIGN: This retrospective study was carried out at the medically assisted procreation centre of the University Hospital Centre in Reunion Island and focuses on HyFoSy performed between 01/01/2018 and 31/12/2020. We aimed to compare HyFoSy with bilateral tubal patency and those with a passage defect. Factors associated with non-visualisation of the contrast medium were investigated using comparison tests and logistic regression. Explanatory variables were patient history and ultrasound characteristics. RESULTS: 137 eligible HyFoSy were included, of which 70.8% could be established for bilateral tubal patency. The assessment of tubal patency decreased in cases of overweight/obesity (62.5% versus 47.4%), previous pelvic surgery (17.5% versus 10.3%) and deep endometriosis (12.5% versus 5.2%), without significant difference. In the logistic regression model, a trend towards significance was observed for body mass index ≥ 25 kg/m² (OR 2.01 [95% CI 0.93-4.35], p= 0.07). CONCLUSION: HyFoSy as a first-line infertility test should be discussed in certain circumstances, due to risk of non-visualisation of tubal patency. In case of poor echogenicity, it should be performed by a trained ultrasonographer or a hysterosalpingography should be preferred. For tubo-pelvic pathologies, a laparoscopy should be discussed for diagnostic and therapeutic purposes. DISCIPLINE: gynaecology, infertility.

Admission into intensive care unit in preeclampsia: a four-year population-based study in Reunion Island.

INTRODUCTION: Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality. The objective of our study was to study risk factors and complications associated with severe preeclampsia requiring intensive care unit (ICU) admission. METHODS: Retrospective comparative study over a period from 1st of January 2015 to 1st of January 2019 in the University's maternity unit of South Reunion (Indian Ocean). Our sampling included all preeclamptic patients who delivered in the Southern part of the island. Patients admitted to intensive care unit (ICU) and those who remained in the maternity unit (controls) were reviewed. RESULTS: Out of 482 preeclampsia cases, 94 women (19.5%) needed a transfer in ICU, of which only 21 (4.3%) needed invasive intensive care. Mean length of stay was 2.4 ± 2.1 days. ICU admission was associated with HELLP syndrome (OR 8.5 [4.9-14.9], p<.001), severe post-partum hemorrhage (OR 5.86 [1.29-26.70], p=.01) and early onset of preeclampsia (<34 weeks gestation), 2.97 [1.9-4.7], p<.001), leading to higher rate of C-section (OR 2.83 [1.67-4.78], p<.001). There were three patients with a history of eclampsia and no case of maternal death was reported. Fetal prognosis was much poorer in maternal ICU admissions than in controls, with outcomes including lower birth weight (1776 vs. 2304 g, p<.001) and higher perinatal morbidity (infant respiratory distress syndrome 3.70 [1.94-7.05], p<.001) and mortality (<.001). CONCLUSIONS: Women needing invasive ICU represented 4.3% of preeclampsia cases. This experience is of interest for lower resource settings such as in countries like Madagascar where very intensive ICU means are very poor, but simpler ICU surveillance is possible. Fetal prognosis was poor though no maternal death was reported. Thus, a multidisciplinary approach of patients with preeclampsia should be encouraged; admission into ICU should be facilitated, as soon as any sign of severity and complications appears.

HPV vaccination hesitancy in Reunion Island.

INTRODUCTION: In Reunion Island (RUN), cervical cancer is the 4th most common cancer in women and standardized mortality rate is 4.8 for 100 000 women. It is preventable by HPV vaccination, yet only 8.1% of girls aged <16 years old are fully vaccinated. OBJECTIVE: To determine factors related to HPV vaccination hesitancy in Reunion Island. STUDY DESIGN: Between January and June 2017, general practitioners, midwives and liberal gynaecologists were invited by email to answer an online self-questionnaire. Questionnaires were also distributed to mothers who had daughters aged between 11 and 19 years old, in 2 middle schools in Southern Reunion. Data was collected using Google Form. RESULTS: 125 health professionals and 85 mothers answered the questionnaire. Knowledge about HPV infection was not sufficient. All people interviewed expressed concerns about HPV vaccination, because of auto-immune reactions, and lack of efficacy. Mothers felt insufficiently encouraged by their general practitioners to vaccinate their children. CONCLUSIONS: In Reunion Island, lack of information and vaccination mistrust from parents as well as from caregivers, are the main factors contributing to low HPV vaccination coverage. Formations intended for caregivers and information campaigns of general population could play a role into raising vaccination coverage; school could enhance teenagers' awareness.

A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.

BACKGROUND: AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants. METHODS: We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity. RESULTS: Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations. CONCLUSIONS: These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.

Inhibitors in AKTion: ATP-competitive vs allosteric.

Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT inhibitors, broadly classified as either ATP-competitive or allosteric, are currently in various stages of clinical development. Herein, we review the evidence for AKT dependence in human tumours and focus on its therapeutic targeting by the two drug classes. We highlight the future prospects for the development and implementation of more effective context-specific AKT inhibitors aided by our increasing knowledge of both its regulation and some previously unrecognised non-canonical functions.

Impact of management on mortality in patients with invasive cervical cancer in Reunion Island.

OBJECTIVE: In Reunion Island, the standardized mortality rate for cervical cancer is 4.8/100,000 women, twice higher than in Metropolitan France. For locally advanced disease, the standard of care includes a treatment by brachytherapy. Nevertheless, brachytherapy was not available on the Island before 2016. The objective of this study was to assess the impact of the management of patients with invasive cervical cancer on mortality in Reunion. METHODS: We have identified all the women hospitalized in one of the health care centers of the Island diagnosed with invasive cervical cancer between 01/01/2010 and 31/12/2015. The guidelines of the French Society of Gynecological Oncology (FSGO) were considered as the reference to evaluate professional practices. The characteristics that had an influence on global survival after log-rank test were included in a multivariate analysis according to the Cox Model. RESULTS: Retrospective analysis identified 303 women meeting inclusion criteria. The assessment of professional practices showed that the decisions on 11.6% of the patients discussed during multidisciplinary meetings, were not applied, consequentially leading to a decrease in survival (p=0.001). A total of 156 patients (51.5%) were administered a treatment in accordance with the guidelines of the FSGO and had a better survival, even after multivariate analysis (HR 2.53 [CI 95% 1.55-4.14], p<10-3). Nonconformity was associated with the lack of access to brachytherapy on the Island. Women on the Island presented low rates of screening tests (cover rates 53.2%). CONCLUSION: The absence of treatment in accordance with the guidelines and decisions taken during multidisciplinary meetings and the absence of brachytherapy were associated to a higher mortality among patients with invasive cervical cancer in Reunion Island. We hope that the implementation of brachytherapy in Reunion will address these deficiencies.

Computer-aided identification of novel anticancer compounds with a possible dual HER1/HER2 inhibition mechanism.

HER1 and HER2 are frequently overexpressed in human tumors where they drive cellular proliferation. For this reason they are considered important targets in anticancer therapy with dual HER1/HER2 inhibitors being recently approved and marketed. In this paper we report the identification of a series of compounds with anticancer activity by a combined virtual screening approach on the kinase domains of HER1 and HER2. 6 hit compounds that present a sub- or low-micromolar activity in two cell-based assays, were initially identified and a subsequent design cycle led to the synthesis of a compound with nanomolar activity in the cell-based assays.

Nestin regulates prostate cancer cell invasion by influencing the localisation and functions of FAK and integrins.

Nestin, an intermediate filament protein and marker of undifferentiated cells, is expressed in several cancers. Nestin is important for neuronal survival and is a regulator of myogenesis but its function in malignancy is ambiguous. We show that nestin downregulation leads to a redistribution of phosphorylated focal adhesion kinase (pFAK, also known as PTK2) to focal adhesions and alterations in focal adhesion turnover. Nestin downregulation also leads to an increase in the protein levels of integrin α5ß1 at the cell membrane, activation of integrin ß1 and an increase in integrin clustering. These effects have striking consequences for cell invasion, as nestin downregulation leads to a significant increase in pFAK- and integrin-dependent matrix degradation and cell invasion. Our results indicate that nestin regulates the localisation and functions of FAK and integrin. Because nestin has been shown to be prevalent in a number of specific cancers, our observations have broad ramifications for the roles of nestin in malignant transformation.

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response.

The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ER+)/HER2+ breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ER+/HER2- (MCF7 and T47D) and ER+/HER2+ (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878±trastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ER+/HER2+ cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ER+/HER2+ cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ER+/HER2+ breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ER+/HER2+, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.