Thyroid dysfunction induced by immune checkpoint inhibitors is associated with a better progression-free survival and overall survival in non-small cell lung cancer: an original cohort study.

BACKGROUND: The objective of this study was to investigate the association between the onset of TD and treatment efficacy in NSCLC patients who initiated anti-PD-1 blockade (Nivolumab®) and to assess the impact of TD severity and subtype on nivolumab efficacy. MATERIALS AND METHODS: This study was performed at a referral oncology center between July 20, 2015 and June 30, 2018. Patients with histologically confirmed stage IIIB/IV NSCLC in progression after one or two lines of treatment and who initiated Nivolumab were included. Thyroid function (TSH ± fT4, fT3) was monitored and patients were classified according to TD status [TD(+) versus TD(-)], severity [moderate thyroid dysfunction: TSH level between 0.1 and 0.4 or 4.0 and 10 mIU/L and severe thyroid dysfunction: TSH ≤ 0.1 or ≥ 10mUI/L) and subtype (isolated hypothyroidism, isolated hyperthyroidism and hyperthyroidism then hypothyroidism)]. Clinical endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 194 eligible patients, 134 patients (median age, 63 yo; 70.1% male) were included. Forty (29.9%) patients were classified in TD(+) and had a longer OS of 29.8 months (95% CI 18.8-NR) versus 8.1 months (95% CI 5.5-11.5) in TD(-) group (p < 0.001). PFS was also longer (8.7 months (95% CI 5.3-15.1) in TD(+) versus 1.7 months (95% CI 1.6-1.9) in TD(-) group (p < 0.001). In Cox proportional hazards analysis, TD remained an independent predictive factor of OS/PFS. Severity and subtype of TD were not correlated with OS/PFS. CONCLUSIONS: This study suggested that TD induced by Nivolumab appears to be an independent predictive factor of survival, irrespective of TD severity and subtype.

Diagnostic value of positron-emission tomography textural indices for malignancy of 18F-fluorodeoxyglucose-avid adrenal lesions.

BACKGROUND: PET Textural indices could have an add-on diagnostic value for diagnosis of malignancy in patients with FDG-avid adrenal lesions. METHODS: Consecutive patients referred for a FDG-PET/CT to our nuclear medicine department from June 2012 to June 2017 were retrospectively screened. Inclusion criteria were: patients with a FDG-avid adrenal lesion (uptake≥liver background); malignant/benign lesion confirmed histologically or with follow-up imaging examination. Pheochromocytomas were not included in the analysis. For each adrenal lesion, 5 quantitative PET parameters (SUVmax, MTV, TLG, TLRmax and TLRmean) were calculated. Thirty-seven textural indices were extracted using LIFEx software®. Diagnostic performance to determine malignancy was assessed with a ROC analysis. Parameters with a significantly AUC>0.5 were selected and groups of highly correlated (r>0.8) parameters were created. A scoring system combining PET and textural indices was examined. RESULTS: PET textural indices were calculated for 53 lesions (37 malignant, 16 benign). Three PET metabolic parameters (SUVmax, TLRmax, TLRmean) and 13 textural indices had an AUC>0.5. Seven groups of highly correlated parameters (r>0.8) were extracted. For PET parameters, SUVmax had the best AUC (0.89 95% CI [0.79-0.98]; cut-off=7.0). For textural indices, ZLNU had the best AUC (0.87 95% CI [0.78-0.96]; cut-off=34.7) and specificity of 100%. Three scores combining the best four textural indices alone (ContrastGLCM, LRHGE, SZE and ZLNU) or with one PET parameters (SUVmax, TLRmax) were developed but did not increase the diagnostic performance (AUC≤0.89). ZLNU was the best parameter to distinguish primary adrenal cancer from adrenal metastases in malignant lesions (P<0.001). CONCLUSIONS: Our study highlighted excellent diagnostic performance of several PET textural indices comparable to that of PET metabolic parameters. However, our results did not find any additional diagnostic value of textural indices when combined with metabolic parameters.

Impact of myo-inositol treatment in women with polycystic ovary syndrome in assisted reproductive technologies.

Polycystic ovary syndrome (PCOS) is marked in 30 to 40% by insulin resistance and hyperandrogenism. Myo-inositol (MI) increases insulin sensitivity, decreases hyperandrogenism and improves the menstrual cycle. Its effect during assisted reproductive technologies (ART) has been studied by many authors. We conducted a review of the literature on the impact of MI administration in PCOS women in assisted reproductive technologies. Myo-inositol is effective in normalizing ovarian function, improving oocyte and embryo quality in PCOS, however further evaluations by large multicentre randomized controlled trials are needed to assess the clinical pregnancy and live birth rates in ART.

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

AIMS/HYPOTHESIS: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown. METHODS: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation. RESULTS: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m2; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA1c, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7. CONCLUSIONS/INTERPRETATIONS: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days. TRIAL REGISTRATION: clinicaltrials.gov NCT04324736.

Correction to: Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

The authors regret a mistake in Table 1.

Comparison between preprandial vs. postprandial insulin aspart in patients with type 1 diabetes on insulin pump and real-time continuous glucose monitoring.

BACKGROUND: The objective was to compare glycemic control between preprandial and postprandial bolus administration (15 min before [PRE] or immediately after the meal [POST]) in patients with type 1 diabetes using insulin pump and real-time continuous glucose monitoring. METHODS: Between September 2015 and February 2016, a single-centre, open randomized, 2-way crossover study of patients on bolus insulin aspart administration was conducted during two 14-day periods and according to 2 administration regimen schedules (PRE/POST or POST/PRE). Inclusion criteria were as follows: patients with type 1 diabetes, ≥18 and ≤ 65 years old, treated with insulin aspart using a Medtronic® insulin pump and trained on functional insulin therapy. Patients were randomly assigned to either regimen schedule. At the beginning of each period, each patient was provided with a standardized high fat meal. Primary outcome was the area under the curve for interstitial glucose above 140 mg/dL per minute (AUC > 140 mg/dL/min) during each period. Secondary outcomes were time spent in hypo/eu/hyperglycemia, glycemic variability indices, and AUC during 4 hours after high fat meal calculated with continuous glucose monitoring data. RESULTS: Twenty-two patients were included. Mean AUC > 140 mg/dL/min was statistically higher in patients on POST (43.70 mg/dL/min; 95%CI: 34.08 to 53.31) versus PRE insulin aspart regimen (37.24 mg/dL/min 95%CI: 27.63 to 46.85) (P = 0.03). Mean interstitial glycemia and glycemic variability indices were also increased (P < 0.05) on POST regimen. The mean AUC 4 hours after the high fat meal was higher on POST regimen but not statistically different (P = 0.06). CONCLUSIONS: In our study, postprandial administration of insulin aspart appears to mildly increase glycemic excursion and glycemic variability.

Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma.

BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.

Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome.

STUDY QUESTION: What are the prevalence and the outcomes of spontaneous pregnancies (SP) in a large cohort of French women with Turner syndrome (TS)? SUMMARY ANSWER: Amongst 480 women with TS, 27 women (5.6%) had a total of 52 SP, with 30 full-term deliveries for 18 women. WHAT IS KNOWN ALREADY: Primary ovarian insufficiency is a classic feature of TS. So far, few studies have evaluated the rate of SP in these patients. STUDY DESIGN, SIZE, DURATION: The French Ministry of Health set up a National Reference Centre for Rare Growth Disorders (CRMERC), including TS. We studied a cohort of adult TS patients from seven endocrine units (Saint-Antoine, Pitié-Salpêtrière, Bicêtre, Lyon, Marseille, Brest, Reims Hospitals) belonging to this centre, between January 1999 and January 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 480 adult patients with TS were included. The patients' clinical characteristics, karyotypes and reproductive histories had been collected, after informed consent, in a web database called CEMARA. Our reference population was issued from a database belonging to the French Health Ministry, collecting pregnancy outcomes in the French general population. In order to find predictive characteristics of SP, TS with spontaneous pregnancies were compared with non-pregnant TS patients from our cohort. MAIN RESULTS AND THE ROLE OF CHANCE: There were 27 patients (5.6%) who had a total of 52 SP. The two predictive factors which correlated with occurrence of a SP were spontaneous menarche and mosaic karyotype. The median delay to conception was 6 months (range 0-84). Miscarriage occurred in 16 pregnancies, 30.8% versus 15% in the general French population (P < 0.01). The remaining pregnancy outcomes were legal abortion (n = 2), medical interruption (n = 3), intrauterine fetal death (n = 1) and delivery at term (n = 30). Caesarean section rates were higher than in the general population, respectively 46.7% versus 21% (P < 0.001). Pregnancy-induced hypertensive disorders (PHDs) occurred in four cases (13.3%), including two cases of mild pre-eclampsia (6.7%). Neither aortic root dilatation nor aortic dissection were observed. The median birthweight was 3030 g (range 2020-3460). Two cases of TS were identified in the 17 daughters issued from this cohort. LIMITATIONS, REASONS FOR CAUTION: It would have been interesting to evaluate AMH levels and SP occurrence, as a predictive factor. Unfortunately, hormonal measurements were missing for some patients. Prospective studies are necessary to display prognostic values of AMH for SP and thus better target fertility preservation programmes in TS patients. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that pregnancy outcomes in SPs are more favourable than those after oocyte donation in TS patients. However, the risk of fetal chromosomal abnormalities remains high. Our study will be useful in order to give patients with TS, their families, paediatricians and physicians involved in reproduction, better counselling concerning their fertility. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Association pour la recherche Claude Bernard, Paris France All authors claim no competing interests. TRIAL REGISTRATION NUMBER: NA.

Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study.

BACKGROUND: The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. METHODS: Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child's environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. RESULTS: We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. CONCLUSIONS: The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. TRIAL REGISTRATION: Clinical-Trial.gov NCT02212522 . Registered August 6, 2014.

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Androgenic steroid excess in women.

Excessive use of anabolic-androgenic steroids (AAS) in sport occurs among professional athletes but increasingly also in amateurs. Prevalence of steroid use has been on the rise for a number of years. While the practice involves mostly men, it also occurs in women with an estimated prevalence of 1.6%. Since 2014, a 'steroid passport' has operated for sports people in competition that is based on longitudinal urinary and blood steroid levels, measured by liquid chromatography and mass spectrometry. Androgen excess stimulates muscle growth and improves muscle performance. However, their consumption carries numerous side effects, including myocardial hypertrophy; altered lipid metabolism and pro-thrombotic effects. The excess of AAS is associated with increased risk of atherosclerosis and cardiovascular events. Data for their effects in women is lacking. Perturbations of the menstrual cycle are common in female athletes, with spaniomenorrhea and even amenorrhea. This can be a consequence of gonadotropin insufficiency due to negative caloric balance, but may also be due to endogenous or exogenous hyperandrogenism. The use of AAS is probably underestimated as a public health issue, particularly in women, and thus presents a prevention challenge for healthcare professionals.

Lessons from prospective longitudinal follow-up of a French APECED cohort.

BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

Polycystic ovary syndrome and adipose tissue.

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder in women of reproductive age. Typically, it is associated with ovulatory dysfunction: dysovulation or anovulation, and symptoms of hyperandrogenism. It incurs risk of metabolic disorders such as diabetes, dyslipidemia and fatty liver. As a key endocrine organ in metabolic homeostasis, adipose tissue is often implicated in these complications. Studies of white adipose tissue (WAT) in PCOS have focused on the mechanism of insulin resistance in this tissue. Clinically, abnormalities in WAT distribution are seen, with decreased waist-to-hip ratio and increased ratio of adipose to lean mass. Such abnormalities are greater when total circulating androgens are elevated. At tissue level, white adipocyte hyperplasia occurs, along with infiltration of macrophages. Secretion of adipokines, cytokines and chemo-attractant proteins is increased in a pro-inflammatory manner, leading to reduced insulin sensitivity via alteration of glucose transporters, and hence decreased glucose uptake. The kinetics of non-esterified fatty acids (or free fatty acids) is also altered, leading to lipotoxicity. In recent years, brown adipose tissue (BAT) has been studied in women with PCOS. Although abundance is low in the body, BAT appears to play a significant role in energy expenditure and metabolic parameters. Both supra-clavicular skin temperature, which reflects BAT activity, and BAT mass are reduced in women with PCOS. Moreover, BAT mass and body mass index (BMI) are inversely correlated in patients. In the adipocyte, increased total circulating androgen levels reduce expression of uncoupling protein 1 (UCP1), a key protein in the brown adipocyte, leading to reduced biogenesis and mitochondrial respiration and hence a reduction in post-prandial thermogenesis. BAT is currently being investigated as a possible new therapeutic application.

Pneumocystis pneumonia in patients with Cushing's syndrome: A French multicenter retrospective study.

OBJECTIVE: Pneumocystis pneumonia (PcP) is an opportunistic infection occurring in immunocompromised patients. Cushing's syndrome (CS) impairs the immune system, and several authors have reported PcP in patients with CS. The present study aimed to characterize PcP occurring in a CS context and its management in French tertiary centers, in order to highlight the similarities in clinical presentation and treatment according to whether prophylaxis is implemented or not. METHODS: This was a multicenter retrospective study conducted in several French University Hospitals and Cancer Centers. Patients with PcP and confirmed CS regardless of etiology were included. We excluded patients with other known causes of acquired immunodeficiency with increased risk of PcP. RESULTS: Twenty-five patients were included. CS etiology was neoplastic in 84.0% of cases. CS clinical presentation associated predominant catabolic signs (76.0%), hypokalemia (91.7%) and lymphopenia (89.5%). CS was intense in most patients, with mean plasma cortisol levels at diagnosis of 2.424±1.102nmol/L and urinary free cortisol>10× the upper limit of normal in 85.0%. In all patients, PcP onset followed introduction of cortisol blockers, at a median 5.5 days. Patients were treated with 1 to 3 cortisol blockers, mainly metyrapone (88%), which significatively lowered plasma cortisol levels to 667±541nmol/L at the onset of PcP (P<0.001). PcP occurred in 7 patients despite prophylaxis. Finally, 60.0% patients were admitted to intensive care, and 20.0% died of PcP. CONCLUSION: High mortality in patients with PcP implies that clinicians should be better informed about this rare infectious complication. Prophylaxis remains controversial, requiring comparative studies.

Genetic testing in prolactinomas: a cohort study.

BACKGROUND: Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on hereditary predisposition to prolactinoma. OBJECTIVE: We studied the prevalence of germline mutations in a large cohort of patients with isolated prolactinomas. MATERIALS AND METHODS: A retrospective study was performed combining genetic and clinical data from patients referred for genetic testing of MEN1, AIP, and CDKN1B between 2003 and 2020. SF3B1 was Sanger sequenced in genetically negative patients. RESULTS: About 506 patients with a prolactinoma were included: 80 with microprolactinoma (15.9%), 378 with macroprolactinoma (74.7%), 48 unknown; 49/506 in a familial context (9.7%). Among these, 14 (2.8%) had a (likely) pathogenic variant (LPV) in MEN1 or AIP, and none in CDKN1B. All positive patients had developed a macroprolactinoma before age 30. The prevalence of germline mutations in patients with isolated macroprolactinoma under 30 was 4% (11/258) in a sporadic context and 15% (3/20) in a familial context. Prevalence in sporadic cases younger than 18 was 15% in men (5/33) and 7% in women (4/57). No R625H SF3B1 germline mutation was identified in 264 patients with macroprolactinomas. CONCLUSIONS: We did not identify any LPVs in patients over 30 years of age, either in a familial or in a sporadic context, and in a sporadic context in our series or the literature. Special attention should be paid to young patients and to familial context.

Strategies for insulin initiation: insights from the French LIGHT observational study.

BACKGROUND: The progressive nature of type 2 diabetes necessitates exogenous insulin use for most patients; basal insulin plus oral anti-diabetes drugs (OADs) is a well-validated way to facilitate insulin initiation. The primary aim of this study was to explore insulin initiation strategies and outcomes for patients using insulin detemir or glargine plus oral anti-diabetes drugs. METHODS: LIGHT was a 3-month, longitudinal observational study conducted across 761 French centres in insulin-naïve type 2 diabetes patients managed under routine clinical care conditions, in either primary or secondary care. Endpoints included changes in HbA(1c) , fasting plasma glucose (FPG), rate of hypoglycaemia, weight, and adverse events. RESULTS: Most physicians initiated a basal analogue to improve glycaemic control (97%), with many delaying beginning treatment for several months (9 ± 9.0 months for general practitioners, 10.2 ± 16.2 months for specialists). Most patients continued oral anti-diabetes drug therapy (95%) and lifestyle measures (92%), with 2-3 blood glucose readings per day and follow-up telephone calls for dose optimization. Mean change in HbA(1c) from baseline was - 1.3%, and - 3.1 mmol/L for fasting plasma glucose (both p < 0.0001). Hypoglycaemia increased from 1.4 to 5.6 events/patient/year (p < 0.0001), and weight decreased on average by 0.5 kg with detemir, with no change in glargine. Most patients (93%) reported being satisfied or very satisfied with their insulin. CONCLUSIONS: Insulin initiation with detemir or glargine can be successfully managed in both primary and secondary care; the benefits of basal analogues (once-daily dosing, low rates of hypoglycaemia compared with neutral protamine Hagedorn) may have contributed to patient acceptance of the regimen.

Prevention of exercise-induced hypoglycemia in 12 patients with type 1 diabetes running the Paris Marathon using continuous glucose monitoring: A prospective, single-center observational study.

OBJECTIVE: To investigate the glycemic balance before, during and after the 2016 Paris Marathon using a real-time continuous glucose monitoring (RT-CGM) system in patients with type 1 diabetes mellitus in a prospective single-center observational study. METHODS: Inclusion criteria were as follows: type 1 diabetes mellitus; age ≥18 years; HbA1c < 9%. Participants performed two 2h-preparatory races (PR) before the Marathon and were monitored with RT-CGM 24h before, during and 72h after each race. Hypoglycemic events were prevented via carbohydrate intake / insulin dose adjustments. The primary outcome was area under the curve (AUC) < 70 and > 200 mg/dl and percentage of time spent in euglycemia, hypoglycemia, and hyperglycemia during the races. RESULTS: Twelve patients (2F/10M; median HbA1c=6.8%) were included and completed the study. Median AUC < 70 and time spent in hypoglycemia (< 70 mg/dl) during the PRs and Marathon were equal to 0. However, no hypoglycemic episodes occurred during Marathon, while two patients experienced hypoglycemia during PR1 and PR2. There was a significant increase in AUC > 200 mg/dl during races between PR2 and Marathon (P = 0.009) although the median time spent > 200mg/dl was not statistically different in Marathon versus PR2 (48.4% versus 18.4%; P = 0.09). Median time spent in euglycemia (70-200 mg/dl) was lower in Marathon versus PR2 (51.6 versus 58%; P = 0.03). CONCLUSION: Our study proposes a medical support protocol for extreme endurance physical activity in patients with type 1 diabetes mellitus. Our results suggest that RT-CGM, coupled with adjustments in carbohydrate intake and insulin doses, appears to be effective to prevent hypoglycemia during and after exercise.

Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype.

Introduction: A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective: This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods: Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results: A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions: In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement: About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.

Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families.

OBJECTIVE: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). DESIGN: Cross-sectional study. SETTING: Endocrinology and reproductive medicine teaching hospital departments. PATIENTS: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. RESULTS: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). CONCLUSIONS: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01177891.