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Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare tumor, typically found in the ethmoid or upper nasal cavity. There is no standard systemic treatment for metastatic/locally advanced disease ineligible for upfront surgery or radiotherapy.Patients treated between 2015 and 2021 in our institution with a fluoropyrimidine plus oxaliplatin and/or irinotecan for advanced ITAC were retrospectively assessed for overall survival (OS), progression-free survival (PFS) and tumoral responses.Six patients without meningeal involvement received chemotherapy (three FOLFOX, two FOLFIRI, one FOLFIRINOX). All achieved a response, including those with brain extension. Median PFS with FOLFOX and FOLFIRI was similar (6.0 months, 95%CI 5.8-NR; 5.8 months, 95%CI 5.8-NR respectively). Three patients had meningeal involvement with meningitis symptoms and received first-line therapy. All had rapid disease progression (median PFS 1.2 months, 95%CI 1.0-NR) DISCUSSION: FOLFOX, FOLFIRI or FOLFIRINOX appear to have anti-tumor efficacy for metastatic or locally advanced unresectable ITAC, except in cases of carcinomatous meningitis. These regimens require further evaluation.

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.

IntroductionCongenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH.MethodsTargeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded.ResultsNGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L.ConclusionNGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Objective Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. Design We investigated the renin–angiotensin–aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. Methods Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. Results The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L–1 (IQR 8.3) versus 10.5 nmol L–1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L–1 s–1 (IQR 1.0) to 0.48 ng L–1 s–1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L–1 s–1 (IQR 0.66) to 0.52 ng L–1 s–1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L–1 to 139.3 ± 1.8 mmol L–1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L–1 to 139.3 ± 1.9 mmol L–1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. Conclusion 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

Objective Using real-world data from patients with growth hormone deficiency (GHD), we evaluated whether clinical practice in France adheres to international guidelines regarding somatropin dose adjustment, and assessed the long-term effectiveness and safety of somatropin. Methods Data were obtained from a national prospective systematic longitudinal routine follow-up programme of naive/non-naive adults with childhood-onset (CO) or adult-onset (AO) GHD treated with Norditropin® (Novo Nordisk A/S). Results Between 2003 and 2006, 331 treatment-naive and non-naive adults with severe GHD were enrolled and followed for a median duration of approximately 5 years; 328 patients were available for analysis. At baseline, mean patient age was 39.2 years; median standard deviation score (SDS) for insulin-like growth factor−1 (IGF-1) level was −2.2 in naive patients, subsequently fluctuating between −0.1 and +0.3 SDS during the study period. Mean GH doses ranged between 0.25 and 0.51 mg/day (naive patients) and 0.39 and 0.46 mg/day (non-naive patients). Despite generally receiving a higher somatropin dose, women (naive/non-naive) tended to have lower IGF-1 levels than men. Median somatropin dose was consistently higher in patients with CO-GHD than patients with AO-GHD. Extreme IGF-1 values ( + 2 SDS) were not systematically accompanied by somatropin dose adjustments. Waist circumference improved in approximately one third of patients, at a mean 3.5 years. Somatropin was well tolerated; there were no cardiovascular or cerebrovascular events during the 5-year analysis period. Conclusion Current clinical practice of physicians in France follows international guidelines regarding somatropin dose adjustment in adults with GHD. However, dose adjustments are not always sufficient, notably in women, and treatment effects may have been delayed due to low somatropin dose (Clinical trial registration NCT01580605 ).

Background Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ∼1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy3. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one. Methods We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC3: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range ( Results Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment. At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively. Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusions Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients. References 1. Pickup ME. Clin Pharmacokinet 1979 4 111-128; 2. Toothaker RD. J Pharm Sci 1982 71 573-576; 3. Merke DP. JCEM 2021 106 e2063-e2077. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Objective: Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) may have poor quality of life (QoL) and low satisfaction with body appearance. We investigated the influence of the patients’ satisfaction with their support on their QoL and body image. Design: Retrospective, comparative, Europe-wide study as part of the multicenter dsd-LIFE study. Methods: 203 women with CAH were included in this study. We investigated the patients’ QoL and body image compared to a healthy control group. The patients’ satisfaction with their treatment and support in childhood and adolescence as well as in adulthood was assessed by questionnaire and its influence on the patients’ body image and QoL was analyzed by multiple regression models. Results: Women with CAH showed worse body image and poorer physical, psychological and social QoL compared to a healthy reference population. The patients’ satisfaction with professional care in the last 12 months was a significant positive predictor for all four domains of QoL (psychological, physical, social, environmental). Dissatisfaction with care in childhood and adolescence and with general support through different stages of life was a significant negative predictor for QoL and body image. Conclusions: These results show that women with CAH have poor QoL and body image compared to a healthy reference population. Psychosocial factors such as general and family support, and social interactions with professionals have a substantial impact on QoL and body image in adult females with CAH. This should be taken into account regarding patient care and multimodal therapy.

The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P ID and II ACE genotypes in both sexes ( P ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.

In this work we propose a new type of symmetrical surface relief diffractive grating for waveguide -based Augmented Reality near-eye display system with a wide Field of View (FoV). We demonstrate that by using a dual-mode symmetrical in-coupling system and angular pupil tiling, we can extend the overall horizontal FoV. Our grating coupler is optimized for the second diffraction orders. The proposed concept is validated numerically via full-wave electromagnetic analysis of a 1D diffraction grating. Measurements of the diffraction efficiency of the micro-fabricated prototype are compared with the results of the numerical simulation.

Objective High glucocorticoid levels in rodents inhibit development of beta cells during fetal life and lead to insulin deficiency in adulthood. To test whether similar phenomena occur in humans, we compared beta-cell function in adults who were exposed to glucocorticoids during the first part of fetal life with that of nonexposed subjects. Research Design and Methods The study was conducted in 16 adult participants exposed to glucocorticoids during the first part of fetal life and in 16 nonexposed healthy participants with normal glucose tolerance who were matched for age, sex, and body mass index (BMI). Exposed participants had been born to mothers who were treated with dexamethasone 1 to 1.5 mg/day from the sixth gestational week (GW) to prevent genital virilization in children at risk of 21-hydroxylase deficiency. We selected offspring of mothers who stopped dexamethasone before the 18th GW following negative genotyping of the fetus. Insulin and glucagon secretion were measured during an oral glucose tolerance test (OGTT) and graded intravenous (IV) glucose and arginine tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic-clamp. Results Age, BMI, and anthropometric characteristics were similar in the 2 groups. Insulinogenic index during OGTT and insulin sensitivity during the clamp were similar in the 2 groups. In exposed subjects, insulin secretion during graded IV glucose infusion and after arginine administration decreased by 17% (P = 0.02) and 22% (P = 0.002), respectively, while glucagon secretion after arginine increased. Conclusion Overexposure to glucocorticoids during the first part of fetal life is associated with lower insulin secretion at adult age, which may lead to abnormal glucose tolerance later in life.

ObjectiveTurner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.Design and methodsThis national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).ResultsMedian age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P ConclusionThese data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

Summary Background Surgery is performed in many individuals with disorders/differences of sex development (DSD). Irreversibility of some surgical procedures, lack of information about the procedures, and lack of follow-up care for physical and psychological outcomes, lead to wish for more knowledge from both surgeons and patients. After the consensus conference in 2006, multidisciplinary care is provided to a higher degree with psychological support and more restricted surgical procedures. Outcome studies after genital surgery often lack of patient's perspective. Objective To describe surgical procedures in relation to diagnosis, to evaluate the outcomes of surgery through genital examination, and through patient's and observer's satisfaction with the anatomical and functional result after genital surgery. Study design In a cross-sectional clinical study performed in six European countries in 2014/15, we have included 500 participants where surgery was performed, from a total of 1040 adolescents (≥16years) and adults with a DSD. Diagnoses included Turner syndrome (n = 301), mixed gonadal dysgenesis (45,XO/46,XY; n = 45), Klinefelter syndrome (n = 218), XYY (n = 1), 46, XY DSD (n = 222) and 46, XX DSD (n = 253). Study protocol included clinical report files, an optional gynecological or urological examination, patient reported outcomes including received surgical interventions, satisfaction with appearance and function after surgery, and impact of the surgical procedure on life. Results Five hundred participants had received genital or breast surgery, with the highest rate in 46, XY DSD and the lowest in Turner syndrome. Altogether; 240 participants had feminizing surgery, 112 had masculinizing surgery, and 217 underwent gonadectomy. Physicians evaluated anatomical appearance at genital examination as poor in less than 10%. Dissatisfaction with anatomical appearance was reported by 22% of the participants, dissatisfaction with function by 20%. Being (very) dissatisfied with anatomical appearance and function was reported by 13% of the study participants. Most participants reported no impact, or positive impact, of the surgical procedures on their lives, but 29% experienced a negative effect of gonadectomy on their life. Discussion There might be a selection bias and/or a recall bias for participating in our studies. Due to poor data quality about surgical procedures performed in the past, we also relied on participants memory about surgical procedures in their past. Ideally, patient reported outcomes should be evaluated both before and after surgical procedures. Conclusion A vast majority are satisfied with appearance and function, but still genital or breast surgery have a long-lasting effect on patient's life. Self-reported satisfaction is usually lower than the observer's evaluation regarding both appearance and function. Download : Download high-res image (217KB) Download : Download full-size image Summary Figure . Satisfaction with anatomy and function after genital surgery in individuals with DSD (appearance: n = 244; function: n = 257) (n = total number of participants).

Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP ( Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.