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Abstract Context Prader–Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. Objective To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. Methods This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. Results Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: −0.07 at week 16 and −0.14 at week 52) and children (−0.06 and −0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders. Conclusion Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.

Objective: To examine the role of Guanfacine Extended Release (GXR) in the management of behavioral disturbances in patients with Prader-Willi Syndrome (PWS). Methods: Twenty from a total of 27 individuals with genetically confirmed PWS, 6–26 years of age, with the following symptoms were identified: significant aggression/agitation, skin picking, and/or symptoms of attention-deficit/hyperactivity disorder (ADHD). Response to GXR for the above noted symptoms was categorized as improved, worsened, or unchanged, while assessing for side effects and tolerability. Results: Eleven of the 20 individuals reported skin-picking, 17 reported aggression/agitation, and 16 reported symptoms of ADHD. Nine (81.8%), 14 (82.3%), and 15 (93.7%) individuals showed an improvement in skin-picking, aggression/agitation, and ADHD, respectively, while on GXR treatment. Two patients with prior complaints of psychotic symptoms did not respond to GXR. Of note, no abnormal weight gain or significant adverse reaction was observed in this group, while on GXR. Conclusions: In this study, GXR demonstrated improvement in symptoms of skin picking, aggression/agitation, and ADHD in patients with PWS. GXR was not effective in reducing psychosis or agitation related to psychotic symptoms. Future studies are warranted to further establish the utility of GXR in PWS patients.

Abstract Context Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. Objective The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. Methods In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. Results DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] −5.94 [0.879] vs −4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] −9.67 [1.429] vs −4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). Conclusion DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Baseline a.m ACTH and Cortisol levels in Children with Prader-Willi-syndrome are no different from general population. Moris Angulo, MD1 & Mariano Castro-Magaña, MD1 1Dept of Peds, NYU-Winthrop Hospital, New York, NY Background Prader-Willi syndrome (PWS) is a multi-system genetic disorder resulting from the lack of expression of the paternal genes from chromosome 15q11.2-q13 due to paternal deletion, uniparental disomy (UPD) or an imprinting center defect. Many of their features are explained by hypothalamic dysfunction, therefore individuals with PWS are at high risk for pituitary hormonal deficiency. When the pituitary begins to fail, there is generally a specific sequential failure of pituitary hormones, starting with GH, continuing through LH and FSH deficiency, and culminating in loss of TSH and ACTH. Generally, ACTH is the last to be lost. A high prevalence (60%) of central adrenal insufficiency (CAI) however, has been reported in Prader-Willi syndrome (PWS) using the metyrapone test. Many children, including infants have undergone stimulation testing to confirm or rule out CAI. Several studies however, using same test and other different testing methods including insulin tolerance test (ITT), low dose/high dose ACTH stimulation, glucagon stimulation tests have reported differing results with prevalence between 0 to 7·5%. Previous study has shown that basal cortisol is closely correlated with adrenal response to stimulation. Methods: We studied 105 children with genetic diagnosis of PWS, age 2 to_(_(y))ears. (60 males and 45 females) after basal Cortisol and ACTH level collected at 0800 h. Sixty eight children (60 %) had deletion I and II, 24 (23%)UPD and 13 had only positive DNA Methylation testing . All participant were already on GH treatment without illness or any other stressful condition during testing. Results: All had normal morning Cortisol and ACTH level but 2 children, age 2 and 5 years with low and 4 y.o. male with increased cortisol level. These 3 children had normal ACTH level. Repeat sample after a week, revealed normal both Cortisol and ACTH level. Conclusion: suggesting that clinically significant adrenal insufficiency in PWS is rare

Background Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. Methods Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. Results Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. Conclusions GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI. Trial registration This study was registered with ClinicalTrials.gov (NCT01009905) on November 9, 2009.

Polyorchidism is defined as the presence of two or more testis. We report an interesting case of Tetraorchidism an extremely rare type of Polyorchidism in a 14-year-old boy with short stature due to Growth hormone deficiency. An extensive review of literature yielded only 200 case reports of Polyorchidism [1]. Most of these are case reports on triorchidism (3 testicles). There has been only 9 case reports of patients with (tetraorchidism) 4 testicles [2]. Most of them has been reported as incidental findings in adults. This case is being reported due to its rarity. Here we elaborate on clinical presentation of Polyorchidism in children and their management plan. More specifically from Pediatric Endocrinology perspective, we discuss the influence of the Polyorchidism on the Tanner staging (by testicular volume), growth and pubertal development in boys. Reference: 1. Amanda Myers, Bradley Morganstern and Ronnie Fine Urology, 2017-06-01, Volume 104, Pages 196-197, 2. Ibrahim H., Roberts M.J., and Hussey D.: Quadruple orchidopexy for torsion testis in an adolescent with polyorchidism: a case report. Urology 2016; 87: pp. 196-199.

Background: The American Norditropin® Studies: Web-Enabled Research (ANSWER) Program and the NordiNet® International Outcome Study (NordiNet® IOS) are complementary, large-scale, non-interventional studies designed to gather long-term data on the effectiveness and safety of Norditropin® (somatropin) treatment in the usual clinical setting. Data were collected in the United States (US) and Europe from 2006 to 2016 in both children and adults. Objective: To assess the clinical outcomes of growth hormone (GH)-treated pediatric patients with Prader-Willi Syndrome (PWS) enrolled in the ANSWER® Program or NordiNet® IOS. Methods: Patient information was entered by participating physicians using a web-based data entry tool. Change from baseline in height standard deviation scores (HSDS) and body mass index standard deviation scores (BMI SDS) were analyzed based on availability of follow-up data. The explanatory variables in the repeated measures model analysis included baseline HSDS/BMI SDS, gender, age, target height, region (US/Europe), and GH dose. Results: From a total of 129 PWS GH-naïve patients, available data for HSDS and BMI SDS analysis included 129 and 98 patients respectively on a GH dose of 0.03 (±0.01) mg/kg/d. In the HSDS analysis with equal number of males and females, the mean age at the start of treatment was 4.42 (±4.51) years, and mean treatment period was 2.48 (±1.31) years. Further analysis determined that baseline age and years on treatment had a significant impact on the change in HSDS (P=0.014 and P<0.0001, respectively. In the BMI SDS analysis, 51% were males. At the start of treatment, the mean age was 5.56 (±4.79) years, with a mean duration of GH treatment of 2.45 (±1.32) years. The mean BMI was 18.04 (±4.9) for NordiNet® patients and 24.68 (±7.75) for ANSWER® patients. The baseline BMI SDS of NordiNet® patients (0.4±1.54) was lower compared with that of ANSWER® patients (1.80±1.68). Longer GH treatment time lead to a greater change in BMI SDS from baseline (P<0.0001). In addition, those patients with a higher BMI at the start of treatment had a greater decrease in BMI over time [t(624)=-8.01, P<0.0001]. Conclusions: GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and longer treatment period resulted in better outcomes for both height and BMI.

Background Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental condition, characterized by hyperphagia, obesity, hormone deficiencies and behavioral/psychological manifestations. DCCR is under investigation as a treatment for hyperphagia in PWS through its actions on hypothalamic circuits involved in appetite regulation including NPY neurons and central inhibition of DMV neurons to improve insulin sensitivity. In addition to these effects, DCCR acts on pancreatic beta cells, to reduce glucose stimulated insulin secretion, which might have additional effects to reduce fat deposition in adipocytes, serum leptin concentrations and insulin resistance. Objectives and methods This analysis characterized changes in hormonal and cardiometabolic parameters in patients with PWS receiving oral daily DCCR. 125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (analysis at 52 weeks). The target DCCR dose for these studies was ≥3.3 mg/kg with an optimal dose of 4.2 - 5.8 mg/kg. Overall, 103 patients received DCCR (100-525 mg/day) for 52 weeks. For all parameters, the baseline measurement was defined as (immediately prior to) start of DCCR treatment. Results Serum leptin, insulin, and HOMA-IR were significantly reduced following 52 weeks of DCCR administration. Results are expressed as Least square (LS) mean change from baseline [Standard Error (SE)]. There were significant decreases in: Leptin (ng/mL) = -11.08[1.26], p<0.001; Insulin (μIU/mL) = -2.5[0.69], p<0.001; and HOMA-IR = -0.5 [0.17], p=0.003. Serum adiponectin (µg/mL) was significantly increased: 1.82[0.41], p < 0.001. Fat mass measured by DXA was stable at 52 weeks. Conclusions The reductions in fasting leptin, insulin and HOMA-IR, and the increase in adiponectin with prolonged DCCR treatment in the absence of reductions in total body fat are consistent with improved insulin sensitivity that may also reflect improvement in leptin sensitivity and healthier body fat distribution, such as reduced visceral adiposity. This could result from both direct pancreatic and hypothalamus-to-periphery actions of DCCR. It remains to be determined if such beneficial metabolic changes also result in reduced systemic inflammation and cardiovascular health. DCCR administration was associated with significant reductions in leptin, insulin, and HOMA-IR, increases in adiponectin and stabilization of body fat. These and other changes in cardiometabolic parameters suggest that DCCR may have long term health benefit in patients with PWS. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

Background Prader-Willi syndrome (PWS), a rare genetic neurobehavioral-metabolic condition, is characterized by hyperphagia, accumulation of excess fat, hypotonia, and behavioral/psychological complications. There are no currently approved medications to treat hyperphagia in patients with PWS; DCCR is under development as a treatment for PWS. Objectives and methods The objective was to evaluate long-term safety of DCCR in individuals with PWS. 125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with oral daily DCCR in multi-center studies conducted at 29 sites in the US and the UK: a 13-week, Phase 3, double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (to 52 weeks and beyond). Enrolled participants had hyperphagia assessed by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). The target DCCR dose was ≥3.3 mg/kg (optimal dose 4.2 - 5.8 mg/kg). 103 patients received DCCR for 52 weeks and 54 patients received DCCR for at least 78 weeks. Results Overall, DCCR was well tolerated with the majority of adverse events (AEs), (77.6%) having grade 1 or 2 severity. Treatment-emergent adverse events (TEAEs) occurred in 98.4% of participants. Drug related TEAEs occurred in 80.0% of participants. Twenty participants experienced serious adverse events (SAEs), for which only two participants were considered drug related (one patient with peripheral/pulmonary edema and another with fluid retention). There were no Suspected Unexpected Serious Adverse Reactions (SUSARs) or SAEs leading to death. The most common TEAEs were hypertrichosis (61.6%), peripheral edema (34.4%), and hyperglycemia (22.4%). TEAEs infrequently resulted in discontinuation of study drug (7.2% of participants). These results are consistent with the observed safety profile of DCCR from prior studies. Consistent with the expected AE of hyperglycemia, fasting glucose rose through Week 26 (mean change from baseline ± SD mmol/L = 0.35±0.81) and returned nearly to baseline by 15 months of treatment (0.11±0.61). HbA1c followed a similar pattern, increasing at 26 weeks (mean change from baseline ± SD % = 0.19±0.50) and returning nearly to baseline by 15 months (0.03±0.38). In participants experiencing hyperglycemia, the AE resolved with continued treatment in about half of cases. Four participants experienced recurrent hyperglycemia. About 90% of cases of peripheral edema resolved while treatment continued, requiring infrequent dose adjustment (7%) or the need for diuretic treatment (3%). Most cases of hypertrichosis (>80%) were mild and only in one instance led to discontinuation. About 35% of cases of hypertrichosis were resolved/resolving at Week 52. Conclusions DCCR was well tolerated beyond 52 weeks of administration. The most common treatment-emergent adverse events were expected based on prior studies of DCCR. These included hypertrichosis, peripheral edema and hyperglycemia, which were typically mild and resolved without treatment in most cases. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:54 p.m. - 1:59 p.m.

Perioperative blood transfusions may have a deleterious effect on the survival of patients with a variety of solid tumors, 1 , 2 possibly because of an immunosuppressive effect 3 , 4 . This possibility is supported by studies in animals in which tumor growth was enhanced after allogeneic transfusion, 5 , 6 although conflicting results have also been reported 7 , 8 . A poor prognosis after blood transfusions has been noted especially in patients with colorectal cancer. In the studies of the effect of blood transfusions in patients with cancer, the patients were given the transfusions either because of their disease or because transfusion was necessary during . . .