Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.

BACKGROUND: Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. METHODS: This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. FINDINGS: Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. INTERPRETATION: These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. FUNDING: Rhythm Pharmaceuticals.

Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management.

Background: Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies. Methods: In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity. Results: Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists. Conclusion: Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.

High Grade Myxofibrosarcoma of Maxillary Sinus: A Case Report and Review of Literature.

Myxofibrosarcoma (MFS) is a soft tissue sarcoma that commonly occurs in late adult life. It is mainly located in the subcutaneous soft tissues of extremities characterized by a high recurrence rate at the original site. MFS of the head and neck is rare, while it occurrence in the maxilla is extremely rare. We report an atypical case of MFS of the maxilla in a 29-year-old male. The tumour was resected with adequate margin and following which post-operative adjuvant radiotherapy was given. This patient has been followed for 2 years to date and has remained disease free. The rarity, the aggressive nature of the pathology, the extent of the tumour and the complex neurovascular structures in close proximity to the site often lead to adverse outcomes. We will be discussing a rare case of a rapidly growing high grade maxillary sinus MFS in a young patient with a history of radiation exposure which posed as a diagnostic challenge. Our case may provide additional diagnostic and treatment experience with regards to managing maxillary sinus myxofibrosarcoma.

Genetic Contributors to Obesity.

Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."

Erratum to "Imaging diagnosis of a giant choledochal cyst in an infant" [Radiology Case Reports 17 (2022) 404-411].

[This corrects the article DOI: 10.1016/j.radcr.2021.10.051.].

Real-World Experience of the Efficacy and Safety of Phentermine Use in Adolescents: A Case Series.

Background: Pharmacotherapy has emerged as a practical option for weight management in pediatrics. This study aims to assess the effectiveness and safety of phentermine use in pediatric patients with obesity. Methods: We performed a retrospective single-center analysis of patients younger than or equal to 18 years of age, over 10 years, who underwent phentermine treatment and recommended lifestyle changes. We evaluated efficacy by the change in the percent of the 95th percentile for BMI (%BMIp95). We deemed a 5% decrease in %BMIp95 as a favorable outcome. Results: We identified 30 pediatric patients who were treated with phentermine. The cohort was primarily female, 63% white, with a mean (standard deviation) baseline age of 15.63 (1.97) years. The average duration of treatment was 10 months, with a period ranging from 2 weeks to 2 years. The average %BMIp95 at the start of treatment was 137%, and that at the time of analysis was 122%, with a mean reduction of 15%. Five patients, 17%, experienced side effects that resolved after dose reduction or discontinuing phentermine. Conclusions: Phentermine monotherapy is an effective and safe means for weight loss in pediatric patients when combined with lifestyle interventions. Twenty-one of 30 (70%) patients achieved at least a 5% decrease in %BMIp95 within a mean duration of treatment of 10 months. We noted no severe adverse events.

Imaging diagnosis of a giant choledochal cyst in an infant.

The usual etiologies of giant abdominal cystic masses in infants are mesenteric cyst, enteric duplication cyst, ovarian cyst in females, cystic lymphangioma, however, the presentation of a choledochal cyst in a gigantic form, is unusual. The primary modality for diagnosis of this entity is ultrasound, followed by MRI. The characteristic ultrasound features of a choledochal cyst are a well-defined cystic lesion which may be found to replace any segment of the biliary tree and is distinctly separate from the gallbladder. The associated anomalies are biliary atresia, gallbladder atresia, hepatic fibrosis and those of the pancreatico-biliary ductal system. MRI with MRCP has a conclusive role in confirming the ultrasound diagnosis. Choledochal cysts are currently classified as proposed by Todani et al, into five types. Herein, we report the case study of a 4-month-old male infant afflicted with a gigantic, Type1 Choledochal cyst, complicated by perforation, which was diagnosed by us at the first instance itself, using ultrasound examination and confirmed by MRI. The diagnosis was further confirmed at surgery and histopathology. The recommended treatment of cyst resection accompanied by a hepatico-jejunostomy bypass procedure, was successfully performed in the reported infant.

A Case of Cervical Teratoma in an Infant.

Cervical teratoma is a rare form of teratoma in neonates and is an unusual cause of cervical masses in them. Teratomas are unusual tumors derived from all 3 germs cell layers: endoderm, mesoderm, and ectoderm, with varying proportions. The cervical teratoma is a rare entity. Its prognosis mostly depends on the risk of neonatal respiratory distress, its extension and potential malignancy. Surgical management must be as complete as possible to avoid recurrences and malignant transformation. We report a case of a cervical immature teratoma in an infant with total excision and cure. No recurrence has been reported. The aim of our study is to review the diagnosis, management and outcomes of congenital cervical teratomas. Cervical teratoma although uncommon should be considered in the differential diagnosis of neck masses in neonates. Teratomas are rare tumors derived from all three germ cell layers affecting the neck in 3% of all cases. An early complete surgical approach to congenital cervical teratomas allows good results with low rates of complication and recurrence.

The Role of Biofilms in Chronic Otitis Media-Active Squamosal Disease: An Evaluative Study.

OBJECTIVES: To study the presence of biofilms in patients of chronic otitis media (COM)-active squamosal disease and to evaluate the microflora and clinical impact of biofilms. METHODS: A total of 35 patients suffering from COM - active squamosal disease was studied. Cholesteatoma sample was collected at the time of mastoid surgery and the same was used to image for biofilms by scanning electron microscope. The said sample was also analyzed microbiologically. RESULTS: Biofilms were present in 25 (72%) patients including 6 cases of fungal biofilms (24%). Biofilms were detected irrespective of the micro-organism growth. No statistically significant relationship was observed between biofilms and discharging ear and complications of COM. Though univariate analysis of our data found some correlation between duration of disease, the extent of cholesteatoma and ossicular necrosis but multivariate analysis revealed no such associations, thereby implying a doubtful association between these factors and biofilm. CONCLUSIONS: Biofilms are an integral part of cholesteatoma ear disease and sometimes harbors fungal isolates.

Evaluation and Management of Early Onset Genetic Obesity in Childhood.

One in five children and adolescents in the United States are diagnosed with obesity and nearly 6% of them are being classified under the severe obesity category. With over 7% of severe obesity being attributed to genetic disorders, in this review we aim to focus on monogenic and syndromic obesity: its etiology, wide spectrum of clinical presentation, criticalness of early identification, and limited management options. Advanced genetic testing methods including microarray and whole genome sequencing are imperative to identify the spectrum of mutations and develop targeted treatment strategies including personalized multidisciplinary care, use of investigational drugs, and explore surgical options in this unique subset of severe pediatric obesity.

Obesity and Metabolic Care of Children of South Asian Ethnicity in Western Society.

South Asians constitute one-fourth of the world's population and are distributed significantly in western countries. With exponentially growing numbers, childhood obesity is of global concern. Children of South Asian ancestry have a higher likelihood of developing obesity and associated metabolic risks. The validity of commonly used measures for quantifying adiposity and its impact on metabolic outcomes differ by race and ethnicity. In this review we aim to discuss the validity of body mass index (BMI) and other tools in screening for adiposity in South Asian children. We also discuss the prevalence of overweight and obesity amongst South Asian children in western countries and the differences in body fat percentage, adiposity distribution, and metabolic risks specific to these children compared to Caucasian children. South Asian children have a characteristic phenotype: lower lean mass and higher body fat percentage favoring central fat accumulation. Hence, BMI is a less reliable predictor of metabolic status in these children than it is for Caucasian children. Furthermore, the relatively lower birth weight and rapid growth acceleration in early childhood of South Asian children increase the risk of their developing cardiometabolic disorders at a younger age than that of Caucasians. We emphasize the need to use modified tools for assessment of adiposity, which take into consideration the ethnic differences and provide early and appropriate intervention to prevent obesity and its complications.

Bariatric surgery in the treatment of adolescent obesity: current perspectives in the United States.

Introduction: Rates of severe obesity in adolescents have increased at an alarming rate. Unfortunately, there are limited successful treatments for severe obesity in adolescents. Metabolic and bariatric surgery (MBS) is the most effective treatment available for adolescents with Class 2 and above severe obesity and has demonstrated variable degrees of sustained long-term weight loss which leads to resolution of multiple associated conditions and an improved quality of life.Areas covered: We discuss the current landscape of MBS in adolescents and evidence to support its long-term safety and efficacy. A literature search through PubMed, ResearchGate and HOLLIS Harvard Library Online Catalog was performed from the date of inception until 3/15/2021. A combination of the following keywords was used: Pediatric metabolic/bariatric surgery; long term outcomes of Pediatric metabolic/bariatric surgery, perioperative assessment, pediatric metabolic/bariatric surgery barriers; attitudes toward metabolic/bariatric surgery.Expert opinion: MBS is emerging as a safe and effective treatment strategy for adolescents with severe obesity, with recent studies demonstrating durable and sustainable weight loss. There remains an urgent need for longitudinal studies to assess durability of weight loss. Obesity stigma and bias, limited access to tertiary care centers, and skepticism around the treatment of obesity poses a major challenge.

Adult obesity and its complications: a pediatric disease?

PURPOSE OF REVIEW: Approximately 2.6 million people die each year secondary to obesity related diseases. The risk of developing serious comorbidities depends on the age of onset as well as duration of obesity. In this review, we discuss trends in BMI trajectories from early childhood to adulthood with latest evidence on comorbidities in adulthood stemming from pediatric obesity and benefits of early intervention and treatment in childhood obesity. RECENT FINDINGS: Childhood obesity poses high risk of metabolic and cardiovascular disorders like type 2 diabetes, hypertension, atherosclerosis, coronary artery disease, and some types of cancer in adulthood. Early life obesity also increases risks of developing menstrual irregularities, infertility, and pregnancy complications. Several grave concerns including malignancies, autoimmune disorders, higher asthma morbidity, and psychiatric implications are found to be associated with childhood obesity. Disease outcomes can be transgenerational, causing suboptimal health in children of mothers with obesity. Encouragingly, many risks associated with childhood obesity can be reduced, delayed, or even reversed by early resolution of obesity necessitating close BMI monitoring and treatment early. SUMMARY: Early identification and aggressive management of childhood obesity is critical in prevention of debilitating comorbidities in adult life. VIDEO ABSTRACT: http://links.lww.com/COE/A19.

Pharmacotherapy in pediatric obesity: current evidence and landscape.

PURPOSE OF REVIEW: Childhood obesity is escalating globally. Lifestyle and behavioral changes, which are the frequently used interventions in clinical practice, lead to only modest improvements in children with established obesity. Bariatric surgery is currently the most effective obesity treatment but has very limited utilization in pediatric obesity and is preferentially used for children with worsening comorbidities. There exists a massive treatment gap for children suffering with obesity especially after the failure of lifestyle modifications. Pharmacotherapy that is an established management tool in adults is very infrequently used in children. Only two medications, Phentermine and Orlistat are approved by the Food and Drug Administration (FDA) for use in adolescent obesity. Herein, we discuss the current landscape and available literature on the use of antiobesity pharmacotherapy in children. RECENT FINDINGS: There are emerging pediatric data about the efficacy of the many weight loss medications that are FDA approved in adults. Moreover, more clinical trials are underway on the rarer, intractable forms of obesity such as monogenic, syndromic, and hypothalamic obesity. SUMMARY: Weight loss medications in children, like adults, have variable efficacy and similar side effect profiles. Rigorous research and improved education of providers about weight loss medications may address the huge treatment gap in severe pediatric obesity.

The role of Helicobacter Pylori and laryngopharyngeal reflux in recurrent tonsillitis.

OBJECTIVES: To detect Helicobacter Pylori [HP] in tonsillar tissue of recurrent tonsillitis cases and assess the possible role of Laryngopharyngeal reflux [LPR] in tonsillar HP infection. METHODS: A prospective study was done on the cited subject in a sample size of 50 paediatric patients [Age group: 6-18 years] suffering from recurrent tonsillitis. LPR was diagnosed by Reflux Symptom index [RSI] and Reflux Finding score [RFS]. A score of more than 7 and 13 was regarded as significant for RFS and RSI respectively. Patients with both scores significant were regarded to be suffering from LPR. Tonsillar specimen after tonsillectomy were subjected to urease test, histopathology [ Modified Giemsa Staining] and culture to detect HP. A minimum of two positive tests of the mentioned three were taken as gold standard to diagnose colonization of HP. Tabulated data was statistically analysed. RESULTS: We recorded an incidence of 9% [18 cases] for LPR in recurrent tonsillitis. No case of HP colonization of tonsils was detected in this case series, even in patients of LPR. CONCLUSION: We conclude that tonsils are not an extra gastric reservoir of HP. In addition, there is no aetiological relationship between recurrent tonsillitis and HP. And lastly, LPR is not a significant factor for colonization of tonsils by HP.

Circumferential Subannular Tympanoplasty: Panacea for revision tympanoplasty.

OBJECTIVE: To evaluate the role of Circumferential Subannular Tympanoplasty [CST] in cases of Revision tympanoplasty. METHODS: A retrospective statistical analysis of data of 81 patients who underwent revision tympanoplasty with CST technique [essentially Type I tympanoplasty] was done. An intact graft at the end of 6 months was regarded as a surgical success. RESULTS: Overall, we recorded a surgical success rate of 97.5% [79 out of 81 cases] with a 100% surgical success for anterior perforations. There was no impact of size or site of perforation on the outcomes of revision tympanoplasty by this technique. In addition, a statistically significant hearing improvement was recorded in the study. The mean pre-operative and post-operative ABG were 33.85 dB and 18.87 dB respectively. The mean ABG closure was 14.89 dB. The value of "p" by Chi square test was found to <.05. CONCLUSION: CST is an excellent technique for revision tympanoplasty and seems to address the shortcomings of conventional onlay and inlay techniques.

Comparison of Measured and Estimated Resting Energy Expenditure in Adolescents and Young Adults With Severe Obesity Before and 1 Year After Sleeve Gastrectomy.

Introduction: Resting energy expenditure (REE) is often evaluated in adults and adolescents with obesity to estimate caloric requirements when advising dietary changes. However, data are lacking regarding the accuracy of methods used to clinically assess REE in adolescents with severe obesity. Moreover, there are no data regarding the effects of sleeve gastrectomy (SG) on REE in adolescents. We evaluated the accuracy and error rate between estimated and measured REE in adolescents with severe obesity and changes in REE following (SG). Materials and Methods: Cross-sectional study (CSS): 64 adolescents and young adults, 14-22 years old, with moderate to severe obesity were enrolled. We measured REE (mREE) by indirect calorimetry and estimated REE (eREE) using Derumeaux (Deru), Mifflin-St Jeor (MS), Harris Benedict (HB), and World Health Organization (WHO) equations. DXA was used to determine body composition. Bland Altman analysis evaluated agreement between eREE and mREE. Longitudinal study: 12 subjects had repeat indirect calorimetry and DXA 1 year after SG. Longitudinal analysis was used to assess changes in REE and body composition. Results: CSS: Median BMI was 45.2 kg/m2 and median age was 18.0 (16.3-19.9) years. mREE correlated strongly with eREE . Bland Altman analysis demonstrated that only a few points were beyond the 1.96 SD limit of disagreement. However, there was considerable overestimation of mREE by most equations. Longitudinal Study: In the subset that underwent SG, after 12-months, absolute REE decreased from 1709 (1567.7-2234) to 1580.5 (1326-1862.5) Calories (p = 0.002); however, the ratio of REE/Total Body Weight (TBW) increased from 13.5 ± 2.3 at baseline to 15.5 ± 2.2 at 1 year (p = 0.043). When evaluating parameters affecting % total weight loss, we found that it correlated positively with REE/TBW at 12 months (R = 0.625; p = 0.03) and negatively with % fat mass at 12 months (R = -0.669; p = 0.024). Discussion: In adolescents with moderate-severe obesity, despite a correlation between mREE using indirect calorimetry and eREE using the Deru, MS, HB, and WHO equations, there is significant over-estimation of REE at the individual level, challenging their clinical utility. One year after SG, REE/TBW increased and strongly correlated with % total weight loss in adolescents.

Suboptimal bone microarchitecure in adolescent girls with obesity compared to normal-weight controls and girls with anorexia nervosa.

BACKGROUND: Despite their higher areal bone mineral density (aBMD), adolescents with obesity (OB) have an increase in fracture risk, particularly of the extremities, compared with normal-weight controls. Whereas bone parameters that increase fracture risk are well characterized in anorexia nervosa (AN), the other end of nutritional spectrum, these data are lacking in adolescents with obesity. OBJECTIVE: Our objective was to compare bone parameters in adolescent girls across the nutritional spectrum, to determine whether suboptimal bone adaptation to increased body weight may explain the increased fracture risk in OB. METHODS: We assessed bone endpoints in 153 adolescent girls 14-21 years old: 50 OB, 48 controls and 55 AN. We used (i) DXA to assess aBMD at the lumbar spine, proximal femur and whole body, and body composition, (ii) high resolution peripheral quantitative CT (HRpQCT) to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and (iii) finite element analysis to assess failure load (a strength estimate) at the distal radius and tibia. All aBMD, microarchitecture and FEA analyses were controlled for age and race. RESULTS: Groups did not differ for age or height. Areal BMD Z-scores at all sites were highest in OB, intermediate in controls and lowest in AN (p < 0.0001). At the radius, cortical area and thickness were higher in OB compared to AN and control groups (p = 0.001) while trabecular area did not differ across groups. Compared to controls, OB had higher cortical porosity (p = 0.003), higher trabecular thickness (p = 0.024), and higher total, cortical and trabecular vBMD and rod BV/TV (p < 0.04). Plate BV/TV did not differ in OB vs. controls, but was higher than in AN (p = 0.001). At the tibia, total, cortical, and trabecular area and cortical thickness were higher in OB vs. controls and AN (p < 0.005). OB also had higher cortical porosity (p < 0.007) and lower trabecular thickness (p < 0.02) than the other two groups. Trabecular number, total and trabecular vBMD, and rod BV/TV were higher in OB vs. controls and AN (p < 0.02), while cortical vBMD and plate BV/TV did not differ in OB vs. the other two groups. Finally, failure load (a strength estimate) was higher in OB at the radius and tibia compared to controls and AN (p < 0.004 for all). However, after adjusting for body weight, failure load was lower in OB vs. controls at both sites (p < 0.05), and lower than in AN at the distal tibia. CONCLUSION: Not all bone parameters demonstrate appropriate adaptation to higher body weight. Cortical porosity and plate BV/TV at the radius and tibia, and cortical vBMD and trabecular thickness at the tibia are particularly at risk. These effects may contribute to the higher risk for fracture reported in OB vs. controls.