Burosumab: Current status and future prospects.

Hypophosphatemic rickets/osteomalacia caused by FGF23 excess is conventionally treated with multiple doses of inorganic phosphate salts and active vitamin D analogs. However, conventional therapy targets the consequences of elevated FGF23 and not the elevated FGF23 itself and is associated with poor adherence and long-term complications such as nephrocalcinosis and secondary/tertiary hyperparathyroidism. Burosumab is a fully human IgG1 monoclonal antibody that binds to and neutralises FGF-23, thereby leading to improvement in phosphate homeostasis and healing of rickets and osteomalacia. Data from phase 2 and 3 trials report overall safety and efficacy and Burosumab is now FDA approved for treatment of XLH and TIO in children and adults. Cost and absence of long-term data are major issues with Burosumab which should be addressed in near future. At present, experts recommend Burosumab use in patients with severe disease or those with mild-moderate disease and a failed response to a trial of conventional therapy.

Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery.

68Ga-DOTANOC PET/CT for Screening and Surveillance of Von Hippel-Lindau (VHL) disease.

Purpose: Hereditary tumor syndrome Von Hippel-Lindau (VHL) disease is characterized by various benign and malignant tumors that are known to express somatostatin receptors (SSTR). We evaluated the role of 68Ga-DOTANOC PET/CT scan in patients with positive germline mutation of the VHL gene, presented initially or on follow-up, for the detection of recurrent or synchronous/metachronous lesions. Methods: Fourteen patients (8 males; 6 females) with mean age 30 ± 9.86 years were retrospectively analyzed, were tested positive for VHL on gene dosage analysis, and underwent 68 Ga-DOTANOC PET/CT scan for disease evaluation. The number and site of lesions were determined. The tracer uptake was analyzed semi-quantitatively by calculating the maximum standardized uptake values (SUVmax) of lesion. Results: Four of the 14 patients underwent scan for initial diagnosis as baseline, 6 patients for post-therapy disease status, and 4 patients for initial diagnosis as well as follow-up evaluation of the disease. A total of 67 lesions were detected in 14 patients. The sites of lesions were cerebellar/vertebral/spinal (17; mean SUVmax = 7.85); pancreatic neuroendocrine tumor (NET) (11; mean SUVmax = 20.64); retina (3; mean SUVmax = 10.46); pheochromocytoma (10; mean SUVmax = 16.32); paragangliomas (3; mean SUVmax = 10.65); pancreatic cyst (9; mean SUVmax = 2.54); and renal cyst (8; mean SUVmax = 1.56) and miscellaneous lesions constituted 6 lesions. Conclusion: Our results show that 68 Ga-DOTANOC PET/CT may be a useful modality for screening and follow-up of associated tumors in patients with germline gene mutation for VHL. It can be used as a one-stop imaging modality for VHL patients and may substitute for separate radiological investigations, making it more convenient for patients in terms of time and cost.

Clinical profile and treatment outcomes among patients with sporadic and multiple endocrine neoplasia syndrome-related primary hyperparathyroidism.

OBJECTIVE: Accurate demarcation between multiple endocrine neoplasia, type 1 (MEN1)- related primary hyperparathyroidism (MPHPT) and sporadic PHPT (SPHPT) is important to plan the management of primary parathyroid disease and surveillance for other endocrine and nonendocrine tumours. The objective of this study is to compare the clinical, biochemical and radiological features and surgical outcomes in patients with MPHPT versus SPHPT and to identify the predictors of MEN1 syndrome in PHPT. DESIGN, PATIENTS AND MEASUREMENTS: This was an ambispective observationalstudy involving 251 patients with SPHPT and 23 patients with MPHPT evaluated at the endocrine clinic of All India Institute of Medical Sciences, New Delhi, India between January 2015 and December 2021. RESULTS: The prevalence of MEN1 syndrome among patients with PHPT was 8.2% and a genetic mutation was identified by Sanger sequencing in 26.1% of patients with MPHPT. Patients with MPHPT were younger (p < .001), had lower mean serum calcium (p = .01) and alkaline phosphatase (ALP; p = .03) levels and lower bone mineral density (BMD) Z score at lumbar spine (p < .001) and femoral neck (p = .007). The prevalence of renal stones (p = .03) and their complications (p = .006) was significantly higher in MPHPT group. On multivariable analysis, factors predictive of MPHPT were hyperplasia on histopathology [OR 40.1, p < .001], ALP levels within reference range [OR 5.6, p = .02] and lumbar spine BMD [OR 0.39 per unit increase in Z score, p < .001]. CONCLUSIONS: Patients with MPHPT have more severe, frequent and early onset of bone and renal involvement despite milder biochemical features. A normal serum ALP, low BMD for age and gender at lumbar spine and histopathology evidence of hyperplasia are predictive factors for MEN1 syndrome in PHPT.

Imaging characteristics of phosphaturic mesenchymal tumors.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with phosphaturic mesenchymal tumors (PMTs). Localization of the causative tumor in these cases is an arduous task since the culprit lesions are usually small, slow-growing, and can be located almost anywhere from head to toe. PURPOSE: To describe the morphological characteristics of histologically proven PMTs on various radiological modalities. MATERIAL AND METHODS: After institutional ethical approval, this retrospective study analyzed 20 cases with a histopathological evidence of PMT. Various imaging characteristics of the tumors on available computed tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated. Descriptive statistical analyses were conducted. RESULTS: The tumors were located in diverse locations: lower extremities (n = 10); head and neck (n = 5); vertebral column (n = 3); pelvis (n = 1); and upper extremities (n = 1). Bone lesions seen on CT had variable morphology: sclerotic (n = 3/8, 37.5%); lytic (n = 3/8, 37.5%), and both lytic and sclerotic (n = 2/8, 25%) with presence of narrow zone of transition in all cases (n = 8/8) and amorphous internal matrix calcifications in 25% of cases (n = 2/8). Of the tumors, 68.4% (n = 13/19) were hypointense on T1 and all of them showed hyperintense signal on T2-weighted and STIR images (n = 19/19) and contrast enhancement (n = 16/16). Of the tumors, 66.7% (n = 6/9) showed restricted diffusion. DOTANOC PET/CT showed tumor uptake in all cases (n = 8/8). CONCLUSION: PMTs may have variable and non-specific tumor appearances on various imaging modalities. However, in an appropriate clinical scenario and a background of suggestive biochemical work-up, the radiologist should keep a high index of suspicion.

Clinical profile and treatment outcomes of patients with ectopic ACTH syndrome compared to Cushing disease: a single-center experience.

PURPOSE: We aimed to evaluate and compare the clinical, biochemical and radiological profile and outcomes of patients with ectopic ACTH syndrome (EAS) and Cushing disease (CD) treated over a period of 10 years (2013-2022). METHODS: In this ambispective observational study, we collected data for 146 patients with ACTH-dependent CS (EAS, n = 23; CD, n = 94; occult ACTH source, n = 29). Relevant details were filled in a predesigned proforma and outcomes were ascertained at the most recent visit. RESULTS: EAS was more common in males (65.2 vs. 27.6%, p < 0.001). Patients with EAS had a shorter duration of symptoms [12 (6-12) vs. 31.5 (15-48) months, p < 0.001] and were more likely to have hypokalemia (82.6 vs. 21.0%, p = 0.001), pedal edema (65.2 vs. 34.2%, p = 0.015), weight loss (34.8 vs. 4.0%, p < 0.001) and systemic infection (30.4 vs. 6.5%, p = 0.006). They also had significantly higher 8 a.m. serum cortisol, midnight serum and salivary cortisol and 8 a.m. plasma ACTH levels. Bronchial carcinoid (n = 10, 43.5%) was the most common etiology of EAS. Bilateral adrenalectomy was performed in 11 (47.8%) patients with EAS. Eight patients (34.8%) with EAS died at the last follow-up, of whom 7 (87.5%) had metastatic disease. In CD group, overall remission rate was 69.4% (56.1%, early and 13.3%, delayed) and 26.3% of patients with an initial remission had recurrence. CONCLUSIONS: Bronchial carcinoid was the most common cause of EAS in our cohort. Bilateral adrenalectomy was performed in approximately every 1 in 2 patients with EAS and approximately every 1 in 3 patients expired till the last follow-up.

Clinical profile of ChAdOx1 nCoV-19- and BBV152-vaccinated individuals among hospitalized COVID-19 patients: a pair-matched study.

Background: COVID-19 infections among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-vaccinated individuals are of clinical concern, especially in those requiring hospitalization. Such real-world data on ChAdOx1 nCoV-19- and BBV152-vaccinated individuals are scarce. Hence, there is an urgent need to understand their clinical profile and outcomes. Methods: A 1:1 pair-matched study was performed among vaccinated and unvaccinated COVID-19 patients admitted between March 2021 and June 2021 at a tertiary care centre in New Delhi, India. The vaccinated group (received at least one dose of ChAdOx1 nCoV-19 or BBV152) was prospectively followed till discharge or death and matched [for age (±10 years), sex, baseline disease severity and comorbidities] with a retrospective group of unvaccinated patients admitted during the study period. Paired analysis was done to look for clinical outcomes between the two groups. Results: The study included a total of 210 patients, with 105 in each of the vaccinated and unvaccinated groups. In the vaccinated group, 47 (44.8%) and 58 (55.2%) patients had received ChAdOx1 nCoV-19 and BBV152, respectively. However, 73 patients had received one dose and 32 had received two doses of the vaccine. Disease severity was mild in 36.2%, moderate in 31.4% and severe in 32.4%. Two mortalities were reported out of 19 fully vaccinated individuals. All-cause mortality in the vaccinated group was 8.6% (9/105), which was significantly lower than the matched unvaccinated group mortality of 21.9% (23/105), p = 0.007. Vaccination increased the chances of survival (OR = 3.8, 95% CI: 1.42-10.18) compared to the unvaccinated group. Conclusion: In the second wave of the pandemic predominated by delta variant of SARS CoV-2, vaccination reduced all-cause mortality among hospitalized patients, although the results are only preliminary.

Spontaneous Remission of Acromegaly After Pituitary Apoplexy in a Middle-Aged Male.

Background: Pituitary apoplexy results from hemorrhage, infarction, or hemorrhagic infarction within a pituitary tumor. Subclinical or clinical apoplexy is not uncommon in acromegaly, owing to the large size of the tumor at initial detection. Growth hormone excess in acromegaly often persists following surgery. However, in rare instances, pituitary apoplexy may present a spontaneous cure to growth hormone excess. Case Report: A 40-year-old male presented with holocranial headache for the past 16 years that had worsened in severity during the prior year. Two months before presentation, he experienced a severe headache that he described as the worst headache of his life. The patient had prominent acromegaloid features that he ignored, as they seemed to cause no harm. The patient had no signs of clinically active disease. Magnetic resonance imaging of the brain revealed a pituitary macroadenoma with evidence of hemorrhage. Serum insulin-like growth factor 1 and oral glucose-suppressed serum growth hormone levels were normal, suggestive of inactive or silent disease. Pituitary apoplexy causing spontaneous remission of acromegaly was diagnosed, and close follow-up was planned for the evolution of hypopituitarism. Conclusion: This case highlights a rare presentation of acromegaly in which an episode of symptomatic pituitary apoplexy revealed the diagnosis of pituitary adenoma and led to the cure of growth hormone hypersecretion.

Formative research to develop diabetes self-management education and support (DSMES) program for adults with Type 1 Diabetes.

BACKGROUND AND AIM: There is a lack of data on effectiveness of diabetes self-management education and support (DSMES) programs for South Asian adults with type 1 diabetes mellitus (T1DM). This formative research was conducted to explore existing practices on the said subject and gather information for planning an intervention program. METHODS AND MATERIALS: We conducted in-depth semi-structured interviews with endocrinologists, dieticians, diabetes educators and adults with T1DM. The participants were selected from a mix of public and private health facilities. Thematic analysis using inductive and deductive approach was undertaken. The intervention was developed and refined using the principles of FUSED and COM-B models. RESULTS: In total, 28 in-depth interviews were conducted, 18 with health care professionals and 10 with adult individuals with T1DM. The results demonstrated deficiencies in the implementation of a structured self-management program for diabetes owing to several patient and healthcare system-related factors. A detailed nutritional counseling was provided at all sites by a qualified dietitian, however, carbohydrate counting was not routinely practiced. The interviews of this formative research revolved around: (a) evaluation of the existing usual care and gaps in implementation of a structured DSMES program, and (b) development of themes that will help in formulation of an intervention package and its effective delivery to the participants. CONCLUSION: This research study comprehensively investigated the existing practices among diabetes-health care professionals caring for persons living with T1DM and rendered insights towards development of a scientific DSMES program.

A guidance on diagnosis and management of hyperglycemia at COVID care facilities in India.

BACKGROUND AND AIMS: Diabetes and coronavirus disease 2019 (COVID-19) share a bidirectional relationship. Hyperglycemia occurring in the setting of either previously diagnosed or undiagnosed diabetes is known to be associated with poor outcomes. Here, we aim to provide a simple and practical guidance on the diagnosis and management of hyperglycemia in admitted patients with COVID-19. METHODS: The guidance is formulated based on experience of authors and relevant literature on the subject searched using Pubmed. RESULTS: Every patient admitted to a COVID care facility should be investigated for hyperglycemia using a combination of tests including capillary blood glucose, fasting plasma glucose and HbA1c. Oral glucose lowering drugs can be considered in patients with mild COVID illness who have mild hyperglycemia [pre-meal blood glucose of <180 mg/dl (10 mmol/L) and post-meal blood glucose of <250 mg/dl (13.9 mmol/L)] and no contraindication to the use of these agents.. All patients with moderate-severe disease and/or hyperglycemia of greater severity should be initiated on insulin therapy. Hyperglycemia should be aggressively screened for and managed in patients receiving systemic glucocorticoids. CONCLUSION: This document provides a broad overview on the diagnosis and management of hyperglycemia at COVID care facilities and should be useful to a wide range of healthcare personnel involved in care of patients with COVID-19.

Is surgery effective for treating hypothalamic hamartoma causing isolated central precocious puberty? A systematic review.

The aim of this review was to determine the role of surgery in treating hypothalamic hamartoma (HH) causing isolated central precocious puberty (CPP). Literature review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patients with isolated CPP due to HH, managed with surgical resection, were included. We found 33 studies, reporting 103 patients (76 pedunculated, 27 sessile). Patients were considered "cured" if the symptoms of PP had regressed and the hormone profile had normalized after surgery. Indications for surgery included hamartoma deemed surgically resectable (n-12), for the purpose of tissue diagnosis (n-3), partial response/failure of preoperative therapy (n-9), and unable to afford/to avoid long-term medical therapy (n-7). The extent of resection was total (TR) (n-39), near total/subtotal (NTR/STR) (n-20), partial (PR) (n-35), or unspecified (n-9). On follow-up (range: 3 months-16 years), 73.6% (56/76) of patients with pedunculated HH were cured, while 17.1% (13/76) had partial relief. Only 3/27 (11.1%) of patients with sessile HH were cured. All patients with a pedunculated hamartoma who underwent TR (n=36) improved, with 88.88% cured of the symptoms. Surgery had no effect in 17/23 (73.9%) patients with sessile HH who underwent PR. Psychological symptoms improved in 10/11 patients. There was no mortality. Permanent complications, in the form of 3rd nerve palsy, occurred in 3.7% (2/54) of the patients. To conclude, in the current era of availability of GnRH analogs, surgical resection in a subset of patients may be acceptable especially for small pedunculated hamartomas.

Primary Sjögren's syndrome manifesting as sclerotic metabolic bone disease.

Primary Sjögren's syndrome (pSS) is a chronic slowly progressive autoimmune disease characterised by lymphocytic infiltration of salivary and lacrimal glands with varying degree of systemic involvement. Renal involvement, a recognised extraglandular manifestation of pSS, is commonly related to tubular dysfunction and generally manifests as distal renal tubular acidosis (RTA), proximal RTA, tubular proteinuria and nephrogenic diabetes insipidus. Untreated long-standing RTA is known to cause metabolic bone disease. Here, we present the report of a patient with sclerotic metabolic bone disease related to pSS with combined distal and proximal RTA and negative workup for other causes of sclerotic bone disease. A significant clinical and biochemical improvement, including recovery of proximal tubular dysfunction, was noted with alkali therapy. This case suggests the need to consider pSS in the diagnostic algorithm of a patient presenting with sclerotic bone disease.

Hyperplastic thyroid nodule masquerading as parathyroid adenoma in a patient with tubercular lymphadenitis induced hypercalcaemia.

Serum intact parathyroid hormone (iPTH) levels are high or high normal in patients with parathyroid adenoma. Rarely these patients can have normal or low serum iPTH values. With sandwich immunometric assays, an exceptionally high serum iPTH level can lead to falsely low measurement due to the 'hook effect'. Here, we describe the case of a 66-year-old female patient with PTH-independent hypercalcaemia which mimicked parathyroid adenoma. A multidisciplinary team approach helped in the diagnosis and management leading to complete recovery.

46, XY complete gonadal dysgenesis with pubertal virilisation due to dysgerminoma/gonadoblastoma.

Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.

Anticancer Drug-induced Thyroid Dysfunction.

Cancer immunotherapy and targeted therapy, though less toxic than conventional chemotherapy, can increase the risk of thyroid dysfunction. Immune checkpoint inhibitors render the cancer cells susceptible to immune destruction, but also predispose to autoimmune disorders like primary hypothyroidism as well as central hypothyroidism secondary to hypophysitis. Tyrosine kinase inhibitors act by blocking vascular endothelial growth factor receptors and their downstream targets. Disruption of the vascular supply from the inhibition of endothelial proliferation damages not only cancer cells but also organs with high vascularity like the thyroid. Interferon-α, interleukin-2 and thalidomide analogues can cause thyroid dysfunction by immune modulation. Alemtuzumab, a monoclonal antibody directed against the cell surface glycoprotein CD52 causes Graves' disease during immune reconstitution. Metaiodobenzylguanidine, combined with 131-iodine, administered as a radiotherapeutic agent for tumours derived from neural crest cells, can cause primary hypothyroidism. Bexarotene can produce transient central hypothyroidism by altering the feedback effect of thyroid hormone on the pituitary gland. Thyroid dysfunction can be managed in the usual manner without a requirement for dose reduction or discontinuation of the implicated agent. This review aims to highlight the effect of various anticancer agents on thyroid function. Early recognition and appropriate management of thyroid disorders during cancer therapy will help to improve treatment outcomes.

Spontaneous Conception, Pericardial Effusion, and Pseudohypertrophic Myopathy Mimicking Muscular Dystrophy in Delayed Presentation of Sheehan Syndrome.

Sheehan syndrome, characterized by postpartum pituitary necrosis, is an important cause of hypopituitarism in developing countries. We report the case of a 50-year-old female with Sheehan syndrome, who had two spontaneous conceptions following severe postpartum hemorrhage in her first delivery and presented 27 years later with moderate pericardial effusion and features of pseudohypertrophic myopathy mimicking muscular dystrophy.