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Abstract The ChAdOx1 nCoV-19 (COVISHIELD) vaccine has emerged as a pivotal tool in the global fight against the COVID-19 pandemic. In our previous study eligible subjects were supplemented with calcifediol, a direct precursor to the biologically active form of vitamin D, calcitriol with an objective to enhance the immunogenicity of the COVISHIELD vaccine. Herein we investigated the effects of calcifediol supplementation on gene expression profiles in individuals who received the COVISHIELD vaccine. Peripheral blood mononuclear cells were isolated from vaccinated individuals with and without calcifediol supplementation at baseline, 3rd and 6th month, and the gene expression profiles were analyzed using high-throughput sequencing. The results revealed distinct patterns of gene expression associated with calcifediol supplementation, suggesting potential molecular mechanisms underlying the beneficial effects of calcifediol in improving the efficacy of COVISHIELD vaccine via augmentation of T cell activation, proliferation and T cell memory responses. Additionally, there was upregulation of NOD like receptor, JAK/STAT and TGF beta signaling pathways. Calcifediol supplementation in vaccinated individuals also downregulated the pathways related to the Coronavirus disease. Taken together, our findings provide valuable insights into the interplay between vitamin D receptor (VDR) signaling and vaccine-induced immune responses and offer another approach in improving vaccination induced antiviral responses.

Introduction: Insulinomas are rare, usually sporadic, and typically benign pancreatic neuroendocrine tumours. Pre-operative localization is challenging and evidence on comparative analysis of anatomic and scintigraphic modalities for pre-operative tumour localization is limited, even in contemporary series. Methods: The current study was designed to study the clinical features and management challenges of insulinomas managed at a tertiary care centre. Clinical features, diagnosis, imaging techniques, surgical procedures, and outcomes details were collated. Pre-operative imaging techniques (CT/MRI, nuclear scintigraphy) were compared with intraoperative and histopathological findings to assess their accuracy of localization. Results: Thirty-seven patients (15 females [42%]; median age 36 years [IQR 28–49]) were included in the study. In four patients (10.8%), the tumour occurred in the setting of multiple endocrine neoplasia type 1 (MEN 1) while the remaining were sporadic. The sensitivity of pre-operative localization was 61.5% (multiphasic CT), 66.6% (multiphasic MRI), 100% (68Ga Exendin-4 PET-CT), and 91.6% (EUS). Three patients with normal multiphasic CT had localization on 68Ga Exendin-4 PET-CT. The positive predictive value (PPV) of both Exendin-PET-CT and EUS was similar at 91.6% and 91.6%, respectively. All patients (except one with nesidioblastosis), who underwent enucleation or partial pancreatic resection, were cured. Conclusion: 68Ga Exendin-4 PET-CT based is a non-invasive imaging modality that has high sensitivity and PPV and can be used as a first-line imaging modality. The overall prognosis of these tumours is good with high cure rates attained following surgical resection.

Acromegaly due to ectopic secretion of growth hormone-releasing hormone (GHRH) is a rare disorder. The signs and symptoms of ectopic acromegaly are indistinguishable from acromegaly due to a somatotroph adenoma. A 35-year-old female presented with secondary amenorrhea for 10 years, intermittent headache, and reduced vision in both eyes for 4 years, which worsened over 4 months before presentation. Additionally, she was diagnosed with uncontrolled diabetes mellitus. On examination, she had coarse facial features, a fleshy nose, and acral enlargement. She had diminished visual acuity (left>right) and bitemporal hemianopia on perimetry. Biochemical investigations revealed elevated IGF-1 [588 ng/ml, reference range (RR) 100–242], markedly elevated basal growth hormone (>80 ng/ml; RR, 0.12–9.88), and hyperprolactinemia in the tumoral range (832 ng/ml; RR, 5–25). MRI sella demonstrated a 22×30×34mm sellar-suprasellar mass with T2 hypointensity. Chest imaging revealed a 75×87×106mm left lung mass, which was found to be a well-differentiated neuroendocrine tumor (NET) on biopsy. Plasma GHRH levels were elevated [38,088 ng/l; RR,

Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves’ disease (GD). Additional/ concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 μg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range

Background: Camurati-Engelmann disease (CED) is a rare bone dysplasia characterized by diffuse diaphyseal osteosclerosis. Skull base involvement in CED can result in hypopituitarism but is seldom reported. Our objective was to report a patient with acquired hypopituitarism due to CED and assess the management challenges. Case Report: A 20-year-old boy presented with lower limb pain. He had walking difficulty in childhood, which was diagnosed as CED and managed with prednisolone. He later discontinued treatment and was lost to follow-up. Current re-evaluation showed short stature (−3.6 standard deviation), low weight (−4.3 standard deviation), and delayed puberty with delayed bone age (13 years). He was found to have secondary hypogonadism (luteinizing hormone level, 0.1 mIU/mL [1.7-8.6 mIU/mL]; follicle-stimulating hormone level, 1.0 mIU/mL [1.5-12.4 mIU/mL]; and testosterone level, 0.087 nmol/L [9-27 nmol/L]), growth hormone deficiency (low insulin-like growth factor I level, 120 ng/mL [226-903 ng/mL] and peak growth hormone level of 7 ng/mL on insulin-induced hypoglycemia), and secondary hypocortisolism (cortisol level, 105 nmol/L [170-550 nmol/L] and adrenocorticotropic hormone level, 6 pg/mL [5-65 pg/mL]). Serum prolactin level was normal (8.3 ng/mL [5-20 ng/mL]), and he was euthyroid on levothyroxine replacement. Magnetic resonance imaging revealed a partially empty sella. Sanger sequencing revealed a missense mutation (p.R218C/c.652C>T) in exon 4 of the TGFβ1 gene. The patient was treated with zoledronate, losartan, and oral prednisolone and continued on levothyroxine and testosterone replacement, which resulted in symptomatic improvement. Discussion: The index case manifested severe CED requiring multimodality therapy. Later, he developed combined pituitary hormone deficiencies, which were managed with thyroid and gonadal hormone replacement with the continuation of glucocorticoids. The partial efficacy of bisphosphonates in CED has been reported in the literature. Conclusion: Skull base involvement in CED can lead to structural and functional hypopituitarism as a result of intracranial hypertension.

Objective: Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expr ession, according to the 2017 WHO classification. Though traditionally defined as low-grad e neoplasms, a substantial proportion of them show recurrence/persistence fo llowing surgery. Methods: We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010–2019). The c linical, radiological, hormonal, histopathological profiles and long-term outcomes of t he three cases identified (two pituicytomas and one spindle cell oncocytoma, SC O) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/ persistence in these tumours. Results: Patients presented with compressive features or hypogonadism. T wo had sellar-suprasellar masses. One had a purely suprasellar mass with a pr e-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, viment in and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration a s determinants of recurrence/persistence. Conclusion: PPTs are rare sellar masses with quintessential TTF-1 positivit y. Recurrent/ persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term su rveillance in these patients.

IntroductionAggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.MethodsThis was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.ResultsThe study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.ConclusionEarly initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.

PurposeNon-functioning pituitary adenomas (NFPAs) exhibit high recurrence rates after surgery. However, the determinants of recurrence are inconsistent in the available literature. The present study sought to investigate the association between nuclear phosphorylated EGFR (pEGFR) levels and recurrence of NFPAs.MethodsTissue microarrays from patients undergoing adenomectomy for NFPAs at our tertiary care center from 2003 to 2015 and having a minimum of 60 months of follow-up (n=102) were accessed. Immunohistochemical analysis (IHC) was performed to determine the expression of nuclear pEGFR T693. h-score was calculated as the product of staining intensity and the number of positively staining cells. Radiological surveillance (MRI) was performed to categorize NFPAs as recurrent or non-recurrent on follow-up.ResultsThe mean age of the cohort was 50 ± 11 years with a male preponderance (61.1%). Recurrence was observed in 46.1% of the patients at a median of 123 months (IQR 72-159) of follow-up. pEGFR T693 positivity was higher in a significantly greater number of recurrent NFPAs as compared to non-recurrent NFPAs (95.7% vs 81%, p=0.02). h-scores were also significantly higher in recurrent NFPAs (122.1 ± 6 vs 81.54 ± 3.3, p

IntroductionEvidence on new-onset endocrine dysfunction and identifying whether the degree of this dysfunction is associated with the severity of disease in patients with COVID-19 is scarce.Patients and MethodsConsecutive patients enrolled at PGIMER Chandigarh were stratified on the basis of disease severity as group I (moderate-to-severe disease including oxygen saturation 94% and without comorbidities) (n=49). Hypothalamo-pituitary-adrenal, thyroid, gonadal axes, and lactotroph function were evaluated. Inflammatory and cell-injury markers were also analysed.ResultsPatients in group I had higher prevalence of hypocortisolism (38.5 vs 6.8%, p=0.012), lower ACTH (16.3 vs 32.1pg/ml, p=0.234) and DHEAS (86.29 vs 117.8µg/dl, p= 0.086) as compared to group II. Low T3 syndrome was a universal finding, irrespective of disease severity. Sick euthyroid syndrome (apart from low T3 syndrome) (80.9 vs 73.1%, p= 0.046) and atypical thyroiditis (low T3, high T4, low or normal TSH) (14.3 vs 2.4%, p= 0.046) were more frequent in group I than group II. Male hypogonadism was also more prevalent in group I (75.6% vs 20.6%, p=0.006) than group II, with higher prevalence of both secondary (56.8 vs 15.3%, p=0.006) and primary (18.8 vs 5.3%, p=0.006) hypogonadism. Hyperprolactinemia was observed in 42.4% of patients without significant difference between both groups.ConclusionCOVID-19 can involve multiple endocrine organs and axes, with a greater prevalence and degree of endocrine dysfunction in those with more severe disease.

AimsInflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation.MethodsForty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence.ResultsThirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up.ConclusionBisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar.Trial registrationClinicalTrials.gov: NCT03289338.

Aims Inflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation. Methods Forty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence. Results Thirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up. Conclusion Bisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar. Trial registration ClinicalTrials.gov:NCT03289338.

ABSTRACT: Objective: Vasculotoxic envenomation is an uncommon cause of hypopituitarism. Most described cases have varying extent of anterior pituitary dysfunction, but posterior pituitary involvement is extremely rare. Methods: Clinical, biochemical, and radiologic evaluation of a young female who presented with secondary amenorrhea was performed. A brief literature review of envenomation-induced hypopituitarism is included. Results: A 26-year-old female presented with secondary amenorrhea since the age of 20 years. She had normal stature. Her past medical history was significant for a vasculotoxic snakebite 12 years back requiring hemodialysis, but no hormonal testing was done at that time. Current evaluation showed anterior hypopituitarism. An insulin-induced hypoglycemia test confirmed deficiencies of cortisol and growth hormone axes (peak values 348 nmol/L and 0.03 ng/mL). There was no diabetes insipidus. Magnetic resonance imaging revealed a hypoplastic anterior pituitary with an ectopic posterior pituitary. In view of normal stature and secondary amenorrhea, a diagnosis of envenomation-induced hypopituitarism with ectopic posterior pituitary (EPP) was made. A brief literature review of envenomation-induced hypopituitarism showed both acute and delayed presentation, male predominance, and variable lag period (weeks to years). Nearly half of all patients were asymptomatic. The most common axis involved in acute presentation was the cortisol axis, whereas the thyroid and gonadotroph axes were commonly involved in delayed hypopituitarism. Conclusion: Vasculotoxic envenomation is a rare cause of acquired hypopituitarism. EPP in the index case was probably due to the “axonal dieback” phenomenon and subsequent regeneration of the axons at a more caudal site. This case, being the first instance of acquired EPP following envenomation, expands the spectrum of envenomation-induced hypopituitarism. Abbreviations: EPP ectopic posterior pituitary HRT hormone replacement therapy

Introduction: Spondylo-epi-metaphyseal dysplasia (SEMD) represents a group of osteo-chondrodysplasias characterized by vertebral, epiphyseal as well as metaphyseal abnormalities. Several genes have been identified underlying the different forms. Methodology and results: Two relatives (cousins) in a family were found to have disproportionate short stature with clinical and radiological features suggestive of SEMD. Metabolic bone profile was normal including parathyroid hormone and 25(OH)vitamin D3. Exome sequencing revealed a missense mutation (p. T120M) in the von-Willebrand factor A-domain of the Matrilin 3 (MATN3) gene that segregates with the disease in the family. Conclusion: We identified a homozygous missense mutation in MATN3, an important structural component of the extracellular matrix of cartilage, as the genetic cause of SEMD in this pedigree. MATN3 mutations have been more commonly associated with multiple epiphyseal dysplasia than SEMD. Recognition of this mutation will aid in enhancing the understanding and expanding the spectrum of this particular skeletal dysplasia.

Context: Glycated hemoglobin A 1 c (HbA 1 c) indicates long-term uncontrolled hyperglycemia in the body, which in diabetic patients leads to various vascular complications as a part of generalized atherosclerosis culminating ultimately into ischemic stroke. Aims: Study aims to show the association between marker of uncontrolled long-term hyperglycemia HbA 1 c and marker of atherosclerosis (Carotid intima media thickness [CIMT] and carotid plaque) in ischemic stroke patients. Subjects and Methods: Carotid sonography using high resolution 7.5 MHz sonography technique was done in each patient to find the occurrence of increased CIMT and presence of plaque according to Mannheim CIMT Consensus (2004-2006). Levels of HbA 1 c measured in blood in both diabetic and non-diabetic patients and a comparison made between them. Finally an association sought between HbA 1 c levels with CIMT and plaque. Results: The average value of HbA 1 c of this cohort was 7.51 ± 1.75% with higher values in diabetic patients (9.29 ± 1.73%). The patients with high CIMT (>0.8 mm) had higher values of HbA 1 c then that of normal CIMT patients and this was nearly significantly (P = 0.06). However, HbA 1 c levels of blood were significantly associated with stroke patients with presence of carotid arteries plaque (P = 0.008). Conclusions: Prediction of future risk and prevention strategies for ischemic stroke could be formulated by utilizing HbA 1 c levels in both diabetic and non-diabetic population.

Malignant peripheral nerve sheath tumor (MPNST) is a rare variety of soft-tissue sarcoma of ecto-mesenchymal origin. Various sites have been mentioned, but it is rare in cauda equina. Only five cases of MPNST of cauda equina are reported till date. A 42-year-old male presented with complaints of weakness in lower limbs for last 5 months with bladder and bowel dysfunction. On magnetic resonance imaging, an isointense lesion on T1 and a hyperintense on T2 imaging was found at terminal spinal cord level. The lesion was excised following laminectomy and showed varied cellularity with thin oval, polyhedral and spindle-shaped cells arranged in bundles on microscopic examination suggesting MPNST. MPNST of cauda equina is rare and is associated with Neurofibromatosis Type-1 or radiation exposure, but is rarer without these risk factors. Prognosis is favorable in these cases.