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Background and context Glucagon-like peptide-1 receptor (GLP-1 R) based imaging has shown higher sensitivity for insulinoma localization as compared to other anatomic/functional imaging. Methodology We reviewed the published English literature for GLP-1 R targeted imaging in insulinoma in PubMed until August 2020 in accordance with PRISMA guidelines using the MeSH terms "((Exendin-4 PET/CT) OR (Exendin-4 SPECT/CT) OR (GLP-1 R imaging)) AND (Insulinoma)". An individual patient data-metanalysis (IPD-MA) was performed, and performance parameters were calculated for the histopathological diagnosis of insulinoma. Main outcome measures True-positive (TP), false-positive (FP), false-negative (FN), true-negative (TN), sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) for insulinoma localization. Results A total of 179 cases (316 lesions) from 16 publications were included for IPD-MA. For insulinoma localization, exendin-4-PET/CT (Sn & PPV: 94%) performed better than exendin-4-SPECT/CT (Sn: 63%, PPV: 94%). The Sn was lower in malignant insulinoma cases whereas the Sp was higher in cases with MEN-1 syndrome. With exendin-4-based imaging, FP uptakes in Brunner's gland, normal pancreas, and other β-cell pathologies and FN results in pancreatic tail lesions and malignancy were seen in a few patients. TN results suggested the correct diagnosis of other endogenous hyperinsulinemic hypoglycaemia (EHH) subtypes. Conclusion For insulinoma localization, exendin-4 PET/CT should be preferred over exendin-4 SPECT/CT because of higher sensitivity and specificity. FP uptakes in Brunner's gland, normal pancreas, and other β-cell pathologies and FN results in tail lesions, and malignant insulinomas are limitations. Higher specificity for insulinoma localization is particularly useful in patients with MEN-1 syndrome.

Contains fulltext : 245825.pdf (Publisher’s version ) (Closed access) BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery). INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. FUNDING: US National Institutes of Health.

To study the effect of prior testosterone replacement therapy (TRT) on the spermatogenic response to combined gonadotropin therapy (CGT) in severe and partial phenotype congenital hypogonadotropic hypogonadism (CHH) patients.Retrospective cohort study.Tertiary care center.Patients of CHH without (n = 17) and with prior TRT (n = 18) were subdivided into severe and partial groups, based on mean testicular volume ≤ 3 cc and 3 cc respectively.Participants were treated with hMG at a dose of 75-150 U 3/week and gradually escalating doses of hCG until maximum dose (2000 U 3/week or 5000 U 2/week) or serum total testosterone of ≥ 3.5 ng/ml was reached.Final mean TV, trough serum testosterone (T), sperm concentration RESULTS: Thirty-five patients (20 severe, baseline mean TV of 3.6 ± 2.7 ml) were started on CGT at 24.8 ± 6.1 years. The median duration of prior TRT was 38 (IQR 10-63.75) months in the exposed group. After 33 ± 12 months, final mean TV was 8.9 ± 5.5 ml, 86% achieved serum testosterone 3.5 ng/ml and 70% achieved spermatogenesis [median 5 (0-12.6) million/ml]. Patients without prior TRT had significantly higher peak sperm count than those with prior- TRT (median 9 vs 0.05 million/ml, p = 0.004). This effect of prior TRT was more pronounced in severe phenotype patients (median 7 vs 0 million/ml, p = 0.01).Prior-TRT may interfere with spermatogenic response to CGT in CHH patients, especially in those with a severe phenotype.

Context Insulinoma needs accurate preoperative localization for minimally invasive surgery. Exendin-4-based imaging has shown promising results. Objective To evaluate performance parameters of exendin-4-based imaging in insulinoma localization and compare with other imaging modalities. Design Retrospective cross-sectional study. Patients We report 14 patients with endogenous hyperinsulinemic hypoglycaemia (EHH) managed at our centre; in whom, the final diagnosis was insulinoma (n = 11), Munchausen syndrome (MS) (n = 2) and inconclusive (n = 1). Retrospective reporting of CECT, 68 Ga-DOTATATE PET/CT and 68 Ga-NODAGA-exendin-4-PET/CT was done. With per-lesion analysis, performance parameters were calculated for the histopathological diagnosis of insulinoma. Main outcome measures True positive (TP), false positive (FP), false negative (FN), true negative (TN), sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) for insulinoma localization. Results In our cohort, 12 histopathologically proven insulinoma lesions [(TP): 11 primary lesions, 1 metastasis] were detected in 11 patients, whereas two patients had MS (TN). Sn and PPV were 75% and 100%, 33.3% and 80% and 83.3% and 71.4% for CECT, 68 Ga-DOTATATE PET/CT and 68 Ga-NODAGA-exendin-4-PET/CT, respectively. With exendin-4-based imaging, FP uptake in normal pancreatic tissue and FN results in the pancreatic tail lesion was seen. In one patient, TN result suggested the correct diagnosis of MS. Conclusion 68 Ga-NODAGA-exendin-4-PET/CT has higher sensitivity than 68 Ga-DOTATATE PET/CT and CECT for insulinoma localization. FP uptake in normal pancreas and FN result in tail lesions are limitations of currently utilized exendin-4-based imaging.

Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagnosis of TIO. Conclusion TIO, a correctable cause of hypophosphatemic rickets, should be considered in children presenting with hypophosphatemic rickets with evident mass on examination/imaging and in refractory cases.

Background Most common incidentally detected sellar-suprasellar region (SSR) masses are pituitary adenomas, followed by craniopharyngioma, rathke’s cleft cyst, hypophysitis, and meningioma. Besides these, certain unusual SSR lesions can sometimes present as diagnostic challenges, where diagnosis is often made post-operatively on histopathology, the pre-operative suspicion of which might have influenced the management strategies. Series describing such masses are few. Objective To present clinical, biochemical, and radiological characteristics and management outcomes of rare SSR lesions other than pituitary adenomas, craniopharyngioma, rathke’s cleft cyst, hypophysitis, and meningioma. Design, setting, patients Retrospective case record analysis of patients with uncommon SSR masses (from January 2006 to December 2016). Results Our series consisted of ten patients, five with neoplastic and five with non-neoplastic lesions. Neoplastic masses included granular cell tumor (n = 2), astrocytoma (n = 1), malignant peripheral nerve sheath tumor (MPNST, n = 1), and metastasis from occult papillary carcinoma of thyroid (n = 1), while non-neoplastic masses were aspergillus abscess (n = 1), sterile abscess (n = 1), and tubercular abscess (n = 1), aneurysm of left internal carotid artery (n = 1), and ruptured dermoid cyst (n = 1). All patients (except one) presented with headache and/or visual disturbance. Only one patient had acromegaly while most others had hypopituitarism. We describe detailed MRI characteristics of each of the lesion. Seven patients underwent trans-sphenoidal surgery. Post-operatively, five patients had permanent diabetes insipidus, while two patients died in early post-operative period. Conclusion Our series expand the differential diagnostic considerations of SSR lesions. Most of the rare SSR masses present with symptoms of mass effects and hypopituitarism. Except for some non-neoplastic lesions like sellar abscesses, aneurysms, and dermoid cysts which can have some specific imaging characteristics that can provide clue to pre-operative diagnosis, most of the other neoplastic masses have overlapping radiological features, and pre-operative suspicion remains difficult.

Objective To report clinical, hormonal and structural effects of CYP11B1 pathogenic variations in Indian patients with 11β-hydroxylase deficiency (11βOHD) and find hormonal criteria that accurately distinguish 11βOHD from 21α-hydroxylase deficiency (21OHD). Design Retrospective record review of genetically diagnosed patients with 11βOHD. Patients and measurements Clinical features, hormonal parameters at diagnosis (by immunoassay) and recent follow-up of 13 genetically proven 11βOHD patients managed at our centre were retrospectively reviewed. ACTH-stimulated serum adrenal steroids (measured by LC-MS/MS) of 11βOHD were compared with those of simple virilizing and non-classic 21OHD. Structural analysis of the observed pathogenic variations was performed by computational modelling. Results Nine (four females) and four (all females) patients had classic and non-classic disease, respectively. All 11βOHD patients had elevated ACTH-stimulated serum 11-deoxycortisol (26.5-342.7 nmol/L) whereas none had elevated serum 17-hydroxyprogesterone (4.2-21.2 nmol/L); both hormonal parameters distinguished 11βOHD from 21OHD with 100% accuracy. ACTH-stimulated serum cortisol, but not 11-deoxycortisol, clearly distinguished classic ( 160 nmol/L) disease. Thirteen (eight novel, two recurrent) pathogenic variants were observed. Only missense mutations were observed among patients with non-classic disease. Computational modelling predicted the possible affection of enzyme structure and function for all the observed missense mutations. Conclusions This first Indian study describes 13 11βOHD patients, including four with the rarer non-classic variant. A total of eight novel pathogenic variants were identified in our study, highlighting regional genetic heterogeneity. Measurement of ACTH-stimulated adrenal steroids by LC-MS/MS will help avoid the misdiagnosis of 11βOHD as 21OHD and has potential to distinguish classic from non-classic 11βOHD.

Context Data are limited regarding prevalence, predictors, and mechanisms of persistent hypogonadotropic hypogonadism (HH) in males with a macroprolactinoma who achieve normoprolactinemia on dopamine-agonist therapy. None of the previous studies provide cutoffs to predict the achievement of eugonadism. Objective The objective of this work is to evaluate the prevalence of persistent HH and its determinants in men with a macroprolactinoma who achieve normoprolactinemia on cabergoline monotherapy. Design and Setting This retrospective study with prospective cross-sectional evaluation took place at a tertiary health care center. Patients Study participants included men with a macroprolactinoma and baseline HH who achieved normoprolactinemia on cabergoline monotherapy. Main Outcome Measures Outcome measures of this study included the prevalence of persistent HH and its predictors. Results Thirty participants (age, 38.3 ± 10.1 years) with baseline tumor size of 4.08 ± 1.48 cm and median (interquartile range) prolactin of 2871 ng/mL (range, 1665-8425 ng/mL) were included. Eight of 30 participants achieved eugonadism after a median follow-up of 3 years. Patients with persistent HH had suppression of the luteinizing hormone (LH)-testosterone axis with sparing of other anterior pituitary hormonal axes, including follicle-stimulating hormone-inhibin B. Baseline prolactin (1674 vs 4120 ng/mL; P = .008) and maximal tumor diameter (2.55 ± 0.36 vs 4.64 ± 1.32 cm; P = .003) were lower in patients who achieved eugonadism. Baseline maximal tumor diameter less than or equal to 3.2 cm (sensitivity: 75%, specificity: 63.6%) and serum prolactin less than or equal to 2098 ng/mL (sensitivity: 87.5%, specificity: 77.3%) best predicted reversal of HH. Conclusion Recovery of the LH-testosterone axis occurred in 26.7% of men with a macroprolactinoma who achieved normoprolactinemia on cabergoline monotherapy. Higher baseline tumor size and serum prolactin predict persistent HH. Our data favor chronic functional modification of the hypothalamic-pituitary-gonadal axis over gonadotroph damage as the cause of persistent HH.

Context Conventional fractionated radiotherapy (CRT) achieves control of pathological hypercortisolism in 75%-80% of patients with persistent or recurrent Cushing's disease (CD), over a mean period of 18-24 months. Medical therapy is recommended as bridge therapy while awaiting RT effect. Objective To determine long-term outcome of CRT and its predictors in CD patients. Design, setting and patients This is a retrospective case record analysis of 42 patients with CD who received CRT as a treatment modality and had at least 12 months post-RT follow-up. The dose delivered was 45 Gy in 25 fractions over 5 weeks. Demographic details, hormonal evaluation and radiological data were extracted from case records. Dexamethasone suppressed cortisol at cut-off of 1.8 µg/dL was used to define remission or recurrence. Possible predictors for remission and recurrence were analysed. Results The mean age at the time of CRT administration was 23.7 ± 10.7 (range: 12-48) years. A total of 29 (69%) patients achieved remission 26.5 ± 28.5 (median: 18, range: 3-120) months after RT, while 13 (31%) patients had persistent disease at last follow-up. There were no significant predictors of disease remission after CRT. Six (20.7%) patients had recurrence after a documented initial remission. Recurrence occurred 66.6 ± 25.9 (median: 74; range: 18 to 90) months after documented remission. Recurrence of the disease was exclusively seen in patients who received peri-RT cabergoline. Peri-CRT use of cabergoline was significantly associated with increased recurrence rates (P = .016). Conclusion Use of cabergoline in the peri-CRT period did not affect initial remission after CRT but was associated with increased recurrence after initial remission in CD.

A 50-year-man presented with debilitating lower-limb proximal muscle weakness and hip pain since 3 years. Investigations (serum calcium (8.9 mg/dL), serum phosphorus (1.5 mg/dL), serum albumin (40 g/L), parathyroid hormone (116 pg/mL (12.30 pmol/L)), 25(OH)D3 (25.2 ng/mL (63 nmol/L)) 1,25(OH)2 D3 (19 pg/mL (45.60 pmol/L)), tubular reabsorption of phosphate of 0.22 and elevated serum fibroblast growth factor 23 (FGF23) (387.7 RU/mL)) were consistent with tumour-induced osteomalacia (TIO). Localisation studies (68Ga DOTATATE positron emission tomography (PET)/CT and 18FDG-PET/CT) did not reveal any lesion. Re-evaluation after 2 and 5 years with 68Ga-DOTANOC PET/CT showed 2×1.4 cm progressively increasing rounded soft tissue enhancing mass close to splenic hilum (SUV max: 26.4). Tumour was resected by laparotomy. Both FGF23 (120 RU/mL on day 3) and serum phosphorus (2.5 mg/dL on day 10) normalised with significant clinical improvement after surgery. Histopathology revealed phosphaturic mesenchymal tumour. Here, we report the first case of intra-abdominal mesenchymal tumour causing TIO diagnosed by serial functional imaging.