Search

The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic–euglycemic clamp, a time, costly, and labor-intensive research tool. A low insulin sensitivity is associated with a complication-risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated-GDR), enabling comparison of IS and its probability of IS <4.45 mg/kg/min (low) or >6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005–0.87 with agreement in detecting low and high glucose disposal rates in the range 49–93% and 89–100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user-friendly tool for individual IS calculations and also offers efficient batch processing of data for research.

A 24-year-old female patient was diagnosed with osteoporosis after presenting with numerous fractures throughout her childhood and adolescence. Risk factors included chronic constipation, severe vitamin D deficiency, and long-term high-dose steroid use for severe eczema. Metabolic bone disorder clinical exome screening (limited panel of metabolic bone disorders and gastrointestinal disorders) was undertaken and revealed a class 4 likely pathogenic variant in the LRP5 gene known to cause osteoporosis. Optimal treatment for patients with this variant is not well defined. A literature review of the condition and potential treatment options is discussed.

A case of recurrent insulinoma spanning 4 decades is described. Following a delayed diagnosis, hyperinsulinemic hypoglycemia was confirmed in a 24-year-old woman during early pregnancy. Initial surgery, culminating in subtotal pancreatectomy, was noncurative. A 1-cm insulinoma was subsequently resected from the head of the pancreas postpartum, with postoperative resolution of hypoglycemia. However, 32 years later, the patient experienced a recurrence of hypoglycemic symptoms. Eventually, a subcentimeter extrapancreatic lesion was identified anterior to the pancreatic head on gallium-68 DOTA-Exendin-4 positron emission tomography/computed tomography. In 2022, a third operation was performed, with excision of a 4 × 3 mm tumor adjacent to the pancreatic head, and histology confirming insulinoma. She was again cured of symptoms.

Primary aldosteronism (PA) is the most common form of secondary hypertension. Accurate subtyping of PA is essential to identify unilateral disease, as adrenalectomy improves outcomes. Subtyping PA requires adrenal vein sampling (AVS), which is technically challenging and results from AVS may not always be conclusive. We present a case of a 37-year-old man with PA whose AVS studies were inconclusive due to apparent bilateral aldosterone suppression (ABAS). As a result, our patient was misdiagnosed as having bilateral PA and medically managed until a repeat AVS showed lateralization to the right adrenal gland. ABAS is an underrecognized phenomenon that may confound the subtyping of PA. We recommend repeating AVS in such cases and discuss strategies to minimize ABAS.

Aim: To develop a free online tool to estimate IS using different metrics and existent formulae and compare estimated IS with measured glucose disposal rate (GDR) from 104 clamp studies. Methods: We prepared an online tool for calculating IS using 17 formulae. Suitable formula(e) are suggested based on available (clinical and research) data. We also compare calculated IS with measured IS (GDR) from clamp studies in 104 adults with T1D (mean±SD) age 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%, 33 with microvascular complications). Logistic regression was used to infer probability of calculated IS being below GDR=4.45 mg/kg/min or above GDR=6.5 mg/kg/min, which represent respectively the median and 75th percentile of measured GDR values. Results: A calculator is available at www.bit.ly/estimated-GDR and an example result in the Figure 1. Estimated IS varied widely, but results interpretation is generally consistent. Conclusion: We developed an interactive tool to estimate IS in T1D for clinical and research use.

INTRODUCTION: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. METHODS: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. RESULTS: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. CONCLUSION: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced h

Background and aim: Low insulin sensitivity (IS) increases Type 1 diabetes (T1D) complication risk and can be estimated by simple formulae developed from complex euglycemic hyperinsulinaemic clamp studies. We aimed to validate these formulae using independent clamp data. Methods: Clamps were performed in 104 T1D adults. Measured glucose disposal rate (GDR) was correlated with eGDR and eLog10 M/I calculated by five IS formulae. Results: Correlations ranged between 0.23–0.40. Two IS formulae (by the authors), using age, sex, HDL-C, HbA1c, pulse pressure, BMI, and waist-hip-ratio had the highest correlation with measured GDR and the best performance in detecting low IS.

BACKGROUND: FDG-PET/CT used for immune checkpoint inhibitor (ICI) response assessment can incidentally identify immune-related adverse events (irAEs), including thyroiditis. This study aimed to correlate the time course of FDG-PET/CT evidence of thyroiditis with clinical and biochemical evolution of thyroid dysfunction. METHODS: A retrospective review was performed by two independent blinded nuclear medicine physicians (NMPs) of thyroidal FDG uptake in 127 patients who underwent PET/CT between January 2016 and January 2019 at baseline and during treatment monitoring of combination ICI therapy for advanced melanoma. Interobserver agreement was assessed and FDG-PET/CT performance defined by a receiver-operating characteristic (ROC) curve using thyroid function tests (TFTs) as the standard of truth. Thyroid maximum standardized uptake value (SUVmax) and its temporal changes with respect to the longitudinal biochemistry were serially recorded. RESULTS: At a median of 3 weeks after commencing ICI, 43/127 (34%) had a diagnosis of thyroiditis established by abnormal TFTs. FDG-PET/CT was performed at baseline and at a median of 11 weeks (range 3-32) following the start of therapy. ROC analysis showed an area under the curve of 0.87 (95% CI 0.80, 0.94) for FDG-PET/CT for detection of thyroiditis with a positive predictive value of 93%. Among patients with biochemical evidence of thyroiditis, those with a positive FDG-PET/CT were more likely to develop overt hypothyroidism (77% versus 35%, p < 0.01). In the evaluation of the index test, there was an almost perfect interobserver agreement between NMPs of 93.7% (95% CI 89.4-98.0), kappa 0.83. CONCLUSION: Increased metabolic activity of the thyroid on routine FDG-PET/CT performed for tumoral response of patients undergoing ICI therapy is generally detected well after routine biochemical diagnosis. Elevation of FDG uptake in the thyroid is predictive of overt clinical hypothyroidism and suggests that an ongoing robust inflammator

The authors regret that in the original article, on the second page, in the section with eGDR equations, variables “sex” and “hypertension” were missing categorical values indicators (“F = 0, M = 1”; “Yes = 1, No = 0”, respectively) required to calculate eGDR. It should be corrected by adding “F = 0, M = 1” in two instances and “Yes = 1, No = 0” in one instance. Also, please note that Miller at al. defined “hypertension” as BP ≥140/90mmHg or use of any anti-hypertensive (drug) treatment. The authors apologise for any inconvenience caused.

CONTEXT: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. OBJECTIVE: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. DESIGN AND SETTING: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. PATIENTS: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. INTERVENTION: Performance (or not) of cytoreductive surgery of the primary tumor. MAIN OUTCOME AND MEASURES: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. RESULTS: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). CONCLUSION: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

SUMMARY: Adrenocortical carcinoma is a rare disease with poor prognosis whose clinical heterogeneity can at times present a challenge to accurate and timely diagnosis. We present the case of a patient who presented with extensive pulmonary lesions, mediastinal and hilar lymphadenopathy and an adrenal mass in whom the oncological diagnosis was initially uncertain. Through the use of immunohistochemistry, biochemistry and genomic testing, an accurate diagnosis of adrenocortical carcinoma was ultimately made which resulted in more directed treatment being administered. The use of multidisciplinary input and genomics to aid in diagnosis and prognosis of adrenocortical carcinoma is discussed. LEARNING POINTS: Adrenocortical carcinomas can present a diagnostic challenge to clinicians given it is a rare malignancy with significant clinical heterogeneity. Specialist multidisciplinary team input is vital in the diagnosis and management of adrenocortical carcinomas. Hormonal testing is recommended in the diagnostic workup of adrenal masses, even in the absence of overt clinical signs/symptoms of hormone excess. Immunostaining for the highly sensitive and specific steroidogenic factor-1 is vital for accurate diagnosis. Genomics can provide prognostic utility in management of adrenocortical carcinoma.

BACKGROUND: Adrenal vein sampling (AVS) is integral to identifying surgically remediable unilateral primary aldosteronism (PA). However, right adrenal vein (AV) cannulation can be challenging, limiting its success. Intra-procedural cortisol assays can improve the reliability of AVS. The aim of this study was to validate the use of semi-quantitative cortisol estimates obtained utilizing a quick cortisol assay (QCA) during AVS procedures at our institution. METHODS: Retrospective review of results of AVS procedures before and after the introduction of the QCA. Twenty-three AVS procedures were performed with the provisional success determined by intra-procedural QCA. Successful AV cannulation was defined by an AV to peripheral vein cortisol ratio ≥ 4.0 (the selectivity index) from laboratory measurements. The control cohort consisted of 23 consecutive procedures prior to introduction of the QCA. RESULTS: QCA correctly predicted all AV cannulation attempts. Successful bilateral AV cannulation increased from 52% to 91% of procedures when performed with the QCA (P = 0.01) and adequate cannulation of the right AV increased from 61% to 91% (P = 0.03). There was no increase in procedural time, number of AV cannulation or sampling attempts. CONCLUSIONS: Point-of-care, semi-quantitative cortisol estimates can be performed accurately during AVS with QCA, facilitating improvements in AVS success rates without increasing procedural time.

Introduction: The “gold standard” measure of insulin sensitivity (IS), a euglycemic hyperinsulinemic clamp, is costly, time- and labour-intensive. Several formulae, developed using clamp data estimate insulin sensitivity, expressed as estimated glucose disposal rate (eGDR) or insulin sensitivity index (eM/I or elog10M/I). Due to clamp complexity and cost these formulae often lacks independent validation. Aim: To validate several formulae estimating IS using independent euglycaemic hyperinsulinemic clamp data. Methods: Euglycemic, hyperinsulinemic clamps were performed in 108 T1D adults (age (mean±SD) 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%; 33 with microvascular complications). Measured GDR (last 30min of the clamp) ranged 0.5 - 9.6 mg/kg/min (median (LQ, UQ) 4.45 (3.04, 6.5 mg/kg/min) were compared with eGDR and eLog10M/I calculated using simple formulae by (1) Williams, (2) Zheng, (3) Dabelea and (4) and (5) (Australia (AU)) authors, all derived from routine clinical chemistry and demographics. eGDR formula (Duca) was not assessed as it includes adiponectin levels. Results: Results are in Table 1. Conclusion: Authors (AU) formulae to estimate IS, including age, sex, HDL-C, BMI, HbA1c, pulse pressure and WHR had highest correlation with measured GDR and better performance (AUROC) in detecting low IS than other formulae.

DESIGN: A retrospective review of the adverse events (AEs) in 78 patients during the glucagon stimulation test (GST) for the assessment of growth hormone deficiency (GHD) before and after protocol amendments which aimed to reduce AEs in a group of patients with a high prevalence of pituitary hormone deficiencies. PATIENTS: Based on our observations of frequent AEs during the standard GST protocol in an initial 25 patients (cohort 1), a modified protocol was introduced to include the routine administration of 20 mg of hydrocortisone pre-GST in a subsequent 53 patients (cohort 2). Post hoc analysis of the effect of glucocorticoid dosing pre-GST on AEs was examined in those receiving <20 mg hydrocortisone (group A, n = 19) vs ≥20 mg hydrocortisone (group B, n = 59). MEASUREMENTS: AEs including hypotension, hypoglycaemia and nausea/vomiting. RESULTS: Of the 78 patients undergoing the GST, 79% had ≥2 hormone deficiencies. Rates of AEs were 41% vs 30% for hypotension, 60% vs 28% for hypoglycaemia (p < .05) and 20% vs 13% for nausea/vomiting in cohort 1 compared with cohort 2, respectively. Post hoc analysis revealed lower rates of AEs in those receiving ≥20 mg hydrocortisone (group B) compared to those receiving <20 mg due to a reduction in hypoglycaemic events (82% vs 26%, p < .001) and hypotension (50% vs 27%, p = .05). Similar numbers of patients in group A and group B met criteria for GHD. CONCLUSIONS: In patients with a high prevalence of pituitary deficiencies, a modified GST protocol of additional stress dose glucocorticoid attenuated the frequency of AEs without appearing to compromise the performance of the GST.

CONTEXT: Insulin autoimmune syndrome (IAS) is characterized by hyperinsulinemic hypoglycemia with elevated anti-insulin antibodies. Most commonly observed in the Japanese population, elsewhere it is rare and associated with autoimmune diseases, plasma cell dyscrasias, or sulfhydryl group medications. The active metabolite of clopidogrel has a sulfhydryl group and here we report a case of clopidogrel-induced IAS. CASE DESCRIPTION: A 67-year-old man was admitted with severe hyperinsulinemic hypoglycemia requiring continuous intravenous infusion of 10% dextrose to sustain euglycemia. His symptoms of hypoglycemia had started after commencing dual antiplatelet therapy (including clopidogrel) for ischemic heart disease 9 months earlier. The hypoglycemia was associated with elevated insulin, proinsulin, c-peptide, and anti-insulin antibody titers as well as the HLA-DRB1*04 haplotype. Multiple localizing studies were negative for an insulinoma. A diagnosis of IAS was thus made. Clopidogrel cessation, oral dexamethasone, and diazoxide therapy were not sufficient to safely wean the dextrose infusion. Plasma exchange was ultimately effective. CONCLUSIONS: This case highlights a case of severe IAS. Given the ubiquity of clopidogrel, IAS should be remembered as a rare adverse effect.

Objectives: Hypophysitis and thyroiditis are among the most commonly reported immune-related adverse events (irAEs) following combined ipilimumab/nivolumab therapy for melanoma. The role of 18F-FDG PET/CT (FDG-PET) in the evaluation of these endocrinopathies has not been systematically assessed. Methods: Between 2016 to 2019, all patients (pts) with advanced melanoma who received combined ipilimumab/nivolumab therapy were reviewed. Pts with a pre-treatment and post-treatment FDG-PET were included. On FDG-PET, PET-hypophysitis was defined as a discernable new uptake in the pituitary fossa and PET-thyroiditis as new diffuse uptake in the thyroid. Pre- and post-treatment SUVmax of pituitary and thyroid gland was measured. ROC analysis was used to derive the optimal threshold for metabolic changes on FDG-PET for distinguishing endocrinopathy. FDG-PET, clinical data and brain MRI were reviewed independently by a Nuclear Medicine physician, endocrinologist, and radiologist, respectively, and then findings were correlated. Results: Of 162 pts, 133 and 134 had assessable FDG-PET for hypophysitis and thyroiditis, respectively, with post-treatment FDG-PET performed at a median 76 days (IQR 52-83, range 18-225) from the start of immunotherapy. Overall 41/133 (29%) pts had PET-hypophysitis, of which 18 were clinically-confirmed, 3 were false-positive and 20 were not clinically-assessable due to receiving high-dose glucocorticoids for a concurrent irAE at the time of imaging, although 6 of these also had supportive contemporaneous MRI findings. For PET-hypophysitis pts, median pre- and post-treatment pituitary SUVmax were 2.7 (IQR 2.5-2.9, range 1.9-3.9) and 4.7 (IQR 3.6-5.5, range 2.6-16.2), with a percentage increase of 63% (IQR 39-94%, range 13-431%). The abnormal PET findings preceded the clinical diagnosis in 7/18 pts by a median of 16 days (range 5-50). FDG-PET was negative for hypophysitis in 12/29 pts with a prior or subsequent clinical diagnosis of hypophysitis. Where t

Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific symptoms. At our centre, subjects undergo periodic imaging to assess tumour response to ICI. We reviewed whether neuroimaging studies can guide us in the diagnosis of hypophysitis and whether early changes can be detected before the onset of the clinical syndrome. Methods: We retrospectively reviewed the medical charts, biochemistry, structural brain imaging and whole-body positron emission tomography (PET) with specific reference to hypophysitis in 162 patients treated with combination ICI at a tertiary melanoma referral centre. Suspected cases were identified based on meeting one or more of the following criteria: 1) A documented diagnosis of hypophysitis or pituitary dysfunction found on chart review, 2) A relative change in pituitary size or appearance from baseline on neuroimaging studies, or 3) An increase in pituitary maximum standardized uptake value (SUVmax) greater than 25% from baseline on 18F-FDG PET. Results: 58/162 patients (36%) met criteria for suspected hypophysitis. Only 4 patients were identified on routine screening of early morning cortisol. 14 patients presented with symptoms leading to biochemical work up. A further 40 patients were found to have suspicious imaging changes, 13 of which went on to receive a formal diagnosis of hypophysitis. Of the remaining 27 patients, 23 were receiving high dose glucocorticoids for concomitant immune related adverse events at the time of the abnormal imaging study.Conclusion: We report the highest incidence to date of suspected hypophysitis in cohort of patients treated with combination ICI. This study highlights the important role of structural and functio

Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred

Aims: Insulin resistance in people with type 1 diabetes (T1D) is associated with increased risk of chronic complications and death. The gold standard to quantify insulin sensitivity, a euglycaemic hyperinsulinaemic clamp, is not applicable to clinical practice. We have employed clamp studies to develop a panel of formulae to estimate insulin sensitivity in adults with T1D for use in clinical practice and trials. Methods: Clamps were conducted in 28 adults with T1D, who were also characterised with 38 clinical and research biomarkers. Exhaustive search analysis was used to derive equations correlating with clamp-quantified glucose disposal rate (GDR), GDR/plasma insulin (M/I) and log 10 M/I. Results: Measured insulin sensitivity correlated with BMI, WHR, HDL-C, adipokines and inflammation markers on univariate analysis. Exhaustive search analysis derived three formulae correlating with clamp-derived GDR and logM/I ( p < 0.0001), accounting for ≈62% of their variability. A formula using gender, age, HDL-C, pulse pressure and WHR performed as well as those containing inflammation and adipokine measures. Conclusions: The performance of formulae using routinely available parameters with/without research biomarkers in clinical studies and trials, particularly related to future complications, relevant lifestyle interventions, insulin delivery modes and insulin sensitisers is merited.

Background: Hypophysitis is one of the commonly reported adverse events related to immune checkpoint inhibitors (ICI), and the incidence is expected to rise with increased use of combined programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associated protein 4 (CTLA4) blockade. The clinical diagnosis can be delayed due to non-specific symptoms. At our centre, subjects undergo periodic imaging to assess tumour response to ICI. We reviewed whether neuroimaging studies can guide us in the diagnosis of hypophysitis and whether early changes can be detected before the onset of the clinical syndrome. Methods: We retrospectively reviewed the medical charts, biochemistry, structural brain imaging and whole-body positron emission tomography (PET) with specific reference to hypophysitis in 162 patients treated with combination ICI at a tertiary melanoma referral centre. Suspected cases were identified based on meeting one or more of the following criteria: 1) A documented diagnosis of hypophysitis or pituitary dysfunction found on chart review, 2) A relative change in pituitary size or appearance from baseline on neuroimaging studies, or 3) An increase in pituitary maximum standardized uptake value (SUVmax) greater than 25% from baseline on 18F-FDG PET. Results: 58/162 patients (36%) met criteria for suspected hypophysitis. Only 4 patients were identified on routine screening of early morning cortisol. 14 patients presented with symptoms leading to biochemical work up. A further 40 patients were found to have suspicious imaging changes, 13 of which went on to receive a formal diagnosis of hypophysitis. Of the remaining 27 patients, 23 were receiving high dose glucocorticoids for concomitant immune related adverse events at the time of the abnormal imaging study.Conclusion: We report the highest incidence to date of suspected hypophysitis in cohort of patients treated with combination ICI. This study highlights the important role of structural and functional neuro

BACKGROUND: Insulinomas are rare tumours of the pancreas and the most common cause of hypoglycaemia in non-diabetic adults. They can be cured by surgery but require precise localization. The aim of this study was to assess the utility of the selective intra-arterial calcium stimulation test (SIACST) in patients with an insulinoma to correctly localize the tumour. METHOD(S): Medical records of patients with a diagnosis of insulinoma or who underwent an SIACST were retrospectively reviewed. Localization of lesions by SIACST was compared to endoscopic ultrasound and radionuclide imaging studies and verified against findings at surgery. RESULT(S): A total of 24 patients (mean age 58years, 16 females, 20 with insulinoma) underwent SIACST. The SIACST correctly localized the insulinoma in 17 of 20 patients (85%). Localization rate for computed tomography was 55% and 75% for endoscopic ultrasound and glucagon-like peptide-1 receptor scan. CONCLUSION(S): SIACST provided incremental diagnostic information in patients with insulinoma who had equivocal non-invasive imaging preoperatively. This technique remains an essential diagnostic tool when a lesion is not localized by other methods.Copyright © 2020 Royal Australasian College of Surgeons.

BACKGROUND: Insulinomas are rare tumours of the pancreas and the most common cause of hypoglycaemia in non-diabetic adults. They can be cured by surgery but require precise localization. The aim of this study was to assess the utility of the selective intra-arterial calcium stimulation test (SIACST) in patients with an insulinoma to correctly localize the tumour. METHODS: Medical records of patients with a diagnosis of insulinoma or who underwent an SIACST were retrospectively reviewed. Localization of lesions by SIACST was compared to endoscopic ultrasound and radionuclide imaging studies and verified against findings at surgery. RESULTS: A total of 24 patients (mean age 58 years, 16 females, 20 with insulinoma) underwent SIACST. The SIACST correctly localized the insulinoma in 17 of 20 patients (85%). Localization rate for computed tomography was 55% and 75% for endoscopic ultrasound and glucagon-like peptide-1 receptor scan. CONCLUSION: SIACST provided incremental diagnostic information in patients with insulinoma who had equivocal non-invasive imaging preoperatively. This technique remains an essential diagnostic tool when a lesion is not localized by other methods.

Purpose: Germline succinate dehydrogenase (SDHx) mutation carriers, especially SDHB, are at increased risk for malignancy and require life-long surveillance. Current guidelines recommend periodic whole-body MRI imaging. We assessed the incremental value of 68Ga-DOTA-octreotate (GaTate) positron emission tomography (PET)/CT compared with conventional imaging in such patients. Methods: SDHx mutation carriers who had GaTate PET/CT were retrospectively reviewed. Detection of lesions were compared with MRI or CT on a per-patient and per-lesion basis. Proof of lesions were based on histopathology or clinical/imaging follow-up. Results: Twenty consecutive patients (median age, 46 years; 10 males) were reviewed. Fourteen patients had SDHB, four, SDHD, one SDHC, and one SDHA mutation. Fifteen had prior surgery and/or radiotherapy. Indications for PET/CT were as follows: 7 patients for surveillance for previously treated disease, 9 residual disease, 2 asymptomatic mutation carriers, and 2 for elevated catecholamines. Median time between modalities was 1.5 months. GaTate PET/CT had higher sensitivity and specificity than conventional imaging. On a per-patient basis: PET/CT sensitivity 100%, specificity 100%; MRI/CT 85% and 50%. Per-lesion basis: PET/CT sensitivity 100%, specificity 75%; MRI/CT 80% and 25%. PET/CT correctly identified additional small nodal and osseous lesions. MRI/CT had more false-positive findings. Change of management resulted in 40% (8/20 patients): 3 received localized treatment instead of observation, 1 changed to observation given extra disease detected, 4 with metastases had radionuclide therapy. Conclusions: GaTate PET/CT provided incremental diagnostic information with consequent management impact in SDHx-pheochromocytoma and paraganglioma. Incorporating this modality as part of a surveillance program seems prudent. Further research is needed to define the optimal surveillance strategy including use of MRI.

Carriers of succinate dehydrogenase (SDHx) mutations are at risk of developing phaeochromocytomas, catecholamine secreting extra-adrenal paragangliomas and non-secretory head and neck paragangliomas and require lifelong surveillance. There is no current consensus on the optimal surveillance strategy. This study describes the outcomes of a cohort of 50 SDHx mutation carriers followed at a tertiary Australian hospital using a surveillance protocol involving annual clinical review with plasma/urine metanephrines and biennial magnetic resonance imaging from skull base to pelvis.

Adrenocortical carcinomas are rare but patients often present with advanced disease and display symptoms of hormone hypersecretion or tumour burden/mass effect. Here we present two cases of adrenocortical carcinoma to highlight the challenges of managing this condition. Case 1: A 48 year old female initially presented with an incidental adrenal mass measuring 42 mm. On triple-phase CT the mass was reported as an adrenal myelolipoma and no further followup was arranged. She represented 3 years later with abdominal bloating, facial plethora, hirsutism and weight gain. Investigations revealed hypercortisolism and hyperandrogenism in the setting of a 16 cm adrenal mass with retroperitoneal lymphadenopathy but no distant metastases. She underwent an open right adrenalectomy and histology was consistent with a 17 cm adrenocortical carcinoma with a high Ki-67 index of 40% and positive lymph nodes. Post-operative workup revealed residual local disease as well as pulmonary metastases. She then received adjuvant therapy with etoposide/doxorubicin/cisplatin and mitotane. Progressive disease was further treated with radionucleotide therapy (I131-metomidate), immunotherapy (PD-1 antibody BGB-A317) and sunitinib. Despite multiple lines of treatment, disease control was never achieved and the patient died 2 years following her initial surgery. Case 2: A 35 year old female presented with weight gain, amenorrhoea, hirsutism and abdominal striae. Workup revealed hyperandrogenism and hypercortisolism with a large right adrenal mass. A 94 mm adrenocortical carcinoma with a Ki-67 index of 30% was resected. She underwent adjuvant therapy with mitotane however follow-up imaging revealed new pulmonary and hepatic metastases. She received first-line chemotherapy with etoposide/doxorubicin/cisplatin as well as mitotane and metyrapone to control florid Cushing's syndrome. She progressed to second-line chemotherapy with capecitabine/gemcitabine however died soon after. An actionable mutation s

Background: Carriers of germline succinate dehydrogenase mutations (SDH) need life-long surveillance for the possible development of phaeochromocytomas and paragangliomas. However, there is no consensus about appropriate surveillance strategies. The aim of this study was to describe the long-term outcomes of a cohort of SDH carriers followed in our clinic. Method: 49 patients were included in this study, 12 were index cases (9 SDHB, 3 SDHD) and 37 were mutation-positive asymptomatic carriers (22 SDHB, 9 SDHD and 6 SDHC). Patients were followed for a mean of 4.4 years (range 1-10). All patients are recommended to undergo biennial MRI imaging of neck/thorax/abdomen/pelvis, annual clinic review and plasma or urine metanephrine testing. Results: 16 paragangliomas (10 SDHB, 6 SDHD) and 1 renal cell carcinoma (SDHB) and no phaeochromocytomas occurred in the 12 index cases (9 SDHB, 3 SDHD). Two index patients with paragangliomas (one abdominal, one head and neck) had widespread metastases on the initial scan. One SDHB and one SDHD index patient developed additional tumours during surveillance. Among the asymptomatic carriers, a total of 23 paragangliomas (22 SDHD and 1 SDHC) were detected in 8 (16%) patients (7 SDHD, 1 SDHC). Of these, 15 were detected on the first surveillance scan (14 SDHD, 1 SDHC) and 8 (all SDHD) were detected on subsequent scans. One patient (SDHD) developed a liver metastasis during surveillance. Of the seven SDHD carriers who had tumours on initial surveillance scan, six had the c.274G>T exon mutation. Average change in tumour size in those undergoing watchful surveillance was −0.12 mm/year (range −4 mm/year to +2 mm/year). Adherence was suboptimal, only 45% of patients attended annual clinic visits, 67% underwent biennial MRIs and 45% had yearly metanephrine testing. Conclusion: Biennial MRI scans appear to be an effective surveillance strategy in the long-term follow up of patients with SDH mutations.

Despite growing evidence for GLP-1R molecular-based imaging, successful localization of insulinomas may require the use of multiple imaging modalities. Not all benign insulinomas express the GLP-1R as expected. Our case demonstrates that there is a still an important role for traditional methods for the anatomical localization of an insulinoma.

Benign insulinomas are rare neuroendocrine tumours most commonly located in the pancreas. They are the most frequent cause of hyperinsulinaemia hypoglycaemia in adults without diabetes. Diagnosis can be challenging, and accurate localisation with surgical excision is the only cure. There is a growing body of evidence for the efficacy of Ga68-DOTA-exendin-4 (glucagon-like peptide-1 (GLP-1)) PET/CT scans, which centres on the premise that a near majority of insulinomas are ubiquitous for the GLP-1 receptor. We describe an 82 year-old woman with a history of fasting hyperinsulinaemic hypoglycaemia associated with neuroglycopaenic symptoms. Triple phase CT scan of the pancreas and a Ga68-DOTATATE PET/CT scan were both unremarkable. A Ga68-GLP-1 PET/CT scan showed diffuse pancreatic uptake consistent suggestive of pancreatic beta cell hyperplasia, or nesidioblastosis. The patient had further testing including an endoscopic ultrasound and calcium stimulation test which localised insulin hypersecretion to the body and tail of pancreas. Surgery revealed an insulinoma which was later con-firmed on immunohistochemistry to be GLP-1 receptor negative. Although GLP-1 scans are being increasingly used in clinical practice for work-up of hypoglycaemic disorders, they are expensive and not readily available. Clinical judgment is always crucial, and the differential of an insulinoma should not be ruled out on the basis of this scan.

Aceruloplasminaemia is an autosomal recessive disorder of iron metabolism which is characterised by diabetes, neurodegeneration and anaemia. It should be considered in the differential diagnosis of adult onset, antibody-negative diabetes associated with persistent mild anaemia and hyperferritinaemia and/or progressive neuropsychiatric impairments.

Aims To explore the challenges in the management of metastatic differentiated thyroid cancer. Introduction Differentiated thyroid cancer (DTC) is the most common form of thyroid cancer. The initial diagnosis of thyroid carcinoma and the distinction between benign and neoplastic disease can be challenging. Radioiodine-refractory metastatic DTC also presents a therapeutic dilemma. Novel targeted agents for advanced radioiodine-refractory metastatic thyroid cancer, such as tyrosine kinase inhibitors (TKIs), are being increasingly used with clinical success, broadening current available therapeutic options. Case report We present the case of a 61-year-old woman with radioiodine-refractory metastatic follicular thyroid carcinoma, which was initially misdiagnosed as benign Hurthle cell adenoma. We focus on the challenges in both the initial diagnosis and the subsequent management of her advanced disease with skeletal dominant metastases. Conclusion The advent of targeted systemic therapies as emerging frontline and salvage therapy is a novel addition to the management of radioiodine-refractory advanced DTC. Further studies to expand the role of sequential and redifferentiation therapy for advanced disease and strategies to reduce skeletalrelated events are still required. How to cite this article Lee MH, Moxey JE, McLachlan S-A, MacIsaac RJ, Sachithanandan N. Dilemmas in Metastatic Differentiated Thyroid Cancer: To irradiate, medicate, or palliate? World J Endoc Surg 2016;8(2):168-171.

Background: Primary hyperaldosteronism (PHA) accounts for 5–10% of patients with hypertension (1). Saline suppression test (SST) is a commonly used confirmatory test in the diagnosis of PHA. Although potassium (K) is checked at baseline with recommendations to adequately replace prior to SST, there are no recommendations to routinely check potassium post-SST. This contrasts guidelines for the fludrocortisone suppression test (FST) which is known to cause hypokalaemia. A previous study monitored K levels post-SST in a subgroup of patients, and found a non-significant decrease (-0.05 0.2 mmol/L) in potassium levels post-SST (2). We report a retrospective series of patients who became hypokalaemic in the 2 h period post-SST. Methods: A retrospective audit was conducted of patients with con-firmed PHA who underwent SST between 2005 and 2015. Pre- and 2 h post-test potassium, aldosterone and renin levels were measured. Results are expressed as mean standard error of the mean (SEM) and number (%). Results: Twenty five patients were included in the final analysis; 13(52%) were males, and mean age 53 10.5 years. Overall, there was no difference in the mean pre- and post-SST potassium levels (p = 0.08). However, there was an inverse correlation between pre-SST K and the change in post-test K levels (p = 0.01); with the highest pre-test K patients experiencing the greatest decline in post-K levels. Eight (32%) were hypokalaemic (K < 3.5 mmol/L) pre-SST and required intravenous or oral K supplements. For patients that were normokalaemic pre-SST, there was a significant decrease in serum potassium levels post-SST (3.7 0.05 vs. 3.5 0.08,p = 0.01). Seven subjects (41%) who were normokalaemic pre-test became hypokalaemic post-SST; and 5 (29%) remained hypokalaemic on day 2. Conclusion: Hypokalaemia is common post-saline suppression test in primary hyperaldosteronism. The pathophysiology remains unclear. We recommend that potassium levels be routinely measured post-test and on day 2 to de

Seventeen subjects with confirmed primary aldosteronism and stable serum potassium (K) levels ≥ 3.5 mmol l-1 underwent saline suppression testing. They were retrospectively evaluated for changes in serum K levels post test. We found that there was a significant decrease in serum K levels post saline suppression test (3.7 ± 0.05 vs 3.5 ± 0.08, P = 0.01). This effect of saline suppression testing on serum K levels is not well described. We conclude that a decrease in serum K is common post-saline suppression test, even in subjects who are normokalemic pretest. The factors which predispose to the decrease in serum K level post saline load remain unclear.

UNLABELLED: This paper details the case of a 77-year-old male with refractory hypoglycaemia due to inoperable metastatic pancreatic neuroendocrine tumour (pNET) co-secreting insulin and gastrin. Multiple medical therapies were trialled with limited success, and we describe the complications experienced by our patient. Somatostatin analogues can ameliorate hypoglycaemia and may have tumour-stabilising effects; however, in our case resulted in paradoxical worsening of hypoglycaemia. This rendered our patient hospital dependent for glycaemic support including continuous dextrose infusion. Although this is a reported adverse effect with initiation of therapy, we describe successful initiation of short-acting octreotide as an inpatient followed by commencement of long-acting octreotide. Hypoglycaemic collapse occurred only after dose titration of long-acting octreotide. We outline the pitfalls of somatostatin analogue therapy and the mechanisms that may contribute to worsening hypoglycaemia. This rare side effect cannot be reliably predicted, necessitating close supervision and glucose monitoring during therapy. Our patient achieved disease stabilisation and gradual resolution of hypoglycaemia with peptide receptor radionuclide therapy (PRRT), an emerging therapeutic option for metastatic neuroendocrine tumours with high efficacy and low toxicity. We present a brief but comprehensive discussion of currently available and novel therapies for insulin secreting pNETs. LEARNING POINTS: Hypoglycaemia due to malignant insulin secreting pNET is frequently severe and may be life-threatening despite supportive therapies.Octreotide can ameliorate hypoglycaemia, and may have anti-proliferative and tumour-stabilising effects in malignant pNETs that are surgically unresectable.Paradoxical worsening of hypoglycaemia may occur with octreotide initiation and dose titration, necessitating close supervision and glucose monitoring.PRRT is emerging as a therapeutic option with high efficacy

1. Hormone replacement therapy (HRT) with oestrogen or oestrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima-medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non-HRT) and those women on long-term HRT with oestrogen alone (HRT-E) or oestrogen plus progestin (HRT- EP). 2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure. 3. Plasma total cholesterol was reduced and high-density lipoprotein-cholesterol was increased in the HRT group compared with the non-HRT group; low-density lipoprotein-cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT-E and HRT-EP subgroups were similar. 4. Carotid IMT was significantly reduced in the HRT group compared with men and non-HRT groups. Results for HRT-E and HRT-EP subgroups were similar. 5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age; SAC was higher in both HRT-E and HRT-EP groups compared with the non-HRT group. Indices of carotid stiffness were similar in men and in non-HRT groups. The HRT-EP group showed increased carotid stiffness compared with the HRT-E group. 6. There is an apparent protective effect of long-term oestrogen therapy on carotid IMT and age-related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.