Search

Background: Metastatic gastroenteropancreatic neuroendocrine neoplasms (GEPNEN) can cause ectopic Cushing’s syndrome (ECS). ECS is highly morbid and medical therapy is complex and can be ineffective. Patients unsuitable for bilateral adrenalectomy (BA) have dismal outcomes. Peptide receptor radionuclide therapy (PRRT) is a rational option for hormone and disease control in ECS caused by NEN with high somatostatin receptor (SSTR) expression. Aim: To describe the characteristics and outcomes of patients with ECS treated with PRRT. Methods: Single-centre, retrospective analysis of imaging, biochemistry and outcomes of seven consecutive patients with ECS caused by metastatic GEPNEN treated with PRRT from 2006 to 2023. Results: Patients were aged 17–75 (female n = 6). The primary site was the pancreas (5/7) and rectum (2/7). Six patients were on medical therapy for ECS at baseline (one had a previous BA). A median of 34.4 GBq of [177Lu]Lu-DOTA-octreotate was given. [90Y]Y-DOTA-octreotate (one patient) and [111In]In-octreotide (one patient) were also used. Five patients had radiosensitising chemotherapy. Five patients had a flare of ECS within 1 week of PRRT cycle 1 (PRRT-C1). Following PRRT-C1, 5/7 patients had complete biochemical resolution of ECS at 1.5–6 months (four ongoing; one recurred after 12 months and had elective BA at 18 months). Best metabolic response on [18F]F-FDG PET/CT: Four patients had a complete metabolic response (CMR), and one had a partial metabolic response. PFS was 3–208 months. Two patients progressed at the first follow-up. The longest ECS remission and CMR continues at >17 years. Conclusion: PRRT can be effective for ECS caused by metastatic SSTR-positive GEPNEN and should be considered in its treatment algorithm.

Congenital hyperinsulinism is the leading cause of persistent hypoglycaemia in infants and children; however, it is uncommon to be diagnosed in adulthood. We describe the cases of two sisters who presented with hyperinsulinaemic hypoglycaemia aged 47 and 57 years old, who were subsequently diagnosed with compound heterozygous likely pathogenic variants in the ABCC8 gene, a known cause of monogenic congenital hyperinsulinism. We discuss the typical presenting features, investigation findings, and treatment strategies for patients with this condition.

Antimicrobial drug resistance within ESKAPE pathogens is a formidable global challenge, necessitating innovative solutions. This review explores a multifaceted strategy incorporating nanotechnology, CRISPR/Cas9, and other cutting-edge approaches to effectively combat multidrug resistance in ESKAPE bacteria. Nanotechnology presents a promising avenue through targeted drug delivery systems like antibiotic nanoparticles and antibiotic–antibody conjugates (AACs). While these nanostructures aim to enhance therapeutic efficacy and mitigate resistance spread, challenges such as anti-PEG antibodies and optimal drug release must be considered. Inspired by successful anticancer nanomedicines, nanotechnology seeks to optimize drug penetration and retention within infected tissues. The revolutionary CRISPR/Cas9 gene-editing technology offers a precise and tailored approach by selectively targeting and modifying bacterial resistance genes. This holds the potential to reverse or eliminate drug resistance in ESKAPE pathogens, though challenges like off-target effects and efficient delivery mechanisms require attention for clinical translation. Additionally, alternative approaches such as fecal microbial transplantation, bacteriophage therapy, and probiotic bacterial replacement are actively explored in clinical trials. These strategies diversify the arsenal against antibiotic resistance by targeting unique vulnerabilities in ESKAPE pathogens. A comprehensive and multidisciplinary strategy is imperative to effectively address antimicrobial drug resistance in ESKAPE pathogens. Integration of nanotechnology, CRISPR/Cas9, and emerging approaches offers a synergistic solution, holding promise in overcoming the challenges posed by these resilient multidrug-resistant bacteria. This review provides insights into current research, challenges, and potential breakthroughs, emphasizing the urgency for collaborative efforts to safeguard global health.

ABSTRACT Background Adrenal vein sampling (AVS), integral to identifying surgically remediable unilateral primary aldosteronism (PA), is technically challenging and subject to fluctuations in cortisol and aldosterone secretion. Intra‐procedural adrenocorticotropic hormone (ACTH), conventionally administered as a 250‐μg bolus and/or 50 μg per hour infusion, increases cortisol and aldosterone secretion and can improve AVS success, but may cause discordant lateralisation compared to unstimulated AVS. Aims To assess if AVS performed with ultra‐low dose ACTH infusion causes discordant lateralisation. Methods Here, we describe our preliminary experience using an ultra‐low dose ACTH infusion AVS protocol. We retrospectively reviewed the results of consecutive AVS procedures (n = 37) performed with and without ultra‐low dose ACTH (1‐μg bolus followed by 1.25 μg per hour infusion). Results Bilateral AV cannulation was successful in 70% of procedures pre‐ACTH and 89% post‐ACTH (p

ABSTRACT 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 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.

Background: Identifying carotid pseudo-occlusion (PO) from true occlusion (TO) has implications in determining the candidacy and feasibility of successful endovascular thrombectomy (EVT) in acute ischemic stroke (AIS). Purpose: We reviewed the computed tomography angiographic (CTA) patterns differentiating a PO from a TO and analyzed the rate of successful recanalization after EVT. Materials and Methods: Patients with AIS and proximal internal carotid artery (ICA) occlusion who underwent EVT from 2014 to 2021 were identified. The patterns of carotid occlusion in CTA were classified into beak, dome, and flat patterns and correlated with microcatheter digital subtraction angiography (DSA) as PO and TO. The rates of successful recanalization in PO and TO were analyzed. Results: Of the 24 patients, 16 (66%) had ICA PO and eight (33%) had TO in DSA. A beak pattern of the proximal ICA on CTA was significantly higher among the PO group patients (87.5% vs. 25%, P = 0.005), and a flat pattern was significantly higher among the TO group patients (50% vs. 12%, P = 0.005). A gradual contrast decline of the proximal ICA on CTA images was seen only in PO group patients (85.7% vs. 0%, P = 0.05). There was no significant difference in the rate of successful recanalization between PO and TO group patients (81.25% vs. 62.5%, P = 0.362). Conclusion: Beak pattern and gradual contrast decline at the proximal ICA occlusion site in CTA are suggestive of carotid PO. Identification of PO in CTA can help in planning intervention strategies and prognostication.

IntroductionHypophysitis 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.MethodsThis 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.ResultsThere 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.ConclusionCareful 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 hypophysitis.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence‐based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA. [ABSTRACT FROM AUTHOR]

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.

Background: Adrenal vein sampling (AVS), integral to identifying surgically remediable unilateral primary aldosteronism (PA), is technically challenging and subject to fluctuations in cortisol and aldosterone secretion. Intra‐procedural adrenocorticotropic hormone (ACTH), conventionally administered as a 250‐μg bolus and/or 50 μg per hour infusion, increases cortisol and aldosterone secretion and can improve AVS success, but may cause discordant lateralisation compared to unstimulated AVS. Aims: To assess if AVS performed with ultra‐low dose ACTH infusion causes discordant lateralisation. Methods: Here, we describe our preliminary experience using an ultra‐low dose ACTH infusion AVS protocol. We retrospectively reviewed the results of consecutive AVS procedures (n = 37) performed with and without ultra‐low dose ACTH (1‐μg bolus followed by 1.25 μg per hour infusion). Results: Bilateral AV cannulation was successful in 70% of procedures pre‐ACTH and 89% post‐ACTH (p < 0.01). Sixty‐nine percent of studies lateralised pre‐ACTH and 55% post‐ACTH, improving to 79% when both groups were combined. Lateralisation was discordant in 11 cases, including eight in which lateralisation was present only on basal sampling, and three in which lateralisation occurred only with ACTH stimulation. Discussion: Overall, the decrease in lateralisation rates with ACTH was higher than previously reported for some protocols utilising conventional doses of ACTH. Our results suggest that AVS performed with ultra‐low dose ACTH can cause discordant lateralisation similar to AVS performed with conventional doses of ACTH. Conclusion: Prospective studies directly comparing low and conventional dose ACTH AVS protocols and long‐term patient outcomes are needed to help define the optimal ACTH dose for accurate PA subtyping. [ABSTRACT FROM AUTHOR]

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.

The role of Civil Society Organizations (CSOs) in pursuing accountability for atrocity crimes through international law is more diverse than ever before, and the breadth of CSO activities and the modalities of their engagement with international justice institutions has been overlooked in the scholarship to date. This article explores various CSO approaches to advancing accountability, including at the International Court of Justice (ICJ), International Criminal Court (ICC), investigative mechanisms (for Syria, Myanmar, and Iraq), and selected United Nations treaty bodies and regional human rights courts. Civil society actors take on many roles, including as advocates, documenters, analysts, victims' representatives, and international law experts. While often described as indispensable to international justice efforts, the relationship between civil society and formal justice mechanisms remains novel and can feel incongruous with traditional and ostensibly independent and impartial legal processes. This is evolving as CSOs enter traditional international justice spaces in diverse ways. This article provides a framework to understand the modalities of CSO engagement with international legal processes, as well as critical challenges. [ABSTRACT FROM AUTHOR]