Roderick J. Bligh-Clifton

Pheochromocytomas (PCs) are rare neuroendocrine tumors found in 20-50% of MEN2 patients. MEN2-related PCs are more often bilateral, identified at a younger age and have a low metastatic potential. They secrete epinephrine as the predominant catecholamine, along with its metabolite metanephrine, and lesser amounts of norepinephrine and normetanephrine. The advent of molecular diagnostic tools has enhanced the identification and stratification of these tumors, revealing a strong genotype-phenotype correlation which is crucial for screening and managing patients. Evaluation involves a combination of structural (CT/MRI) and functional imaging. MIBG remains helpful for PC assessment but novel PET ligands (18F-DOPA, 68Ga-DOTATATE, 18F-FDG) aid in the detection of extra-adrenal paragangliomas, recurrence, and metastatic disease. The treatment paradigm has shifted toward personalized medicine, incorporating genetic insights to tailor interventions, particularly surgical approaches and novel therapeutics such as radiolabeling of somatostatin analogs with lutetium and tyrosine kinase inhibitors.

Immune checkpoint inhibitors (ICIs) have an expanding role in the management of numerous cancers. Hyperglycaemia is commonly seen in patients treated with ICIs. However, the differential diagnosis for hyperglycaemia is broad, and incorrect diagnosis can have serious consequences. Herein we review the available literature on causes of hyperglycaemia in ICI treated patients and expert guidelines on management and provide an updated synthesis of expert multidisciplinary recommendations. Our key recommendations are as follows: Intensity of screening for hyperglycaemia should be based on a patient's risk level, including assessment of factors such as corticosteroid use, pre-existing diabetes, baseline HbA1c and fasting blood glucose levels (BGL). People with new onset hyperglycaemia should undergo initial assessment to determine severity and aetiology, including bedside capillary BGL, and formal bloods including lipase, C-peptide with matching glucose, electrolytes and renal function and in some cases type 1 diabetes autoantibodies. People with BGL >15mmol/L (or those receiving SGLT2 inhibitors with BGL >10mmol/L) should additionally have ketones measured. Patients with a high risk of diabetic ketoacidosis (BGL>15 mmol/L, ketones >2 mmol/L) and/or risk of hyperosmolar hyperglycaemic state (BGL persistently >20 mmol/L or reading 'HI') should be referred directly to hospital for emergency assessment and management. Further management of hyperglycaemia should be tailored to the underlying cause(s).

Objective: This review summarises the latest evidence on effects of exercise on falls prevention, bone mineral density (BMD) and fragility fracture risk in postmenopausal women, explores hypotheses underpinning exercise-mediated effects on BMD and sheds light on innovative concepts to better understand and harness the skeletal benefits of exercise. Results: Multimodal exercise programs incorporating challenging balance exercises can prevent falls. Emerging clinical trial evidence indicates supervised progressive high-intensity resistance and impact training (HiRIT) is efficacious in increasing lumbar spine BMD and is safe and well-tolerated in postmenopausal women with osteoporosis/osteopenia. There remains uncertainty regarding durability of this load-induced osteogenic response and safety in patients with recent fractures. Muscle-derived myokines and small circulating extracellular vesicles have emerged as potential sources of exercise-induced muscle-bone crosstalk but require validation in postmenopausal women. Exercise has the potential for multi-modal skeletal benefits with i) HiRIT to build bone, and ii) challenging balance exercises to prevent falls, and ultimately fractures. The therapeutic effect of such exercise in combination with osteoporosis pharmacotherapy should be considered in future trials.

Pheochromocytomas and paragangliomas (PPGLs) are rare neural crest-derived tumors with malignant potential and a highly variable natural history, where some patients achieve a cure through surgical resection, while others experience an aggressive and protracted disease course characterized by recurrence and metastasis. While currently no definitive curative treatment exists for metastatic PPGL, ongoing trials and advances in biology of the disease present a beacon of hope. We present a case that illustrates a 15-year treatment journey, illustrating the complexity of metastatic PPGL treatment with different modalities, each with distinct efficacy and toxicity profiles. The choice of treatment is often an art, as much as it is based on evidence, as the clinician must balance among several factors, including tumor-related (pace of progression, tumor burden) and patient-related (functional status, symptoms, general health) ones. Through a stepwise approach, this discussion aims to provide insights into the evolving landscape of metastatic PPGL management.

Background: Poorly differentiated thyroid carcinoma (PDTC) accounts for 5% of all thyroid cancers and is responsible for a large proportion of thyroid cancer-related deaths. The optimal treatment approach is not clear. This study aimed to evaluate the effect of postoperative intensity-modulated radiotherapy (IMRT) on the treatment of resectable PDTC. Additionally, treatment-related morbidity, characteristics of 131I-refractory disease, and factors affecting survival were assessed. Methods: The study included consecutive PDTC cases from 1997 to 2018, defined according to Turin criteria and treated in two tertiary referral centers. Surgery, IMRT, 131I, and systemic therapies were administered based on multidisciplinary team recommendations. The primary study outcome was 5-year local control after IMRT in cases with positive resection margins (micro- and macroscopic). The secondary outcomes were treatment-related morbidity within 30-days after completion of treatment (Clavien-Dindo and Common Terminology Criteria for Adverse Events [CTC-AE] 5.0), 131I-refractory disease characteristics using standardized definitions, and factors influencing survival. Results: Among 51 PDTC cases, 53% presented with metastatic disease. Adjuvant IMRT improved 5-year local control (100% vs. 17.5%; p = 0.02), with a higher number of grades 1 to 3 complications (p = 0.005) versus cases without IMRT. Within 13 months, 131I-refractory disease occurred in 62.7% of the patients and was more common in non-survivors (86.6% vs. 52.8%; p = 0.01). Positive resection margins and extrathyroidal extension were associated with poor survival in the univariate analysis, but were not significant in the multiple regression analysis. Conclusions: Adjuvant IMRT may reduce thyroid bed recurrence in resectable PDTC with positive resection margins, but is associated with increased treatment-related complications. 131I-refractory disease occurs frequently, with non-survivors progressing earlier to 131I resistance.