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SUMMARY: Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient's serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team. LEARNING POINTS: Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects. Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia. Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.

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BACKGROUND: Ambulatory blood pressure (ABP) monitoring in type 2 diabetes (T2DM) is not yet routine in clinical practice. OBJECTIVES: To quantify abnormal ABP patterns and their associations with diabetic complications, and to assess the reliability of office blood pressure (OBP) for assessing BP in T2DM. METHODS: In a cross-sectional study, eligible patients with T2DM underwent OBP and 24- hour ABP measurements under standardized conditions and screening for diabetic complications. RESULTS: 56 patients (mean age 67 ± 10 years, males 50%) completed assessment. 43(73%) had a known history of hypertension. Non-dipping and nocturnal systolic hypertension (SHT) were prevalent in 31(55%) and 32(57%) patients, respectively. 16(29%) demonstrated masked phenomenon, but only three (7%) demonstrated white coat effect. Nocturnal SHT had a significant association with composite microvascular complications independent of daytime systolic BP control (adjusted odds ratio (OR) 1.72(CI 1.41-4.25). There was no association between other abnormal ABP patterns and diabetic complications. The sensitivity and specificity of OBP for diagnosing HT or assessing BP control was 59% and 68% respectively. The positive and negative predictive values were 74% and 52% respectively. CONCLUSION: Non-dipping, reverse dipping, nocturnal SHT and masked phenomenon are highly prevalent in patients with T2DM with or without a known history of hypertension. Compared with non-dipping, nocturnal SHT may be a stronger predictor of end organ damage. The reliability of OBP for assessing BP in T2DM is only modest. Patients with T2DM are likely to benefit from routine ABP monitoring.

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Immune checkpoint inhibitors are the mainstay of treatment for advanced melanoma, and their use is being increasingly implicated in the development of autoimmune endocrinopathies. We present a case of a 52-year-old man with metastatic melanoma on combination nivolumab and ipilumimab therapy who developed concurrent hypophysitis, type 1 diabetes mellitus (T1DM) and diabetes insipidus. He presented prior to third cycle of combination treatment with a headache, myalgias and fatigue. Biochemistry and MRI pituitary confirmed anterior pituitary dysfunction with a TSH: 0.02 mU/L (0.5-5.5 mU/L), fT4: 5.2 pmol/L (11-22 pmol/L), fT3: 4.0 pmol/L (3.2-6.4 pmol/L), cortisol (12:00 h): <9 nmol/L (74-286 nmol/L), FSH: 0.7 IU/L (1.5-9.7 IU/L), LH: <0.1 IU/L (1.8-9.2 IU/L), PRL: 1 mIU/L (90-400 mIU/L), SHBG: 34 nmol/L (19-764 nmol/L) and total testosterone: <0.4 nmol/L (9.9-27.8 nmol/L). High-dose dexamethasone (8 mg) was administered followed by hydrocortisone, thyroxine and topical testosterone replacement. Two weeks post administration of the third cycle, he became unwell with lethargy, weight loss and nocturia. Central diabetes insipidus was diagnosed on the basis of symptoms and sodium of 149 mmol/L (135-145 mmol/L). Desmopressin nasal spray was instituted with symptom resolution and normalization of serum sodium. Three weeks later, he presented again polyuric and polydipsic. His capillary glucose was 20.8 mmol/L (ketones of 2.4 mmol), low C-peptide 0.05 nmol/L (0.4-1.5 nmol/L) and HbA1c of 7.7%. T1DM was suspected, and he was commenced on an insulin infusion with rapid symptom resolution. Insulin antibodies glutamic acid decarboxylase (GAD), insulin antibody-2 (IA-2) and zinc transporter-8 (ZnT8) were negative. A follow-up MRI pituitary revealed findings consistent with recovering autoimmune hypophysitis. Immunotherapy was discontinued based on the extent of these autoimmune endocrinopathies. LEARNING POINTS: The most effective regime for treatment of metastatic melanoma is combination immunotherapy with nivolumab and ipilumimab, and this therapy is associated with a high incidence of autoimmune endocrinopathies.Given the high prevalence of immune-related adverse events, the threshold for functional testing should be low.Traditional antibody testing may not be reliable to identify early-onset endocrinopathy.Routine screening pathways have yet to be adequately validated through clinical trials.

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AIMS: Telomeres undergo shortening with cell division, accelerated by increased oxidative stress. We aimed to demonstrate shortened telomeres in the offspring of mothers who have diabetes as a consequence of exposure to increased oxidative stress during intrauterine development. METHODS: We examined the level of glycaemia (glucose, HbA1c, fructosamine), oxidative stress (lipid peroxidation) and the levels of antioxidant enzymes (Superoxide dismutase (SOD) and Selenium dependent glutathione peroxidase) and correlate these findings with mean telomere length (TL) in maternal and foetal blood in groups of pregnant women with pre-gestational diabetes (PGD), gestational diabetes (GD) and a euglycaemic control group. RESULTS: Foetal and maternal glucose, maternal HbA1c, and foetal insulin and C-peptide were higher in the PGD group with the GD group being intermediate. Markers of oxidative stress did not vary between groups with the exception of foetal SOD activity that was highest in the GD group. There were no detectable differences in maternal or foetal TL between study groups. An exploratory analysis looking at correlations between glycaemic and oxidative stress parameters and TL revealed a negative correlation between maternal and foetal glucose and TL across the whole study population. This relationship held for the short-term marker of glycaemic control, fructosamine. CONCLUSIONS: We were unable to show significant telomere shortening in the offspring of mothers with PGD or GD. Exploratory analysis revealed a relationship between foetal TL and short-term glycaemia particularly in PGD. It is possible that increased telomerase activity can compensate for long-term increased oxidative stress but not for short-term dysglycaemia.

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BACKGROUND: The National Heart Foundation (NHF) and Cardiac Society of Australia and New Zealand (CSANZ) Acute Coronary Syndrome (ACS) guidelines recommend the use of a high sensitivity troponin assay (hsTrop) in the assessment of patients presenting with ACS. A troponin delta of 50% compared with the previously recommended 20% is advocated by the guidelines to aid in the clinical diagnosis of ACS. We sought to determine the clinical impact of the updated recommendation to use 50% troponin delta for patients presenting with chest pain to the emergency department. METHOD: We retrospectively collected data for all patients >18 years presenting with chest or abdominal pain with a hsTrop test performed between January-June 2012. Patients with a STEMI, lacked serial hsTrop, were on dialysis or had trauma-related pain were excluded. RESULTS: Of the 1054 eligible patients, 422 (40%) with serial hsTrop had at least one abnormal troponin (>14 ng/ml). 73 (6.9%) fell within 20-50%. Twenty-seven had clinical or ECG evidence suggestive of ACS and were referred for further cardiac investigations. Of the remainder, five patients were medically managed for ACS, 38 patients with non-cardiac chest pain had no further tests. At 1 year follow-up, of the patients that did not undergo further investigations, 6 patients represented with ACS; there was no cardiac mortality. CONCLUSION: Our data showed a number of patients that would be potentially missed with the implementation of a 50% troponin. However, this loss of sensitivity was mitigated by the use of clinical acumen.

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