Dr Christopher Rowe

Aims: Hyperglycaemia following antenatal corticosteroids is common in women with diabetes in pregnancy, and validated algorithms to maintain pregnancy-specific glucose targets are lacking. The Pregnancy-IVI, an intravenous-insulin (IVI) algorithm, has been validated in gestational diabetes; however, its performance in pre-existing diabetes (Type 1 and Type 2 diabetes) is not known. We hypothesised that Pregnancy-IVI would be superior to a generic Adult-IVI protocol (prior standard of care) following betamethasone in women with pre-existing diabetes. Methods: A retrospective cohort study enrolled all women with pre-existing diabetes at a tertiary centre receiving betamethasone and treated with IVI according to one of two protocols: Adult-IVI (n¿=¿73, 2014¿2017) or Pregnancy-IVI (n¿=¿62, 2017¿2020). The primary outcome was on-IVI glycaemic time-in-range (capillary blood glucose (BGL) 3.8¿7.0¿mmol/L). Secondary outcomes included time with critical hyperglycaemia (BGL¿>¿10¿mmol/L); occurrence of maternal hypoglycaemia (BGL¿<¿3.8¿mmol/l) and incidence of neonatal hypoglycaemia (BGL¿=¿2.5¿mmol/L). Analysis was stratified by diabetes type. Results: Overall, Pregnancy-IVI achieved a higher proportion of on-IVI time-in-range (70%, IQR 56¿78%) compared to Adult-IVI (52%, IQR 41¿69%, p¿<¿0.0001). The duration of critical hyperglycaemia with Pregnancy-IVI was also reduced (2% [IQR 0¿7] vs 8% [IQR 4¿17], p¿<¿0.0001), without an increase in hypoglycaemia. Glycaemic variability was significantly reduced with Pregnancy-IVI. No difference in the rate of neonatal hypoglycaemia was observed. The Pregnancy-IVI was most effective in women with Type 1 diabetes. Conclusion: The Pregnancy-IVI algorithm is safe and effective when used following betamethasone in type 1 diabetes in pregnancy. Further study of women with type 2 diabetes is required.

Multidisciplinary team (MDT) meetings are the mainstay of the decision-making process for patients presenting with complex clinical problems such as papillary thyroid carcinoma (PTC). Adherence to guidelines by MDTs has been extensively investigated; however, scarce evidence exists on MDT performance and variability where guidelines are less prescriptive. We evaluated the consistency of MDT management recommendations for T1 and T2 PTC patients and explored key variables that may influence therapeutic decision making. A retrospective review of the prospective database of all T1 and T2 PTC patients discussed by the MDT was conducted between January 2016 and May 2021. Univariate analysis (with Bonferroni correction significance calculated at p < 0.006) was performed to establish clinical variables linked to completion thyroidectomy and Radioactive iodine (RAI) recommendations. Of 468 patients presented at thyroid MDT, 144 pT1 PTC and 118 pT2 PTC met the selection criteria. Only 18% (n = 12) of pT1 PTC patients initially managed with hemithyroidectomy were recommended completion thyroidectomy. Mean tumour diameter was the only variable differing between groups (p = 0.003). pT2 patients were recommended completion thyroidectomy in 66% (n = 16) of instances. No measured variable explained the difference in recommendation. pT1 patients initially managed with total thyroidectomy were not recommended RAI in 71% (n = 55) of cases with T1a status (p = 0.001) and diameter (p = 0.001) as statistically different variables. For pT2 patients, 60% (n = 41) were recommended RAI post-total thyroidectomy, with no differences observed among groups. The majority of MDT recommendations were concordant for patients with similar measurable characteristics. Discordant recommendations for a small group of patients were not explained by measured variables and may have been accounted for by individual patient factors. Further research into the MDT decision-making process is warranted.

Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell¿released NGF.

Objective: Post-thyroidectomy hypocalcaemia is a significant cause of morbidity and prolonged hospitalization, usually due to transient parathyroid gland damage, treated with calcium and vitamin D supplementation. We present a randomized, double-blinded placebo-controlled trial of preoperative loading with high-dose cholecalciferol (300¿000 IU) to reduce post-thyroidectomy hypocalcaemia. Patients and Measurements: Patients (n¿=¿160) presenting for thyroidectomy at tertiary hospitals were randomized 1:1 to cholecalciferol (300¿000¿IU) or placebo 7¿days prior to thyroidectomy. Ten patients withdrew prior to surgery. The primary outcome was post-operative hypocalcaemia (corrected calcium <2.1¿mmol/L in first 180¿days). Results: The study included 150 patients undergoing thyroidectomy for Graves¿ disease (31%), malignancy (20%) and goitre (49%). Mean pre-enrolment vitamin D was 72¿±¿26¿nmol/L. Postoperative hypocalcaemia occurred in 21/72 (29%) assigned to cholecalciferol and 30/78 (38%) participants assigned to placebo (P¿=¿0.23). There were no differences in secondary end-points between groups. In pre-specified stratification, baseline vitamin D status did not predict hypocalcaemia, although most individuals were vitamin D replete at baseline. Post-hoc stratification by day 1 parathyroid hormone (PTH) (<10¿pg/mL, low vs =10¿pg/mL, normal) was explored due to highly divergent rates of hypocalcaemia in these groups. Using a Cox regression model, the hazard ratio for hypocalcaemia in the cholecalciferol group was 0.56 (95%CI 0.32-0.98, P¿=¿0.04) after stratification for Day 1 PTH. Further clinical benefits were observed in these subgroups. Conclusions: Pre-thyroidectomy treatment with high-dose cholecalciferol did not reduce the overall rate of hypocalcaemia following thyroidectomy. In subgroups stratified by day 1 PTH status, improved clinical outcomes were noted.

Aims: Marked hyperglycaemia is common following betamethasone administration in women with gestational diabetes (GDM), and may contribute to neonatal hypoglycaemia. Validated protocols to deliver glycaemic stability following betamethasone are lacking. We hypothesized that an intravenous insulin (IVI) protocol for pregnancy-specific glycaemic targets (Pregnancy-IVI) would achieve greater at-target glycaemic control than a generic adult intravenous insulin protocol (Adult-IVI), and may reduce neonatal hypoglycaemia. Methods: A retrospective cohort study of the performance Adult-IVI and Pregnancy-IVI following betamethasone in GDM, sequentially implemented at a tertiary hospital, without change in indication for IVI. Cases were identified by electronic record search. Primary outcome was percentage of on-IVI time with at-target glycaemia [blood glucose level (BGL) 3.8¿7¿mmol/l]. Secondary outcomes were time with critical hyperglycaemia (BGL >¿10¿mmol/l), occurrence of maternal hypoglycaemia (BGL <¿3.8¿mmol/l), and incidence of neonatal hypoglycaemia (BGL =¿2.5¿mmol/l) if betamethasone was administered within 48¿h of birth. Results: The cohorts comprised 151 women (Adult-IVI n¿=¿86; Pregnancy-IVI n¿=¿65). The primary outcome was 68% time-at-target [95% confidence interval (CI) 64¿71%) for Pregnancy-IVI compared with 55% (95% CI 50¿60%) for Adult-IVI (P¿=¿0.0002). Critical maternal hyperglycaemia (0% vs. 2%, P¿=¿0.02) and hypoglycaemia (2% vs. 12%, P¿=¿0.02) were both lower with Pregnancy-IVI than Adult-IVI. Neonatal hypoglycaemia was less common after Pregnancy-IVI (29%) than after Adult-IVI (54%, P¿=¿0.03). A multiple logistic regression model adjusting for potential confounders gave an odds ratio for neonatal hypoglycaemia with Pregnancy-IVI of 0.27 (95% CI 0.10¿0.76, P¿=¿0.01). Conclusions: An IVI protocol designed for pregnancy effectively controlled maternal hyperglycaemia following betamethasone administration in GDM. This is the first intervention to show a reduction in betamethasone-associated neonatal hypoglycaemia, linked with optimum maternal glycaemic control.

Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.

Aims To assess the relationship between insulin resistance (IR), retinopathy and maculopathy in young adults with Type 1 diabetes mellitus. Methods A cross-sectional study at a regional Australian tertiary hospital. Retinal pathology, assessed by colour fundus photography, was correlated with two surrogate measures of IR: estimated Glucose Disposal Rate (eGDR) and Insulin Sensitivity Score (ISS), where lower scores reflect greater IR. Results 107 patients were recruited, with mean age 24.7¿years, 53% male, and mean duration of disease 10.8¿years. Mean eGDR scores (5.6¿vs 8.0 p¿<¿0.001) and ISS (4.7¿vs 7.9, p¿<¿0.001) were lower in subjects having at least moderate non-proliferative diabetic retinopathy (NPDR; relative to nil/mild-NPDR). Similarly, mean eGDR (4.2¿vs 6.2, p¿=¿0.001) and ISS (3.8¿vs 6.1, p¿=¿0.003) were lower in patients with maculopathy. Multivariate logistic regression modelling was used to control for confounding. For retinopathy severity, a unit increase in eGDR or ISS (representing lower IR) was associated with a 50% decrease in odds of moderate-NPDR or worse (eGDR OR 0.5, 95%CI 0.32¿0.77, p¿=¿0.002; ISS OR 0.49, 95%CI 0.29¿0.84, p¿=¿0.01). A unit increase in eGDR or ISS was associated with a 46¿56% decrease in odds of maculopathy (eGDR OR 0.54, 95%CI 0.37¿0.81, p¿=¿0.003; ISS OR 0.44, 95%CI 0.22¿0.88, p¿=¿0.02). Conclusions IR correlates with more severe retinopathy in young adults with Type 1¿DM. This is the first description of a correlation between IR and maculopathy in Type 1¿DM, warranting further evaluation. Prospective studies examining whether reducing IR can improve microvascular complications are required.