Covalent Bruton tyrosine kinase inhibitors (BTKis) and the BCL2 inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n=5). The cohort was heavily pre-treated (median lines of prior therapy: 4) and enriched for adverse disease genetics (complex karyotype: 12/12 tested, 100%; del(17p)/TP53 mutations: 15/17, 88%). The median time to progression on prior venetoclax was 24 (range 6-94) months, and on prior BTKi was 25 (range 1-55) months. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in six. The median overall survival after progression on second-line TA was 3.6 (95%CI 2-11) months. Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

Aims/hypothesisThe pancreatic ATP-sensitive potassium (KATP) channel plays a pivotal role in linking beta cell metabolism to insulin secretion. Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively. To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. Here, we report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation.MethodsA male patient was diagnosed with diabetes shortly after birth. At 5 months of age, genetic testing revealed he carried a homozygous KCNJ11 mutation, G324R, (Kir6.2-G324R) and he was successfully transferred to sulfonylurea therapy (0.2 mg kg−1 day−1). Neither heterozygous parent was affected. Functional properties of wild-type, heterozygous and homozygous mutant KATP channels were examined after heterologous expression in Xenopus oocytes.ResultsFunctional studies indicated that the Kir6.2-G324R mutation reduces the channel ATP sensitivity but that the difference in ATP inhibition between homozygous and heterozygous channels is remarkably small. Nevertheless, the homozygous patient developed neonatal diabetes, whereas the heterozygous parents were, and remain, unaffected. Kir6.2-G324R channels were fully shut by the sulfonylurea tolbutamide, which explains why the patient’s diabetes was well controlled by sulfonylurea therapy.Conclusions/interpretationThe data demonstrate that tiny changes in KATP channel activity can alter beta cell electrical activity and insulin secretion sufficiently to cause diabetes. They also aid our understanding of how the Kir6.2-E23K variant predisposes to type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3964-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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What's new?• KCNJ11 mutations causing permanent neonatal diabetes are treated with sulfonylureas, but not all individuals are able to transfer completely from insulin to sulfonylureas.• Our data highlight that combining sulfonylurea treatment with insulin in those who are unable to fully transfer may still lead to clinically meaningful outcomes.• We demonstrate improvements in endogenous insulin production, HbA 1c , glycaemic variability and hypoglycaemia awareness.• These changes were not observed at initial doses of glibenclamide and improvements required higher sustained doses of glibenclamide.• Combining insulin and sulfonylureas should be considered in those with permanent neonatal diabetes who are not able to transfer to sulfonylurea therapy alone. AbstractBackground Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be

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There is an oversupply of Australian junior doctors, but significant training bottlenecks are developing, and geographical maldistribution in rural and remote areas remains. Last year, the Federal Minister for Immigration rejected a Department of Health recommendation for the removal of 41 health roles from the Skilled Occupation List after concerns that rural and regional communities would be left without access to medical services in areas currently serviced by international medical graduates. In an effort to achieve workforce self-sufficiency, Australia must ensure access to high-quality vocational training places in rural and regional settings while managing immigration of overseas-trained health professionals.