ObjectiveInsulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes.Research design and methodsWe reviewed 1444 patients treated with ICIs over 6 years at our cancer center, and from the 1163 patients who received programmed cell death protein 1 (PD-1) inhibitors, we identified 21 such cases, 12 of which developed new-onset insulin-dependent diabetes and 9 experienced worsening of pre-existing type 2 diabetes.ResultsICI-induced diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The median age was 61 years, and body mass index was 31 kg/m2, which are both higher than expected for spontaneous type 1 diabetes. Other immune-related adverse events occurred in 62%, the most common being immune mediated thyroid disease. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months; 67% presented with diabetic ketoacidosis and 83% with low or undetectable C-peptide. Autoantibodies were elevated in 5/7 (71%) at the time of new-onset diabetes. Diabetes did not resolve during a median follow-up of 1 year.ConclusionsPD-1 inhibitors can lead to insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes, with a frequency of 1.8 %. The underlying mechanism appears similar to spontaneous type 1 diabetes but there is a faster progression to severe insulin deficiency. Better characterization of ICI-induced diabetes will improve patient care and enhance our understanding of immune-mediated diabetes.

Background: Thyroid immune-related adverse events (IRAEs) have been reported more frequently with programmed cell death protein-1 (PD-1) inhibitors than cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, but there is limited data describing endocrinopathies from programmed cell death protein-ligand 1 (PD-L1) inhibitors. This study characterizes thyroid IRAEs in cancer patients treated with PD-L1 inhibitors and examines the impact on overall survival. Methods: This is a retrospective cohort study of cancer patients treated with atezolizumab and avelumab at the Mayo Clinic, Rochester, Minnesota, from June 1, 2016 to January 30, 2018, and followed for a median of 10.1 months. Thyroid IRAEs were characterized as new onset hypothyroidism, thyrotoxicosis, and worsening of preexisting hypothyroidism. Results: Of 91 patients treated with a PD-L1 inhibitor, 19 (21%) developed new onset thyroid dysfunction, of whom 14 presented with hypothyroidism and 5 with thyrotoxicosis (3 progressed to hypothyroidism and 2 returned to euthyroidism), and 4 (4%) had worsening of pre-existing hypothyroidism. Thyroid IRAEs occurred after a median of two doses (6 weeks), 48% required thyroid hormone replacement, and none required steroids or discontinuation of immunotherapy. Two out of four patients with thyroid peroxidase (TPO) antibody >9 IU/mL at baseline developed thyroid IRAEs. Median TPO antibody titer was not different between those with and without thyroid IRAEs but was higher in those with overt than those with subclinical hypothyroidism (5 vs. 0.3 IU/mL, p = 0.003) and those prescribed thyroid hormone replacement as compared with observation (5.5 vs. 0.3, p = 0.008). Diffusely increased thyroid 18-fluorodeoxyglucose ( 18 FDG) uptake on positron emission tomography (PET) scan occurred in 71% with thyroid IRAE as compared with 6% without thyroid IRAEs ( p = 0.001). Patients who developed thyroid IRAEs had longer overall survival ( p = 0.027) and lower mortality (hazard ratio 0.49 [95% CI 0.25-0.99], p = 0.034) after adjusting for potential confounders. Conclusions: PD-L1 inhibitors lead to immune-mediated thyroiditis, the most frequent endocrine IRAE. In most cases, management is supportive without requiring steroids or discontinuation of immunotherapy. Diffusely increased thyroid 18 FDG uptake on PET scan may predict the occurrence of thyroiditis, whereas TPO antibodies may help identify its severity. Thyroiditis may be a biomarker for antitumor immune response, highlighting the need to further characterize its underlying mechanism.

No abstract

Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series. Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity. Diagnosis is based on a combination of clinical and radiological features that help differentiate this condition from other sclerosing bone dysplasias. LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis. The exact etiology of classic sporadically occurring melorheostosis remains unknown, with possible causes being somatic LEMD3 mutations, somatic mutations in the bone morphogenetic protein/transforming growth factor-beta pathway, mutations in multiple genes, or other non-genetic causes. Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy. Melorheostosis may present as mixed or atypical osseous involvement in addition to the classically described "dripping candle wax" appearance of hyperostosis. Some patients may have overlap with osteopoikilosis or Buschke-Ollendorff syndrome. In the future, better characterization of genetic and developmental factors predisposing to melorheostosis may lead to the development of targeted therapy for this condition, as well as for more commonly encountered skeletal abnormalities.