Diabetic ketoacidosis as a hallmark of autoimmune diabetes occurring after two cycles of cemiplimab.

INTRODUCTION: Clinical indications of immune checkpoint inhibitors have expanded to a variety of malignancies. Nearly 50% of patients with advanced cutaneous squamous cell carcinoma, respond to the programmed-death 1 inhibitor cemiplimab. To date, insulin-dependent diabetes mellitus has been documented with the use of several immune checkpoint inhibitors but not cemiplimab. CASE REPORT: We report herein the first case of a patient with cutaneous squamous cell carcinoma who developed diabetic ketoacidosis and insulin-dependent diabetes mellitus following only two cycles of cemiplimab. A score of 6 on the Naranjo nomogram makes the causality relationship between cemiplimab use and the insulin-dependent diabetes mellitus probable. MANAGEMENT AND OUTCOME: The patient's developed diabetic ketoacidosis was managed with intravenous fluids and intravenous insulin, with a prompt resolution. Cemiplimab was discontinued, and the patient was discharged on long-acting and short-acting insulin therapy, with a follow-up with endocrinology. DISCUSSION/CONCLUSIONS: The mechanism by which cemiplimab caused insulin-dependent diabetes mellitus is most likely due to lack of endogenous insulin production in the setting of immune-mediated loss of pancreatic beta-cells. Patients may benefit from fasting blood glucose monitoring and early immune checkpoint inhibitor discontinuation where elevated serum glucose is detected.

PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype.

Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non-germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1-altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

CD4+ T-cell help enhances NK cell function following therapeutic HIV-1 vaccination.

UNLABELLED: Increasing data suggest that NK cells can mediate antiviral activity in HIV-1-infected humans, and as such, novel approaches harnessing the anti-HIV-1 function of both T cells and NK cells represent attractive options to improve future HIV-1 immunotherapies. Chronic progressive HIV-1 infection has been associated with a loss of CD4(+) T helper cell function and with the accumulation of anergic NK cells. As several studies have suggested that cytokines produced by CD4(+) T cells are required to enhance NK cell function in various infection models, we hypothesized that reconstitution of HIV-1-specific CD4(+) T-cell responses by therapeutic immunization would restore NK cell activity in infected individuals. Using flow cytometry, we examined the function of CD4(+) T cells and NK cells in response to HIV-1 in subjects with treated chronic HIV-1 infection before and after immunization with an adjuvanted HIV-1 Gp120/NefTat subunit protein vaccine candidate provided by GlaxoSmithKline. Vaccination induced an increased expression of interleukin-2 (IL-2) by Gp120-specific CD4(+) T cells in response to HIV-1 peptides ex vivo, which was associated with enhanced production of gamma interferon (IFN-γ) by NK cells. Our data show that reconstitution of HIV-1-specific CD4(+) T-cell function by therapeutic immunization can enhance NK cell activity in HIV-1-infected individuals. IMPORTANCE: NK cells are effector cells of the innate immune system and are important in the control of viral infection. Recent studies have demonstrated the crucial role played by NK cells in controlling and/or limiting acquisition of HIV-1 infection. However, NK cell function is impaired during progressive HIV-1 infection. We recently showed that therapeutic immunization of treated HIV-1-infected individuals reconstituted strong T-cell responses, measured notably by their production of IL-2, a cytokine that can activate NK cells. The current study suggests that reconstitution of T-cell function by therapeutic vaccination can enhance NK cell activity in individuals with chronic HIV-1 infection. Our findings provide new insights into the interplay between adaptive and innate immune mechanisms involved in HIV-1 immunity and unveil opportunities to harness NK cell function in future therapeutic vaccine strategies to target HIV-1.

Iodine-induced neonatal hypothyroidism secondary to maternal seaweed consumption: a common practice in some Asian cultures to promote breast milk supply.

Mild iodine deficiency is a recognised problem in Australia and New Zealand. However, iodine excess can cause hypothyroidism in some infants. We highlight two cases which illustrate the risks of excess dietary iodine intake during pregnancy and breastfeeding. They also describe a cultural practice of consuming seaweed soup to promote breast milk supply. Although most attention recently has been on the inadequacy of iodine in Australian diets, the reverse situation should not be overlooked. Neither feast nor famine is desirable.

Immune checkpoint inhibitor-mediated myasthenia gravis with focal subclinical myocarditis progressing to symptomatic cardiac disease.

The advent of immune checkpoint inhibitors (ICIs) for cancer therapy has heralded increasing frequency of immune-related adverse events including endocrinopathies, hepatitis, colitis and rarely myocarditis and myasthenia gravis (MG). The heterogeneity in clinical presentations regardless of organ-specific involvement can lead to delayed recognition and management of these events and adverse health outcomes. We describe a case of ICI-induced subclinical focal myocarditis that was recognised and treated in the broader context of MG. It is essential that patients with ICI-induced MG should be screened and monitored for myocarditis, a potentially fatal complication.

Incidence of cystic fibrosis in five different states of Brazil as determined by screening of p.F508del, mutation at the CFTR gene in newborns and patients.

Cystic Fibrosis (CF) is one of the most common single-gene defects in European descent populations with an incidence of about 1 in every 2500 live births and carrier frequency of approximately 1 in 25. The most common mutation at the CF transmembrane conductance regulator (CFTR) gene is a deletion (p.F508del) of the phenylalanine codon 508; its frequency, however, is not the same throughout the world. The purpose of this paper is to document an application of a two-tier survey design in different states of Brazil, from which regional differences of the incidence of CF and frequency of CF-causing mutation(s) carriers can be for the first time estimated. We present data on genotype distributions in reference to p.F508del mutation in samples of newborns, adult controls and CF patients from five Brazilian states, in which a total of 2683 newborns born to Brazilian white parents and 500 African-Brazilians adult controls were screened, as well as 300 CF patients (262 European descents and 38 African descents) were genotyped. Our results suggest that the CF-incidence in different parts of Brazil may differ by almost 20-fold. For the five different states as a whole, nearly 48% of the CF-alleles carry the p.F508del mutation, which places the estimates of disease incidence and carrier frequencies for the Brazilian European descents as 1 in 7576 live births and 2.3%, respectively. The implications for prevention of CF and other rare Mendelian diseases through such surveys of mutation screening are discussed.

Horner's syndrome after placement of a peripherally inserted central catheter.

We describe a delayed case of Horner's syndrome after the use of a peripherally inserted central line. Central vein thrombosis, a well-recognized complication of central venous access, led to temporary injury to the sympathetic tract in the neck. Presentation of Horner's syndrome with central venous access in place should be further investigated to rule out central vein thrombosis.

The development and validation of the Self-directed Learning Scales (SLS).

This article describes the development and validation of the Self-directed Learning Scales (SLS) using data from 14,846 secondary students. Self-directed learning refers to a process whereby the learner consciously and actively directs his/her actions in the learning process. The SLS comprised a battery of subscales measuring students' goal setting, planning, academic motivation, academic self-efficacy, inquiry and information processing, strategic help-seeking, management of learning resources, and self-monitoring. Rasch analysis following factor analyses provided evidence in support of the validity of SLS for use with secondary students. Two original subscales were merged with other subscales on the basis of the analyses, resulting in 19 subscales with strong psychometric properties in the Self-directed Learning Scales.

How to perform first aid.

RATIONALE AND KEY POINTS: This article aims to help nurses to perform first aid in a safe, effective and patient-centred manner. First aid comprises a series of simple, potentially life-saving steps that an individual can perform with minimal equipment. Although it is not a legal requirement to respond to an emergency situation outside of work, nurses have a professional duty to respond and provide care within the limits of their competency. First aid is the provision of immediate medical assistance to an ill or injured person until definitive medical treatment can be accessed. First aid can save lives and it is essential that nurses understand the basic principles. REFLECTIVE ACTIVITY: Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. Your skill in performing first aid and any areas where you may need to extend your knowledge. 2. How reading this article will change your practice. Subscribers can upload their reflective accounts at: rcni.com/portfolio .