Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte ...antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.
Wright et al. discuss the increased reporting of immune checkpoint inhibitor (CPI)-associated diabetes. They analyzed VigiBase, the World Health Organization's database of individual case safety ...reports, and detected 283 cases of new-onset DM from 2014 to April 2018 following treatment with CPI using the following preferred terms according to MedDRA (Medical Dictionary for Regulatory Activities): diabetic ketoacidosis (DKA), diabetic ketosis, type 1 diabetes mellitus, or fulminant type 1 diabetes mellitus; any one of these was sufficient to define CPI-DM. They noted a marked increase in reporting of CPI-DM over this time period, with over 50% of cases reported in 2017. Overall, half of the patients with DM presented in DKA (50.2%); 5.6% of all cases were also on steroids at diagnosis of DM, and 6.4% were on noninsulin diabetes medications in addition to insulin. Prior and/or subsequent cancer therapies are unknown, but no other immunomodulatory medications were reported.
Abstract
Immune checkpoint inhibitors (ICI) are cancer therapies that are approved for use in at least 19 different cancers. They function by stimulating immune cell responses against cancer, and ...their toxicities comprise a host of autoinflammatory syndromes that may impact any organ system. Endocrine toxicities occur in as high as 25% to 50% of ICI recipients, depending on the treatment regimen used. These toxicities vary in severity from mild, asymptomatic cases of subclinical hypothyroidism to severe, fatal cases of adrenal crisis, thyroid dysfunction, or diabetic ketoacidosis. Thus, timely recognition and treatment is critical. Herein, we present clinical cases of ICI-induced thyroid dysfunction, hypophysitis, and insulin-dependent diabetes mellitus. We use these cases to discuss the screening, diagnosis, and management of ICI-associated endocrine dysfunction.
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy
. The pathogenesis ...of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1
Ctla4
mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration
. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1
Ctla4
mice, we identify clonal effector CD8
T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1
Ctla4
mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8
T cells. The cardiac-specific protein α-myosin, which is absent from the thymus
, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8
T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a ...subset expressing autoantibodies associated with the early stages of T1D.
MRI was performed in individuals with recent-onset stage 3 T1D (
= 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants (
= 57) and in autoantibody-positive individuals without diabetes (
= 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition.
Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL;
< 0.001), including when normalized by individual weight (
< 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis (
< 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort (
= 0.017) but smaller than that of the control cohort (
= 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient (
= 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution.
These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
• Paleobotanists have long used models based on leaf size and shape to reconstruct paleoclimate. However, most models incorporate a single variable or use traits that are not physiologically or ...functionally linked to climate, limiting their predictive power. Further, they often underestimate paleotemperature relative to other proxies. • Here we quantify leaf-climate correlations from 92 globally distributed, climatically diverse sites, and explore potential confounding factors. Multiple linear regression models for mean annual temperature (MAT) and mean annual precipitation (MAP) are developed and applied to nine well-studied fossil floras. • We find that leaves in cold climates typically have larger, more numerous teeth, and are more highly dissected. Leaf habit (deciduous vs evergreen), local water availability, and phylogenetic history all affect these relationships. Leaves in wet climates are larger and have fewer, smaller teeth. Our multivariate MAT and MAP models offer moderate improvements in precision over univariate approaches (± 4.0 vs 4.8°C for MAT) and strong improvements in accuracy. For example, our provisional MAT estimates for most North American fossil floras are considerably warmer and in better agreement with independent paleoclimate evidence. • Our study demonstrates that the inclusion of additional leaf traits that are functionally linked to climate improves paleoclimate reconstructions. This work also illustrates the need for better understanding of the impact of phylogeny and leaf habit on leaf-climate relationships.
Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes ...corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.
Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across ...locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Individuals with type 1 diabetes (T1D) have a smaller pancreas, but longitudinal changes in pancreas size and shape are unclear.
Objective
We monitored changes in pancreas size and ...shape after diagnosis with T1D.
Design
We conducted a prospective cohort study at an academic medical center between 2014 and 2022.
Patients and Healthy Controls
Individuals with T1D (n = 91) or controls (n = 90) underwent magnetic resonance imaging (MRI) of the pancreas, including longitudinal MRI in 53 individuals with new-onset T1D.
Intervention
Interventions included MRI and continuous glucose monitoring (CGM).
Main Outcome Measures
Pancreas size and shape were measured from MRI. For participants who used CGM, measures of glycemic variability were calculated.
Results
On longitudinal imaging, pancreas volume and pancreas volume index normalized for body weight declined during the first year after diagnosis. Pancreas volume index continued to decline through the fifth year after diagnosis. A cross-sectional study of individuals with diabetes duration up to 60 years demonstrated that pancreas size in adults negatively correlated with age and disease duration, whereas pancreas volume and pancreas volume index remained stable in controls. Pancreas volume index correlated inversely with low blood glucose index, a measure of risk for hypoglycemia. Pancreas shape was altered in individuals with T1D and further diverged from controls over the first 5 years after diagnosis. Pancreas size and shape are altered in nondiabetic individuals at genetic risk for T1D. Combined pancreas size and shape analysis better distinguished the pancreas of individuals with T1D from controls than size alone.
Conclusions
Pancreas size declines most rapidly near the clinical diagnosis of T1D and continues to decline throughout adulthood. Declines in pancreas size are accompanied by changes in pancreas shape.
Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to left ventricular dysfunction. The contribution of altered myocardial ...insulin action, independent of associated changes in systemic metabolism, is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function.
In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced, and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrate glutamate and the fatty acid derivative palmitoyl-carnitine were observed. Mitochondria also were uncoupled when exposed to palmitoyl-carnitine, in part as a result of increased reactive oxygen species production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reductions in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in tricarboxylic acid cycle and fatty acid oxidation proteins in mitochondria suggests that defects in fatty acid and pyruvate metabolism and tricarboxylic acid flux may explain the mitochondrial dysfunction observed.
Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which, together with reduced tricarboxylic acid and fatty acid oxidative capacity, impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart.
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