Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated ...incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.
Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.
This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.
Immune checkpoint blockade (CPB) utilizing such agents as ipilimumab, nivolumab, or pembrolizumab has revolutionized melanoma therapy and has seen continued utilization in numerous other malignancies ...in recent years. However, these agents come at the price of inflammatory immune-related adverse events. Despite the increasing recognition of biochemical thyroid dysfunction associated with CPB, information regarding potential imaging findings is sparse. We describe the first 2 cases of acute thyroiditis following CPB presenting as diffuse thyromegaly documented by computed tomography, ultrasound, and iodine uptake imaging. Given the rise in the use of CPB, it is important for radiologists to recognize potential imaging manifestations of therapy immune-related adverse events to avoid erroneous diagnosis and to prompt the biochemical investigation of thyroid function.
Ipilimumab and nivolumab for melanoma induced smoldering myocarditis remitting with steroids. Rechallenge with nivolumab produced steroid-refractory myocarditis confirmed by electron microscopy. ...Tacrolimus and mycophenolate transiently reduced inflammation, but antithymocyte globulin induced remission. Cardiomyopathy with fatty infiltration ensued, but the patient succumbed to rampant melanoma progression after lymphocyte depletion. (Level of Difficulty: Advanced.)
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Ipilimumab and nivolumab for melanoma induced smoldering myocarditis remitting with steroids. Rechallenge with nivolumab produced steroid-refractory…
Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly ...targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new ...consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
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•Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma•Global acetylome and phosphoproteome surveys identify new regulatory mechanisms•QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT•Antigen presentation defects may render MSI tumors resistant to checkpoint blockade
Proteogenomic analyses of prospectively collected endometrial carcinomas provide insights into the role of underlying molecular pathways and the immune landscape that drive disease.
More than 60% of supratentorial ependymomas harbor a
(ZR
) gene fusion (formerly
). To study the biology of ZR
, we developed an autochthonous mouse tumor model using
electroporation (IUE) of the ...embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZR
tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZR
-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZR
dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZR
activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZR
target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. SIGNIFICANCE: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (
- and
-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of
-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.
.
Service accreditation is a structured process of recognising and promoting performance and adherence to standards. Typically, accreditation agencies either receive standards from an authorized body ...or develop new and upgrade existing standards through research and expert views. They then apply standards, criteria and performance indicators, testing their effects, and monitoring compliance with them. The accreditation process has been widely adopted. The international investments in accreditation are considerable. However, reliable evidence of its efficiency or effectiveness in achieving organizational improvements is sparse and the value of accreditation in cost-benefit terms has yet to be demonstrated. Although some evidence suggests that accreditation promotes the improvement and standardization of care, there have been calls to strengthen its research base.In response, the ACCREDIT (Accreditation Collaborative for the Conduct of Research, Evaluation and Designated Investigations through Teamwork) project has been established to evaluate the effectiveness of Australian accreditation in achieving its goals. ACCREDIT is a partnership of key researchers, policymakers and agencies.
We present the framework for our studies in accreditation. Four specific aims of the ACCREDIT project, which will direct our findings, are to: (i) evaluate current accreditation processes; (ii) analyse the costs and benefits of accreditation; (iii) improve future accreditation via evidence; and (iv) develop and apply new standards of consumer involvement in accreditation. These will be addressed through 12 interrelated studies designed to examine specific issues identified as a high priority. Novel techniques, a mix of qualitative and quantitative methods, and randomized designs relevant for health-care research have been developed. These methods allow us to circumvent the fragmented and incommensurate findings that can be generated in small-scale, project-based studies. The overall approach for our research is a multi-level, multi-study design.
The ACCREDIT project will examine the utility, reliability, relevance and cost effectiveness of differing forms of accreditation, focused on general practice, aged care and acute care settings in Australia. Empirically, there are potential research gains to be made by understanding accreditation and extending existing knowledge; theoretically, this design will facilitate a systems view of accreditation of benefit to the partnership, international research communities, and future accreditation designers."Accreditation of health-care organisations is a multimillion dollar industry which shapes care in many countries. Recent reviews of research show little evidence that accreditation increases safety or improves quality. It's time we knew about the cost and value of accreditation and about its future direction." Professor John Øvretveit, Karolinska Institute, Sweden, 7 October 2009.
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