Randall Skovbjerg (jumperwallet79)

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AAs). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TILs) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DCs). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of MCPyV+ MCC patients had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope-rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicate that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity. Copyright ©2020, American Association for Cancer Research.Fluctuations in serum creatinine (SCr) during hospitalization may provide additional prognostic value beyond baseline renal function. This study aimed to identify groups of patients with distinct creatinine trajectories over hospital stay and assess them in terms of clinical characteristics and short-term mortality. This retrospective study included 35 853 unique adult admissions to a tertiary referral center between January 2012 and January 2016 with at least three SCr measurements within the first 9 days of stay. Individual SCr courses were determined using linear regression or linear-splines model and grouped into clusters. SCr trajectories were described as median SCr courses within clusters. Almost half of the patients presented with changing, mainly declining SCr concentration during hospitalization. In comparison to patients with an increase in SCr, those with a significant decline were younger, more often admitted via the emergency department, more often required a higher level of care, had fewer comorbidities and the more pronounced the fall in SCr, the greater the observed difference. Regardless of baseline renal function, an increase in SCr was related to the highest in-hospital mortality risk among compared clusters. Also, patients with normal renal function at admission followed by decreasing SCr were at higher risk of inpatient death, but lower 90-day postdischarge mortality than patients with a stable SCr. Acute changes in inpatient SCr convey important prognostic information and can only be interpreted by looking at their evolution over time. Recognizing underlying causes and providing adequate care is crucial for improving adverse prognosis. © American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.Case summaryA 10-year-old boy presented with severe progressive generalised weakness on a background of 3 days of diarrhoea and vomiting. Vital signs were normal. Peripheral neurological examination revealed grade 1-2 power in all limbs, hypotonia and hyporeflexia. Sensation was fully intact. Cranial nerve examination and speech were normal. The ECG (figure 1) and initial venous blood gas (figure 2) are shown.edpract;archdischild-2019-318286v1/F1F1F1Figure 1ECG.edpract;archdischild-20