Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum.

BackgroundIntra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH.MethodsMultiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors).ResultsOverall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; pConclusionOur transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping

Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageTo describe the prevalence of, risk factors for, and prognostic importance of gastrointestinal (GI) bleeding and use of acid suppressants in acutely ill adult intensive care patients.We included adults without GI bleeding who were acutely admitted to the intensive care unit (ICU) during a 7-day period. The primary outcome was clinically important GI bleeding in ICU, and the analyses included estimations of baseline risk factors and potential associations with 90-day mortality.A total of 1,034 patients in 97 ICUs in 11 countries were included. Clinically important GI bleeding occurred in 2.6 % (95 % confidence interval 1.6-3.6 %) of patients. The following variables at ICU admission were independently associated with clinically important GI bleeding: three or more co-existing diseases (odds ratio 8.9, 2.7-28.8), co-existing liver disease (7.6, 3.3-17.6), use of renal replacement therapy (6.9, 2.7-17.5), co-existing coagulopathy (5.2, 2.3-11.8), acute coagulopathy (4.2, 1.7-10.2), use of acid suppressants (3.6, 1.3-10.2) and higher organ failure score (1.4, 1.2-1.5). In ICU, 73 % (71-76 %) of patients received acid suppressants; most received proton pump inhibitors. In patients with clinically important GI bleeding, crude and adjusted odds for mortality were 3.7 (1.7-8.0) and 1.7 (0.7-4.3), respectively.In ICU patients clinically important GI bleeding is rare, and acid suppressants are frequently used. Co-existing diseases, liver failure, coagulopathy and organ failures are the main risk factors for GI bleeding. Clinically important GI bleeding was not associated with increased adjusted 90-day mortality, which largely can be explained by severity of comorbidity, other organ failures and age.Aase and Ejnar Danielsens Foundation Ehrenreichs Foundation Scandinavian Society of Anaesthesia and Intensive Care Medicine (SSAI) Danish Society of Anaesthesiology and Intensive care Medicine (DASAIM) Danish Medical Associatio