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Abstract Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.

Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348)

Objective: Evaluation of intestinal viability is essential in surgical decision-making in patients with acute intestinal ischemia. There has been no substantial change in the mortality rate (30%–93%) of patients with acute mesenteric ischemia (AMI) since the 1980s. As the accuracy from the first laparotomy alone is 50%, the gold standard is a second-look laparotomy, increasing the accuracy to 87%–89%. This study investigates the use of machine learning to classify intestinal viability and histological grading in pig jejunum, based on multivariate time-series of bioimpedance sensor data. Approach: We have previously used a bioimpedance sensor system to acquire electrical parameters from perfused, ischemic and reperfused pig jejunum (7  +  15 pigs) over 1–16 h of ischemia and 1–8 h of reperfusion following selected durations of ischemia. In this study we compare the accuracy of using end-point bioimpedance measurements with a feedforward neural network (FNN), versus the accuracy when using a recurrent neural network with long short-term memory units (LSTM-RNN) with bioimpedance data history over different periods of time. Main results: Accuracies in the range of what has been reported clinically can be achieved using FNN’s on a single bioimpedance measurement, and higher accuracies can be achieved when employing LSTM-RNN on a sequence of data history. Significance: Intraoperative bioimpedance measurements on intestine of suspect viability combined with machine learning can increase the accuracy of intraoperative assessment of intestinal viability. Increased accuracy in intraoperative assessment of intestinal viability has the potential to reduce the high mortality and morbidity rate of the patients. [ABSTRACT FROM AUTHOR]

Objective: Bioimpedance has been used to investigate changes in electrical parameters during ischemia in various tissues. The small intestine is a multi-layered structure, with several distinct tissue types, and ischemia related changes occur at different times in the different intestinal layers. When investigating how the electrical properties in the small intestine is affected by ischemia, some researchers have used ex vivo models while others have used in vivo models. In this study, we compare ischemic time development of electrical parameters in ischemic in vivo versus ex vivo small intestine. Approach: Measurements were performed using a two-electrode setup, with a Solartron 1260/1294 impedance gain-phase analyser. Electrodes were placed on the surface of ischemic pig jejunum, applying a voltage and measuring the resulting electrical admittance. In each pig, 4 segments of the jejunum were made ischemic by clamping the mesenteric arteries and veins, resulting in a 30 cm central zone of warm ischemia and edema. The in vivo part of the experiment lasted 10 h, after which 3 pieces of perfused small intestine were resected, stored in Ringer-acetat at 38 °C, and measured during a 10 h ex vivo experiment. Main results and significance: We found significant differences (p  <  0.0001) between the values of electric parameters when comparing the in vivo and ex vivo measurements as a function of ischemic time development. We also observed some similarities in the trends. In vivo, we measured an overall decrease in impedance during the duration of the experiment, probably as a result from the formation of edema. Ex vivo, the low frequency impedance increased initially for approximately 3 h before starting to decrease. [ABSTRACT FROM AUTHOR]