Platform combining statistical modeling and patient-derived organoids to facilitate personalized treatment of colorectal carcinoma.

BACKGROUND: We propose a new approach for designing personalized treatment for colorectal cancer (CRC) patients, by combining ex vivo organoid efficacy testing with mathematical modeling of the results. METHODS: The validated phenotypic approach called Therapeutically Guided Multidrug Optimization (TGMO) was used to identify four low-dose synergistic optimized drug combinations (ODC) in 3D human CRC models of cells that are either sensitive or resistant to first-line CRC chemotherapy (FOLFOXIRI). Our findings were obtained using second order linear regression and adaptive lasso. RESULTS: The activity of all ODCs was validated on patient-derived organoids (PDO) from cases with either primary or metastatic CRC. The CRC material was molecularly characterized using whole-exome sequencing and RNAseq. In PDO from patients with liver metastases (stage IV) identified as CMS4/CRIS-A, our ODCs consisting of regorafenib [1 mM], vemurafenib [11 mM], palbociclib [1 mM] and lapatinib [0.5 mM] inhibited cell viability up to 88%, which significantly outperforms FOLFOXIRI administered at clinical doses. Furthermore, we identified patient-specific TGMO-based ODCs that outperform the efficacy of the current chemotherapy standard of care, FOLFOXIRI. CONCLUSIONS: Our approach allows the optimization of patient-tailored synergistic multi-drug combinations within a clinically relevant timeframe.

Clinical Presentation and Gene Expression of Acute Alcohol-Induced Microvesicular Steatosis Mimicking Alcoholic Hepatitis.

Acute alcoholic microvesicular steatosis (MIC) may complicate heavy alcohol intake and present as alcoholic hepatitis (AH) syndrome. However, detailed clinical, biological, and histologic data associated with MIC are scarce. We compared the clinical presentation, histologic features, and hepatic transcriptomic of patients presenting with AH due to either MIC or severe alcoholic steatohepatitis (ASH). In this case-control study, patients who drank heavily (>100 g/day) with the AH syndrome were included either in the MIC group (>50% severe microvesicular steatosis, no inflammation) or in the severe ASH group (polynuclear neutrophil infiltration, macrosteatosis, ballooned hepatocytes). All patients received standard supportive care plus steroids for those with severe ASH and were followed up for 3 months. Whole-liver transcriptome profiling was performed on liver snap-frozen biopsies. Compared to ASH (n = 24, mean age 49.3 years), patients in the MIC group (n = 12, mean age 49.1 years) had a higher reported alcohol intake (P < 0.01), lower Model for End-Stage Liver Disease score (P < 0.05), lower hepatic venous pressure gradient (P < 0.01), higher alanine aminotransferase (P < 0.02) and gamma-glutamyltransferase (P < 0.001), higher triglycerides (P < 0.001) and total cholesterol (P < 0.002), but similar bilirubin levels (P = 0.54). At histology, patients with MIC had a lower fibrotic stage compared to those with ASH (P < 0.001). A higher density of megamitochondria was seen in MIC compared to ASH (P < 0.05). During follow-up, death or transplantation occurred in 4/12 (33%) patients with MIC and 7/24 (29%) patients with severe ASH. Differential hepatic gene expression in MIC compared to ASH included down-regulation of genes related to inflammation and fibrosis and up-regulation of genes involved in lipid metabolism and mitochondrial function. Conclusion: MIC is an acute, noninflammatory, potentially severe alcoholic liver injury mimicking ASH, is associated with a lower fibrosis stage, and has a distinct gene expression profile.