Mesenchymal Stem Cell Extracellular Vesicles as a New Treatment Paradigm in Solid Abdominal Organ Transplantation: A Case Series.

Solid abdominal organ transplantation is fraught with variable rates of rejection and graft versus host disease (GVHD). We sought to determine the safety and efficacy of an advanced extracellular vesicle (EV) investigational product (IP) derived from mesenchymal stem cells (MSC) in the transplant patient population. Seven separate emergency investigational new drug (eNIDs) were filed with the Food and Drug Administration (FDA) for the emergency treatment of rejection of an isolated intestinal graft (n = 2), liver allograft graft (n = 2), modified multivisceral graft (n = 3), and GVHD in isolated intestinal transplant patients (n = 2). Fifteen milliliters of IP was administered intravenously on Day 0, 2, 4, and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to IP. All patients had improvement in clinical symptoms within 24 h, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation/rejection within 7 days of IP administration. Systemic use of a MSC-derived EV IP was successful in achieving histological clearance of intestinal, liver, and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD.

Lymphocytic Colitis With Enterocolic Lymphocytic Phlebitis.

Enterocolic lymphocytic phlebitis is a rare lymphocytic vasculitis afflicting the gastrointestinal veins without involving the arterial system. Lymphocytic colitis is a more common pathology described as lymphocytic inflammation of the colonic epithelium. Concurrence of both these pathologies is extremely rare. We describe a 53-year-old man presenting with chronic watery diarrhea, abdominal pain, and weight loss. Colonoscopic examination revealed normal-appearing mucosa, but biopsy findings revealed lymphocytic colitis with coexisting enterocolic lymphocytic phlebitis. The patient was started on oral budesonide and responded to the treatment with symptomatic and histopathological resolution.

Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.