Mohamad Mouchli

Risk Factors and Outcomes of De Novo Cancers (excluding Nonmelanoma Skin Cancer) After Liver Transplantation for Primary Sclerosing Cholangitis.

Background Patients with primary sclerosing cholangitis (PSC) may be at higher risk of malignancy after liver transplantation (LT) compared to other LT recipients. We aimed to determine the cumulative incidence of/risk factors for long-term cancer-related mortality in patients with PSC after LT. Methods All adult patients underwent LT for PSC without cholangiocarcinoma from 1984 to 2012, with follow-up through June 2015. We estimated cumulative incidence, risk factors, and mortality from de novo malignancies after LT. Results Two hundred ninety-three patients were identified (mean [SD] age, 47 [12] years; 63.3% males; 2.4% smoking at LT). Over a median of 11.5 years (range, 6.4-18.6 years), 64 patients (21.8%) developed 73 nonskin cancers, including 46 solid-organ cancers (renal, 11; colorectal, 11; prostate, 7; breast, 5; pancreas, 5; ovarian/endometrial/vulvar cancers, 3; and de novo cholangiocarcinoma, 4). Twenty-two patients developed hematologic malignancies (posttransplant lymphoproliferative diseases, 18; Hodgkin disease, 2; and myelodysplastic syndrome, 2). Five patients developed melanoma. The 1-, 5-, 10-, and 20-year cumulative incidences of cancer were 2.1%, 8.6%, 18.7%, and 27%, respectively. Mortality of patients with PSC who developed cancer was higher than that of patients with PSC without cancer (hazard ratio, 2.2; P < 0.01). On multivariate analysis, recipients age and elevated pre-LT international normalized ratio were associated with increased risk of de novo (nonskin) malignancy. Conclusion The 10-year cumulative risk of cancer after LT for advanced-stage PSC was 18.7%, with posttransplant lymphoproliferative diseases, colorectal cancer, and renal cell cancer being the most common. Post-LT de novo nonskin cancer decreased overall posttransplant survival. Only recipients age and elevated international normalized ratio at LT were associated with increased nonskin cancer risk.

Molecular characterization of colorectal adenomas with and without malignancy reveals distinguishing genome, transcriptome and methylome alterations

The majority of colorectal cancer (CRC) arises from precursor lesions known as polyps. The molecular determinants that distinguish benign from malignant polyps remain unclear. To molecularly characterize polyps, we utilized Cancer Adjacent Polyp (CAP) and Cancer Free Polyp (CFP) patients. CAPs had tissues from the residual polyp of origin and contiguous cancer; CFPs had polyp tissues matched to CAPs based on polyp size, histology and dysplasia. To determine whether molecular features distinguish CAPs and CFPs, we conducted Whole Genome Sequencing, RNA-seq, and RRBS on over 90 tissues from 31 patients. CAPs had significantly more mutations, altered expression and hypermethylation compared to CFPs. APC was significantly mutated in both polyp groups, but mutations in TP53, FBXW7, PIK3CA, KIAA1804 and SMAD2 were exclusive to CAPs. We found significant expression changes between CAPs and CFPs in GREM1, IGF2, CTGF, and PLAU, and both expression and methylation alterations in FES and HES1. Integrative analyses revealed 124 genes with alterations in at least two platforms, and ERBB3 and E2F8 showed aberrations specific to CAPs across all platforms. These findings provide a resource of molecular distinctions between polyps with and without cancer, which have the potential to enhance the diagnosis, risk assessment and management of polyps.

Peripheral Neutrophil to Lymphocyte Ratio Improves Prognostication in Colon Cancer

Micro‐Abstract Distinction of patients at a higher mortality risk beyond stage‐only prognostication is an active area of cancer research. Preoperative neutrophil to lymphocyte ratio (NLR) correlates with survival outcomes in colorectal cancer. In this study, the predictive value of NLR in 2536 patients with respectable tumors was compared with the American Joint Committee on Cancer and Memorial Sloan Kettering Cancer Center models. NLR improved the prognostication of these staging systems. Background: We studied the role of peripheral neutrophil to lymphocyte ratio (NLR) on survival outcomes in colon and rectal cancer to determine if its inclusion improved prognostication within existing staging systems. Patients and Methods: Disease‐free (DFS) and overall survival (OS) hazard ratios (HRs) of pretreatment NLR were calculated for 2536 patients with stage I to III colon or rectal cancer and adjusted for age, positive/total number of nodes, T stage, and grade. The association of NLR with clinicopathologic features and survival was evaluated and compared with the American Joint Committee on cancer (AJCC) TNM staging and Memorial Sloan Kettering Cancer Center (MSKCC) models. Results: High NLR was significantly associated with worse DFS (HR, 1.36; 95% confidence interval [CI], 1.08‐1.70; P = .009) and OS (HR, 1.65; 95% CI, 1.29‐2.10; P < .0005) in all stages for patients with colon, but not rectal, cancer. High NLR was significantly associated with site‐specific worse prognosis, which was stronger in the left versus right colon; an inverse relationship with grade was found. The impact of high NLR on DFS and OS occurred early, with the majority of deaths within 2 years following surgery. Adjusted HRs for 5‐year and 2‐year outcomes in colon cancer per each additional 2‐unit increase in NLR were 1.15 (95% CI, 1.08‐1.23) and 1.20 (95% CI, 1.10‐1.30), respectively. The addition of NLR enhanced the prognostic utility of TNM (TNM alone vs. TNM + NLR: concordance index, 0.60 vs. 0.68), and MSKCC (MSKCC alone vs. MSKCC + NLR: concordance index, 0.71 vs. 0.73) models for colon cancer patients. Conclusion: NLR is an independent prognostic variable for nonmetastatic colon cancer that enhances existing clinical staging systems.

Colonoscopy surveillance for high risk polyps does not always prevent colorectal cancer

AIM To determine the frequency and risk factors for colorectal cancer (CRC) development among individuals with resected advanced adenoma (AA)/traditional serrated adenoma (TSA)/advanced sessile serrated adenoma (ASSA). METHODS Data was collected from medical records of 14663 subjects found to have AA, TSA, or ASSA at screening or surveillance colonoscopy. Patients with inflammatory bowel disease or known genetic predisposition for CRC were excluded from the study. Factors associated with CRC developing after endoscopic management of high risk polyps were calculated in 4610 such patients who had at least one surveillance colonoscopy within 10 years following the original polypectomy of the incident advanced polyp. RESULTS 84/4610 (1.8%) patients developed CRC at the polypectomy site within a median of 4.2 years (mean 4.89 years), and 1.2% (54/4610) developed CRC in a region distinct from the AA/TSA/ASSA resection site within a median of 5.1 years (mean 6.67 years). Approximately, 30% (25/84) of patients who developed CRC at the AA/TSA/ASSA site and 27.8% (15/54) of patients who developed CRC at another site had colonoscopy at recommended surveillance intervals. Increasing age; polyp size; male sex; right-sided location; high degree of dysplasia; higher number of polyps resected; and piecemeal removal were associated with an increased risk for CRC development at the same site as the index polyp. Increasing age; right-sided location; higher number of polyps resected and sessile endoscopic appearance of the index AA/TSA/ASSA were significantly associated with an increased risk for CRC development at a different site. CONCLUSION Recognition that CRC may develop following AA/TSA/ASSA removal is one step toward improving our practice efficiency and preventing a portion of CRC related morbidity and mortality.

Natural History of Established and de Novo Inflammatory Bowel Disease after Liver Transplantation for Primary Sclerosing Cholangitis

Abstract Background The course of inflammatory bowel disease (IBD) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is poorly understood. We describe the natural history of established IBD after LT (including risk of disease progression, colectomy, and neoplasia) and de novo IBD. Methods In a retrospective cohort, we identified all patients with PSC who underwent LT for advanced PSC at Mayo Clinic, Rochester, Minnesota. Risk factors were identified using multivariate Cox proportional hazard analysis. Results Three hundred seventy-three patients were identified (mean age, 47.5 ± 11.7 years; 64.9% male). Over a median (range) of 10 (5.5–17.1) years, 151 patients with PSC-IBD with an intact colon at the time of LT were studied. Post-LT, despite transplant-related immunosuppression, 56/151 (37.1%) required escalation of therapy, whereas 87 had a stable course (57.6%) and 8 patients (5.3%) improved. The 1-, 5-, and 10-year risks of progression of IBD were 4.0%, 18.5%, and 25.5%, respectively. On multivariate analysis, tacrolimus-based immunosuppression post-LT were associated with unfavorable course, and azathioprine use after LT was associated with improved course post-LT. Of 84 patients with no evidence of IBD at the time of LT, 22 (26.2%) developed de novo IBD post-LT. The 1-, 5-, and 10-year cumulative incidences of de novo IBD were 5.5%, 20.0%, and 25.4%, respectively. On univariate analysis, mycophenolate mofetil use after LT was associated with increased risk of de novo IBD, but azathioprine use after LT seemed to be protective. Conclusions The 10-year cumulative probability of IBD flare requiring escalation of therapy after LT for PSC was 25.5%, despite immunosuppression for LT. The 10-year cumulative risk of de novo IBD after LT for PSC was 25.4%. Transplant-related immunosuppression may modify the risk of de novo IBD, with an increased risk with mycophenolate and a decreased risk with azathioprine.