Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features Among Commercially Insured Adults in the United States.

BACKGROUND:  The incidence of colorectal cancer (CRC) in patients younger than 50 has been rising over the last several decades, accounting for up to 25% of total cases. Despite the screening age recently being lowered to 45, a significant proportion of cases would still arise at younger ages prior to screening. Nonfamilial early-onset CRC remains a particular concern. Identification of risk factors and clinical features in this age group is needed to improve detection. METHODS: In this retrospective cohort analysis using claims data from the Truven Health MarketScan® Commercial Claims insurance database from 2007 to 2017, patients were identified with colon and rectal cancer, compared across three age groups (ages 18-40, 40-50, and >50), and analyzed for risk factors and clinical features. RESULTS: Female sex was more prevalent in the younger age group compared to age >50 (54% and 51.9% vs. 49.6%), with little change noted between rectal cancer age groups by sex. A higher percentage of younger patients were in the obese age groups compared with older groups for colon cancer, particularly the morbidly obese with BMI >40 (24.94%, 25.75%, and 21.34% in the three age groups). Abdominal pain was a common presenting symptom identified in the age groups <50 compared with age >50 (25% and 19% vs. 14%), along with hematochezia, weight loss, and anemia. CONCLUSIONS: Morbid obesity and female sex may be important risk factors among patients with early-onset CRC. The presence of abdominal pain was more common among the early-onset CRC cohort.

Surgery in Nonalcoholic Cirrhosis: Clinical Outcomes, Healthcare Utilization, and Cost Analysis.

BACKGROUND: Patients with cirrhosis are at increased risk of complications following surgery due to multiple factors, including portal hypertension and alterations in hemostasis. Improvements in perioperative management as well as risk stratification scores have helped improve outcomes, but gaps remain in our understanding of the cost and morbidity of cirrhotic patients who undergo surgery. METHODS: We conducted a case-control study using the IBM Electronic Health Record (EHR) MarketScan Commercial Claims (MSCC) database from January 1, 2007 to December 31, 2017. Nonalcoholic cirrhotic patients who underwent surgery were identified based on International Classification of Diseases, Ninth Revision (ICD-9)/Tenth Revision (ICD-10) codes for multiple surgical categories and matched with controls with cirrhosis who did not undergo surgery in this time period. A total of 115,512 patients were identified with cirrhosis, of whom 19,542 (16.92%) had surgery. Medical history and comorbidities were compiled, and outcomes in the six-month period following surgery were analyzed between matched groups. A cost analysis was performed based on claims data. RESULTS: Nonalcoholic cirrhotic patients who underwent surgery had a higher comorbidity index at baseline compared with controls (1.34 vs. 0.88, P<0.0001). Mortality was increased in the surgery group (4.68% vs. 2.38%, P<0.001) in the follow-up period. The surgical cohort had higher rates of adverse hepatic outcomes, including hepatic encephalopathy (5.00% vs. 2.50%, P<0.0001), spontaneous bacterial peritonitis (0.64% vs. 0.25%, P<0.001), and higher rates of septic shock (0.66% vs. 0.14%, P<0.001), intracerebral hemorrhage (0.49% vs. 0.04%, P<0.001), and acute hypoxemic respiratory failure (7.02% vs. 2.31%, P<0.001). Healthcare utilization analysis revealed increased total claims per patient in the surgical cohort (38.11 vs. 28.64, P<0.0001), higher inpatient admissions (6.05 vs. 2.35, P<0.0001), more outpatient visits (19.72 vs. 15.23, P<0.0001), and prescription claims per patient (11.76 vs. 10.61, P<0.0001) in the postsurgical period. The likelihood of at least one inpatient stay was higher in the surgical cohort (51.63% vs. 22.32%, P<0.0001), and inpatient stays were longer (4.99 days vs. 2.09 days, P<0.0001). The total cost of health services was significantly increased per patient in the postoperative period for patients undergoing surgery ($58,246 vs. $26,842, P<0.0001), largely due to increased inpatient costs ($34,446 vs. $10,789, P<0.0001). CONCLUSION: Nonalcoholic cirrhotics undergoing surgery experienced worse outcomes with respect to adverse hepatic events and complications, including septic shock and intracerebral hemorrhage. Claims and cost analysis showed a significant increase in health expenditure in the surgical group, largely due to the cost of more frequent and longer inpatient admissions.

Reduction in Gastrointestinal Cancers in Cirrhotic Patients Receiving Rifaximin vs Lactulose Only Therapy for Hepatic Encephalopathy.

Background Rifaximin and/or lactulose therapy is widely used in cirrhotic patients for the prevention and treatment of hepatic encephalopathy. The incidence of gastrointestinal cancers in these patients on lactulose, rifaximin, and/or combination therapy is unknown. We investigated the possible effect of lactulose and rifaximin on cancer risk in patients with cirrhosis using the MarketScan database. Methods A retrospective cohort study was conducted using the Truven Health MarketScan Commercial Claims databases from 2007-2017. An index date was defined for each participant as the earliest date of cirrhosis diagnosis. A baseline period for each participant was defined as the 12 months prior to the first medication date while the study follow-up period represented the period from the initiation of the medication to its cessation. ANOVA was used to compare all continuous measures of age and duration of medication. Wald Chi-square tests were performed to test the associations between the study groups. Results A total of 12,409 patients were included in our study. The rifaximin only cohort had the greatest reduction in risk of developing colon cancer, esophageal cancer, and stomach cancer compared to the other groups. Rifaximin reduced the risk of colon cancer and esophageal cancer by 59.42% and 70.37%, respectively, compared to patients taking lactulose only. Patients in the lactulose plus rifaximin cohort had the highest rate of development of pancreatic cancer (lactulose plus rifaximin vs rifaximin only vs lactulose only, 0.45% vs 0.24% vs 0.21%; P < 0.0001) and liver and intrahepatic bile duct cancers (11.73% vs 5.84% vs 5.49%; P < 0.0001). Conclusion Colon, esophageal, and gastric cancers had a marked incidence reduction in the rifaximin only cohort compared to the other cohorts studied.

Association of Bariatric Surgery With Cardiovascular Outcomes in Adults With Severe Obesity and Nonalcoholic Fatty Liver Disease.

Importance: There are no approved treatments for nonalcoholic fatty liver disease (NAFLD) despite its association with obesity and increased risk of cardiovascular disease (CVD). Objective: To examine the association between bariatric surgery and CVD risk in individuals with severe obesity and NAFLD. Design, Setting, and Participants: This large, population-based retrospective cohort study obtained data from the MarketScan Commercial Claims and Encounters database from January 1, 2007, to December 31, 2017. Participants included insured adults aged 18 to 64 years with NAFLD and severe obesity (body mass index ≥40) without a history of bariatric surgery or CVD before NAFLD diagnosis. Baseline characteristics were balanced between individuals who underwent surgery (surgical group) and those who did not (nonsurgical group) using inverse probability of treatment weighting. Data were analyzed from March 2020 to April 2021. Exposures: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy, and other bariatric procedures) vs nonsurgical care. Main Outcomes and Measures: The main outcome was the incidence of cardiovascular events (primary or secondary composite CVD outcomes). The primary composite outcome included myocardial infarction, heart failure, or ischemic stroke, and the secondary composite outcome included secondary ischemic heart events, transient ischemic attack, secondary cerebrovascular events, arterial embolism and thrombosis, or atherosclerosis. Cox proportional hazards regression models with inverse probability treatment weighting were used to examine the associations between bariatric surgery, modeled as time varying, and all outcomes. Results: The study included 86 964 adults (mean [SD] age, 44.3 [10.9] years; 59 773 women [68.7%]). Of these individuals, 30 300 (34.8%) underwent bariatric surgery and 56 664 (65.2%) received nonsurgical care. All baseline covariates were balanced after applying inverse probability treatment weighting. In the surgical group, 1568 individuals experienced incident cardiovascular events compared with 7215 individuals in the nonsurgical group (incidence rate difference, 4.8 [95% CI, 4.5-5.0] per 100 person-years). At the end of the study, bariatric surgery was associated with a 49% lower risk of CVD (adjusted hazard ratio [aHR], 0.51; 95% CI, 0.48-0.54) compared with nonsurgical care. The risk of primary composite CVD outcomes was reduced by 47% (aHR, 0.53 [95% CI, 0.48-0.59), and the risk of secondary composite CVD outcomes decreased by 50% (aHR, 0.50; 95% CI, 0.46-0.53) in individuals with vs without surgery. Conclusions and Relevance: Results of this study suggest that, compared with nonsurgical care, bariatric surgery was associated with significant reduction in CVD risk in individuals with severe obesity and NAFLD.

Evaluation of a U.S. National Cohort to Determine Utilization in Colectomy Rates for Ulcerative Colitis Among Ethnicities.

BACKGROUND: Colectomy is the curative management for ulcerative colitis (UC). Multiple studies have reported racial disparities for colectomy before the advent of anti-TNF alpha agents. The aim of this study was to describe racial and geographic differences in colectomy rates among hospitalized patients with UC after anti-TNF therapy was introduced. METHODS: We examined all patients discharged from the hospital between 2010 and 2014 with a primary diagnosis of UC or of complications of UC. The data were evaluated for race and colectomy rates among the hospitalized patients with UC. RESULTS: The unadjusted national colectomy rate among hospitalized patients with UC between 2010 and 2014 was 3.90 per 1000 hospitalization days (95% confidence interval, 3.72-4.08). The undajusted colectomy rates in African American (2.33 vs 4.35; P < 0.001) and Hispanic patients (3.99 vs 4.35; P ≤ 0.009) were considerably lower than those for White patients. After adjustment for confounders, the incidence rate ratio for African American as compared to White patients was 0.43 (95% confidence interval, 0.32-0.58; P < 0.001). Geographic region of the United States also showed significant variation in colectomy rates, with western regions having the highest rate (4.76 vs 3.20; P < 0.001). CONCLUSIONS: Racial and geographical disparities persist for the rate of colectomy among hospitalized patients with UC. The national database analysis reveals that colectomy rates for hospitalized African American and Hispanic patients were lower than those for White patients. Further studies are important to determine the social and biologic foundations of these disparities.

The Spontaneous Regression of Primary Gastrointestinal Malignancies: An Observational Review.

The spontaneous regression or remission (SR) of cancer, often described as the partial or complete disappearance of a malignant tumor in the absence of all medical treatment and therapy, is a well-documented phenomenon. With efforts ongoing to establish cancer treatments that limit undesirable outcomes and adverse effects, these uncommon occurrences of SR carry significant implications for novel therapies and warrant further investigation. While several case studies have reported instances of SR in gastrointestinal (GI) malignancies, a comprehensive review of previous manifestations of SR in the GI tract remains lacking. The inclusion criteria for the rare phenomenon are also in need of an appropriate update that takes recent scientific advancements and emerging new medical technologies into account. Our analysis of 390 cases of SR in the GI tract focuses primarily on neoplasms of the hepatobiliary system and proposes an updated version of the older inclusion criteria for spontaneous regression.

Training of computational algorithms to predict NAFLD activity score and fibrosis stage from liver histopathology slides.

BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), has been increasing for decades. Since the mainstay is lifestyle modification in this mainly asymptomatic condition, there is a need for accurate diagnostic methods. OBJECTIVES: This study proposes a method with a computer-aided diagnosis (CAD) system to predict NAFLD Activity score (NAS scores-steatosis, lobular inflammation, and ballooning) and fibrosis stage from histopathology slides. METHODS: A total of 87 pathology slides pairs (H&E and Trichrome-stained) were used for the study. Ground-truth NAS scores and fibrosis stages were previously identified by a pathologist. Each slide was split into 224 × 224 patches and fed into a feature extraction network to generate local features. These local features were processed and aggregated to obtain a global feature to predict the slide's scores. The effects of different training strategies, as well as training data with different staining and magnifications were explored. Four-fold cross validation was performed due to the small data size. Area Under the Receiver Operating Curve (AUROC) was utilized to evaluate the prediction performance of the machine-learning algorithm. RESULTS: Predictive accuracy for all subscores was high in comparison with pathologist assessment. There was no difference among the 3 magnifications (5x, 10x, 20x) for NAS-steatosis and fibrosis stage tasks. A larger magnification (20x) achieved better performance for NAS-lobular scores. Middle-level magnification was best for NAS-ballooning task. Trichrome slides are better for fibrosis stage prediction and NAS-ballooning score prediction task. NAS-steatosis prediction had the best performance (AUC 90.48%) in the model. A good performance was observed with fibrosis stage prediction (AUC 83.85%) as well as NAS-ballooning prediction (AUC 81.06%). CONCLUSIONS: These results were robust. The method proposed proved to be effective in predicting NAFLD Activity score and fibrosis stage from histopathology slides. The algorithms are an aid in having an accurate and systematic diagnosis in a condition that affects hundreds of millions of patients globally.

Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and increased risk of cancer. The impacts of bariatric surgery on cancer risk in NAFLD patients are unknown. We investigated the effect of bariatric surgery on cancer risk in patients with NAFLD and severe obesity using the MarketScan database. METHODS: We conducted a retrospective cohort study of 18 to 64 years old newly diagnosed NAFLD patients with severe obesity between 2007 and 2017. We used Cox proportional hazard models to examine the association between bariatric surgery, modeled as a time-varying covariate, and the risks of any cancer and obesity-related cancer, while accounting for confounding using inverse probability of treatment weighting (IPTW). RESULTS: A total of 98,090 patients were included in the study, 33,435 (34.1%) received bariatric surgery. In those without surgery, 1898 incident cases of cancer occurred over 115,890.11 person-years of follow-up, compared with 925 cancer cases over 67,389.82 person-years among surgery patients (crude rate ratio, 0.84; 95% CI, 0.77- 0.91). The IPTW-adjusted risk of any cancer and obesity-related cancer was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.76-0.89) and 25% (hazard ratio, 0.65; 95% CI, 0.56-0.75), respectively, in patients with versus without bariatric surgery. The adjusted risks of any cancer and obesity-related cancer were significantly lower in cirrhotic versus non-cirrhotic patients who underwent surgery. In cancer-specific models, bariatric surgery was associated with significant risk reductions for colorectal, pancreatic, endometrial, thyroid cancers, hepatocellular carcinoma, and multiple myeloma. CONCLUSION: Bariatric surgery was associated with significant reductions in the risks of any cancer and obesity-related cancer in NAFLD patients with severe obesity.

The Microbiome and Hepatocellular Carcinoma.

The human microbiome is a vast and complex system encompassing all of the microbes and their genes that occupy the environmentally exposed surfaces of the human body. The gut microbiota and its associated microbiome play an integral role in mammalian metabolism and immune tolerance as well as in immunocompetence. Disruptions in the human gut microbiome are associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. The persistence of this inflammation has been shown to induce the accumulation of genetic and epigenetic changes leading to hepatocellular carcinoma (HCC). Therefore, the importance and prognostic influence of the gut microbiome on hepatocarcinogenesis has been increasingly studied in recent years. This review discusses the mechanisms by which imbalances in the gut microbiome disturb the gut-liver axis to impact hepatocarcinogenesis, including disruption of the intestinal barrier, changes in bile acid metabolism, and reduction in tumor-suppressing microRNA. Furthermore, this review summarizes recent advances in potential microbiome-based therapeutic opportunities in HCC.

miR-206 as a Biomarker for Response to Mesalamine Treatment in Ulcerative Colitis.

Background: MicroRNAs (miRNAs) are important post-translational regulators. Elevated levels of miR-206 in ulcerative colitis (UC) were associated with suppression of anti-inflammatory A3 adenosine receptor (A3AR) expression. However, the relationship of miR-206 to histologic remission in UC patients remains unknown. This study correlates expression levels of miR-206 with histologic remission in patients treated via long-term mesalamine treatment to identify a possible mode of action for this mainstay drug for UC. Methods: Expression of miR-206 and its target A3AR were analyzed in HT29 cell line before and after mesalamine treatment (2 mM) at different time points (0, 4, 12, and 24 hours) by qRT-PCR and western blot analysis. Expression of miR-206 and pathological scores of colonoscopic biopsy specimens were studied in 10 UC patients treated with mesalamine treatment for 2 to 6 years. Results: miR-206 transcripts decreased 2.23-fold (P = 0.0001) 4 hours after 2 mM mesalamine treatment in HT29 colon cells compared with untreated controls. However, the mRNA/protein levels of A3AR increased by 4-fold (P = 0.04) and 2-fold, respectively, in same cells. miR-206 relative expression decreased significantly in patients treated with 4.8 g of mesalamine (P = 0.002) but not with 2.4 g (P = 0.35). Tissue assessment of sequential mesalamine-treated colonoscopic biopsies indicate a strong correlation between downregulation of miR-206 and histologic improvement (R = 0.9111). Conclusion: Mesalamine treatment has an effect on epithelial miRNAs. Downregulation of miR-206 by long-term mesalamine treatment may confer a protective effect in inducing and maintaining histologic remission. Thus, miR-206 expression levels can be utilized as a possible biomarker for therapeutic response to mesalamine treatment.

Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis.

BACKGROUND: The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown. AIM: This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy. METHODS: Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables. RESULTS: The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score. CONCLUSION: This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.

Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux.

Gastroesophageal reflux disease (GERD) clinically predisposes to columnar Barrett's metaplasia (BM) in the distal esophagus. We demonstrate evidence supporting the cellular origin of BM from reprograming or transcommitment of resident normal esophageal squamous (NES) epithelial cells in response to acid and bile (A + B) exposure using an in vitro cell culture model. The hTERT-immortalized NES cell line NES-B10T was exposed 5 min/day to an A + B mixture for 30 wk. Morphological changes, mRNA, and protein expression levels for the inflammatory marker cyclooxygenase-2; the lineage-determining transcription factors TAp63 (squamous), CDX2, and SOX9 (both columnar); and the columnar lineage markers Villin, Muc-2, CK8, and mAb Das-1 (incomplete phenotype of intestinal metaplasia) were assessed every 10 wk. Markers of columnar lineage and inflammation increased progressively, while squamous lineage-determining transcriptional factors were significantly decreased both at the mRNA and/or protein level in the NES-B10T cells at/after A + B treatment for 30 wk. Distinct modifications in morphological features were only observed at/after 30 wk of A + B exposure. These changes acquired by the NES-B10T 30-wk cells were retained even after cessation of A + B exposure for at least 3 wk. This study provides evidence that chronic exposure to the physiological components of gastric refluxate leads to repression of the discernable squamous transcriptional factors and activation of latent columnar transcriptional factors. This reflects the alteration in lineage commitment of the precursor-like biphenotypic, NES-B10T cells in response to A + B exposure as the possible origin of BM from the resident NES cells.NEW & NOTEWORTHY This study provides evidence of the origins of Barrett's metaplasia from lineage transcommitment of resident esophageal cells after chronic exposure to gastroesophageal refluxate. The preterminal progenitor-like squamous cells alter their differentiation and develop biphenotypic characteristics, expressing markers of incomplete-type columnar metaplasia. Development of these biphenotypic precursors in vitro is a unique model to study pathogenesis of Barrett's metaplasia and esophageal adenocarcinoma.