Epidemiology, risk factors, and clinical effect of infections by multiresistant bacteria in cirrhosis are poorly known. This work was a prospective evaluation in two series of cirrhotic patients admitted with infection or developing infection during hospitalization. The first series was studied between 2005 and 2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011 (162 bacterial infections in 110 patients). In the first series, 32% of infections were community acquired (CA), 32% healthcare associated (HCA), and 36% nosocomial. Multiresistant bacteria (92 infections; 18%) were isolated in 4%, 14%, and 35% of these infections, respectively ( P < 0.001). Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL- E ; n = 43) was the main multiresistant organism identified, followed by Pseudomonas aeruginosa (n = 17), methicillin-resistant Staphylococcus aureus (n = 14), and Enterococcus faecium (n = 14). The efficacy of currently recommended empirical antibiotic therapy was very low in nosocomial infections (40%), compared to HCA and CA episodes (73% and 83%, respectively; P < 0.0001), particularly in spontaneous bacterial peritonitis, urinary tract infection, and pneumonia (26%, 29%, and 44%, respectively). Septic shock (26% versus 10%; P < 0.0001) and mortality rate (25% versus 12%; P = 0.001) were significantly higher in infections caused by multiresistant strains. Nosocomial origin of infection (hazard ratio [HR], 4.43), long-term norfloxacin prophylaxis (HR, 2.69), recent infection by multiresistant bacteria (HR, 2.45), and recent use of β-lactams (HR, 2.39) were independently associated with the development of multiresistant infections. Results in the second series were similar to those observed in the first series. Conclusions : Multiresistant bacteria, especially ESBL-producing Enterobacteriaceae , are frequently isolated in nosocomial and, to a lesser extent, HCA infections in cirrhosis, rendering third-generation cephalosporins clinically ineffective. New antibiotic strategies tailored according to the local epidemiological patterns are needed for the empirical treatment of nosocomial infections in cirrhosis. (Hepatology 2012)

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death.¹ Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of hereditary CRC, accounting for 1% to 3% of all these tumors. It is an autosomal-dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes (ie, MSH2, MLH1, MSH6, and PMS2).² The abnormal function of these genes leads to accumulation of errors during DNA replication, especially in repetitive sequences known as microsatellites. As a result, tumors of patients with Lynch syndrome characteristically demonstrate MMR deficiency, defined as the presence of microsatellite instability (MSI) or loss of the MMR protein expression, which is the hallmark of this disorder.^3,4

Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤50 years old (n = 188), a group of sporadic CRC >50 years (MSS n = 89; MSI n = 46), and a group of Lynch syndrome CRCs (n = 20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. Mean LINE-1 methylation levels (±SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥65% LINE-1 methylation had significantly better overall survival (p = 0.026, log rank test). LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.

Purpose: microRNAs (miRNA) are small noncoding transcripts that play an important role in carcinogenesis. miRNA expression profiles have been shown to discriminate between different types of cancers. The aim of this study was to analyze global miRNA signatures in various groups of colorectal cancers (CRC) based on the presence of microsatellite instability (MSI). Experimental Design: We analyzed genome-wide miRNA expression profiles in 54 CRC tissues [22 with Lynch syndrome, 13 with sporadic MSI due to MLH1 methylation, 19 without MSI (or microsatellite stable, MSS)] and 20 normal colonic tissues by miRNA microarrays. Using an independent set of MSI-positive samples (13 with Lynch syndrome and 20 with sporadic MSI), we developed a miRNA-based predictor to differentiate both types of MSI by quantitative reverse transcriptase PCR. Results: We found that the expression of a subset of nine miRNAs significantly discriminated between tumor and normal colonic mucosa tissues (overall error rate = 0.04). More importantly, Lynch syndrome tumors displayed a unique miRNA profile compared with sporadic MSI tumors; miR-622, miR-1238, and miR-192 were the most differentially expressed miRNAs between these two groups. We developed a miRNA-based predictor capable of differentiating between types of MSI in an independent sample set. Conclusions: CRC tissues show distinct miRNA expression profiles compared with normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in colorectal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease. Clin Cancer Res; 17(19); 6239–49. ©2011 AACR.

Pancreatic ductal adenocarcinoma is one of the most aggressive forms of cancer, and the third leading cause of cancer-related mortality in the United States. Although important advances have been made in the last decade, the mortality rate of pancreatic ductal adenocarcinoma has not changed appreciably. This review summarizes a rapidly emerging model of pancreatic cancer research, focusing on 3-dimensional organoids as a powerful tool for several applications, but above all, representing a step toward personalized medicine.