Adam C. Yopp

Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.

The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: A meta-analysis

Objectives:The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease.Methods:We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model.Results:Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20–1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12–1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27–2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96–1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed.Conclusions:PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.

Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.

ABSTRACTBACKGROUNDAlthough surveillance for hepatocellular carcinoma (HCC) is recommended in high-risk patients, several studies have suggested it is being underutilized in clinical practice. The aim of our study was to quantify utilization rates for HCC surveillance among patients with cirrhosis and summarize patterns of association between utilization rates and patient socio-demographic characteristics.DATA SOURCESWe performed a systematic literature review using the Medline database from January 1990 through March 2011 and a manual search of national meeting abstracts from 2008–2010.METHODSTwo investigators independently extracted data on patient populations, study methods, and results using standardized forms. A pooled surveillance rate with 95% confidence intervals was calculated. Pre-specified subgroup analysis was performed to find correlates of surveillance utilization.RESULTSWe identified nine studies that met inclusion criteria. The pooled surveillance rate was 18.4% (95%CI 17.8%–19.0%). Surveillance rates were significantly higher among patients followed in subspecialty gastroenterology clinics compared to those followed in primary care clinics (51.7% vs. 16.9%, p < 0.001). Non-Caucasians and patients of low socioeconomic status had lower surveillance rates than their counterparts.CONCLUSIONSUtilization rates for HCC surveillance are low, although they are significantly higher among patients followed in subspecialty clinics. Current studies fail to determine why HCC surveillance is not being performed. Future efforts should focus on identifying appropriate intervention targets to increase surveillance rates and reduce socio-demographic disparities.

Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail?

OBJECTIVES:Only 40% of patients with hepatocellular carcinoma (HCC) are diagnosed at an early stage, suggesting breakdowns in the surveillance process. The aim of our study was to assess the reasons behind surveillance process failures among patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C), which prospectively collected HCC surveillance data on a large cohort of patients.METHODS:Binary regression analysis was used to identify predictors of consistent surveillance, which was defined as having an ultrasound and alpha-fetoprotein every 12 months. Surveillance failures among patients who developed HCC were classified into one of three categories: absence of screening, absence of follow-up, or absence of detection.RESULTS:Over a mean follow-up of 6.1 years, 692 (68.9%) of 1,005 patients had consistent surveillance. Study site was the strongest predictor of consistent surveillance (P<0.001). After adjusting for study site, patient-level predictors of consistent surveillance included platelet count >150,000/mm3 (hazard ratio (HR) 1.28; 95% confidence interval (CI): 1.05–1.56) and complete clinic visit adherence (HR 1.72, 95% CI: 1.11–2.63). Of 83 patients with HCC, 23 (27.7%) were detected beyond Milan criteria. Three (13%) had late-stage HCC due to the absence of screening, 4 (17%) due to the absence of follow-up, and 16 (70%) due to the absence of detection.CONCLUSIONS:Surveillance process failures, including absence of screening or follow-up, are common and potentially contribute to late-stage tumors in one-third of cases. However, the most common reason for finding HCC at a late stage was an absence of detection, suggesting better surveillance strategies are needed.

An Essential Mesenchymal Function for miR-143/145 in Intestinal Epithelial Regeneration

Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.

Failure rates in the hepatocellular carcinoma surveillance process

Hepatocellular carcinoma (HCC) surveillance is underutilized among patients with cirrhosis. Understanding which steps in the surveillance process are not being conducted is essential for designing effective interventions to improve surveillance rates. The aim of our study was to characterize reasons for failure in the HCC surveillance process among a cohort of cirrhotic patients with HCC. We conducted a retrospective cohort study of cirrhotic patients diagnosed with HCC at a large urban safety-net hospital between 2005 and 2011. Patients were characterized by receipt of HCC surveillance over a two-year period before HCC diagnosis. Among patients without HCC surveillance, we classified reasons for failure into four categories: failure to recognize liver disease, failure to recognize cirrhosis, failure to order surveillance, and failure to complete surveillance despite orders. Univariate and multivariate analyses were conducted to identify predictors of failures. We identified 178 patients with HCC, of whom 20% had undergone surveillance. There were multiple points of failure—20% had unrecognized liver disease, 19% had unrecognized cirrhosis, 38% lacked surveillance orders, and 3% failed to complete surveillance despite orders. Surveillance was more likely among patients seen by hepatologists [OR, 6.11; 95% confidence interval (CI), 2.5–14.8] and less likely in those with alcohol abuse (OR, 0.14; 95% CI, 0.03–0.65). Although a retrospective analysis in a safety-net hospital, our data suggest that only one in five patients received surveillance before HCC diagnosis. There are multiple points of failure in the surveillance process, with the most common being failure to order surveillance in patients with known cirrhosis. Future interventions must target multiple failure points in the surveillance process to be highly effective. Cancer Prev Res; 5(9); 1124–30. ©2012 AACR.

Role of preoperative biliary drainage of liver remnant prior to extended liver resection for hilar cholangiocarcinoma

BACKGROUND In patients with hilar cholangiocarcinoma, ipsilateral en bloc hepatic resection improves survival but is associated with increased morbidity. Preoperative biliary drainage of the future liver remnant (FLR) and contralateral portal vein embolization (PVE) may improve perioperative outcome, but their routine use is controversial. This study analyses the impact of FLR volume and preoperative biliary drainage on postoperative hepatic insufficiency and mortality rates. METHODS Patients who underwent hepatic resection and for whom adequate imaging data for FLR calculation were available were identified retrospectively. Patient demographic, operative and perioperative data were recorded and analysed. The volume of the FLR was calculated based on the total liver volume and the volume of the resection that was actually performed using semi-automated contouring of the liver on preoperative helical acquired scans. In patients subjected to preoperative biliary drainage, the preoperative imaging was reviewed to determine if the FLR had been decompressed. Hepatic insufficiency was defined as a postoperative rise in bilirubin of 5 mg/dl above the preoperative level that persisted for >5 days postoperatively. Operative mortality was defined as death related to the operation, whenever it occurred. RESULTS Sixty patients were identified who underwent hepatic resection between 1997 and 2007 and for whom imaging data were available for analysis. During this period, preoperative biliary drainage of the FLR was used selectively and PVE was used in only one patient. The mean age of the patients was 64 +/- 11.6 years and 68% were male. The median length of stay was 14 days and the overall morbidity and mortality were 53% and 10%, respectively. Preoperative FLR volume was a predictor of hepatic insufficiency and death (P= 0.03). A total of 65% of patients had an FLR volume > or = 30% (39/60) of the total volume. No patient in this group had hepatic insufficiency, but there were two operative deaths (5%), both occurring in patients who underwent preoperative biliary drainage. By contrast, in the group with FLR < 30% (21/60, 35%), hepatic insufficiency was seen in five patients and operative mortality in four patients, and were strongly associated with lack of preoperative biliary drainage of the FLR (P = 0.009). Patients with an FLR > or = 30% were more likely to have radiographic evidence of ipsilateral lobar atrophy and hypertrophy of the FLR (46.2% vs. 9.5% in patients with FLR < 30%; P = 0.004). CONCLUSIONS In patients undergoing liver resection for hilar cholangiocarcinoma, FLR volume of < 30% of total liver volume is associated with increased risk for hepatic insufficiency and death. Preoperative biliary drainage of the FLR appears to improve outcome if the predicted volume is < 30%. However, in patients with FLR > or = 30%, preoperative biliary drainage does not appear to improve perioperative outcome and, as many of these patients have hypertrophy of the FLR, PVE is likely to offer little benefit.

Racial, Social, and Clinical Determinants of Hepatocellular Carcinoma Surveillance

OBJECTIVES Less than 1 in 5 patients receive hepatocellular carcinoma surveillance; however, most studies were performed in racially and socioeconomically homogenous populations, and few used guideline-based definitions for surveillance. The study objective was to characterize guideline-consistent hepatocellular carcinoma surveillance rates and identify determinants of hepatocellular carcinoma surveillance among a racially and socioeconomically diverse cohort of cirrhotic patients. METHODS We retrospectively characterized hepatocellular carcinoma surveillance among cirrhotic patients followed between July 2008 and July 2011 at an urban safety-net hospital. Inconsistent surveillance was defined as at least 1 screening ultrasound during the 3-year period, annual surveillance was defined as screening ultrasounds every 12 months, and biannual surveillance was defined as screening ultrasounds every 6 months. Univariate and multivariate analyses were conducted to identify predictors of surveillance. RESULTS Of 904 cirrhotic patients, 603 (67%) underwent inconsistent surveillance. Failure to recognize cirrhosis was a significant barrier to surveillance use (P < .001). Inconsistent surveillance was associated with insurance status (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.03-1.98), multiple primary care visits per year (OR, 2.63; 95% CI, 1.86-3.71), multiple hepatology visits per year (OR, 3.75; 95% CI, 2.64-5.33), African American race (OR, 0.61; 95% CI, 0.42-0.99), nonalcoholic steatohepatitis cause (OR, 0.60; 95% CI, 0.37-0.98), and extrahepatic cancer (OR, 0.43; 95% CI, 0.24-0.77). Only 98 (13.4%) of 730 patients underwent annual surveillance, and only 13 (1.7%) of 786 had biannual surveillance. CONCLUSIONS Only 13% of patients with cirrhosis receive annual surveillance, and less than 2% of patients receive biannual surveillance. There are racial and socioeconomic disparities, with lower rates of hepatocellular carcinoma surveillance among African Americans and underinsured patients.

Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis

Purpose To compare overall survival between patients who received neoadjuvant therapy (NAT) followed by resection and those who received upfront resection (UR)-as well as a subgroup of UR patients who also received adjuvant therapy-for early-stage resectable pancreatic adenocarcinoma. Patients and Methods Adult patients with resected, clinical stage I or II adenocarcinoma of the head of the pancreas were identified in the National Cancer Database from 2006 to 2012. Patients who underwent NAT followed by curative-intent resection were matched by propensity score with patients whose tumors were resected upfront. Overall survival was compared by using a Cox proportional hazards regression model. Early postoperative and oncologic outcomes were evaluated. Results We identified 15,237 patients with clinical stage I or II resected pancreatic head adenocarcinoma. From the NAT group, 2,005 patients (95%) were matched with 6,015 patients who underwent UR. The NAT group was associated with improved survival compared with UR (median survival, 26 months v 21 months, respectively; stratified log-rank P < .01; hazard ratio, 0.72; 95% CI, 0.68 to 0.78). Patients in the UR group had higher pathologic T stage (pT3 and T4: 86% v 73%; P < .01), higher positive lymph nodes (73% v 48%; P < .01), and higher positive resection margin (24% v 17%; P < .01). Compared with a subset of UR patients who received adjuvant therapy, NAT patients had a better survival (adjusted hazard ratio, 0.83; 95% CI, 0.73 to 0.89). Conclusion NAT followed by resection has a significant survival benefit compared with UR in early-stage, resected pancreatic head adenocarcinoma. These findings support the use of NAT, particularly as a patient selection tool, in the management of resectable pancreatic adenocarcinoma.

Practice Patterns and Attitudes of Primary Care Providers and Barriers to Surveillance of Hepatocellular Carcinoma in Patients with Cirrhosis

BACKGROUND & AIMS Fewer than 20% of patients with cirrhosis undergo surveillance for hepatocellular carcinoma (HCC), therefore these tumors often are detected at late stages. Although primary care providers (PCPs) care for 60% of patients with cirrhosis in the United States, little is known about their practice patterns for HCC surveillance. We investigated factors associated with adherence to guidelines for HCC surveillance by PCPs. METHODS We conducted a web-based survey of all 131 PCPs at a large urban hospital. The survey was derived from validated surveys and pretested among providers; it included questions about provider and practice characteristics, self-reported rates of surveillance, surveillance test and frequency preference, and attitudes and barriers to HCC surveillance. RESULTS We obtained a clinic-level response rate of 100% and a provider-level response rate of 60%. Only 65% of respondents reported annual surveillance and 15% reported biannual surveillance of patients for HCC. Barriers to HCC surveillance included not being up-to-date with HCC guidelines (68% of PCPs), difficulties in communicating effectively with patients about HCC surveillance (56%), and more important issues to manage in the clinic (52%). Approximately half of PCPs (52%) reported using ultrasound or measurements of α-fetoprotein in surveillance; 96% said that this combination was effective in reducing HCC-related mortality. However, many providers incorrectly believed that clinical examination (45%) or levels of liver enzymes (59%) or α-fetoprotein alone (89%) were effective surveillance tools. CONCLUSIONS PCPs have misconceptions about tests to detect HCC that contribute to ineffective surveillance. Reported barriers to surveillance include suboptimal knowledge about guidelines, indicating a need for interventions, including provider education, to increase HCC surveillance effectiveness.