Sean P. Cleary

Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing

Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in HCC. We performed whole‐exome sequencing on 87 HCCs and matched normal adjacent tissues to an average coverage of 59×. The overall mutation rate was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations that altered the amino acid sequence (range, 2‐381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly affected gene families include the nucleotide‐binding domain and leucine‐rich repeat‐containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2‐KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC. (Hepatology 2013;58:1693–1702)

Prognosis and Results After Resection of Very Large (≥10 cm) Hepatocellular Carcinoma

IntroductionFew potentially curative treatment options exist besides resection for patients with very large (≥10xa0cm) hepatocellular carcinoma (HCC). We sought to examine the outcomes and risk factors for recurrence after resection of ≥10xa0cm HCC.MethodsPerioperative and long-term outcomes were examined for 189 consecutive patients from 1993 to 2004 who underwent potentially curative resection of HCC ≥10xa0cm (nu2009=u200924; 13%) vs. those with HCC <10xa0cm (nu2009=u2009165; 87%). Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan–Meier analysis and patient, tumor, and treatment characteristics were compared using univariate and multivariate analysis.ResultsMedian follow-up was 34xa0months. Tumors ≥10xa0cm were more likely to be symptomatic, of poorer grade, and have vascular invasion (pu2009<u20090.05). Twelve patients (50%) underwent an extended resection of more than four hepatic segments or resection of adjacent organs for oncologic clearance (diaphragm-2, inferior vena cava (IVC)-2, median sternotomy-1). Postoperative complications were more common after resection of >10xa0cm HCC (12/24, 50% vs. 35/165, 21%; pu2009=u20090.04). Median DFS was significantly shorter in patients with large HCC (≥10xa0cm) group compared to patients with smaller HCC (8.4 vs. 38xa0months; pu2009=u20090.001), but overall survival was not different between the two groups (5-year survival 54% vs. 53%; pu2009=u20090.43). Seventeen patients (71%) with very large HCC developed recurrences (12 intrahepatic, five systemic); eight of these patients (47%) underwent additional therapy (resection-4, TACE-3, RFA-1). Pathological positive margins and vascular invasion were significant determinants of DFS in tumors ≥10xa0cm (pu2009<u20090.05), but only vascular invasion was an independent risk factor for recurrence after multivariate analysis (HR 0.17; 95% CI: 0.04–0.8). Median OS after recurrence was 24xa0months.ConclusionSurgical resection is the optimal therapy for very large (≥10xa0cm) HCC. Although recurrences are common after resection of these tumors, overall survival was not significantly different from patients after resection of smaller HCC in this series.

An analysis of resection vs transplantation for early hepatocellular carcinoma: defining the optimal therapy at a single institution.

BackgroundThe reported survival after liver transplantation (OLT) for early hepatocellular carcinoma (HCC) is superior to the results of liver resection (LR), but few analyses have considered long waiting times and patient drop-offs due to tumor progression.MethodsFrom 1995–2005, 347 patients with HCC were evaluated at our institution and underwent either LR (nxa0=xa0174) or placed on the OLT waiting list (nxa0=xa0173). Patients who only underwent ablation were not included. After eliminating patients with 1) incidental tumors after OLT, 2) tumors outside of Milan criteria, 3) preoperative vascular invasion prior to LR and 4) Child-Pugh Class C cirrhosis prior to OLT, 261 patients (LRxa0=xa0121; OLTxa0=xa0140) were included in this analysis.ResultsMedian follow-up time was 35 months. Median waiting time for OLT was 7.7 months; during this time, 30 patients were taken off the waiting list. Overall survival (OS) from time of listing or LR was not different between the two groups; 1, 3, and 5 year OS after LR was 89%, 75%, and 56% compared with 90%, 70%, and 64% for OLT (Pxa0=xa0.84). Only patients who waited <4 months for OLT (nxa0=xa067) had better survival than those who underwent LR (Pxa0=xa0.05). Patients who waited longer that four months for OLT had a 2.5× higher risk of death in a Cox multivariate model [odds ratio (OR) 2.5; 95% confidence interval (CI): 1.3–5; Pxa0=xa0.007].ConclusionUnless waiting time is short (<4 months), the survival of patients with early HCC is similar between LR and LT.

Comparison of outcomes and costs between laparoscopic distal pancreatectomy and open resection at a single center.

BackgroundThe cost implications of laparoscopic distal pancreatectomy (LDP) and a detailed breakdown of hospital expenditures has not been presented in the literature to date. This study aimed to compare hospital costs and short-term clinical outcomes between LDP and open distal pancreatectomy (ODP).MethodsThe authors evaluated all the distal pancreatic resections performed at their center between January 2004 and March 2010. Parametric and nonparametric statistical analysis was used to compare hospital departmental and total hospital costs as well as oncologic and surgical outcomes.ResultsA total of 118 cases (42 laparoscopic resections, including 5 conversions, and 76 open resections) were analyzed. The demographic characteristics were similar between the groups except for a predominance of females in the laparoscopic group (Pxa0=xa00.036). The indications for surgery differed by a paucity of malignant tumors being approached laparoscopically (Pxa0<xa00.001). Intraoperatively, there were no differences in estimated blood loss, operating room time, or transfusion requirement. The pathologic outcomes did not differ significantly. The median hospital length of stay (LOS) was 5xa0days (range 3–31xa0days) for the LDP cohort and 7xa0days (range 4–19xa0days) for the ODP cohort (Pxa0<xa00.001). Postoperative pancreatic fistula occurred for 22 patients, with a higher proportion observed in the LDP group (28.57%; nxa0= 12) than in the open group (13.16%; nxa0=xa010; Pxa0=xa00.05). However, the rates for grade B and higher grade fistula were higher in the ODP group (0 LDP and 4 ODP). The median preadmission and operative costs did not differ significantly. The ODP cohort had significantly higher costs in all other hospital departments, including the total cost.ConclusionLDP is both a cost-effective and safe approach for distal pancreatic lesions. This series showed a shorter LOS and lower total hospital costs for LDP than for ODP, accompanied by equivalent postoperative outcomes.

Up-front Hepatic Resection for Metastatic Colorectal Cancer Results in Favorable Long-term Survival

BackgroundHepatic metastasis from colorectal cancer (CRC) is best managed with a multimodal approach; however, the optimal timing of liver resection in relation to administration of perioperative chemotherapy remains unclear. Our strategy has been to offer up-front liver resection for patients with resectable hepatic metastases, followed by post–liver resection chemotherapy. We report the outcomes of patients based on this surgical approach.MethodsA retrospective review of all patients undergoing liver resection for CRC metastases over a 5-year period (2002–2007) was performed. Associations between clinicopathologic factors and survival were evaluated by the Cox proportional hazard method.ResultsA total of 320 patients underwent 336 liver resections. Median follow-up was 40 (range 8–80) months. The majority (nxa0=xa0195, 60.9xa0%) had metachronous disease, and most patients (nxa0=xa0286, 85xa0%) had a major hepatectomy (>3 segments). Thirty-six patients (11xa0%) received preoperative chemotherapy, predominantly for downstaging unresectable disease. Ninety-day mortality was 2.1xa0%, and perioperative morbidity occurred in 68 patients (20.2xa0%). Actual disease-free survival at 3 and 5xa0years was 46.2xa0% and 42xa0%, respectively. Actual overall survival (OS) at 3 and 5xa0years was 63.7xa0% and 55xa0%, respectively. Multivariate analysis identified four factors that were independently associated with differences in OS (hazard ratio; 95xa0% confidence interval): size of metastasis >6xa0cm (2.2; 1.3–3.5), positive lymph node status of the primary CRC (N1 (2.0; 1.0–3.8), N2 (2.4; 1.2–4.9)), synchronous disease (2.1; 1.3–3.5), and treatment with chemotherapy after liver resection (0.42; 0.23–0.75).ConclusionsUp-front surgery for patients with resectable CRC liver metastases, followed by chemotherapy, can lead to favorable OS.

Clinical and Economic Comparison of Laparoscopic to Open Liver Resections Using a 2-to-1 Matched Pair Analysis: An Institutional Experience

BACKGROUNDnSurgical resection of hepatic lesions is associated with intraoperative and postoperative morbidity and mortality. Our center has introduced a laparoscopic liver resection (LLR) program over the past 3 years. Our objective is to describe the initial clinical experience with LLR, including a detailed cost analysis.nnnSTUDY DESIGNnWe evaluated all LLRs from 2006 to 2010. Each was matched to 2 open cases for number of segments removed, patient age, and background liver histology. Model for End-Stage Liver Disease (MELD) and the Charlson comorbidity index were calculated retrospectively. Nonparametric statistical analysis was used to compare surgical and economic outcomes. Analyses were performed including and excluding converted cases.nnnRESULTSnFifty-seven patients underwent attempted LLR. Demographic characteristics were similar between groups. Estimated blood loss was lower in the LLR vs the open liver resection (OLR) group, at 250 mL and 500 mL, respectively (p < 0.001). Median operating room times were 240 minutes and 270 minutes in the LLR and OLR groups, respectively (p = 0.14). Eight cases were converted to open (14%): 2 for bleeding, 2 for anatomic uncertainty, 1 for tumor size, 1 for margins, 1 for inability to localize the tumor, and 1 for adhesions. Median length of stay was lower for LLR at 5 days vs 6 days for OLR (p < 0.001). There was no difference in frequency of ICU admission, reoperation, 30-day emergency room visit, or 30-day readmission rates. Median overall cost for LLR was lower at

Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk

11,376 vs

Predictors of peri-opertative morbidity and liver dysfunction after hepatic resection in patients with chronic liver disease

12,523 for OLR (p = 0.077).nnnCONCLUSIONSnOur experience suggests that LLR confers the clinical advantages of reduced operating room time, estimated blood loss, and length of stay while decreasing overall cost. LLR, therefore, appears to be a clinically and fiscally advantageous approach in properly selected patients.

Laparoscopic versus open liver resection for hepatocellular carcinoma at a North-American Centre: a 2-to-1 matched pair analysis.

Individual susceptibility to the toxic effects of cigarette smoke may be modified by inherited variability in carcinogen metabolism. The purpose of the present study was to investigate pancreatic cancer risk associated with cigarette smoking and 33 variants within carcinogen metabolism genes and examine whether these variants modify the association between smoking and pancreatic cancer. A population-based study was conducted with 455 pancreatic cancer cases and 893 controls. Epidemiological and smoking data were collected from questionnaires and variants were genotyped by mass spectrometry. Age- and sex-adjusted odds ratio (ASOR) and multivariate-adjusted odds ratio (MVOR) estimates were obtained using multivariate logistic regression, and interactions between each variant and smoking were investigated. Current smoker status [MVOR = 2.29, 95% confidence interval (95% CI): 1.62, 3.22], 10-27 pack-years (MVOR = 1.57, 95% CI: 1.13, 2.18), >27 pack-years (MVOR = 1.77, 95% CI: 1.27, 2.46) and longer durations of smoking (19-32 years: MVOR = 1.46, 95% CI: 1.05, 2.05; >32 years: MVOR = 1.78, 95% CI: 1.30, 2.45) were associated with increased pancreatic cancer risk. CYP1B1-4390-GG (ASOR = 0.36, 95% CI: 0.15, 0.86) and Uridine 5-diphospho glucuronosyltransferase 1 family, polypeptide A7-622-CT (ASOR = 0.77, 95% CI: 0.60, 0.99) were associated with reduced risk. N-acetyltransferase 1-640-GT/GG (ASOR = 1.75, 95% CI: 1.00, 3.05), GSTM1 (rs737497)-GG (ASOR = 1.41, 95% CI: 1.02, 1.95), GSTM1 gene deletion (ASOR = 4.89, 95% CI: 3.52, 6.79) and glutathione S-transferase theta-1 gene deletion (ASOR = 4.41, 95% CI: 2.67, 7.29) were associated with increased risk. Significant interactions were observed between pack-years and EPHX1-415 (P = 0.04) and smoking status and N-acetyltransferase 2-857 (P = 0.03). Variants of carcinogen metabolism genes are independently associated with pancreatic cancer risk and may modify the risk posed by smoking.

Planned versus unplanned portal vein resections during pancreaticoduodenectomy for adenocarcinoma

BACKGROUNDnHepatic resection in patients with chronic liver disease (CLD) is associated with a risk of post-operative liver failure and higher morbidity than patients without liver disease. There is no universal risk stratification scheme for CLD patients undergoing resection.nnnOBJECTIVESnThe aim of the present study was to evaluate the association between routine pre-operative laboratory investigations, model for end-stage liver disease (MELD), indocyanine green retention at 15 min (ICG15) and post-operative outcomes in CLD patients undergoing liver resection.nnnMETHODSnA retrospective review of patients undergoing resection for hepatocellular carcinoma (HCC) at the University Health Network was preformed. ICG15 results, pre- and post-operative laboratory results were obtained from clinical records. Adjusted odds ratios (AOR) were calculated for associations between pre-operative factors and post-operative outcomes using multivariate logistic regression adjusting for patient age and number of segments resected.nnnRESULTSnBetween 2001 and 2005, 129 CLD patients underwent surgical resection for HCC. Procedures included 51 (40%) resections of ≤ 2 segments, 52 (40%) hemihepatectomies and 25 (19%) extended hepatic resections. Thirty- and 90-day post-operative mortality was 1.6% and 4.1%, respectively. Prolonged (>10 days) hospital length of stay (LOS) was independently associated with an ICG15 >15% {AOR [95% confidence interval (CI)]= 8.5 (1.4-51)} and an international normalized ratio (INR) > 1.2 [AOR (95% CI) = 5.0 (1.4-18.6)]. An ICG15 > 15% and MELD score were independent predictors of prolonged LOS. An ICG15 > 15% was also independently associated with MELD > 20 on post-operative day 3 [AOR (95% CI) = 24.3 (1.8-319)].nnnCONCLUSIONSnElevated ICG retention was independently associated with post-operative liver dysfunction and morbidity. The utility of ICG in combination with other biochemical measures to predict outcomes after hepatic resection in CLD patients requires further prospective study.