Peng Chung Cheow

Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers

The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non–O. viverrini–related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini–related and non–O. viverrini–related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non–O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion

Cholangiocarcinoma (CC) and hepatocellularcarcinoma (HCC) are two main forms of liver malignancies, which exhibit differences in drug response and prognosis. Immunohistotochemical staining for cytokeratin markers has been used to some success in the differential diagnosis of CC from HCC. However, there remains a need for additional markers for increased sensitivity and specificity of diagnosis. In this study, we have identified a p38 MAP kinase, p38δ (also known as MAPK13 or SAPK4) as a protein that is upregulated in CC relative to HCC and to normal biliary tract tissues. We performed microarray gene expression profiling on 17 cases of CC, 12 cases of adjacent normal liver tissue, and three case of normal bile duct tissue. p38δ was upregulated in 16 out of 17 cases of CC relative to normal tissue. We subsequently performed immunohistochemical staining of p38δ in 54 cases of CC and 54 cases of HCC. p38δ staining distinguished CC from HCC with a sensitivity of 92.6% and a specificity of 90.7%. To explore the possible functional significance of p38δ expression in CC, we examined the effects of overexpression and knockdown of p38δ expression in human CC cell lines. Our results indicate that p38δ is important for motility and invasion of CC cells, suggesting that p38δ may play an important role in CC metastasis. In summary, p38δ may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma.

Background and Aims Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. Methods Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992–2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. Results A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. Conclusion The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.

A Study Into the Risk of Exacerbation of Chronic Hepatitis B After Liver Resection for Hepatocellular Carcinoma

Liver resection is commonly performed for solitary hepatocellular carcinoma (HCC) in well-compensated cirrhotic and noncirrhotic patients. Data concerning exacerbation of chronic hepatitis B (ECHB) post-liver resection are scant. To determine the incidence, risk factors, and clinical outcomes of ECHB in patients who underwent hepatic resection for HCC. The methods consisted of a retrospective review of consecutive patients with chronic hepatitis B virus (HBV) infection who had undergone liver resection for HCC from January 2002 to December 2004. Seventy-seven patients underwent 82 liver resections; the mean age was 58.0u2009±u200912.1xa0years; 87% male; 20% hepatitis B e-antigen positive. Incidence of all causes of postoperative hepatitis was 25.6% (nu2009=u200921), and ECHB was 8.5% (nu2009=u20097). Both groups had their peak alanine aminotransferases, 231.0xa0IU/L (74–1,400) and 312xa0IU/L (147–1,400), respectively, observed at dayxa084 postresection. Three patients died as a result of ECHB within 4xa0months postsurgery. One- and 2-year survival rates were poorest for the ECHB group at 42.9 and 21.4%, compared with those with postoperative hepatitis due to other causes at 60.3 and 45.2% and those without postoperative hepatitis at 87.7 and 73.5% (pu2009<u20090.001). Liver resection for HCC in patients with chronic HBV infection carries a risk for ECHB, and affected patients have poorer clinical outcomes. There is a need for close monitoring of these patients preoperatively and in the early postoperative period.

Laparoscopic liver resection for posterosuperior and anterolateral lesions—a comparison experience in an Asian centre

BACKGROUNDnMinimally invasive surgery has been one of the recent developments in liver surgery, laparoscopic liver resection (LLR) was initially performed for benign lesions at easily accessible locations. As the surgical techniques, technology and experience improved over the past decades, LLR surgery had evolved to tackle malignant lesions, major resections and even in difficult locations without compromising safety and principles of oncology. It was also shown to be beneficial in cirrhotic patients. We describe our initial experience with LLR in a population with significant proportion having cirrhosis, emphasising our approach for lesions in the posterosuperior (PS) segments of the liver (segments 1, 4a, 7, and 8).nnnMETHODSnA review of patients undergoing LLR in single institution from 2006 to 2015 was performed from a prospective surgical database. Clinicopathological, operative and perioperative parameters were analyzed to compare outcomes in patients who underwent LLR for PS vs. anterolateral lesions (AL).nnnRESULTSnLLR was performed in consecutive 197 patients, with a mean age of 60 years. The indications for resection were hepatocellular carcinoma (HCC) (n=105; 53%), colorectal cancer liver metastasis (n=31; 16%), other malignancies (n=19; 10%) and benign lesions (n=42; 21%). A significant proportion had liver cirrhosis (25.9%). More females underwent surgery in the AL group and indications for surgery were similar between both groups. Major liver resection was performed more frequently for the PS group than for the AL group (P<0.001) and significantly more PS resections was performed in our latter experience (P=0.02). The mean operative time and the conversion rate were significantly greater in the PS group than in the AL group (P≤0.001 and 0.03, respectively). However, the estimated blood loss (EBL), rate of blood transfusion and mean postoperative stay were similar in the two groups (P=0.04, 0.88 and 0.92, respectively). The overall 90-day morbidity and mortality rate was 21.3% and 0.5% respectively, with no differences between the two groups. Surrogates of difficulty such as operative time, blood loss, conversion and outcomes e.g., morbidity and mortality, were similar in patients who underwent PS resections with or without cirrhosis.nnnCONCLUSIONSnLLR in selected patients is technically feasible and safe including cirrhotic patients with lesions in the PS segments.

Surgical Treatment of Neuroendocrine Liver Metastases

Management of Neuroendocrine liver metastases (NELM) is challenging. The presence of NELM worsens survival outcome and almost 10% of all liver metastases are neuroendocrine in origin. There is no firm consensus on the optimal treatment strategy for NELM. A systematic search of the PubMed database was performed from 1995–2010, to collate the current evidence and formulate a sound management algorithm. There are 22 case series with a total of 793 patients who had undergone surgery for NELM. The overall survival ranges from 46–86% at 5 years, 35–79% at 10 years, and the median survival ranges from 52–123 months. After successful cytoreductive surgery, the mean duration of symptom reduction is between 16–26 months, and the 5-year recurrence/progression rate ranges from 59–76%. Five studies evaluated the efficacy of a combination cytoreductive strategy reporting survival rate of ranging from 83% at 3 years to 50% at 10 years. To date, there is no level 1 evidence comparing surgery versus other liver-directed treatment options for NELM. An aggressive surgical approach, including combination with additional liver-directed procedures is recommended as it leads to long-term survival, significant long-term palliation, and a good quality of life. A multidisciplinary approach should be established as the platform for decision making.

GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

Factors associated with and consequences of open conversion after laparoscopic distal pancreatectomy: initial experience at a single institution

Laparoscopic distal pancreatectomy (LDP) is increasingly adopted today. This study aims to determine factors associated with and consequences of open conversion after LDP.

Correction: The Singapore Liver Cancer Recurrence (SLICER) Score for Relapse Prediction in Patients with Surgically Resected Hepatocellular Carcinoma

There is an error in the order of authors. The correct order is: Soo Fan Ang1*, Elizabeth Shu-Hui Ng1, Huihua Li2,3, Yu-Han Ong1, Su Pin Choo1, Joanne Ngeow1, Han Chong Toh1, Kiat Hon Lim4, Hao Yun Yap5, Chee Kiat Tan6, London Lucien Peng Jin Ooi7, Peng Chung Cheow7, Alexander Yaw Fui Chung7, Pierce Kah Hoe Chow8,9, Kian Fong Foo1, Min-Han Tan1* n n1 Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore, 2 Health Services Research, Singapore General Hospital, Singapore, Republic of Singapore, 3 Centre for Quantitative Medicine, Duke-National University of Singapore Graduate Medical School, Singapore, Republic of Singapore, 4 Department of Pathology, Singapore General Hospital, Singapore, Republic of Singapore, 5 Department of General Surgery, Singapore General Hospital, Singapore, Republic of Singapore, 6 Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Republic of Singapore, 7 Department of Hepatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Republic of Singapore, 8 Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore, 9 Office of Clinical Sciences, Duke-National University of Singapore Graduate Medical School, Singapore, Republic of Singapore.