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Ian JY Wee,1 Fiona NN Moe,1 Rehena Sultana,2 Reiko WT Ang,1 Pearly PS Quek,3 Brian Kim Poh Goh,1 Chung Yip Chan,1 Peng Chung Cheow,1 Alexander YF Chung,1 Prema Raj Jeyaraj,1 Ye Xin Koh,1 Peter OP Mack,1 London Lucien PJ Ooi,1 Ek Khoon Tan,1 Jin Yao Teo,1 Juinn Huar Kam,1 Jacelyn SS Chua,1 Ashley WY Ng,1 Jade SQ Goh,1 Pierce KH Chow1,4 1Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore; 2Center of Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore; 3Ministry of Health Holdings, Singapore, Singapore; 4Surgery Academic Clinical Program, Duke-NUS Medical School, Singapore, SingaporeCorrespondence: Pierce KH Chow, Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore, Tel +65 6576 2151, Email pierce.chow@duke-nus.edu.sgObjective: We aimed to prognosticate survival after surgical resection of HCC stratified by stage with amalgamation of the modified Barcelona Clinic Liver Cancer (BCLC) staging system and location of tumour.Methods: This single-institutional retrospective cohort study included patients with HCC who underwent surgical resection between 1st January 2000 to 30th June 2016. Participants were divided into 6 different subgroups: A-u) Within MC with Unilobar lesions; A-b) Within MC + Bilobar lesions; B1-u) Out of MC + within Up-To-7 + Unilobar lesions; B1-b) Out of MC + within Up-to-7 + Bilobar lesions; B2-u) Out of MC + Out of Up-To-7 + Unilobar lesions; B2-b) Out of MC + Out of Up-To-7 + Bilobar lesions. A separate survival analysis was conducted for solitary HCC lesions according to three subgroups: A-S (Within MC); B1-S (Out of MC + within Up-To-7); B2-S (Out of MC + out of Up-To-7).Results: A total of 794 of 1043 patients with surgical resection for HCC were analysed. Groups A-u (64.6%), A-b (58.4%) and B1-u (56.2%) had 5-year cumulative overall survival (OS) rates above 50% after surgical resection and median OS exceeding 60 months (P = 0.0001). The 5-year cumulative recurrence-free survival rates (RFS) were 40.4% (group A-u), 38.2% (group A-b), 36.3% (group B1-u), 24.6% (group B2-u), and 7.3% (group B2-b)(P=0.0001). For solitary lesions, the 5-year OS for the subgroups were A-S (65.1%), B1-S (56.0%) and B2-S (47.1%) (P = 0.0003). Compared to A-S, there was also a significant trend towards relatively poorer OS as the lesion sizes increased in B1-S (HR 1.46, 95% CI 1.03– 2.08) and B2-S (HR 1.65, 95% CI 1.25– 2.18).Conclusion: We adopted a novel approach combining the modified BCLC B sub-classification and dispersion of tumour to show that surgical resection in intermediate stage HCC can be robustly prognosticated. We found that size prognosticates resection outcomes in solitary tumours.Keywords: hepatocellular carcinoma, surgical resection, Barcelona clinic liver cancer

Introduction: The perceived mental health of individuals in Canada who faced health care barriers during the COVID-19 pandemic is underexplored., Methods: We analyzed data collected March to June 2021 from adults who reported needing health care services within the past 12 months in the Survey on Access to Health Care and Pharmaceuticals during the Pandemic. Unadjusted and adjusted logistic regression analyses examined the associations between health care barriers (appointment scheduling problems, delaying contacting health care) and high self-rated mental health and perceived worsening mental health compared to before the pandemic, overall and stratified by gender, age group, number of chronic health conditions and household income tertile., Results: Individuals who experienced pandemic-related appointment changes or had appointments not yet scheduled were less likely to have high self-rated mental health (aOR = 0.81 and 0.64, respectively) and more likely to have perceived worsening mental health (aOR = 1.50 and 1.94, respectively) than those with no scheduling problems. Adults who delayed contacting health care for pandemic-related reasons (e.g. fear of infection) or other reasons were less likely to have high self-rated mental health (aOR = 0.52 and 0.45, respectively) and more likely to have perceived worsening mental health (aOR = 2.31 and 2.43, respectively) than those who did not delay. Delaying contacting health care for pandemic-related reasons was associated with less favourable perceived mental health in all subgroups, while the association between perceived mental health and pandemic-related appointment changes was significant in some groups., Conclusion: Health care barriers during the pandemic were associated with less favourable perceived mental health. These findings could inform health care resource allocation and public health messaging., Competing Interests: The authors have no conflicts of interest.

The aim of the present study was to compare the relations between subtypes of social withdrawal and socio-emotional adjustment in Chinese children and early adolescents. Participants included 571 children (M age  = 9.62 years) and 345 adolescents M age  = 12.12 years) in mainland China. Social withdrawal subtypes (i.e., shyness, unsociability, social avoidance) and indices of socio-emotional adjustment were assessed via self-reports, peer nominations, and teacher ratings. Shyness tended to be more strongly associated with emotional maladjustment in early adolescence, whereas unsociability was more strongly associated with socio-emotional difficulties in childhood. For social avoidance, associations with indices of negative adjustment (i.e., social anxiety, emotional symptoms, peer problems) were stronger in childhood, however, associations with indices of positive adjustment (i.e., life satisfaction, well-being) were stronger in early adolescence., (© 2023 Society for Research on Adolescence.)

Background: The Public Health Agency of Canada monitors the psychological and social well-being of Canadian youth using the Children's Intrinsic Needs Satisfaction Scale (CINSS). Validation analyses of the CINSS have been conducted, but not in the 2019 Canadian Health Survey on Children and Youth (CHSCY), a more recent and representative national survey with a different sampling frame, collection method and other measured outcomes. This study tested the validity of the CINSS in the 2019 CHSCY., Data and Methods: Data were collected in all provinces and territories from February 11 to August 2, 2019. The CINSS was administered to respondents aged 12 to 17 years and was designed to assess relatedness, autonomy and competence at home, at school and with friends. Descriptive statistics for CINSS items and subscales were obtained. Confirmatory factor analysis (CFA) was conducted to test how well a correlated traits correlated uniqueness (CTCU) model fit the CINSS data. Associations with mental health and other psychosocial variables were examined., Results: In general, items within the CINSS were correlated in expected ways, and support was found for a CTCU model in the CFA. While response distributions on the CINSS items were skewed, the CINSS subscales had acceptable internal consistency and were associated with self-rated mental health, happiness, life satisfaction, perceived stress, bullying victimization and behaviour problems in line with expectations., Interpretation: This study supports the validity of the CINSS. Inclusion of the CINSS in future youth health surveys would allow for continued public health surveillance of the psychological and social well-being of youth in Canada.

Introduction: Social isolation and loneliness are associated with poorer mental health among older adults. However, less is known about how these experiences are independently associated with positive mental health (PMH) during the COVID-19 pandemic., Methods: We analyzed data from the 2020 and 2021 cycles of the Survey on COVID-19 and Mental Health to provide estimates of social isolation (i.e. living alone), loneliness and PMH outcomes (i.e. high self-rated mental health, high community belonging, mean life satisfaction) in the overall older adult population (i.e. 65+ years) and across sociodemographic groups. We also conducted logistic and linear regressions to separately and simultaneously examine how social isolation and loneliness are associated with PMH., Results: Nearly 3 in 10 older adults reported living alone, and over a third reported feelings of loneliness due to the pandemic. When examined separately, living alone and loneliness were each associated with lower PMH. When assessed simultaneously, loneliness remained a significant independent factor associated with all three PMH outcomes (overall and across all sociodemographic groups), but living alone was only a significant factor for high community belonging in the overall population, for males and for those aged 65 to 74 years., Conclusion: Overall, social isolation and loneliness were associated with poorer wellbeing among older adults in Canada during the pandemic. Loneliness remained a significant factor related to all PMH outcomes after adjusting for social isolation, but not vice versa. The findings highlight the need to appropriately identify and support lonely older adults during (and beyond) the pandemic., Competing Interests: The authors have no conflicts of interest.

Findings from the 2020 Survey on COVID-19 and Mental Health (SCMH) suggested that the positive mental health of adults in Canada was lower during the second wave of the pandemic (fall 2020) than in 2019. With 2021 SCMH data from winter/spring 2021, we find in the current study that average life satisfaction and the prevalence of high self-rated mental health, high community belonging and perceptions of stable/improved mental health were even lower during the third wave of the pandemic as compared to the second wave in the overall adult population and in most sociodemographic groups., Competing Interests: The authors have no conflicts of interest.

The COVID-19 pandemic has affected surgical education and training significantly. The main impact to surgical residency training is the reduction in number of patients (in caseload and case mix) and the conversion of face-to-face meetings into virtual ones for CME and clinical governance-related events. Assessment of surgical residents by examination (namely the Joint Specialty Fellowship Examination with the College of Surgeons of Hong Kong and the Royal College of Surgeons of Edinburgh) was cancelled at the peak of the pandemic, with resumption after acceptable COVID compatible adjustment was made to the format. The migration of CME events into a web-based one has resulted in greater connectivity with more audience. The potential and challenges of virtual format in surgical education include strategy and resources for sustainability; choice of optimal model for effective learning and surgical skills acquisition. In a post-COVID world, the model of blended learning is likely to remain., Competing Interests: The authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd.)

The goal of the present study was to examine the moderating effect of emotion regulation in the longitudinal relations between rejection sensitivity and indices of adjustment among Chinese children. Participants were N  = 590 children ( M age = 11.25 years, SD  = 1.33) attending public elementary and middle schools in Shanghai, P.R. China. Measures of anxious rejection sensitivity and socio-emotional functioning were collected via self-reports and peer nominations. Among the results, rejection sensitivity significantly predicted higher levels of later internalizing problems. Moreover, emotion regulation significantly moderated (i.e. buffering effect) the relations between rejection sensitivity and later peer and emotional difficulties. The current findings suggest that rejection sensitivity poses developmental risk over time, but emotion regulation may serve as a protective factor for Chinese youth. Results are discussed in terms of the implications of rejection sensitivity and emotion regulation in Chinese culture.

Purpose: NUF2 has been implicated in multiple cancers recently, suggesting NUF2 may play a role in the common tumorigenesis process. In this study, we aim to perform comprehensive meta-analysis of NUF2 expression in the cancer types included in the Cancer Genome Atlas (TCGA)., Materials and Methods: RNA-sequencing data in 31 cancer types in the TCGA data and 11 independent datasets were used to examine NUF2 expression. Silencing NUF2 using targeting shRNAs in hepatocellular carcinoma (HCC) cell lines was used to evaluate NUF2's role in HCC in vitro and in vivo., Results: NUF2 up-regulation is significantly observed in 23 out of the 31 cancer types in the TCGA datasets and validated in 13 major cancer types using 11 independent datasets. NUF2 overexpression was clinically important as high NUF2 was significantly associated with tumor stages in eight different cancers. High NUF2 was also associated with significantly poorer patient overall survival and disease-free survival in eight and six cancers, respectively. We proceeded to validate NUF2 overexpression and its negative association with overall survival at the protein level in an independent cohort of 40 HCC patients. Compared to the non-targeting controls, NUF2 knockdown cells showed significantly reduced ability to grow, migrate into a scratch wound and invade the 8 μm porous membrane in vitro. Moreover, NUF2 knockdown cells also formed significantly smaller tumors than control cells in mouse xenograft assays in vivo., Conclusion: NUF2 up-regulation is a common feature of many cancers. The prognostic potential and functional impact of NUF2 up-regulation warrant further studies.

Introduction: The impact of liver cirrhosis on the difficulty of minimal invasive liver resection (MILR) remains controversial and current difficulty scoring systems do not take in to account the presence of cirrhosis as a significant factor in determining the difficulty of MILR. We hypothesized that the difficulty of MILR is affected by the presence of cirrhosis. Hence, we performed a 1:1 matched-controlled study comparing the outcomes between patients undergoing MILR with and without cirrhosis including the Iwate system and Institut Mutualiste Montsouris (IMM) system in the matching process., Methods: Between 2006 and 2019, 598 consecutive patients underwent MILR of which 536 met the study inclusion criteria. There were 148 patients with cirrhosis and 388 non-cirrhotics. One-to-one coarsened exact matching identified approximately exact matches between 100 cirrhotic patients and 100 non-cirrhotic patients., Results: Comparison between MILR patients with cirrhosis and non-cirrhosis in the entire cohort demonstrated that patients with cirrhosis were associated with a significantly increased open conversion rate, transfusion rate, need for Pringles maneuver, postoperative, stay, postoperative morbidity and postoperative 90-day mortality. After 1:1 coarsened exact matching, MILR with cirrhosis were significantly associated with an increased open conversion rate (15% vs 6%, p = 0.03), operation time (261 vs 238 min, p  < 0.001), blood loss (607 vs 314 mls, p  = 0.002), transfusion rate (22% vs 9%, p  = 0.001), need for application of Pringles maneuver (51% vs 34%, p  = 0.010), postoperative stay (6 vs 4.5 days, p  = 0.004) and postoperative morbidity (26% vs 13%, p  = 0.029)., Conclusion: The presence of liver cirrhosis affected both the intraoperative technical difficulty and postoperative outcomes of MILR and hence should be considered an important parameter to be included in future difficulty scoring systems for MILR., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Liver resection (LR) is the main modality of treatment for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Post-hepatectomy liver failure (PHLF) remains the most dreaded complication. We aim to create a prognostic score for early risk stratification of patients undergoing LR., Methodology: Clinical and operative data of 472 patients between 2000 and 2016 with HCC or CRLM undergoing major hepatectomy were extracted and analysed from a prospectively maintained database. PHLF was defined using the 50-50 criteria., Results: Liver cirrhosis and fatty liver were histologically confirmed in 35.6% and 53% of patients. 4.7% (n = 22) of patients had PHLF. A 90-day mortality was 5.1% (n = 24). Pre-operative albumin-bilirubin score (p = 0.0385), prothrombin time (p < 0.0001) and the natural logarithm of the ratio of post-operative day 1 to pre-operative serum bilirubin (SB) (ln( POD1 Bil/ pre-op Bil); p < 0.0001) were significantly independent predictors of PHLF. The PHLF prognostic nomogram was developed using these factors with receiver operating curve showing area under curve of 0.88. Excellent sensitivity (94.7%) and specificity (95.7%) for the prediction of PHLF (50-50 criteria) were achieved at cut-offs of 9 and 11 points on this model. This score was also predictive of PHLF according to Peak Bil > 7 and International Study Group for Liver Surgery criteria, intensive care unit admissions, length of stay, all complications, major complications, re-admissions and mortality (p < 0.05)., Conclusions: The PHLF nomogram ( https://tinyurl.com/SGH-PHLF-Risk-Calculator ) can serve as a useful tool for early identification of patients at high risk of PHLF before the 'point of no return'. This allows enforcement of closer monitoring, timely intervention and mitigation of adverse outcomes.

Background: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers. With the increasing incidence of ICC over the past two decades in Asia, it is essential to differentiate between HCC and ICC. However, ICC may mimic the radiological appearance of HCC on computed tomography scans (CT) and magnetic resonance imaging (MRI), leading to misdiagnosis of ICC. The objective of this study is to evaluate and describe the association of specific pre-operative imaging characteristics (arterial enhancement, portal venous washout) in patients with histologically proven resected ICC in our centre., Methods: Data on patients with histology-proven ICC and mixed hepatocellular-cholangiocarcinomas (HCC-CC) who had undergone surgical resection at Singapore General Hospital (SGH) were identified from a prospectively maintained database. Pre-operative cross-sectional imaging reports were analysed., Results: Ninety-one patients underwent resection between 1 January 2000 and 31 December 2016. Among those with no risk factors for HCC, a significant percentage of patients with ICC (24.3%) show imaging characteristics of both arterial phase hyperenhancement and non-peripheral venous washout. Among patients with risk factors for HCC, between 20.0 and 33.3% of patients with pure ICC fulfilled the imaging criteria for HCC, and this proportion was generally even higher in the mixed HCC-CC group., Conclusions: A significant proportion of patients with pure ICC showed pre-operative imaging characteristics which fulfilled the diagnostic criteria for HCC. The differential of ICC should be borne in mind in populations where both malignancies are endemic.

Background: Minimally invasive pancreatic surgeries (MIPS) are increasingly adopted worldwide. However, it remains uncertain if these reported experiences are reproducible throughout the world today. This study examines the safety and evolution of MIPS at a single institution in Southeast Asia., Methods: This is a retrospective review of 150 consecutive patients who underwent MIPS between 2006 and 2018 of which 135 cases (90%) were performed since 2012. To determine the evolution of MIPS, the study population was stratified into 3 equal groups of 50 patients. Comparison was also made between pancreatoduodenectomies (PD), distal pancreatectomies (DP) and other pancreatic surgeries., Results: One hundred and fifty patients underwent MIPS (103 laparoscopic, 45 robotic and 2 hand-assisted). Forty-three patients underwent PD, 93 DP and 14 other MIPS. There were 21 (14.0%) open conversions. There was an exponential increase in caseload over the study period. Comparison across the 3 time periods demonstrated that patients were significantly more likely to have a higher American Society of Anesthesiologists score, older, undergo PD and a longer operation time. The conversion rate decreased from 28% to 0% and increased again to 14% across the 3 time periods. Comparison between the various types of MIPS demonstrated that patients who underwent PD were significantly older, more likely to have symptomatic tumours, had longer surgery time, increased blood loss, increased frequency of extended pancreatectomies, increased frequency of hybrid procedures, longer post-operative stay, increased post-operative morbidity rate and increased post-operative major morbidity rate., Conclusion: The case volume of MIPS increased rapidly at our institution over the study period. Furthermore, although the indications for MIPS expanded to include more complex procedures in higher risk patients, there was no change in key perioperative outcomes., Competing Interests: None

Background: Resection of colorectal liver metastases (CLM) has been established as the standard of care. This study aims to compare the change in clinicopathological characteristics of patients who underwent curative resection of CLM across two time periods-2000 to 2010 (P1) and 2011 to 2016 (P2) and evaluate the prognostic impact of these characteristics on survival outcomes., Methods: Patients who undergo liver resection for CLM at Singapore General Hospital from January 2000 to December 2016 were identified from a prospectively maintained database. The primary end point was overall survival., Results: There were 183/318 (57.5%) patients and 135/318 (42.5%) patients in P1 and P2, respectively. There was a lower proportion of patients who had nodal metastases from primary colorectal cancer and clinical risk score (CRS) less than 3 in P2 when compared to P1. There was no difference in survival between both time periods. Independent predictors of survival for the cohort were CEA levels ≥ 200 ng/ml, primary tumour grade and lymph nodal status. Independent predictors of poor survival in P1 were poorly differentiated colorectal cancer and nodal metastases while in P2, independent predictors of poor survival were multiple liver metastases and nodal metastases., Conclusion: Nodal metastases from primary colorectal cancer are an independent predictor of poor survival across time for resectable CLM. Although there is no difference in survival between the two time periods, patients with multiple liver metastases should be carefully considered prior to surgery as it is also an independent predictor of overall survival.

Introduction: Although hepatectomy is the mainstay of curative therapy for hepatocellular carcinoma (HCC), post-operative complications remain high. Presently there is conflicting data on the impact of morbidity on oncologic outcomes. We sought to identify predictors for the occurrence of post-hepatectomy complications, as well as to analyse the impact on overall survival (OS) and recurrence-free survival (RFS)., Materials and Methods: We performed a retrospective review of 888 patients who underwent resection for HCC from 2001 to 2016 in our institution., Results: A total of 237 patients (26.7%) developed 254 complications of Clavien-Dindo Grade ≥2. Hepatitis B (p = 0.0397), elevated ASA score (p = 0.0002), higher platelet counts (p = 0.0277), raised pre-operative APRI scores (p = 0.0105) and bloodloss (p < 0.0001) were independently associated with the development of complications. After propensity-score matching, 458 patients were compared in a 1:1 ratio (229 with complications versus 229 without). Patients with complications had significantly longer median length of stay (9 days [IQR 7-15] versus 6 days [IQR 5-8], p < 0.0001), higher 90-day mortality rates as well as inferior OS (p = 0.0139), but there was no difference in RFS (p = 0.4577). Age (p = 0.0006), elevated Child Pugh points (p < 0.0001), microvascular invasion (p = 0.0002), multifocal tumours (p = 0.0002), R1 resection (p = 0.0443) and development of complications (p = 0.0091) were independent predictors of inferior OS., Conclusion: Post-operative morbidity affected both short-term and OS outcomes after hepatectomy for HCC. Hepatitis B, higher ASA scores, elevated preoperative APRI and increased blood loss were found to predict a higher likelihood of developing complications. This may potentially be mitigated by careful patient selection and adopting strict measures to minimise intraoperative bleeding., Competing Interests: Declaration of competing interest The authors confirm that this manuscript has not been published elsewhere previously, and has not been submitted for publication elsewhere.Dr Goh BK has received travel grants and honorarium from Transmedic the local distributor of the Da Vinci robotic platform, Johnson and Johnson, Medtronic and Baxter. The authors have no other conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Backgrounds/aims: This study aims to describe our experience with minimally-invasive distal pancreatectomies, with emphasis on the comparison between robotic distal pancreatectomy (RDP) and laparoscopic distal pancreatectomy (LDP)., Methods: Retrospective review of 102 consecutive RDP and LDP from 2006 to 2019 was performed., Results: There were 27 and 75 patients who underwent RDP and LDP, respectively. There were 12 (11.8%) open conversions and 16 (15.7%) patients had major (＞grade 2) morbidities. Patients who underwent RDP had significantly higher rates of splenic preservation (44.4% vs. 13.3%, p=0.002), higher rates of splenic-vessel preservation (40.7% vs. 9.3%, p=0.001), higher median difficulty score (5 vs. 3, p=0.002) but longer operation time (385 vs. 245 minutes, p＜0.001). The rate of open conversion tended to be lower with RDP (3.7% vs. 14.7%, p=0.175)., Conclusions: In our institution practice, both RDP and LDP were safe and effective. The use of RDP appeared to be complementary to LDP, allowing us to perform more difficult procedures with comparable postoperative outcomes.

Background: An objective algorithm for the management of suspected appendicitis guided by the Alvarado Score had previously been proposed. This algorithm was expected to reduce computed tomography (CT) utilization without compromising the negative appendectomy rate. This study attempts to validate the proposed algorithm in a randomized control trial., Methods: A randomized control trial comparing the management of suspected acute appendicitis using the proposed algorithm compared to current best practice, with the rate of CT utilization as the primary outcome of interest. Secondary outcomes included the percentage of missed diagnosis, negative appendectomies, length of stay in days, and overall cost of stay in dollars., Results: One hundred sixty patients were randomized. Characteristics such as age, ethnic group, American Society of Anesthesiologist score, white cell count, and symptom duration were similar between the two groups. The overall CT utilization rate of the intervention arm and the usual care arm were similar (93.7% vs 92.5%, p = 0.999). There were no differences in terms of negative appendectomy rate, length of stay, and cost of stay between the intervention arm as compared to the usual care arm (p = 0.926, p = 0.705, and p = 0.886, respectively). Among patients evaluated with CT, 75% (112 out of 149) revealed diagnoses for the presenting symptoms., Conclusion: The proposed AS-based management algorithm did not reduce the CT utilization rate. Outcomes such as missed diagnoses, negative appendectomy rates, length of stay, and cost of stay were also largely similar. CT utilization was prevalent as 93% of the study cohort was evaluated by CT scan., Trial Registration: The study has been registered at ClinicalTrials.gov (NCT03324165, Registered October 27 2017).

Background: The evidence is conflicting regarding the effect of delays from the time of diagnosis to surgery on the survival in patients with hepatocellular carcinoma. We sought to investigate the impact of time to surgery on overall survival for patients who underwent curative resection for primary hepatocellular carcinoma., Methods: We performed a retrospective review of all patients who underwent liver resection for primary hepatocellular carcinoma between the years 2000 and 2015. Using 30-, 60-, and 90-day cutoffs, we investigated the effect of time to surgery on survival outcomes by dichotomizing the patients and using inverse probability of treatment weighting to ensure comparability. We also investigated time to surgery in prognostic subgroups by modeling the statistical interaction between time to surgery and the relevant prognostic variable in multivariable Cox models., Results: A total of 863 patients underwent liver resection for primary hepatocellular carcinoma during the study period. Using 30-, 60-, and 90-day cutoffs, time to surgery did not have a significant bearing on overall survival. For elderly patients (>70 years), patients with Child-Pugh B liver disease, American Society of Anesthesiologists status 2/3, tumor size >5cm, tumor size ≥10cm and presence of extrahepatic invasion, hazard ratio decreased and overall survival improved as time to surgery increased. However, for patients with liver cirrhosis or portal hypertension, increasing time to surgery was found to portend higher risks of death., Conclusion: Time to surgery does not have a significant bearing on overall survival, and modest delays even appear to be associated with improved survival in specific subsets of patients. The importance of these findings is that patients with hepatocellular carcinoma should be fully optimized before and not rushed to surgery because of concerns of tumor progression and a diminished survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC., (©2019 American Association for Cancer Research.)

Background: Repeat liver resection (RLR) for recurrent HCC (rHCC) is a widely accepted treatment modality. However, early recurrence rate is high, frequently resulting in futile resection. We performed this study to evaluate preoperative factors, including the value of inflammatory indices, in predicting early (<1 year) recurrence in patients who underwent RLR for rHCC. This may help clinicians better select patients for RLR, while excluding cases in which RLR for rHCC would likely be futile., Methods: This is a retrospective study of 80 patients where 90 operative cases of RLR and 84 cases of early recurrence (<1 year) post-RLR were evaluated. Preoperative predictors of early recurrence and overall survival (OS) were assessed., Results: There were 31 (34.4%) early recurrences with a 5-year OS of 38.9%. Elevated platelet-to-lymphocyte ratio (PLR) >103.6 was a significant independent preoperative predictor of both early recurrence, relative risk (RR) 4.284 (P = 0.001) and OS, RR 2.139 (P = 0.027), while alphafetoprotein (AFP) ≥ 200 was a significant independent preoperative predictor of early recurrence only, RR 11.655 (P = 0.030). Patients were followed-up at a median of 14.3 months with 54.8% developing intrahepatic recurrences and 19.4% developing extrahepatic recurrences., Conclusion: Both, elevated PLR and AFP ≥ 200 were independent predictors of early (<1 year) recurrence after RLR for rHCC, while only an elevated PLR was an independent preoperative prognosticators of overall survival. Indication for RLR should be carefully discussed in patients with relapsed HCC with an elevated PLR, due to the potential of early recurrence and poor overall survival.

Introduction: Spontaneous rupture of HCC (srHCC) is a life-threatening sequela of HCC characterized by a high mortality. Liver resection (LR) is the ideal therapeutic strategy as it not only arrests hemorrhage but also remove the offending tumour. We sought to determine the impact of spontaneous rupture on the survival outcomes of patients after LR by performing a propensity score matched (PSM) analysis comparing patients who underwent LR for srHCC versus non-ruptured (nrHCC)., Methods: From 2000 to 2015, a total of 67 patients who underwent LR for srHCC which met the study criteria were included. 1:2 PSM was performed comparing 49 of 67 patients with srHCC with 98 nrHCC selected from a cohort of 724 patients who underwent LR during the study period., Results: Median survival following LR for srHCC was 21.9 months, while 5-year overall survival (OS) and disease-free survival (DFS) was 43.1% and 19.4% respectively. After 1:2 PSM analysis, there was no significant difference between LR for srHCC (n = 49) versus nrHCC (n-98) in terms of OS [21.9 (interquartile range (IQR), 11.8-44.0 vs 27.4 (IQR, 6.9-57.8) months, HR 1.02, CI 0.63-1.66, p = 0.94], DFS [11.8 (IQR, 5.6-25.6) vs 13.77 (IQR,4.5-34.9) HR 0.74, CI 0.54-1.02, p = 0.06] and length of stay [8 (IQR, 7-11) vs 7 (IQR, 6-10) HR 0.93, CI 0.0.68-1.29), p = 0.68]., Conclusion: LR for clinically stable patients with srHCC provides survival and recurrence outcomes that are comparable to patients with nrHCC., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Hepatocellular carcinoma is the second most deadly cancer with late presentation and limited treatment options, highlighting an urgent need to better understand HCC to facilitate the identification of early-stage biomarkers and uncover therapeutic targets for the development of novel therapies for HCC., Methods: Deep transcriptome sequencing of tumor and paired non-tumor liver tissues was performed to comprehensively evaluate the profiles of both the host and HBV transcripts in HCC patients. Differential gene expression patterns and the dys-regulated genes associated with clinical outcomes were analyzed. Somatic mutations were identified from the sequencing data and the deleterious mutations were predicted. Lastly, human-HBV chimeric transcripts were identified, and their distribution, potential function and expression association were analyzed., Results: Expression profiling identified the significantly upregulated TP73 as a nodal molecule modulating expression of apoptotic genes. Approximately 2.5% of dysregulated genes significantly correlated with HCC clinical characteristics. Of the 110 identified genes, those involved in post-translational modification, cell division and/or transcriptional regulation were upregulated, while those involved in redox reactions were downregulated in tumors of patients with poor prognosis. Mutation signature analysis identified that somatic mutations in HCC tumors were mainly non-synonymous, frequently affecting genes in the micro-environment and cancer pathways. Recurrent mutations occur mainly in ribosomal genes. The most frequently mutated genes were generally associated with a poorer clinical prognosis. Lastly, transcriptome sequencing suggest that HBV replication in the tumors of HCC patients is rare. HBV-human fusion transcripts are a common observation, with favored HBV and host insertion sites being the HBx C-terminus and gene introns (in tumors) and introns/intergenic-regions (in non-tumors), respectively. HBV-fused genes in tumors were mainly involved in RNA binding while those in non-tumors tissues varied widely. These observations suggest that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts may occur during tumorigenesis., Conclusions: Transcriptome sequencing of HCC patients reveals key cancer molecules and clinically relevant pathways deregulated/mutated in HCC patients and suggests that while HBV may integrate randomly during chronic infection, selective expression of functional chimeric transcripts likely occur during the process of tumorigenesis.

Backgrounds/aims: Solid pseudopapillary neoplasm (SPPN) is typically seen in young healthy females who would likely benefit from minimally-invasive pancreatectomy (MIP). A few comparative studies have suggested that MIP is associated with favorable outcomes when compared to the open approach for SPPN. This study aims to mitigate potential selection bias by performing a matched case-control study comparing MIP vs open pancreatectomy (OP) for SPPN., Methods: We performed a single-institution retrospective electronic chart review of all patients who underwent surgery for pathologically confirmed SPPN between 2000 and 2017. A 2:1 matched comparison using age, gender, tumor size and the type of pancreatectomy was performed between OP and MIP., Results: A total of 40 patients with a median age of 40.3 years (range 16.5-64.4) and female sex predominance (n=34, 85.0%) underwent surgery during the study period. Nine patients underwent MIP. Matched comparison between 18 OP and 9 MIP demonstrated that MIP was associated with a longer median operating time (305 vs 180 min, p =0.046) and shorter median postoperative stay (6 vs 9 days, p =0.015). There were no significant differences in intraoperative blood loss, blood transfusion requirements, postoperative morbidity (including postoperative pancreatic fistula) and mortality, resection margins, lymph node yield and long-term survival., Conclusions: MIP is a safe and viable option in the management of SPPN with the benefit of a shorter postoperative length of stay at the expense of a longer operation time. There was no significant difference in oncologic outcomes between both groups of patients.

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non-structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression in vitro . Small homologous RNA-mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death in vitro . HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors in vivo . Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.-Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence., (© 2019 UICC.)

The goal of the present study was to empirically examine different conceptual mechanisms previously postulated to underlie the development of social avoidance in childhood. Participants were N = 601 children (321 boys, 280 girls) attending elementary schools (M age  = 10.21 years) and middle schools (M age  = 12.77 years) in Shanghai, P.R. China. Measures of motivations for social withdrawal (shyness, unsociability, social avoidance) and socio-emotional adjustment were collected using self-reports and peer nominations at two time-points separated by 9 months. Results from cross-lagged panel analyses indicated that: (1) social avoidance and symptoms of social anxiety were not reciprocally related over time; (2) Time 1 social avoidance predicted incremental change in Time 2 peer problems (whereas Time 1 peer problems did not predict incremental change in Time 2 social avoidance); and (3) Time 1 symptoms of depression significantly predicted incremental change in Time 2 social avoidance (whereas Time 1 social avoidance did not predict incremental change in Time 2 symptoms of depression). These results provide evidence in support of depressive symptoms (but not symptoms of social anxiety or peer problems) as a salient predictor of social avoidance. Results are discussed in terms of the development and implications of social avoidance in Chinese culture.

Background and Objectives: Spontaneous rupture of Hepatocellular Carcinoma (srHCC) is a life-threatening emergency. We sought to identify the pre-operative predictors of early tumor recurrence/mortality including the role of inflammatory indices after partial hepatectomy for srHCC., Methods: Between 2000-2015, 79 patients with srHCC were identified to have undergone upfront partial hepatectomy following srHCC. Clinicopathologic data were retrospectively analyzed to identify pre-operative predictors of early (<1 year) recurrence and mortality., Results: Seventy-nine patients were identified to have undergone partial hepatectomy for srHCC. The 1-year mortality and 1-year recurrence rate in our series was 30.3% and 41.8% respectively. On multivariate analyses, free tumor rupture and a tumor size > 10 cm were identified to be independent predictors of early recurrence while an alpha fetoprotein (AFP) > 200 ng/mL was an independent predictor of early mortality. Neutrophil-to-lymphocyte ratio > 3 and prognostic nutritional index < 40 were predictors of early recurrence while PLR > 180 was a predictor of early mortality on univariate analyses but not multivariate analyses., Conclusions: Tumor size > 10 cm, free tumor rupture, and an AFP > 200 ng/mL were useful predictors in avoiding "futile surgery" in patients with srHCC undergoing a partial hepatectomy. Preoperative inflammatory markers appear to be less useful as predictors of early recurrence/mortality in this cohort of patients., (© 2018 Wiley Periodicals, Inc.)

Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9 N-terminal, especially T172. Interestingly, T172 phosphorylation was correlated with cancer patient prognosis and enriched in tumours. Thus, our results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth., (© 2018 The Authors.)

The purpose of this study was to provide additional psychometric support for the Preference for Solitary Play Interview (PSPI) and to examine the associations between self-reported preference for solitary play and indices of adjustment in early childhood. Participants were N = 340 children attending kindergarten and grade 1. Children completed the PSPI, and teachers provided assessments of children's socio-emotional and school adjustment. In support of the validity of the PSPI, preference for solitary play was positively associated with asocial behaviours. Further, preference for solitary play displayed an indirect (but not direct) association with peer exclusion via asocial behaviours. Findings are discussed in terms of the social and behavioural implications of preference for solitary play in early childhood. Statement of contribution What is already known on this subject? Children who spend more time alone are at increased risk of adjustment difficulties. However, some individuals desire to spend time alone because of an appreciation for solitude. A preference for solitude is not associated with negative adjustment in adults and older youth. What does this study add? This study is among the first to examine self-reported preference for solitary in early childhood. Preference for solitude may not be related to emotional or school difficulties in young children. However, a heightened display of solitary behaviours may still evoke negative responses from peers., (© 2018 The British Psychological Society.)

Backgrounds/aims: To determine the prevalence of post-hepatectomy liver failure/insufficiency (PHLF/I) in patients undergoing extensive hepatic resections for hepatocellular carcinoma (HCC) and to assess the predictive value of preoperative factors for post-hepatectomy liver failure or insufficiency (PHLF/I)., Methods: A retrospective review of patients who underwent liver resections for HCC between 2001 and 2013 was conducted. Preoperative parameters were assessed and analyzed for their predictive value of PHLF/I. Definitions used included the 50-50, International Study Group of Liver Surgery (ISGLS) and Memorial Sloan Kettering Cancer Centre (MSKCC) criteria., Results: Among the 848 patients who underwent liver resections for HCC between 2001 and 2013, 157 underwent right hepatectomy (RH) and extended right hepatectomy (ERH). The prevalence of PHLF/I was 7%, 41% and 28% based on the 50-50, ISGLS and MSKCC criteria, respectively. There were no significant differences in PHLF/I between RH and ERH. Model for End-Stage Liver Disease (MELD) score and bilirubin were the strongest independent predictors of PHLF/I based on the 50-50 and ISGLS/MSKCC criteria, respectively. Predictive models were developed for each of the criteria with multiple logistic regression., Conclusions: MELD score, bilirubin, alpha-fetoprotein and platelet count showed significant predictive value for PHLF/I (all p <0.05). A composite score based on these factors serves as guideline for physicians to better select patients undergoing extensive resections to minimize PHLF.

Backgrounds/aims: Hilar cholangiocarcinomas (HCCAs) are tumors that involve the biliary confluence; at present, radical surgery offers the only chance of long-term survival, but this can be challenging given the complexity of the hilar anatomy. Blumgart and Jarnagin described a preoperative staging system that incorporates the effect of local tumor extent and its impact on adjacent structures and that has been demonstrated to correlate better with actual surgical resectability. The primary aim of this study is to describe the correlation between preoperative Blumgart-Jarnagin staging and its correlation with surgical resectability., Methods: Patients who underwent surgical resection for hilar cholangiocarcinoma at Singapore General Hospital between January 1, 2002, and January 1, 2013, were identified from a prospectively maintained institutional database. All patients were staged based on the criteria described by Blumgart and Jarnagin. Correlation with surgical resectability was then determined., Results: A total of 19 patients were identified. Overall resectability was 57.8% (n=11). Patients with Blumgart-Jarnagin stage T1 had the highest rates of resectability at 80%; patients with stage T2 and T3 disease had resectability rates of 25% and 40% respectively. Median overall survival was 13.6 months., Conclusions: The Blumgart-Jarnagin staging system is useful for predicting tumor resectability in HCCA.

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro . Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4 high GADD45B low was significantly poorer compared to patients with ACSL4 low GADD45B high , thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4 high GADD45B low . In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4 high GADD45B low expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits., Competing Interests: The authors declare no conflict of interest.

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.

This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U-test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh -1 m -2 ): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g.-1679TA, AUC 0-∞ /dose/BSA (hm -5 ): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition.

AT rich interactive domain 1A (ARID1A) is one of the most commonly mutated genes in a broad variety of tumors. The mechanisms that involve ARID1A in ampullary cancer progression remains elusive. Here, we evaluated the frequency of ARID1A and KRAS mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania, correlated with clinical and pathological tumor features, and assessed the functional role of ARID1A . In the ampullary adenocarcinomas, the frequency of KRAS and ARID1A mutations was 34.7% and 8.2% respectively, with a loss or reduction of ARID1A protein in 17.2% of the cases. ARID1A mutational status was significantly correlated with ARID1A protein expression level (P=0.023). There was a significant difference in frequency of ARID1A mutation between Romania and Singapore (2.7% versus 25%, P=0.04), suggestive of different etiologies. One somatic mutation was detected in the ampullary adenoma group. In vitro studies indicated the tumor suppressive role of ARID1A . Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease, as well as identification of therapeutic targets in ARID1A mutated ampullary cancers.

Background: This study aims to compare the early perioperative outcomes of robotic-assisted laparoscopic distal pancreatectomy (RDP) versus laparoscopic distal pancreatectomy (LDP)., Methods: The clinicopathologic features of 45 consecutive patients who underwent minimally-invasive distal pancreatectomy from 2006 to 2015 were retrospectively reviewed., Results: Thirty-nine patients who met our study criteria were included. Eight patients underwent RDP and 31 had LDP. There were 10 (25.6%) open conversions. Six (15.4%) patients had major (> grade 2) morbidities and there was no in-hospital mortality. There were 14 (35.9%) grade A and 9 (23.1%) grade B pancreatic fistulas. Comparison between RDP and LDP demonstrated no significant difference between the patients' baseline characteristics except there was increased frequency of spleen-preserving pancreatectomies (3 (37.5%) vs 25 (80.6%), P=0.016) and splenic-vessel preservation (5 (62.5%) vs 4 (12.9%), P=0.003) in RDP. Comparison between outcomes demonstrated that RDP was associated with a longer median operation time (452.5 (range, 300-685) vs 245 min (range, 85-430), P=0.001) and increased frequency of the procedure completed purely laparoscopically (8 (100%) vs 18 (58.1%), P=0.025)., Conclusions: RDP can be safely adopted and is equivalent to LDP in most perioperative outcomes. It is also associated with a decreased frequency of the need for hand-assistance laparoscopic surgery or open conversion but needed a longer operation time. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The goal of this study was to explore associations among maternal agreeableness, child temperament (i.e., emotion dysregulation), and children's social adjustment at school. Participants were 146 children in kindergarten and Grade 1 (76 girls; M age = 67.78 months, SD = 10.81 months). Mothers provided ratings of their own agreeableness and their child's temperament, and teachers assessed indices of children's socioemotional functioning at school. Among the results, maternal agreeableness moderated associations between child dysregulation and aspects of adjustment at school. Specifically, at higher levels of maternal agreeableness, the relations between child dysregulation and both anxiety with peers and their prosocial behavior were attenuated. Overall, the results suggest that maternal agreeableness may serve as a protective factor for dysregulated children. Implications for research and practice are discussed.

Objective: The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis., Design: Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study., Results: Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells., Conclusions: The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival. Silencing MELK inhibited cell growth, invasion, stemness and tumorigenicity of HCC cells by inducing apoptosis and mitosis. We further showed that the overexpression of MELK in HCC samples strongly correlated with the cell cycle- and mitosis-related genes which are directly regulated as part of the forkhead transcription factor FoxM1-related cell division program. Together, our data establish MELK as an oncogenic kinase involved in the pathogenesis and recurrence of HCC and could provide a promising molecular target to develop therapeutic strategies for patients with advanced HCC., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients., Objectives: We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers., Designs: Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined., Results: High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10 -5 ). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10 -5 )., Conclusions: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence., Design: PRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1., Results: PRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling., Conclusions: We identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)