Publications by authors named "Pierce Chow"

254 Publications

Catheter-Directed Computed Tomography Hepatic Angiography for Yttrium-90 Selective Internal Radiotherapy of Hepatocellular Carcinoma Reduces Prophylactic Embolization of Extrahepatic Vessels.

Cardiovasc Intervent Radiol 2020 Mar 8;43(3):478-487. Epub 2019 Nov 8.

Office of Academic and Clinical Development, Duke-NUS Medical School, Singapore, Singapore.

Objectives: To determine the rate of prophylactic embolization of extrahepatic vessels in patients undergoing yttrium-90 selective internal radiotherapy (Y SIRT) for hepatocellular carcinoma (HCC) with the use of catheter-directed computed tomography hepatic angiography (CD-CTHA).

Materials And Methods: This retrospective study included 186 HCC patients who received Y SIRT from May 2010 to June 2015 in a single institution. All procedures were performed in a hybrid angiography-CT suite equipped with digital subtraction angiography (DSA) and CD-CTHA capabilities. CD-CTHA was performed during pre-treatment hepatic angiography. Y SIRT was administered approximately 2 weeks later. Selective prophylactic embolization of extrahepatic vessels was performed if extrahepatic enhancement was seen on CD-CTHA or if an extrahepatic vessel opacified on DSA/CD-CTHA despite the final microcatheter position for Y microsphere delivery being beyond the origin of this vessel.

Results: Thirty-five patients (18.8%) required selective embolization of extrahepatic vessels. Technical success of Y SIRT was 99.5%. Two patients (1.1%) developed radiation-induced gastrointestinal ulceration, and one (0.54%) developed radiation-induced pneumonitis. Extrahepatic uptake of Y microspheres was seen in the gallbladder of one patient without significant complications.

Conclusion: The use of CD-CTHA in Y SIRT of HCC was associated with a low rate of prophylactic embolization of extrahepatic vessels while maintaining a high technical success rate of treatment and low rate of complications.

Level Of Evidence: Level 4, case series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00270-019-02362-yDOI Listing
March 2020

Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma: Inverse probability of treatment weighting using propensity scores and propensity score adjustment.

Surgery 2020 02 31;167(2):417-424. Epub 2019 Oct 31.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital; Duke NUS Medical School, Singapore. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2019.09.022DOI Listing
February 2020

Changing trends and outcomes associated with the adoption of minimally invasive pancreatic surgeries: A single institution experience with 150 consecutive procedures in Southeast Asia.

J Minim Access Surg 2020 Oct-Dec;16(4):404-410

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Academia, Singapore.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/jmas.JMAS_127_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597893PMC
October 2019

Critical Appraisal of the Impact of the Systematic Adoption of Advanced Minimally Invasive Hepatobiliary and Pancreatic Surgery on the Surgical Management of Mirizzi Syndrome.

World J Surg 2019 12;43(12):3138-3152

Department of Hepatopancreatobiliary and Transplantation Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore.

Background: Minimally invasive surgery (MIS) for Mirizzi syndrome (MS) remains a technically challenging procedure with a high open conversion rate. We critically evaluated the impact of the systematic adoption of MI-HBP surgery on the surgical outcomes of MS.

Methods: Ninety-five patients who underwent surgery for MS were retrospectively reviewed. Systematic adoption of advanced MI-HBP surgery started in 2012. The cohort was classified into a preadoption (2002-2012) (Era 1, n = 58) and post-adoption (2013-2017) (Era 2, n = 37). Furthermore, Era 2 was divided into a cohort operated by advanced minimally invasive surgeons (AMIS) (Era 2 AMIS, n = 19) and those by other surgeons (Era 2 others, n = 19).

Results: Comparison between Era 2 and Era 1 demonstrated a significant increase in the frequency of MIS attempted (89% vs 33%, p < 0.01), increase in the use of choledochoplasty (24% vs 2%, p < 0.01), increase operation time (180 min vs 150 min, p = 0.03) and significantly lower open conversion rate (24% vs 58%, p < 0.01). Comparison between Era 2 AMIS and Era 2 others demonstrated a significantly greater adoption of MIS (100% vs 78%, p = 0.046) with lower open conversion rate (5% vs 50%, p = 0.005). Comparison between all attempted MIS cases with open procedures demonstrated a significantly higher proportion of subtotal cholecystectomies performed (40% vs 23%, p = 0.04), choledochoplasty (17% vs 2%, p = 0.04) and shorter hospital stay (4 days vs 9 days, p < 0.01).

Conclusions: Systematic adoption of advanced MI-HBP surgery allowed surgeons to perform MIS for MS more frequently and with a significantly lower open conversion rate. Patients who underwent successful MIS had the shortest hospital stay compared to patients who underwent open surgery or required open conversion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-019-05164-yDOI Listing
December 2019

Outcome of minimally-invasive versus open pancreatectomies for solid pseudopapillary neoplasms of the pancreas: A 2:1 matched case-control study.

Ann Hepatobiliary Pancreat Surg 2019 Aug 30;23(3):252-257. Epub 2019 Aug 30.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

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, =0.046) and shorter median postoperative stay (6 vs 9 days, =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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14701/ahbps.2019.23.3.252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728256PMC
August 2019

Lgr5 pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis.

Proc Natl Acad Sci U S A 2019 09 5;116(39):19530-19540. Epub 2019 Sep 5.

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 169857 Singapore;

Emerging evidence suggests that hepatocytes are primarily maintained by self-renewal during normal liver homeostasis, as well as in response to a wide variety of hepatic injuries. However, how hepatocytes in distinct anatomic locations within the liver lobule are replenished under homeostasis and injury-induced regeneration remains elusive. Using a newly developed bacterial artificial chromosome (BAC)-transgenic mouse model, we demonstrate that expression in the liver is restricted to a unique subset of hepatocytes most adjacent to the central veins. Genetic lineage tracing revealed that pericentral Lgr5 hepatocytes have a long lifespan and mainly contribute to their own lineage maintenance during postnatal liver development and homeostasis. Remarkably, these hepatocytes also fuel the regeneration of their own lineage during the massive and rapid regeneration process following two-thirds partial hepatectomy. Moreover, Lgr5 hepatocytes are found to be the main cellular origin of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) and are highly susceptible to neoplastic transformation triggered by activation of Erbb pathway. Our findings establish an unexpected self-maintaining mode for a defined subset of hepatocytes during liver homeostasis and regeneration, and identify Lgr5 pericentral hepatocytes as major cells of origin in HCC development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1908099116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765306PMC
September 2019

Comprehensive analysis of transcriptome profiles in hepatocellular carcinoma.

J Transl Med 2019 08 20;17(1):273. Epub 2019 Aug 20.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-019-2025-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701074PMC
August 2019

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Sci Rep 2019 07 18;9(1):10464. Epub 2019 Jul 18.

Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3 cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-46872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639394PMC
July 2019

Preoperative Predictors Including the Role of Inflammatory Indices in Predicting Early Recurrence After Re-resection for Recurrent Hepatocellular Carcinoma.

World J Surg 2019 10;43(10):2587-2594

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Singapore, 169608, Singapore.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-019-05051-6DOI Listing
October 2019

Persistent changes in liver methylation and microbiome composition following reversal of diet-induced non-alcoholic-fatty liver disease.

Cell Mol Life Sci 2019 Nov 22;76(21):4341-4354. Epub 2019 May 22.

Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Singapore.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic liver disease that is thought to be reversible by changing the diet. To examine the impact of dietary changes on progression and cure of NAFLD, we fed mice a high-fat diet (HFD) or high-fructose diet (HFrD) for 9 weeks, followed by an additional 9 weeks, where mice were given normal chow diet. As predicted, the diet-induced NAFLD elicited changes in glucose tolerance, serum cholesterol, and triglyceride levels in both diet groups. Moreover, the diet-induced NAFLD phenotype was reversed, as measured by the recovery of glucose intolerance and high cholesterol levels when mice were given normal chow diet. However, surprisingly, the elevated serum triglyceride levels persisted. Metagenomic analysis revealed dietary-induced changes of microbiome composition, some of which remained altered even after reversing the diet to normal chow, as illustrated by species of the Odoribacter genus. Genome-wide DNA methylation analysis revealed a "priming effect" through changes in DNA methylation in key liver genes. For example, the lipid-regulating gene Apoa4 remained hypomethylated in both groups even after introduction to normal chow diet. Our results support that dietary change, in part, reverses the NAFLD phenotype. However, some diet-induced effects remain, such as changes in microbiome composition, elevated serum triglyceride levels, and hypomethylation of key liver genes. While the results are correlative in nature, it is tempting to speculate that the dietary-induced changes in microbiome composition may in part contribute to the persistent epigenetic modifications in the liver.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-019-03114-4DOI Listing
November 2019

Impact of spontaneous rupture on the survival outcomes after liver resection for hepatocellular carcinoma: A propensity matched analysis comparing ruptured versus non-ruptured tumors.

Eur J Surg Oncol 2019 Sep 9;45(9):1652-1659. Epub 2019 Apr 9.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-National University of Singapore (NUS) Medical School, Singapore. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejso.2019.03.044DOI Listing
September 2019

External validation of the Japanese difficulty scoring system for minimally-invasive distal pancreatectomies.

Am J Surg 2019 11 15;218(5):967-971. Epub 2019 Mar 15.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Level 5 Academia, 169856, Singapore; Duke NUS Medical School, Singapore.

Introduction: Preoperative prediction of the difficulty of surgery would be useful for surgeons embarking on MIDP. A novel difficulty scoring system(DSS) was recently developed in Japan but has not been externally validated. This study aims to externally validate the DSS determine its association with important clinical outcome parameters.

Methods: Retrospective review of 90 patients who underwent MIDP from 2006 to 2018. The patients were stratified into 3 groups (low, intermediate and high difficulty) according to the DSS with some minor modifications.

Results: Difficulty of MIDP was classified as low in 45(50%), intermediate in 32(35.5%) and high in 13(14.4%). Comparison between the baseline characteristics across the 3 difficulty groups demonstrated a significant difference in the frequency of malignant tumors, larger tumor size, frequency of extended pancreatectomies and use of robotic assistance. There was statistically significant increase in operation time, blood loss and blood transfusion rate across the 3 groups from low to high difficulty.

Conclusion: The DSS correlated significantly with operation time, blood loss and blood transfusion rate. These findings support the validity of the system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjsurg.2019.03.012DOI Listing
November 2019

Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma.

Hepatology 2019 03;69(3):943-958

Department of General Surgery, Singapore General Hospital, Singapore.

The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635738PMC
March 2019

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue.

J Pharm Sci 2019 05 12;108(5):1736-1745. Epub 2018 Dec 12.

Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore. Electronic address:

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2018.12.002DOI Listing
May 2019

Laparoscopic Liver Resection Difficulty Score-a Validation Study.

J Gastrointest Surg 2019 03 12;23(3):545-555. Epub 2018 Nov 12.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Singapore, 169856, Singapore.

Objective(s): The technical complexity of laparoscopic liver resection (LLR) poses unique challenges distinct from open surgery. An objective scoring system was developed that preoperatively quantifies the difficulty of LRR to help guide surgeon decision-making regarding the feasibility and safety of minimally invasive approaches. The aim of this multiinstitutional study was to externally validate this scoring system.

Methods: Patients who underwent LLR at two institutions were reviewed. LLR difficulty score (LDS) was calculated based on patient, tumor, and anatomic characteristics by two independent, blinded hepatobiliary surgeons. Surrogates of case complexity (e.g., conversion rate, operative time) were used for validation of this index.

Results: From 2006 to 2016, 444 LLR were scored as low (n = 94), intermediate (n = 98), and high difficulty (n = 152) with respective conversion rates of 5.3%, 15.7%, and 25%. Cases of higher LDS correlated with larger mean blood loss (203 ml vs. 331 ml vs. 635 ml). Mean operative and Pringle maneuver used were associated with increasing LDS (155 min vs. 202 min vs. 315 min and 14.4% vs. 29.7% vs. 45.1% respectively). These operative surrogates of difficulty correlated significantly with the LDS (all p < 0.0001).

Conclusions: This comprehensive external validation of the LDS is robust and applicable in diverse patient populations. This LDS serves as a useful objective predictor of technical difficulty for LLR to help surgeons in selecting patients according to their individual operative experience and is valuable for preoperative risk estimation and stratification in randomized trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11605-018-4036-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545446PMC
March 2019

Pre-operative predictors of early recurrence/mortality including the role of inflammatory indices in patients undergoing partial hepatectomy for spontaneously ruptured hepatocellular carcinoma.

J Surg Oncol 2018 Dec 6;118(8):1227-1236. Epub 2018 Nov 6.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25281DOI Listing
December 2018

Perioperative Outcomes of Laparoscopic Repeat Liver Resection for Recurrent HCC: Comparison with Open Repeat Liver Resection for Recurrent HCC and Laparoscopic Resection for Primary HCC.

World J Surg 2019 Mar;43(3):878-885

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore.

Background: This study aims to determine the safety and efficacy of laparoscopic repeat liver resection (LRLR) for recurrent hepatocellular carcinoma (rHCC).

Methods: Twenty patients underwent LRLR for rHCC between 2015 and 2017. The control groups consisted of 79 open RLR (ORLR) for rHCC and 185 LLR for primary HCC. We undertook propensity score-adjusted analyses (PSA) and 1:1 propensity score matching (PSM) for the comparison of LRLR versus ORLR. Comparison of LRLR versus LLR was done using multivariable regression models with adjustment for clinically relevant covariates.

Results: Twenty patients underwent LRLR with three open conversions (15%). Both PSA and 1:1-PSM demonstrated that LRLR was significantly associated with a shorter stay, superior disease-free survival (DFS) but longer operation time compared to ORLR. Comparison between LRLR versus LLR demonstrated that patients undergoing LRLR were significantly older, had smaller tumors, longer operation time and decreased frequency of Pringle's maneuver applied. There was no difference in other key perioperative outcomes.

Conclusion: The results of this study demonstrate that in highly selected patients; LRLR for rHCC is feasible and safe. LRLR was associated with a shorter hospitalization but longer operation time compared to ORLR. Moreover, other than a longer operation time, LRLR was associated with similar perioperative outcomes compared to LLR for primary HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-018-4828-yDOI Listing
March 2019

Perioperative Outcomes of Laparoscopic Minor Hepatectomy for Hepatocellular Carcinoma in the Elderly.

World J Surg 2018 12;42(12):4063-4069

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore.

Introduction: This study aims to evaluate the safety and feasibility of laparoscopic minor hepatectomy (LMH) in elderly patients with hepatocellular carcinoma (HCC).

Methods: A total of 40 consecutive elderly (≥ 70 years) patients were compared with 94 young patients (< 70 years). The 40 patients were also compared with 85 consecutive elderly patients who underwent open minor hepatectomies (OMH). After 1:1 propensity-score matching (PSM), 32 LMHs were compared with 32 OMHs in elderly patients.

Results: Comparison between the baseline characteristics of elderly and young HCC patients showed that elderly patients were significantly more likely to have comorbidities, ASA score > 2, non-hepatitis B, previous liver resection and larger tumor size. Comparison between perioperative outcomes demonstrated that elderly patients were significantly more likely to have a longer operation time, increased blood loss, increased need for blood transfusion, longer Pringles duration and longer postoperative stay. Comparison between LMH and OMH in elderly patients demonstrated no significant difference in baseline characteristics except the LMH cohort were significantly more likely to have > 1 comorbidity, higher platelet count and lower median AFP level. Comparison between outcomes before and after PSM demonstrated that LMH was associated with longer operation time, increased blood loss, longer Pringles duration but decreased postoperative pulmonary complications and shorter postoperative stay compared to OMH.

Conclusion: LMH is safe and feasible in elderly patients with HCC. However, LMH in elderly patients is associated with poorer perioperative outcomes compared to LMH in young patients. Comparison between LMH and OMH in elderly patients demonstrated advantages in terms of decreased pulmonary complications and shorter length of stay at the expense of increased operation time and blood loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-018-4741-4DOI Listing
December 2018

Controlling injectability and in vivo stability of thermogelling copolymers for delivery of yttrium-90 through intra-tumoral injection for potential brachytherapy.

Biomaterials 2018 10 17;180:163-172. Epub 2018 Jul 17.

Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, 7 Engineering Drive 1, Singapore, 117574, Singapore. Electronic address:

Intra-tumoral injection of radiopharmaceuticals such as yttrium-90 (Y) or phosphorus-32 (P) is an important route for brachytherapy in unresectable solid tumors such as locally advanced hepatocellular carcinoma. However, the injected radiopharmaceuticals can potentially leak out from the tumor site due to high intra-tumoral pressure. In this study, we demonstrated the use of thermogelling copolymers that can be injected into tumor and subsequently solidify as hydrogels within the tumor that can potentially overcome the above problem. To this end, a series of thermogelling polyurethane copolymers with varying compositions were designed and synthesized from Pluronic F127, poly(3-hydroxylbutyrate), and poly(propylene glycol), which were characterized in terms of their molecular structures, compositions, phase diagrams, rheological properties, and injectability and body temperature stability in vitro and in vivo. The analyses of our data elucidated the injectability of the copolymer solutions at low temperatures, and the stability of the hydrogels at the body temperature. This provided the basis on which we could identify one copolymer with balanced composition as the most suitable candidate for intra-tumoral injection and for prevention of the leakage. Finally, the injectability and in vivo stability of the copolymer solution and hydrogel loaded with Y were further demonstrated in a mouse tumor model, and the in vivo biodistribution of Y showed that the radionuclide could be retained at the tumor site, indicating that the Y-loaded copolymer has a great potential for tumor radio-brachytherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2018.07.023DOI Listing
October 2018

Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.

Gut 2019 05 3;68(5):916-927. Epub 2018 Jul 3.

Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore.

Background And Aims: Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics.

Methods: We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays.

Results: In-depth interrogation of the immune landscapes showed that regulatory T cells (T) and CD8 resident memory T cells (T) were enriched in HBV-related HCC, whereas Tim-3CD8 T cells and CD244 natural killer cells were enriched in non-viral-related HCC. NGS of isolated T and T from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. T and T from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1 T could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that T and T contributed to overall patient survival: T were associated with a poor prognosis and T were associated with a good prognosis in HCC.

Conclusion: We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-316510DOI Listing
May 2019

Changing trends and outcomes associated with the adoption of minimally invasive hepatectomy: a contemporary single-institution experience with 400 consecutive resections.

Surg Endosc 2018 11 2;32(11):4658-4665. Epub 2018 Jul 2.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Level 5, 20 College Road, Academia, Singapore, 169856, Singapore.

Background: Several studies published mainly from pioneers and early adopters have documented the evolution of minimally invasive hepatectomy (MIH). However, questions remain if these reported experiences are applicable and reproducible today. This study examines the changing trends, safety, and outcomes associated with the adoption of MIH based on a contemporary single-institution experience.

Methods: This is a retrospective review of 400 consecutive patients who underwent MIH between 2006 and 2017 of which 360 cases (90%) were performed since 2012. To determine the evolution of MIH, the study population was stratified into four equal groups of 100 patients. Analyses were also performed of predictive factors and outcomes of open conversion.

Results: Four hundred patients underwent MIH of which 379 (94.8%) were totally laparoscopic/robotic. Eighty-eight (22.0%) patients underwent major hepatectomy and 160 (40.0%) had resection of tumors located in the posterosuperior segments. There were 38 (9.5%) open conversions. Comparison across the four groups demonstrated that patients were older, had higher ASA score, and had increased frequency of previous abdominal surgery and repeat liver resections. There was also an increase in the proportion of patients who underwent totally laparoscopic/robotic surgery, major liver resection, resection of ≥ 3 segments, and multiple resections. Comparison of outcomes demonstrated that there was a significant decrease in open conversion rate, longer operation time, and increased use of Pringles maneuver. The presence of cirrhosis and institution experience (1st 100 cases) were independent predictors of open conversion. Patients who required open conversion had significantly increased operation time, blood loss, blood transfusion rate, morbidity, and mortality.

Conclusion: The case volume of MIH performed increased rapidly at our institution over time. Although the indications of MIH expanded to include higher risk patients and more complex hepatectomies, there was a decrease in open conversion rate and no change in other perioperative outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00464-018-6310-1DOI Listing
November 2018

The Asia Pacific Consensus Statement on Laparoscopic Liver Resection for Hepatocellular Carcinoma: A Report from the 7th Asia-Pacific Primary Liver Cancer Expert Meeting Held in Hong Kong.

Liver Cancer 2018 Mar 9;7(1):28-39. Epub 2017 Dec 9.

Department of Surgery, Ageo Central General Hospital, Ageo, Japan.

Background: Laparoscopic liver resection has been gaining momentum, and it has become an accepted practice after the two international consensus conferences where experts worked up guidelines to standardize this approach and improve its safety. However, most laparoscopic hepatectomies were performed in patients with liver metastases. The concurrent presence of liver cirrhosis with hepatocellular carcinoma (HCC) poses a great challenge to clinicians trying to establish a routine use of laparoscopic liver resection for HCC.

Summary: The first Asia Pacific consensus meeting on laparoscopic liver resection for HCC was held in July 2016 in Hong Kong. A group of expert liver surgeons with experience in both open and laparoscopic hepatectomy for HCC convened to formulate recommendations on the role and perspective of laparoscopic liver resection for primary liver cancer. The recommendations consolidate the most recent evidence pertaining to laparoscopic hepatectomy together with the latest thinking of practicing clinicians involved in laparoscopic hepatectomy, and give detailed guidance on how to deploy the treatment effectively for patients in need.

Key Message: The panel of experts gathered evidence and produced recommendations providing guidance on the safe practice of laparoscopic hepatectomy for patients with HCC and cirrhosis. The inherent advantage of the laparoscopic approach may result in less blood loss if the procedure is performed in experienced centers. The laparoscopic approach to minor hepatectomy, particularly left lateral sectionectomy, is a preferred practice for HCC at experienced centers. Laparoscopic major liver resection for HCC remains a technically challenging operation, and it should be carried out in centers of excellence. There is emerging evidence that laparoscopic liver resection produces a better oncological outcome for HCC when compared with radiofrequency ablation, particularly when the lesions are peripherally located. Augmented features in laparoscopic liver resection, including indocyanine green fluorescence, 3D laparoscopy, and robot, will become important tools of surgical treatment in the near future. A combination of all of these features will enhance the experience of the surgeons, which may translate into better surgical outcomes. This is the first consensus workforce on laparoscopic liver resection for HCC, which is a unique condition that occurs in the Asia Pacific region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000481834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892359PMC
March 2018

Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy.

Gut 2018 10 30;67(10):1845-1854. Epub 2018 Mar 30.

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.

Objective: As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.

Design: Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD- (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.

Results: Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.

Conclusions: Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2017-315201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145285PMC
October 2018

Initial experience with robotic hepatectomy in Singapore: analysis of 48 resections in 43 consecutive patients.

ANZ J Surg 2019 03 7;89(3):201-205. Epub 2018 Mar 7.

Hepatopancreatobiliary Unit, Department of General Surgery, Changi General Hospital, Singapore.

Background: Presently, the adoption of laparoscopic hepatectomy is rapidly increasingly worldwide. However, the application of robotic hepatectomy (RH) remains limited and its role remains undefined today.

Methods: A retrospective review of 43 consecutive patients who underwent RH at two institutions in the Singapore Health Services Group.

Results: Forty-three consecutive patients underwent 48 resections during the study period. Seven (16.3%) patients underwent major resections and seven (16.3%) underwent right posterior sectionectomies. Nineteen (44.2%) patients had tumours located in the difficult posterosuperior segments, five had multiple resections and three underwent repeat resections for recurrent tumours. RH was performed for malignant tumours in 32 (74%) patients and 16 (37.2%) had cirrhosis. Seven RH was performed with other concomitant procedures including three colectomies, three hilar lymphadenectomies and one portal vein ligation. The median operation time was 360 min (range 75-825) and the median blood loss was 300 mL (range 25-4500). There was one (2.3%) open conversion for bleeding. The median post-operative stay was 4 days (range 2-33) and there was one (2.3%) readmission. There was one (2.3%) major (>grade 2 morbidity) in a patient with concomitant anterior resection who underwent reoperation for anastomotic leak. There was no 90 day/in-hospital mortality. Comparison between RH for tumours in the anterolateral segments versus posterosuperior segments demonstrated no significant difference in perioperative outcomes.

Conclusion: Our initial experience demonstrated that RH is safe, feasible and associated with excellent post-operative outcomes. It can be performed successfully with low morbidity even for complex resections such as major hepatectomies, posterior sectionectomies, tumours in difficult posterosuperior segments and repeat liver resections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.14417DOI Listing
March 2019

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

J Clin Oncol 2018 07 2;36(19):1913-1921. Epub 2018 Mar 2.

Pierce K.H. Chow, Su Pin Choo, Choon-Hua Thng, and Khee Chee Soo, National Cancer Centre Singapore; Pierce K.H. Chow and Mihir Gandhi, Duke-NUS Medical School; Mihir Gandhi, Say-Beng Tan, Ganesh Lekurwale, and Wei Ming Liew, Singapore Clinical Research Institute; Say-Beng Tan, SingHealth; Peng Chung Cheow, Albert Su-Chong Low, Anthony S.W. Goh, Kiang Hiong Tay, Richard H.G. Lo, Brian K.P. Goh, and David C.E. Ng, Singapore General Hospital; Kieron Lim, National University Hospital; Kenneth S.W. Mak, Khoo Teck Puat Hospital, Singapore; Maung Win Khin, Yangon GI and Liver Centre, Yangon, Myanmar; Ariunaa Khasbazar, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Janus Ong, The Medical City, Pasig, and University of the Philippines Manila, Manila; Ian H.Y. Cua, St Luke's Medical Center-Global City, Taguig; Rolley R. Lobo, Davao Doctors Hospital, Davao; Catherine S.C. Teh, Makati Medical Center, Makati City, Philippines; Chanisa Chotipanich, Chulabhorn Hospital, Bangkok, Thailand; Laurentius A. Lesmana, Cipto Mangunkusumo Hospital, and University of Indonesia, Jakarta; Tjakra W. Manuaba, Sanglah Hospital, Denpasar, Indonesia; Boon Koon Yoong, University of Malaya Medical Centre, Kuala Lumpur; Aloysius Raj, Penang Adventist Hospital, Penang; Chiong Soon Law, Sarawak General Hospital, Kuching, Malaysia; Yun Hwan Kim, Korea University Anam Hospital; Yun Won Jong, Severance Hospital; Ho-Seong Han, Seoul National University Bundang Hospital; Si-Hyun Bae, Seoul St Mary's Hospital; Hyun-Ki Yoon, Asan Medical Center, Seoul, Republic of Korea; Rheun-Chuan Lee, Taipei Veterans General Hospital; Po-Chin Liang, National Taiwan University Hospital, Taipei; Chien-Fu Hung, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Cheng-Yuan Peng, China Medical University Hospital, Taichung, Taiwan; Adam Bartlett, Auckland City Hospital, Auckland, New Zealand; Kenneth Y.Y. Kok, The Brunei Cancer Centre, Jerudong, Brunei Darussalam; and Val Gebski, University of Sydney, National Health and Medical Research Council Clinical Trials Centre, Camperdown, New South Wales, Australia.

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 (Y) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.76.0892DOI Listing
July 2018

Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma.

Gut 2019 02 13;68(2):335-346. Epub 2018 Feb 13.

Duke-NUS Medical School, Singapore.

Objectives: Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response.

Design: Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE.

Results: TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8 T cells, CD56 NK cells and CD8 CD56 NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GBCD8 T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8 and CD4 T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1/Tim-3CD8 T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs.

Conclusion: High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2017-315485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352403PMC
February 2019

Prospective study to determine early hypertrophy of the contra-lateral liver lobe after unilobar, Yttrium-90, selective internal radiation therapy in patients with hepatocellular carcinoma.

Surgery 2018 05 3;163(5):1008-1013. Epub 2018 Jan 3.

Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore. Electronic address:

Background: Liver resection is a major curative option in patients presenting with hepatocellular carcinoma. An inadequate functional liver remnant is a major limiting factor precluding liver resection. In recent years, hypertrophy of the functional liver remnant after selective internal radiation therapy hypertrophy has been observed, but the degree of hypertrophy in the early postselective internal radiation therapy period has not been well studied.

Methods: We conducted a prospective study on patients undergoing unilobar, Yttrium-90 selective internal radiation therapy for hepatocellular carcinoma to evaluate early hypertrophy at 4-6 weeks and 8-12 weeks after selective internal radiation therapy.

Results: In the study, 24 eligible patients were recruited and had serial volumetric measurements performed. The median age was 66 years (38-75 years). All patients were either Child-Pugh Class A or B, and 6/24 patients had documented, clinically relevant portal hypertension; 15 of the 24 patients were hepatitis B positive. At 4-6 weeks, modest hypertrophy was seen (median 3%; range -12 to 42%) and this increased at 8-12 weeks (median 9%; range -12 to 179%). No preprocedural factors predictive of hypertrophy were identified.

Conclusion: Hypertrophy of the functional liver remnant after selective internal radiation therapy with Yttrium-90 occurred in a subset of patients but was modest and unpredictable in the early stages. Selective internal radiation therapy cannot be recommended as a standard treatment modality to induce early hypertrophy for patients with hepatocellular carcinoma. (Surgery 2017;160:XXX-XXX.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2017.10.014DOI Listing
May 2018

A Retrospective Review of the Diagnostic and Management Challenges of Mirizzi Syndrome at the Singapore General Hospital.

Dig Surg 2018 30;35(6):491-497. Epub 2017 Nov 30.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore.

Background: Mirizzi syndrome (MS) occurs when gallstone impaction in Hartmann's pouch results in extrinsic obstruction of the common bile duct, and fistulation may occur.

Methods: We retrospectively reviewed electronic records of patients surgically treated for MS from November 2001 to June 2012. Patient presentations, diagnostic methods, treatments and complications were recorded.

Results: Sixty-four patients were grouped according to a classification proposed by Beltran et al. [World J Surg 2008; 32: 2237-2243]. Forty-three (66.2%), 18 (27.7%) and 3 (4.6%) patients were classified as types I, II, and III respectively. Magnetic-resonance-cholangiopancreaticography was the most sensitive imaging modality, suggesting MS in 24 (88.9%), followed by CT scan (40%) and ultrasonography (11.4%). Forty-four underwent Endoscopic-retrograde-cholangiopancreaticography and 29 (65.9%) suggested the presence of MS. MS was accurately diagnosed pre-operatively in 48 (73.8%) patients. In type I, 40 (93.0%) patients underwent cholecystectomy, while 3 required hepaticojejunostomy. In type II, 12 (66.7%) underwent cholecystectomy and 5 (27.8%) required hepatico-enteric anastomosis. In type III, 1 underwent cholecystectomy and 2 (66.7%) required hepatico-enteric anastomosis. Laparoscopic cholecystectomy was attempted in 20 (30.8%) patients and 13 (65.0%) required conversion. Twenty-nine (44.6%) underwent intra-operative-cholangioscopy, 30 (46.2%) underwent intra-operative-cholangiogram and 41 (63.1%) underwent intra-operative T-tube placement. Six (9.2%) experienced intra-operative complications, 12 (18.5%) experienced post-operative complications and 10 (15.4%) experienced late complications.

Conclusion: MS is a challenging condition and multimodal diagnostic approach has the greatest yield in achieving accurate pre-operative diagnosis. If suspicion is high, a trial of laparoscopic dissection with low threshold for open conversion is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000484256DOI Listing
January 2019

Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma.

Mol Oncol 2018 01 12;12(1):89-113. Epub 2017 Dec 12.

Bioinformatics Institute, Singapore.

Currently, molecular markers are not used when determining the prognosis and treatment strategy for patients with hepatocellular carcinoma (HCC). In the present study, we proposed that the identification of common pro-oncogenic pathways in primary tumors (PT) and adjacent non-malignant tissues (AT) typically used to predict HCC patient risks may result in HCC biomarker discovery. We examined the genome-wide mRNA expression profiles of paired PT and AT samples from 321 HCC patients. The workflow integrated differentially expressed gene selection, gene ontology enrichment, computational classification, survival predictions, image analysis and experimental validation methods. We developed a 24-ribosomal gene-based HCC classifier (RGC), which is prognostically significant in both PT and AT. The RGC gene overexpression in PT was associated with a poor prognosis in the training (hazard ratio = 8.2, P = 9.4 × 10 ) and cross-cohort validation (hazard ratio = 2.63, P = 0.004) datasets. The multivariate survival analysis demonstrated the significant and independent prognostic value of the RGC. The RGC displayed a significant prognostic value in AT of the training (hazard ratio = 5.0, P = 0.03) and cross-validation (hazard ratio = 1.9, P = 0.03) HCC groups, confirming the accuracy and robustness of the RGC. Our experimental and bioinformatics analyses suggested a key role for c-MYC in the pro-oncogenic pattern of ribosomal biogenesis co-regulation in PT and AT. Microarray, quantitative RT-PCR and quantitative immunohistochemical studies of the PT showed that DKK1 in PT is the perspective biomarker for poor HCC outcomes. The common co-transcriptional pattern of ribosome biogenesis genes in PT and AT from HCC patients suggests a new scalable prognostic system, as supported by the model of tumor-like metabolic redirection/assimilation in non-malignant AT. The RGC, comprising 24 ribosomal genes, is introduced as a robust and reproducible prognostic model for stratifying HCC patient risks. The adjacent non-malignant liver tissue alone, or in combination with HCC tissue biopsy, could be an important target for developing predictive and monitoring strategies, as well as evidence-based therapeutic interventions, that aim to reduce the risk of post-surgery relapse in HCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748488PMC
January 2018

The SIRveNIB and SARAH trials and the role of SIR-Spheres® Y-90 resin microspheres in the management of hepatocellular carcinoma.

Future Oncol 2017 10 4;13(25):2213-2216. Epub 2017 Oct 4.

NHMRC Clinical Trials Center, University of Sydney, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2017-0395DOI Listing
October 2017