Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma.

BACKGROUND: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC). METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples. RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate. DISCUSSION/CONCLUSION: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine.

Healthcare System Impact on Deceased Organ Donation and Transplantation: A Comparison Between the Top 10 Organ Donor Countries With 4 Countries in Southeast Asia.

The need for organ donation is constantly increasing. Some countries have made improvements, while others, such as countries in Southeast Asia (SEA), have some of the lowest rates of deceased donors (pmp). This review aims to compare 14 countries with regards to many variables related to healthcare systems. Countries leading in deceased organ donation spend more on health and education, which is associated with increased potential for deceased organ donation. Out-of-pocket expenditure, is also associated with a decrease in deceased organ donation. Countries in SEA are lacking in healthcare resources such as workforce and materials, which are both necessary for a successful transplant program. Most countries in SEA have an excellent foundation for successful organ donation systems, including proper legislation, government support, and brain death laws along with an overall acceptance of brain death diagnosis. Priorities should include improving coordination, donor identification, and healthcare worker education. Countries in SEA have a lot of potential to increase deceased organ donation, especially by investing in healthcare and education. There is no one size fits all for organ donation programs and countries in SEA should focus on their strengths and take cultural differences into consideration when planning interventions.

Application of Proteomics in Pancreatic Ductal Adenocarcinoma Biomarker Investigations: A Review.

Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with a poor prognosis is usually detected at the advanced stage of the disease. The only US Food and Drug Administration-approved biomarker that is available for PDAC, CA 19-9, is most useful in monitoring treatment response among PDAC patients rather than for early detection. Moreover, when CA 19-9 is solely used for diagnostic purposes, it has only a recorded sensitivity of 79% and specificity of 82% in symptomatic individuals. Therefore, there is an urgent need to identify reliable biomarkers for diagnosis (specifically for the early diagnosis), ascertain prognosis as well as to monitor treatment response and tumour recurrence of PDAC. In recent years, proteomic technologies are growing exponentially at an accelerated rate for a wide range of applications in cancer research. In this review, we discussed the current status of biomarker research for PDAC using various proteomic technologies. This review will explore the potential perspective for understanding and identifying the unique alterations in protein expressions that could prove beneficial in discovering new robust biomarkers to detect PDAC at an early stage, ascertain prognosis of patients with the disease in addition to monitoring treatment response and tumour recurrence of patients.

Robotic-assisted thermal ablation of liver tumours.

OBJECTIVE: This study aimed to assess the technical success, radiation dose, safety and performance level of liver thermal ablation using a computed tomography (CT)-guided robotic positioning system. METHODS: Radiofrequency and microwave ablation of liver tumours were performed on 20 patients (40 lesions) with the assistance of a CT-guided robotic positioning system. The accuracy of probe placement, number of readjustments and total radiation dose to each patient were recorded. The performance level was evaluated on a five-point scale (5-1: excellent-poor). The radiation doses were compared against 30 patients with 48 lesions (control) treated without robotic assistance. RESULTS: Thermal ablation was successfully completed in 20 patients with 40 lesions and confirmed on multiphasic contrast-enhanced CT. No procedure related complications were noted in this study. The average number of needle readjustment was 0.8 ± 0.8. The total CT dose (DLP) for the entire robotic assisted thermal ablation was 1382 ± 536 mGy.cm, while the CT fluoroscopic dose (DLP) per lesion was 352 ± 228 mGy.cm. There was no statistically significant (p > 0.05) dose reduction found between the robotic-assisted versus the conventional method. CONCLUSION: This study revealed that robotic-assisted planning and needle placement appears to be safe, with high accuracy and a comparable radiation dose to patients. KEY POINTS: • Clinical experience on liver thermal ablation using CT-guided robotic system is reported. • The technical success, radiation dose, safety and performance level were assessed. • Thermal ablations were successfully performed, with an average performance score of 4.4/5.0. • Robotic-assisted ablation can potentially increase capabilities of less skilled interventional radiologists. • Cost-effectiveness needs to be proven in further studies.

Robot-assisted radiofrequency ablation of primary and secondary liver tumours: early experience.

OBJECTIVE: Computed tomography (CT)-compatible robots, both commercial and research-based, have been developed with the intention of increasing the accuracy of needle placement and potentially improving the outcomes of therapies in addition to reducing clinical staff and patient exposure to radiation during CT fluoroscopy. In the case of highly inaccessible lesions that require multiple plane angulations, robotically assisted needles may improve biopsy access and targeted drug delivery therapy by avoidance of the straight line path of normal linear needles. METHODS: We report our preliminary experience of performing radiofrequency ablation of the liver using a robotic-assisted CT guidance system on 11 patients (17 lesions). RESULTS/CONCLUSION: Robotic-assisted planning and needle placement appears to have high accuracy, is technically easier than the non-robotic-assisted procedure, and involves a significantly lower radiation dose to both patient and support staff. KEY POINTS: • An early experience of robotic-assisted radiofrequency ablation is reported • Robotic-assisted RFA improves accuracy of hepatic lesion targeting • Robotic-assisted RFA makes the procedure technically easier with significant lower radiation dose.

A genomic enhancer signature associates with hepatocellular carcinoma prognosis.

Background & Aims: Lifestyle and environmental-related exposures are important risk factors for hepatocellular carcinoma (HCC), suggesting that epigenetic dysregulation significantly underpins HCC. We profiled 30 surgically resected tumours and the matched adjacent normal tissues to understand the aberrant epigenetic events associated with HCC. Methods: We identified tumour differential enhancers and the associated genes by analysing H3K27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) and Hi-C/HiChIP data from the resected tumour samples of 30 patients with early-stage HCC. This epigenome dataset was analysed with previously reported genome and transcriptome data of the overlapping group of patients from the same cohort. We performed patient-specific differential expression testing using multiregion sequencing data to identify genes that undergo both enhancer and gene expression changes. Based on the genes selected, we identified two patient groups and performed a recurrence-free survival analysis. Results: We observed large-scale changes in the enhancer distribution between HCC tumours and the adjacent normal samples. Many of the gain-in-tumour enhancers showed corresponding upregulation of the associated genes and vice versa, but much of the enhancer and gene expression changes were patient-specific. A subset of the upregulated genes was activated in a subgroup of patients' tumours. Recurrence-free survival analysis revealed that the patients with a more robust upregulation of those genes showed a worse prognosis. Conclusions: We report the genomic enhancer signature associated with differential prognosis in HCC. Findings that cohere with oncofoetal reprogramming in HCC were underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC. Impact and Implications: Lifestyle and environmental-related exposures are the important risk factors of hepatocellular carcinoma (HCC), suggesting that tumour-associated epigenetic dysregulations may significantly underpin HCC. We profiled tumour tissues and their matched normal from 30 patients with early-stage HCC to study the dysregulated epigenetic changes associated with HCC. By also analysing the patients' RNA-seq and clinical data, we found the signature genes - with epigenetic and transcriptomic dysregulation - associated with worse prognosis. Our findings suggest that systemic approaches are needed to consider the surrounding cellular environmental and epigenetic changes in HCC tumours.

Endoscopic Ultrasound-Guided Biliary Drainage: Endoscopic Ultrasound-Guided Hepaticogastrostomy in Malignant Biliary Obstruction.

Patients with unresectable malignant biliary obstruction often require biliary drainage to decompress the biliary system. Endoscopic Retrograde Cholangiopancreatography (ERCP) is the primary biliary drainage method whenever possible. Percutaneous Transhepatic Biliary Drainage (PTBD) is used as a salvage method if ERCP fails. Endoscopic Ultrasound-Guided Biliary Drainage (EUS-BD) provides a feasible alternative biliary drainage method where one of the methods is EUS guided Hepaticogastrostomy (EUS-HGS). Here we describe the EUS-HGS technique in a case of unresectable malignant hilar biliary obstruction to achieve biliary drainage. Presented here is the case of a 71-year-old female with painless jaundice and weight loss for 2 weeks. Computed Tomography (CT) imaging showed a 4 x 5 cm hilar tumor with lymphadenopathy and liver metastasis. EUS fine needle biopsy (FNB) of the lesion was consistent with cholangiocarcinoma. Her bilirubin levels were 212 µmol/L (<15) during presentation. A linear echoendoscope was used to locate the left dilated intrahepatic ducts (IHD) of the liver. The segment 3 dilated IHD was identified and punctured using a 19 G needle. Contrast was used to opacify the IHDs under fluoroscopic guidance. The IHD was cannulated using a 0.025-inch guidewire. This was followed by the dilation of the fistula tract using a 6 Fr electrocautery dilator along with a 4 mm biliary balloon dilator. A partially covered metallic stent of 10 cm in length was deployed under fluoroscopic guidance. The distal part opens in the IHD and the proximal part was deployed within the working channel of the echoendoscope that subsequently released into the stomach. The patient was discharged three days after the procedure. Follow up performed in the second and fourth weeks showed that the bilirubin levels were 30 µmol/L and 14 µmol/L, respectively. This indicates that EUS-HGS is a safe method for biliary drainage in unresectable malignant biliary obstruction.

Non-alcoholic fatty liver disease and obesity among adult donors are major challenges to living-donor liver transplantation: A single-center experience.

OBJECTIVES: Obesity and non-alcoholic fatty liver disease (NAFLD) are rampant in South East Asia. There is paucity of data exploring its' impact on donor suitability for living donor liver transplantation (LDLT). We aimed to describe and examine the factors related to non-utilization of potential donors in our LDLT programme. METHODS: This is an analysis of prospectively collected data on potential donors for an adult LDLT programme, between January 2017 and December 2019. RESULTS: Fifty-five donors for 33 potential recipients were evaluated. The mean age was 31.6 ± 8.5 years, 52.7% were female and the ethnic divisions were: Chinese (50.9%), Indian (25.5%) and Malay (23.6%). The mean body mass index (BMI) among potential donors was 25.1 ± 4.0 kg/m2; 25.5% of donors had normal BMI, 23.6% were overweight and 50.9% were obese. Using the CAP modality of Fibroscan®, we identified the following grades of hepatic steatosis: 36.6% S0, 19.5% S1, 2.4% S2 and 41.5% S3. The non-utilization rate of our donors was 74.5% (41/55) and the main reasons were significant hepatic steatosis and/or obesity. Compared to suitable donors, unsuitable donors had significantly greater mean BMI, mean CAP scores, higher rates of dyslipidaemia and NAFLD. CONCLUSION: NAFLD and obesity represent major challenges to an emerging LDLT programme in Malaysia.

Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study.

Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.

Early identification of the critical view of safety in laparoscopic cholecystectomy using indocyanine green fluorescence cholangiography: A randomised controlled study.

BACKGROUND: Achieving critical view of safety (CVS) is vital during laparoscopic cholecystectomy (LC). There is no known study determining use of indocyanine green fluorescence cholangiography (ICGFC) in early identification of CVS during LC. This study aims to compare use of ICGFC in LC against conventional LC in early identification of CVS. METHODOLOGY: Patients undergoing LC in a single centre were randomized into ICGFC-LC and conventional LC. Surgery was performed by a single surgeon and the time taken to achieve CVS from the time of gallbladder fundus retraction was measured. Difficulty level for each surgery was rated and analysed using a modified scoring system (Level 1- Easy to Level 4-Very difficult). RESULTS: 63 patients were recruited where mean time (min) to achieve CVS was 22.3 ± 12.9 in ICGFC-LC (n = 30) and 22.8 ± 14.3 in conventional LC (p = 0.867). The time taken to achieve CVS was shorter in ICGFC-LC group across all difficulty levels, although not significant (p > 0.05). No major complication was observed in the study. CONCLUSIONS: This study had shown ICGFC-LC reduces time to CVS across all difficulty levels but not statistically significant. ICGFC-LC maybe useful in difficult LC and in surgical training. TRIAL REGISTRATION: Clinical Trials NCT04228835. STUDY GRANT: UMMI Surgical - Karl Storz Distributor (Malaysia).

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.

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.

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

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

Liver cancer in Malaysia: epidemiology and clinical presentation in a multiracial Asian population.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an important cancer in Malaysia. This study aimed to determine the epidemiological characteristics and clinical presentations of patients in a multiracial population consisting of three major Asian races: Malays, Chinese and Indians. METHODS: Consecutive patients with HCC were prospectively studied from 2006 to 2009. HCC was diagnosed principally on multiphasic computed tomography and magnetic resonance imaging scans of the liver. The tumor was staged according to the Barcelona Clinic Liver Cancer (BCLC) classification. RESULTS: Altogether, 348 patients were diagnosed with HCC. There were 239 (68.7%) Chinese patients, 71 (20.4%) Malays and 38 (10.9%) Indians, with the median age of 62.5 years and the male to female ratio of 3.4:1. The predominant etiology in Malay and Chinese patients was hepatitis B virus infection (>60%) and in Indian patients was alcohol intake (26.3%) and cryptogenic cause (29.0%). Hepatitis C was seen in 18.3% of Malays, but less than 10% in Chinese and Indians. BCLC staging was: Stage A, 120 (34.5%); Stage B, 75 (21.6%); Stage C, 84 (24.1%); and Stage D, 69 (19.8%). A larger proportion of Indian than Chinese and Malays patients (44.7%) presented with stage D disease. Portal vein invasion was noted in 124 patients (35.6%) and extrahepatic metastases in 68 (19.5%). Surgical resection and radiofrequency ablation with curative intent was carried out in >90% of stage A patients and transarterial chemoembolization in 49.3% and 21.4% of stages B and C patients, respectively. CONCLUSIONS: HCC is most common among Chinese, followed by Malays and Indians in Malaysia. The etiology of HCC shows a peculiar racial pattern.

Jaundice and life-threatening hemobilia: an uncommon presentation of choledochal cyst.

Hemobilia with jaundice as a result of cholestasis and bleeding from choledochal cyst is uncommon. Ascertaining the diagnosis is often challenging and delayed diagnosis can lead to significant consequences due to hemodynamic instability, particularly in elderly patients. Although surgery remains the definitive treatment modality, interventional radiology for hemostasis has been increasingly recognized as an option. In this manuscript, we described two Malaysian cases of jaundice and hemobilia associated with choledochal cysts and the challenges related with clinical diagnosis and management.

Survival analysis of cholangiocarcinoma: a 10-year experience in Malaysia.

AIM: To investigate the clinical features and survival of patients treated for cholangiocarcinoma in our institution and to analyze the factors affecting their survival. METHODS: This retrospective cohort study assessed patients diagnosed with cholangiocarcinoma between January 1997 and December 2007 at the University Malaya Medical Centre in Malaysia. The clinical data and associated outcomes were collected using a structured proforma. RESULTS: Of the 69 patients diagnosed with cholangiocarcinoma, 38 (55%) were male; mean patient age was 61 years. Twelve patients (17%) had intrahepatic, 38 (55%) had perihilar and 19 (28%) had distal tumors. Only 12 patients underwent curative surgery, including seven R0 resections. Only one patient died within 30 d after surgery. The overall median survival was 4 mo, whereas the median survival of R0 resected patients was 16 mo. The overall 1-, 2- and 3-year cumulative survival rates were 67%, 17% and 17%, respectively. Survival rates were significantly associated with curative resection (P = 0.002), intrahepatic tumor (P = 0.003), negative margin status (P = 0.013), early tumor stage (P = 0.016), higher tumor differentiation (P = 0.032) and absence of jaundice (P = 0.038). Multivariate analysis showed that tumor location was a significant independent predictor of patient survival. CONCLUSION: Curative, margin-negative resection of early stage, well-differentiated intrahepatic tumors is associated with improved patient survival.