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.

Impact of introduction of an enhanced recovery protocol on the outcomes of laparoscopic liver resections: A propensity-score matched study.

BACKGROUND: Presently, data on the impact of enhanced recovery protocols on the outcomes of laparoscopic liver resection remain limited. We performed propensity matched analysis comparing the outcomes between patients undergoing laparoscopic liver resection before and after the introduction of an enhanced recovery protocol. METHODS: Between 2013 and 2019, 462 consecutive patients underwent laparoscopic liver resection by 3 surgeons of which 360 met the study inclusion criteria. There were 89 patients who underwent surgery under an enhanced recovery protocol and 271 without an enhanced recovery protocol. One-to-one propensity matched analysis was performed for 84 enhanced recovery protocol patients and 84 nonenhanced recovery protocol patients. RESULTS: Comparisons between propensity matched cohorts revealed that patients who received laparoscopic liver resection with enhanced recovery protocol had reduced median blood loss (200 vs 300 mL, P = .013), postoperative stay (3 vs 4 days, P = .003), and lower open conversion rates (0% vs 8.3%, P = .008). There was no difference in other key perioperative outcomes such as operation time, postoperative morbidity, postoperative major morbidity, and 30-day readmission rates. CONCLUSION: A combined approach of enhanced recovery protocol and laparoscopic liver resection was associated with improved perioperative outcomes as opposed to laparoscopic liver resection alone.

Short- and long-term outcomes after minimally invasive versus open spleen-saving distal pancreatectomies.

INTRODUCTION: This study aimed to compare the perioperative outcomes of patients who underwent minimally invasive spleen-preserving distal pancreatectomy (MI-SPDP) versus open surgery SPDP (O-SPDP). It also aimed to determine the long-term vascular patency after spleen-saving vessel-preserving distal pancreatectomies (SSVDPs). METHODS: A retrospective review of 74 patients who underwent successful SPDP and met the study criteria was performed. Of these, 67 (90.5%) patients underwent SSVDP, of which 38 patients (21 open, 17 MIS) had adequate long-term post-operative follow-up imaging to determine vascular patency. RESULTS: Fifty-one patients underwent open SPDP, whereas 23 patients underwent minimally invasive SPDP, out of which 10 (43.5%) were laparoscopic and 13 (56.5%) were robotic. Patients who underwent MI-SPDP had significantly longer operative time (307.5 vs. 162.5 min, P = 0.001) but shorter hospital stay (5 vs. 7 days, P = 0.021) and lower median blood loss (100 vs. 200 cc, P = 0.046) compared to that of O-SPDP. Minimally-invasive spleen-saving vessel-preserving distal pancreatectomy (MI-SSVDP) was associated with poorer long-term splenic vein patency rates compared to O-SSVDP (P = 0.048). This was particularly with respect to partial occlusion of the splenic vein, and there was no significant difference between the complete splenic vein occlusion rates between the MIS group and open group (29.4% vs. 28.6%, P = 0.954). The operative time was statistically significantly longer in patients who underwent robotic surgery versus laparoscopic surgery (330 vs. 173 min, P = 0.008). CONCLUSION: Adoption of MI-spleen-preserving distal pancreatectomy (SPDP) is safe and feasible. MI-SPDP is associated with a shorter hospital stay, lower blood loss but longer operation time compared to O-SPDP. In the present study, MI-SSVDP was associated with poorer long-term splenic vein patency rates compared to O-SSVDP.

Clinicopathological-Associated Regulatory Network of Deregulated circRNAs in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Here, we present a novel strategy to identify key circRNA signatures of clinically relevant co-expressed circRNA-mRNA networks in pertinent cancer-pathways that modulate prognosis of HCC patients, by integrating clinic-pathological features, circRNA and mRNA expression profiles. Through further integration with miRNA expression profiles, clinically relevant competing-endogenous-RNA (ceRNA) networks of circRNA-miRNA-mRNAs were constructed. At least five clinically relevant nodal-circRNAs, co-expressed with numerous genes, were identified from the circRNA-mRNA networks. These nodal circRNAs upregulated proliferation (except circRaly) and transformation in cells. The most upregulated nodal-circRNA, circGPC3, associated with higher-grade tumors and co-expressed with 33 genes, competes with 11 mRNAs for two shared miRNAs. circGPC3 was experimentally demonstrated to upregulate cell-cycle and migration/invasion in both transformed and non-transformed liver cell-lines. circGPC3 was further shown to act as a sponge of miR-378a-3p to regulate APSM (Abnormal spindle-like microcephaly associated) expression and modulate cell transformation. This study identifies 5 key nodal master circRNAs in a clinically relevant circRNA-centric network that are significantly associated with poorer prognosis of HCC patients and promotes tumorigenesis in cell-lines. The identification and characterization of these key circRNAs in clinically relevant circRNA-mRNA and ceRNA networks may facilitate the design of novel strategies targeting these important regulators for better HCC prognosis.

Repeat hepatectomy versus radiofrequency ablation in management of recurrent hepatocellular carcinoma: an average treatment effect analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with high rates of recurrence post-resection. Repeat hepatectomy (RH) and radiofrequency ablation (RFA) are the mainstays for managing recurrent HCC following initial curative resection. This retrospective study aims to determine the average treatment effect of RH and RFA in patients with recurrent HCC. PATIENTS AND METHODS: From 2000 to 2016, a total of 219 consecutive patients with recurrent HCC who underwent either RH or RFA were included in the study. The analysis was performed using inverse probability of treatment weighting (IPTW), and propensity score-matched (PSM) methods. RESULTS: The minor and major post-operative morbidity after propensity score-matched analysis for the RH group was 30.0% and 6.0%, respectively, and 19.2% and 0.0% (p = 0.1006), respectively, for the RFA group. After propensity score matching, the median OS for RH and RFA was 85.5 (IQR, 33.5-not reached) and 53.3 months (IQR, 27.5-not reached) (p = 0.8474), respectively. There was no significant difference in 90-day mortality between both groups (p = 0.1287). RH showed improved long-term overall survival over RFA at the third [71.3% versus 65.7% (p = 0.0432)], fifth [59.9% versus 45.4% (p = 0.0271)] and tenth [35.4% versus 32.2% (p = 0.0132)] year follow-up, respectively. Median time to recurrence was 11.1 (IQR, 5.0-33.2) and 28.0 months (IQR, 9.1-not reached) (p = 0.0225) for the RFA and RH group, respectively. CONCLUSIONS: RH confers a late survival benefit compared with RFA for patients with recurrent HCC despite a higher morbidity rate.

Highly deregulated lncRNA LOC is associated with overall worse prognosis in Hepatocellular Carcinoma patients.

Although numerous long non-coding RNAs (lncRNAs) were reported to be deregulated in Hepatocellular Carcinoma (HCC), experimentally characterized, and/or associated with patient's clinical characteristics, there is, thus far, minimal concerted research strategy to identify deregulated lncRNAs that modulate prognosis of HCC patients. Here, we present a novel strategy where we identify lncRNAs, which are not only de-regulated in HCC patients, but are also associated with pertinent clinical characteristics, potentially contributing to the prognosis of HCC patients. LOC101926913 (LOC) was further characterized because it is the most highly differentially expressed amongst those that are associated with the most number of clinical features (tumor-stage, vascular and tumor invasion and poorer overall survival). Experimental gain- and loss-of-function manipulation of LOC in liver cell-lines highlight LOC as a potential onco-lncRNA promoting cell proliferation, anchorage independent growth and invasion. LOC expression in cells up-regulated genes involved in GTPase-activities and downregulated genes associated with cellular detoxification, oxygen- and drug-transport. Hence, LOC may represent a novel therapeutic target, modulating prognosis of HCC patients through up-regulating GTPase-activities and down-regulating detoxification, oxygen- and drug-transport. This strategy may thus be useful for the identification of clinically relevant lncRNAs as potential biomarkers/targets that modulate prognosis in other cancers as well.

Resected pancreatic adenocarcinoma: An Asian institution's experience.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is highly lethal. Surgery offers the only chance of cure, but 5-year overall survival (OS) after surgical resection and adjuvant therapy remains dismal. Adjuvant trials were mostly conducted in the West enrolling fit patients. Applicability to a general population, especially Asia has not been described adequately. AIM: We aimed to evaluate the clinical outcomes, prognostic factors of survival, pattern, and timing of recurrence after curative resection in an Asian institution. METHODS AND RESULTS: The clinicopathologic and survival outcomes of 165 PDAC patients who underwent curative resection between 1998 and 2013 were reviewed retrospectively. Median age at surgery was 62.0 years. 55.2% were male, and 73.3% had tumors involving the head of pancreas. The median OS of the entire cohort was 19.7 months. Median OS of patients who received adjuvant chemotherapy was 23.8 months. Negative predictors of survival include lymph node ratio (LNR) of >0.3 (HR = 3.36, P = .001), tumor site involving the body or tail of pancreas (HR = 1.59, P = .046), presence of perineural invasion (PNI) (HR = 2.36, P = .018) and poorly differentiated/undifferentiated tumor grade (HR = 1.86, P = .058). The median time to recurrence was 8.87 months, with 66.1% and 81.2% of patients developing recurrence at 12 months and 24 months respectively. The most common site of recurrence was the liver. CONCLUSION: The survival of Asian patients with resected PDAC who received adjuvant chemotherapy is comparable to reported randomized trials. Clinical characteristics seem similar to Western patients. Hence, geographical locations may not be a necessary stratification factor in RCTs. Conversely, lymph node ratio and status of PNI ought to be incorporated.

Use of Reinforced Staplers Decreases the Rate of Postoperative Pancreatic Fistula Compared to Bare Staplers After Minimally Invasive Distal Pancreatectomies.

Background: Postoperative pancreatic fistula (POPF) is the most common and important cause of morbidity after distal pancreatectomy. Various transection and closure techniques of the pancreatic stump have been proposed with no robust evidence unanimously supporting one technique over the other. This study aims to compare the outcomes of minimally invasive distal pancreatectomy (MIDP) performed with reinforced stapler (RS) versus bare stapler (BS) with particular attention to the POPF. Methods: Retrospective review of 90 consecutive elective MIDP performed at a single institution between 2014 and 2019 was performed. The primary outcome was POPF as defined by the latest International Study Group of Pancreatic Fistula classification. MIDP with RS was adopted by two surgeons who subsequently performed all their consecutive surgeries with RS. Results: There were 25 and 65 patients who underwent MIDP with RS and BS, respectively. There were 8 (8.9%) open conversions and 17 (18.9%) patients experienced a POPF. Patients who underwent MIDP with RS had a significantly lower POPF rate (4% versus 24.6%, P = .025), lower major (>grade 2) morbidity rate (4% versus 21.5%, P = .046), and lower readmission rate (4% versus 27.7%, P = .014). On multivariate analysis, only the use of BS and obesity (body mass index ≥27.5) was independently associated with the development of a POPF. Conclusion: MIDP performed with RS was associated with a significantly lower rate of POPF, major morbidity, and readmissions compared to BS. The use of RS was protective against POPF.

Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma.

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.

Consensus Guidelines for the Use of Fluorescence Imaging in Hepatobiliary Surgery.

OBJECTIVE: To establish consensus recommendations for the use of fluorescence imaging with indocyanine green (ICG) in hepatobiliary surgery. BACKGROUND: ICG fluorescence imaging has gained popularity in hepatobiliary surgery in recent years. However, there is varied evidence on the use, dosage, and timing of administration of ICG in clinical practice. To standardize the use of this imaging modality in hepatobiliary surgery, a panel of pioneering experts from the Asia-Pacific region sought to establish a set of consensus recommendations by consolidating the available evidence and clinical experiences. METHODS: A total of 13 surgeons experienced in hepatobiliary surgery and/or minimally invasive surgery formed an expert consensus panel in Shanghai, China in October 2018. By the modified Delphi method, they presented the relevant evidence, discussed clinical experiences, and derived consensus statements on the use of ICG in hepatobiliary surgery. Each statement was discussed and modified until a unanimous consensus was achieved. RESULTS: A total of 7 recommendations for the clinical applications of ICG in hepatobiliary surgery were formulated. CONCLUSIONS: The Shanghai consensus recommendations offer practical tips and techniques to augment the safety and technical feasibility of ICG fluorescence-guided hepatobiliary surgery, including laparoscopic cholecystectomy, liver segmentectomy, and liver transplantation.

Impact of Microsurgical Anastomosis of Hepatic Artery on Arterial Complications and Survival Outcomes After Liver Transplantation.

Hepatic artery (HA) complications after liver transplant (LT) can lead to biliary complications, graft failure, and mortality. Although microsurgery has been established to improve anastomotic outcomes, it prolongs surgical time and has not reached widespread adoption at all transplant centers. We investigated the incidences of arterial, biliary complications and outcomes after using microsurgery to anastomose HA during LT. Retrospective cohort of consecutive LT performed from 2006 to 2018 was reviewed for operative details and postoperative outcomes. Cox-regression models were used to investigate the relationship between variables and outcomes. Eighty (62.5%) LTs (Group 1) were performed without and compared with 48 (Group 2) with microsurgical anastomosis of HA. Both groups were comparable in terms of arterial and biliary anastomoses performed. Incidence of early HA thrombosis was similar (6.2% vs 2.1%, P = .28). Group 2 had lower incidence of short- and long-term arterial complications, especially amongst living donor liver transplantations (LDLT) (5.3% vs 35.0%, P = .022). On multivariate analysis, microsurgery was associated with lower risk (hazard ratio [HR] 0.09, 95% confidence interval [CI] 0.01-0.71) of, and LDLT had higher risk (HR 4.23, 95% CI 1.46-12.27) of arterial complications. Biliary complications were associated with LDLT (HR 3.91, 95% CI 1.30-11.71) and dual biliary anastomoses (HR 5.26, 95% CI 1.15-24.08) but not with occurrence of HA complications. Worse patient survival was associated with the occurrence of any HA complication (HR 4.11, 95% CI 1.78-9.48). Hepatic arterial complications can be reduced using microsurgical techniques for the anastomosis, resulting in improved patient survival outcomes after liver transplantation.

Outcome of minimally invasive liver resection for extrapancreatic biliary malignancies: A single-institutional experience.

BACKGROUND: Minimally invasive liver resection (MILR) has been increasingly adopted over the past decade, and its application has been expanded to the management of extrapancreatic biliary malignancies (EPBMs). We aimed to evaluate the peri- and post-operative outcome of patients undergoing MILR for suspected EPMB. METHODS: Forty-four consecutive patients who underwent MILR with a curative intent for EPBM at Singapore General Hospital between 2011 and 2018 were identified from a prospectively maintained surgical database. Clinical and operative data were analysed and compared to provide information and make comparisons on peri- and post-operative outcomes. RESULTS: A total of 26, 5 and 13 patients underwent MILR for intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHC) and gallbladder carcinoma (GBCA), respectively. Six major hepatectomies were performed, of which one was laparoscopic assisted and another was robot assisted. Ten patients underwent posterosuperior segmentectomies. There was one open conversion. The mean operative time was 266.5 min, and the mean blood loss was 379 ml. The mean length of hospital stay was 4.7 days with no incidences of 30- and 90-day mortality. The rate of recurrence-free survival (RFS) was 75% (at least 12-month follow-up). There was a significantly higher rate of robot-assisted procedures in patients undergoing MILR for GBCA/PHC as compared to ICC (P = 0.034). Patients undergoing posterosuperior segmentectomies required longer operative time (P = 0.018) with an increased need for (P = 0.001) and duration of (P = 0.025) Pringles manoeuvre. There were no differences in operative time, blood loss, morbidity, mortality or RFS between the above groups. CONCLUSION: Minimally invasive surgery can be adopted safely with a low open conversion rate for EPBMs.

Novel method of intraoperative liver tumour localisation with indocyanine green and near-infrared imaging.

INTRODUCTION: Fluorescence imaging (FI) with indocyanine green (ICG) is increasingly implemented as an intraoperative navigation tool in hepatobiliary surgery to identify hepatic tumours. This is useful in minimally invasive hepatectomy, where gross inspection and palpation are limited. This study aimed to evaluate the feasibility, safety and optimal timing of using ICG for tumour localisation in patients undergoing hepatic resection. METHODS: From 2015 to 2018, a prospective multicentre study was conducted to evaluate feasibility and safety of ICG in tumour localisation following preoperative administration of ICG either on Day 0-3 or Day 4-7. RESULTS: Among 32 patients, a total of 46 lesions were resected: 23 were hepatocellular carcinomas (HCCs), 12 were colorectal liver metastases (CRLM) and 11 were benign lesions. ICG FI identified 38 (82.6%) lesions prior to resection. The majority of HCCs were homogeneous fluorescing lesions (56.6%), while CLRM were homogeneous (41.7%) or rim-enhancing (33.3%). The majority (75.0%) of the lesions not detected by ICG FI were in cirrhotic livers. Most (84.1%) of ICG-positive lesions detected were < 1 cm deep, and half of the lesions ≥ 1 cm in depth were not detected. In cirrhotic patients with malignant lesions, those given ICG on preoperative Day 0-3 and Day 4-7 had detection rates of 66.7% and 91.7%, respectively. There were no adverse events. CONCLUSION: ICG FI is a safe and feasible method to assist tumour localisation in liver surgery. Different tumours appear to display characteristic fluorescent patterns. There may be no disadvantage of administering ICG closer to the operative date if it is more convenient, except in patients with liver cirrhosis.

Validation and comparison of the Iwate, IMM, Southampton and Hasegawa difficulty scoring systems for primary laparoscopic hepatectomies.

BACKGROUND: Various difficulty scoring systems (DSS) have been formulated to grade the complexity of laparoscopic hepatectomies (LH). This study aims to externally validate and compare 4 contemporary DSS including the Iwate, Institut Mutualiste Montsouris (IMM), Southampton and Hasegawa DSS in predicting the intraoperative technical difficulty and postoperative outcomes after LH. METHODS: Retrospective review of 548 consecutive patients who underwent LH of which 455 met the study inclusion criteria. Outcomes measures of technical difficulty included operation time, Pringles maneuver, blood loss and blood transfusion rate. Postoperative outcomes measured included morbidity, major morbidity and postoperative hospital stay. RESULTS: There was a statistically significant progressive increase in blood loss, blood transfusion rate, operation time and postoperative stay associated with all 4 DSS. There was also good calibration with respect to blood loss, operation time, Pringles maneuver, open conversion rate, postoperative morbidity, postoperative major morbidity and postoperative stay for all 4 DSS. The Southampton score demonstrated the poorest calibration in terms of operation time and discrimination in terms of application of Pringles maneuver and major morbidity amongst all 4 systems. CONCLUSION: All 4 DSS significantly correlated with outcome measures associated with intraoperative technical difficulty and postoperative outcomes. The Southampton DSS was the poorest system in our cohort of patients.

Impact of liver cirrhosis on the difficulty of minimally-invasive liver resections: a 1:1 coarsened exact-matched controlled study.

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

Adoption of Robotic Liver, Pancreatic and Biliary Surgery in Singapore: A Single Institution Experience with Its First 100 Consecutive Cases.

INTRODUCTION: Presently, robotic hepatopancreatobiliary surgery (RHPBS) is increasingly adopted worldwide. This study reports our experience with the first 100 consecutive cases of RHPBS in Singapore. METHODS: Retrospective review of a single-institution prospective database of the first 100 consecutive RHPBS performed over 6 years from February 2013 to February 2019. Eighty-six cases were performed by a single surgeon. RESULTS: The 100 consecutive cases included 24 isolated liver resections, 48 pancreatic surgeries (including 2 bile duct resections) and 28 biliary surgeries (including 8 with concomitant liver resections). They included 10 major hepatectomies, 15 pancreaticoduodenectomies, 6 radical resections for gallbladder carcinoma and 8 hepaticojejunostomies. The median operation time was 383 minutes, with interquartile range (IQR) of 258 minutes and there were 2 open conversions. The median blood loss was 200ml (IQR 350ml) and 15 patients required intra-operative blood transfusion. There were no post-operative 90-day nor in-hospital mortalities but 5 patients experienced major (> grade 3a) morbidities. The median post-operative stay was 6 days (IQR 5 days) and there were 12 post-operative 30-day readmissions. Comparison between the first 50 and the subsequent 50 patients demonstrated a significant reduction in blood loss, significantly lower proportion of malignant indications, and a decreasing frequency in liver resections performed. CONCLUSION: Our experience with the first 100 consecutive cases of RHPBS confirms its feasibility and safety when performed by experienced laparoscopic hepatopancreatobiliary surgeons. It can be performed for even highly complicated major hepatopancreatobiliary surgery with a low open conversion rate.

Comparison between long and short-term venous patencies after pancreatoduodenectomy or total pancreatectomy with portal/superior mesenteric vein resection stratified by reconstruction type.

BACKGROUND: Venous reconstruction has been recently demonstrated to be safe for tumours with invasion into portal vein and/or superior mesenteric vein. This study aims to compare the patency between various venous reconstructions. METHODS: This is retrospective study of 76 patients who underwent pancreaticoduodenectomy or total pancreatectomy with venous reconstruction from 2006 to 2018. Patient demographics, tumour histopathology, morbidity, mortality and patency were studied. Kaplan-Meier estimates were performed for primary venous patency. RESULTS: Sixty-two patients underwent pancreaticoduodenectomy and 14 underwent total pancreatectomy. Forty-seven, 19 and 10 patients underwent primary repair, end-to-end anastomosis and interposition graft respectively. Major morbidity (Clavien-Dindo >grade 2) and 30-day mortality were 14/76(18.4%) and 1/76(1.3%) respectively. There were 12(15.8%) venous occlusion including 4(5.3%) acute occlusions. Overall 6-month, 1-year and 2-year primary patency was 89.1%, 92.5% and 92.3% respectively. 1-year primary patency of primary repair was superior to end-to-end anastomosis and interposition graft (primary repair 100%, end-to-end anastomosis 81.8%, interposition graft 66.7%, p = 0.045). Pairwise comparison also demonstrated superior 1-year patency of primary repair (adjusted p = 0.037). There was no significant difference between the cumulative venous patency for each venous reconstruction method: primary repair 84±6%, end-to-end anastomosis 75±11% and interposition graft 76±15% (p = 0.561). CONCLUSION: 1-year primary venous patency of primary repair is superior to end-to-end anastomosis and interposition graft.

Impact of multidisciplinary tumour boards (MTB) on the clinicopathological characteristics and outcomes of resected colorectal liver metastases across time.

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

Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC. METHODS: Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis. RESULTS: IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB. CONCLUSIONS: A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.