Consensus statements on endoscopic ultrasound-guided tissue acquisition. Guidelines from the Asian Endoscopic Ultrasound Group.

OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.

A case series of emergency pancreaticoduodenectomies: What were their indications and outcomes?

Emergency pancreaticoduodenectomy (EPD) is a rarely performed operation. It is important to know the indications and outcomes of EPD to have a better understanding of its application in clinical practice. A review of eight consecutive cases of EPD was done. Between January 2003 and December 2021, 8 out of 370 patients (2.2%) in a single center received pancreaticoduodenectomy as emergency. There were six males and two females with a median age of 45.5 years. The indications were trauma in three patients, bleeding tumors in two patients, and one patient each in obstructing duodenal tumor, postoperative complication and post-endoscopic retrograde cholangiopancreatography (ERCP) complication. The median operative time and blood loss were 427.5 minutes and 1,825 mL, respectively. There was no operative mortality. Seven patients (87.5%) had postoperative complications. Three patients (37.5%) developed postoperative grade B pancreatic fistula. The median postoperative hospital stay was 23.5 days. Five patients were still alive while three patients survived for 13, 31, and 42 months after the operation. The causes of death were recurrent tumors in two patients, and sepsis in one patient. According to this case series, EPD is associated with increased morbidity and pancreatic fistula, but is still deserved in life-threatening situations and long-term survival is possible after EPD.

Limited liver resections in the posterosuperior segments: international multicentre propensity score-matched and coarsened exact-matched analysis comparing the laparoscopic and robotic approaches.

BACKGROUND: Limited liver resections (LLRs) for tumours located in the posterosuperior segments of the liver are technically demanding procedures. This study compared outcomes of robotic (R) and laparoscopic (L) LLR for tumours located in the posterosuperior liver segments (IV, VII, and VIII). METHODS: This was an international multicentre retrospective analysis of patients who underwent R-LLR or L-LLR at 24 centres between 2010 and 2019. Patient demographics, perioperative parameters, and postoperative outcomes were analysed; 1 : 3 propensity score matching (PSM) and 1 : 1 coarsened exact matching (CEM) were performed. RESULTS: Of 1566 patients undergoing R-LLR and L-LLR, 983 met the study inclusion criteria. Before matching, 159 R-LLRs and 824 L-LLRs were included. After 1 : 3 PSM of 127 R-LLRs and 381 L-LLRs, comparison of perioperative outcomes showed that median blood loss (100 (i.q.r. 40-200) versus 200 (100-500) ml; P = 0.003), blood loss of at least 500 ml (9 (7.4 per cent) versus 94 (27.6 per cent); P < 0.001), intraoperative blood transfusion rate (4 (3.1 per cent) versus 38 (10.0 per cent); P = 0.025), rate of conversion to open surgery (1 (0.8 per cent) versus 30 (7.9 per cent); P = 0.022), median duration of Pringle manoeuvre when applied (30 (20-46) versus 40 (25-58) min; P = 0.012), and median duration of operation (175 (130-255) versus 224 (155-300); P < 0.001) were lower in the R-LLR group compared with the L-LLR group. After 1 : 1 CEM of 104 R-LLRs with 104 L-LLRs, R-LLR was similarly associated with significantly reduced blood loss and a lower rate of conversion to open surgery. CONCLUSION: Based on a matched analysis of well selected patients, both robotic and laparoscopic access could be undertaken safely with good outcomes for tumours in the posterosuperior liver segments.

A retrospective comparative study of robotic distal pancreatectomy with or without splenic vessel and spleen preservation.

BACKGROUND: Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP). METHODS: Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group. RESULTS: The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group. CONCLUSION: Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS.

Comparison of Survival Outcomes in Transarterial Ethanol Ablation and Liver Resection for Solitary Hepatocellular Carcinoma ≤ 5 cm in Patients Stratified by Liver Function.

PURPOSE: To compare the survival outcomes of patients treated with transarterial ethanol ablation (TEA) with those treated with liver resection (LR) for solitary HCC less than 5 cm in diameter, in patients stratified according to liver function using ALBI grade. MATERIALS AND METHODS: This retrospective study approved by the Institutional Committee included all treatment-naïve patients with solitary HCC (≤ 5 cm) and Child-Pugh score 5, and who had received TEA (33 patients) or LR (192 patients) between 2004 and 2012. Treatment outcomes were compared between patients treated with TEA and LR after a period of at least 7 years of follow-up. Comparison was repeated for those patients with ALBI grade 2 or 3. RESULTS: Both overall survival (OS, months) and recurrence-free survival (RFS months) were significantly longer in the LR group (OS: LR 129.7[119.5, 140], TEA 69.1[55.9, 82.3], P < 0.0001; RFS: LR 91.3[43.5, 139.1], TEA 13.8 [11, 16.5], P < 0.0001). In patients with ALBI grade 2 or 3, there was no significant difference between the groups in OS or RFS (OS: LR 43.1[0, 91.2], TEA 55.4 [43.7, 67.2], P = 0.65; RFS: LR 17.8 [11.4, 24.2], TEA 11.9 [6.7, 17.1], P = 0.132). Transient epigastric discomfort and low-grade fever without consequence occurred in 8 patients (8/33 or 24.2%) in the TEA group. CONCLUSION: The overall survival after LR for HCCs ≤ 5 cm was superior to that after TEA but similar when compared in patients with ALBI grade 2 or 3, the ALBI grade is useful for patient selection for TEA or LR for HCCs ≤ 5 cm.

What is the pancreatic duct size limit for a safe duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy? A retrospective study.

BACKGROUNDS/AIMS: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) remains a dreadful complication. Duct-to-mucosa pancreaticojejunostomy (DTMPJ) is a commonly performed anastomosis after PD. This study aims to evaluate whether there is a size limit of pancreatic duct below which POPF rate increases significantly after DTMPJ. METHODS: A retrospective study was performed from a database with prospectively collected data on consecutive patients undergoing DTMPJ. RESULTS: Between the years 2003 and 2019, a total of 288 patients with DTMPJ were recruited. POPF occurred in 56.3% of the patients, of which 43.8% were biochemical leak, 8.7% were grade B, and 1.4% were grade C. Overall operative morbidity was 51.4%, of which 19.1% were major complications. Five patients (1.7%) died within 90 days of operation. Patients with grade B/C POPF had significantly soft pancreas (p < 0.001), smaller duct size (p = 0.031), and a diagnosis of carcinoma of the pancreas (p = 0.027). When a clinically significant POPF rate was analysed based on the pancreatic duct diameter, pancreatic duct size ≤ 1 mm had the highest POPF rate (35.7%). There was a significant difference in POPF rate between adjacent ductal diameter ≤ 1 mm and > 1 mm to 2 mm (35.7% vs 13.3%; p = 0.040). Multivariable analysis showed that for the soft pancreas, pancreatic duct diameter ≤ 1 mm was the only significant predictive factor for POPF (p = 0.027). CONCLUSIONS: DTMPJ can be safely performed for pancreatic duct > 1 mm without significantly increased POPF risk.

Defining the endoscopic ultrasound features of chronic pancreatitis in Asians: a multicenter validation study.

BACKGROUND: Although endoscopic ultrasound (EUS) features and criteria have been described in chronic pancreatitis, challenges remain with interoperator variability and ease of adoption. The aim of this study was to define and validate the EUS features of chronic pancreatitis in a multicenter prospective study in Asia. METHOD: The study was divided into two parts: the first part was conducted to derive the EUS features of chronic pancreatitis with adequate interoperator agreement; the second was to prospectively evaluate these features in a multicenter cross-sectional study and determine the optimal combination of features for the diagnosis of chronic pancreatitis. Prospectively enrolled cases had standard internationally validated radiologic or histologic features of chronic pancreatitis, and controls were patients without chronic pancreatitis who underwent EUS examination. RESULTS: The top six EUS features that had good interobserver agreement (mean kappa 0.73, range 0.60 - 0.90) were selected to be further evaluated in part II of the study. These included: hyperechoic foci with shadowing, lobularity with honeycombing, cysts, dilated main pancreatic duct, dilated side branches, and calculi in the main pancreatic duct. A total of 284 subjects (132 cases, 152 controls) were enrolled from 12 centers in Asia. All six features had high accuracy ranging from 63.3 % to 89.1 %. Two or more of these six EUS features accurately defined chronic pancreatitis (sensitivity 94.7 %, specificity 98.0 %), with an area under the receiver operating curve of 0.986. CONCLUSION: This multicenter Asian study characterized and defined the EUS features of chronic pancreatitis. This provides a useful tool in clinical practice and further research in pancreatic cancer surveillance.

Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition.

Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-ß1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-ß1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.

Development of a Novel Inflammation-Based Index for Hepatocellular Carcinoma.

BACKGROUND: The aim of current study was to (1) construct and validate a novel hepatocellular carcinoma (HCC)-specific inflammatory index; (2) compare the performances of the Integrated Liver Inflammatory Score (ILIS) to existing 4 inflammatory indices in HCC; (3) explore the association between the inflammatory indices and systemic/intratumoral inflammatory markers. METHODS: Two cohorts from Hong Kong (HK; n = 1,315) and Newcastle (n = 574) were studied. A novel index was constructed from the HK training set (n = 627). The index was constructed from the training set by combing independent prognostic circulating parameters, followed by validating in the validation set of HK cohort (n = 688) and the Newcastle cohort. Its prognostic performance was compared to 4 inflammatory indices, namely, the neutrophil to lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutrition index, and systemic immune-inflammation index, were compared in the HK cohort. Circulating cytokines and intratumoral gene expression were analyzed in a subset of patients with available samples and correlated with the inflammatory indices. RESULTS: In the training set of the HK cohort, the ILIS, was generated: -0.057 × albumin (g/L) + 0.978 × log (Bilirubin, µmol/L) + 1.341 × log (alkaline phosphatase, IU/L) + 0.086 × Neutrophil (109/L) + 0.301 × log (alpha-fetoprotein, µg/L). With cutoff of 2.60 and 3.87, the ILIS could categorize patients into 3 risk groups in the both validation cohorts. ILIS outperforms other inflammatory indices and remains an independent prognosticator for overall survival after adjustment with Barcelona Clinic Liver Cancer (hazard ratio 31.90, p < 0.001). The ILIS had the best prognostic performances as compared to other inflammatory indices. In exploratory analyses, the ILIS correlated with circulating inflammatory cytokines (e.g., IL-8) but not with any intratumoral inflammatory gene expression. CONCLUSIONS: ILIS is an HCC-specific prognostic index built on 5 readily available blood parameters. Its versatility is validated both Eastern and Western population of HCC. The score is correlated with levels of circulating cytokines.

An unusual cause of upper gastrointestinal bleeding due to recurrent hepatocellular carcinoma: A case report.

INTRODUCTION: Upper gastrointestinal bleeding (UGIB) in patients suffering from hepatocellular carcinoma (HCC) is usually due to oesophageal or gastric varices secondary to portal hypertension. Very rarely, HCC can directly invade into the stomach or duodenum resulting in UGIB. PRESENTATION OF CASE: A 62-year-old man presented to the emergency department for haematemesis and tarry stool. He was a hepatitis B carrier and had received open radiofrequency ablation and wedge resection for HCC previously. Urgent endoscopy and contrast computed tomography confirmed recurrent HCC invading into the duodenum. The patient received radical resection and remained disease free for 7 years after the operation. DISCUSSION: Direct invasion into gastrointestinal tract by HCC is rare. Different modalities of treatment have been reported in the literature with variable success. En-bloc resection should be considered if surgically feasible in order to achieve good haemostasis and possible long term survival. CONCLUSION: Upper gastrointestinal bleeding is a rare presentation of hepatocellular carcinoma and long term survival can be achieved by curative surgery.

Transarterial Ethanol Ablation for Small Hepatocellular Carcinoma (≤ 3 cm): A Comparative Study Versus Radiofrequency Ablation.

PURPOSE: The objective was to evaluate the local treatment efficacy of transarterial ethanol ablation (TEA) as compared to radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This was a retrospective study between January 2005 and April 2017, in which the treatment outcomes of all patients who received either percutaneous TEA or RFA for HCC tumors of size ≤ 3 cm, of Child-Pugh grade A or B, received no prior treatment other than surgical resection, were compared. For TEA, a mixture of absolute ethanol and ethiodized oil at a proportion of 1:2 by volume was administered superselectively into the tumor via a microcatheter placed at the feeding arteries. The TEA group and the RFA group consisted of 68 consecutive patients (88 treated target tumors) and 129 consecutive patients (129 tumors), respectively. RESULTS: Technical success was achieved in all the target tumors in both groups. Grade 3 complication (CIRSE Classification) of prolonged fever occurred in 3 cases with multi-focal and large tumors in the TEA group. There was no statistically significant difference in complete response rate between the TEA group (84/88 or 95.5%) and the RFA group (188/195 or 96.4%) (p = 0.7). Time to progression in the TEA group [median 11.9 months, interquartile range (IQR) 5.6-18 months] was not statistically different from that in the RFA group (median 9.5 months, IQR 3.5-18.7 months) (p = 0.773). CONCLUSION: TEA could be an effective alternative of RFA for the local treatment of small HCC; it is especially valuable for tumors of unfavorable location.

Positive Hepatitis B Core Antibody Is Associated With Cirrhosis and Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD). METHODS: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection. RESULTS: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity. DISCUSSION: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.

Laparoscopic Hepatectomy (with or without Robotic Assistance) versus Radiofrequency Ablation as a Minimally Invasive Treatment for Very Early-Stage or Early-Stage Hepatocellular Carcinoma.

BACKGROUND: The advantages of radiofrequency ablation (RFA) over hepatectomy as a treatment for early-stage hepatocellular carcinoma (HCC) include reduced morbidity and more rapid recovery. Although minimally invasive surgery provides similar benefits, few studies have compared the long-term oncological outcomes of these techniques. This study aimed to compare the outcomes of minimally invasive hepatectomy (MIH) and RFA. METHODS: Patients who underwent MIH or RFA for HCC between January 2005 and January 2015 were included in a propensity score matching analysis. Only patients who underwent minimally invasive procedures for small HCC were included. Baseline clinical and laboratory parameters were retrieved from the hospital database and analyzed. RESULTS: Two hundred and twenty-five patients underwent MIH or RFA for HCC during the study period. Propensity score matching yielded 59 patient-pairs. The complication rates did not differ statistically between the 2 groups (p = 0.309). However, MIH provided significantly better overall (p = 0.005) and disease-free survival outcomes (p < 0.001) than RFA. CONCLUSIONS: Compared with RFA, MIH provided better long-term survival outcomes in patients with early-stage HCC, with no increase in the incidence of complications. When feasible, MIH should be considered a first-line treatment for this patient population.

A robotic flexible endoscope with shared autonomy: a study of mockup cholecystectomy.

BACKGROUND: Endoscope is the eye of surgeon in minimally invasive surgery (MIS). Prevailing handheld endoscopes are manually steered, which can cause endoscope-instrument fencing. Robotic endoscopes can reduce the fatigue but could not reduce collisions. Handheld endoscopes with a flexible bending tip can reduce the shaft pivoting and collisions. However, its steering is challenging. In this paper, we present a robotic flexible endoscope with auto-tracking function and compare it with the conventional rigid endoscopes. METHODS: A robotic flexible endoscope (RFE) with shared autonomy is developed. The RFE could either track the instruments automatically or be controlled by a foot pedal. A mockup cholecystectomy was designed to evaluate the performance. Five surgeons were invited to perform the mockup cholecystectomy in an abdominal cavity phantom with a manual rigid endoscope (MRE), a robotic rigid endoscope (RRE), and the RFE. Space occupation, time consumption, and questionnaires based on the NASA task load index were adopted to evaluate the performances and compare the three endoscope systems. An ex vivo experiment was conducted to demonstrate the feasibility of using the RFE in a biological tissue environment. RESULTS: All surgeons completed the mockup cholecystectomy with the RFE independently. Failure occurred in the cases involving the RRE and the MRE. Inside the body cavity, the space occupied when using the RFE is 17.28% and 23.95% (p < 0.05) of that when using the MRE and the RRE, respectively. Outside the body cavity, the space occupied when using the RFE is 14.60% and 15.53% (p < 0.05) of that by using MRE and RRE. Time consumed in the operations with MRE, RRE, and RFE are 28.3 s, 93.2 s and 34.8 s, respectively. Questionnaires reveal that the performance of the RFE is the best among the three endoscope systems. CONCLUSIONS: The RFE provides a wider field of view (FOV) and occupies less space than rigid endoscopes.

Clinical application of Albumin-Bilirubin (ALBI) score: The current status.

Prognosis of patients that have undergone liver resection can be predicted preoperatively. Albumin-Bilirubin (ALBI) is a useful score to evaluate liver function objectively. This score is simple to use, uses objective parameters, and can stratify patients into grades. In combination with other liver cancer scores, the prognosis and survival of patients can be evaluated with more accuracy. Current literatures supporting the use of the ALBI score relating to prognosis of post hepatectomy, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), radiotherapy and systemic therapy are available. Therefore, ALBI score is worthy of clinical application. The following is a review of the current literatures on the ALBI score.

International consensus statement on robotic pancreatic surgery.

The robotic surgical system has been applied to various types of pancreatic surgery. However, controversies exist regarding a variety of factors including the safety, feasibility, efficacy, and cost-effectiveness of robotic surgery. This study aimed to evaluate the current status of robotic pancreatic surgery and put forth experts' consensus and recommendations to promote its development. Based on the WHO Handbook for Guideline Development, a Consensus Steering Group* and a Consensus Development Group were established to determine the topics, prepare evidence-based documents, and generate recommendations. The GRADE Grid method and Delphi vote were used to formulate the recommendations. A total of 19 topics were analyzed. The first 16 recommendations were generated by GRADE using an evidence-based method (EBM) and focused on the safety, feasibility, indication, techniques, certification of the robotic surgeon, and cost-effectiveness of robotic pancreatic surgery. The remaining three recommendations were based on literature review and expert panel opinion due to insufficient EBM results. Since the current amount of evidence was low/meager as evaluated by the GRADE method, further randomized controlled trials (RCTs) are needed in the future to validate these recommendations.

A comparability study of immunohistochemical assays for PD-L1 expression in hepatocellular carcinoma.

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.

The ATP-binding cassette transporter ABCF1 is a hepatic oncofetal protein that promotes chemoresistance, EMT and cancer stemness in hepatocellular carcinoma.

ATP-binding cassette (ABC) transporters mediate multidrug resistance and cancer stem cell properties in various model systems. Yet, their biological significance in cancers, especially in hepatocellular carcinoma (HCC), remains unclear. In this study, we investigated the function of ABCF1 in HCC and explored its potential as a therapeutic target. ABCF1 was highly expressed in fetal mouse livers but not in normal adult livers. ABCF1 expression was upregulated in HCCs. These results demonstrate that ABCF1 functions as a hepatic oncofetal protein. We further demonstrated elevated ABCF1 expression in HCC cells upon acquiring chemoresistance. Suppression of ABCF1 by siRNA sensitized both parental cells and chemoresistant cells to chemotherapeutic agents. Reversely, ABCF1 overexpression promoted chemoresistance and drug efflux. In addition, overexpression of ABCF1 enhanced migration, spheroid and colony formation and epithelial-mesenchymal transition (EMT) induction. RNA sequencing analysis revealed EMT inducers HIF1α/IL8 and Sox4 as potential mediators for the oncogenic effect of ABCF1 in HCC progression. Together, this study illustrates that ABCF1 is a novel potential therapeutic target for HCC treatment.

Novel biomarkers GEP/ABCB5 regulate response to adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor (GEP) and ATP-dependent binding cassette (ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. METHODS: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low (GEP-/ABCB5-), intermediate (either GEP+/ABCB5- or GEP-/ABCB5+) and high (GEP+/ABCB5+). Early recurrence (recurrence within 2 years after resection) and disease-free survival were analyzed. RESULTS: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone (P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. CONCLUSIONS: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group (either GEP+/ABCB5- or GEP-/ABCB5+). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE.