Prognosis prediction of PDAC via detection of O-glycan altered extracellular vesicles in perioperative sera.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy due to the difficulty in diagnosis and poor prognosis because of the high recurrence rate, necessitating reliable biomarkers to improve the diagnosis and prognosis. However, the existing markers have limitations. We previously identified extracellular vesicles (EVs) recognized by O-glycan-binding lectins (Amaranthus caudatus agglutinin [ACA]) as a novel diagnostic biomarker for PDAC using an EV-counting system (ExoCounter). This retrospective study analyzed changes in ACA-positive EVs in perioperative PDAC serum and its association with prognosis using ExoCounter. Absolute EV levels in the pre- and postoperative sera of 44 patients who underwent curative pancreatectomy for PDAC were quantified using ExoCounter. The carbohydrate antigen 19-9 levels declined in most samples postoperatively, and presented no correlation with poor prognosis. In contrast, ACA-positive EVs increased in serum at 7 days postoperatively in 27 of 44 patients (61.4%). We therefore divided participants with ACA-positive EVs before and after surgery into elevation and decline groups. The overall survival (OS) and recurrence-free survival (RFS) of patients with higher ACA-positive EVs were significantly shorter than those with lower ACA-positive EVs (26.1 months vs. not reached, P = 0.018; 11.9 vs. 38.6 months, P = 0.013). Multivariable analysis revealed that ACA-positive EV elevation in postoperative serum was an independent prognostic factor for poor OS (hazard ratio [HR] = 3.891, P = 0.023) and RFS (HR = 2.650, P = 0.024). The detection of ACA-positive EVs in perioperative serum may be used to predict the prognosis of PDAC in the early postoperative period.

Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Comparison Between Plastic and Metallic Biliary Stent Placement for Preoperative Patients with Pancreatic Head Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Optimal preoperative biliary drainage for patients with pancreatic cancer before pancreatoduodenectomy remains unclear. This study aimed to investigate the comparison of efficacy and safety between a metallic stent (MS) and a plastic stent (PS). METHODS: Comparative studies on the use of MS and PS for pancreatic cancer before pancreatoduodenectomy were systematically searched using the MEDLINE and Web of Science databases. Pre- and postoperative data also were extracted. Random-effects meta-analyses were performed to compare post-endoscopic retrograde cholangiopancreatography (ERCP) complications as well as intra- and postoperative outcomes between the two arms of the study, and pooled odds ratios (ORs) or mean differences (MDs) were calculated with 95 percent confidence intervals (CIs). RESULTS: The study analyzed 12 studies involving 683 patients. Insertion of MS was associated with a lower incidence of re-intervention (OR, 0.06; 95% CI 0.03-0.15; P < 0.001), increased post-ERCP adverse events (OR, 2.22; 95% CI 1.13-4.36; P = 0.02), and similar operation time (MD, 18.0 min; 95% CI -29.1 to 65.6 min; P = 0.46), amount of blood loss (MD, 43.0 ml; 95% CI -207.1 to 288.2 ml; P = 0.73), and surgical complication rate (OR, 0.78; 95% CI 0.53-1.15; P = 0.21). The cumulative stent patency rate after 3 months was higher in the MS group than in the PS group (70-100 % vs 30.0-45.0 %). CONCLUSION: For biliary drainage in patients with pancreatic cancer during this era of multidisciplinary treatment, MS use might be the first choice because MS provides a more durable biliary drainage and a similar risk of postoperative outcomes compared with PS.

Perioperative Lymphopenia is Associated with Increased Risk of Recurrence and Worse Survival Following Hepatectomy for Hepatocellular Carcinoma.

INTRODUCTION: Immune dysregulation may be associated with cancer progression. We sought to investigate the prognostic value of perioperative lymphopenia on short- and long-term outcomes among patients undergoing resection of hepatocellular carcinoma (HCC). METHODS: Patients undergoing resection of HCC between 2000 and 2020 were identified using an international database. The incidence and impact of perioperative lymphopenia [preoperative, postoperative day (POD) 1/3/5], defined as absolute lymphocyte count (ALC) <1000/µL, on short- and long-term outcomes was assessed. RESULTS: Among 1448 patients, median preoperative ALC was 1593/µL [interquartile range (IQR) 1208-2006]. The incidence of preoperative lymphopenia was 14.0%, and 50.2%, 45.1% and 35.6% on POD1, POD3 and POD5, respectively. Preoperative lymphopenia predicted 5-year overall survival (OS) [lymphopenia vs. no lymphopenia: 49.1% vs. 66.1%] and 5-year disease-free survival (DFS) [25.0% vs. 41.5%] (both p < 0.05). Lymphopenia on POD1 (5-year OS: 57.1% vs. 71.2%; 5-year DFS: 30.0% vs. 41.1%), POD3 (5-year OS: 57.3% vs. 68.9%; 5-year DFS: 35.4% vs. 42.7%), and POD5 (5-year OS: 53.1% vs. 66.1%; 5-year DFS: 32.8% vs. 42.3%) was associated with worse long-term outcomes (all p < 0.05). Patients with severe lymphopenia (ALC <500/µL) on POD5 had worse 5-year OS and DFS (5-year OS: 44.7% vs. 54.3% vs. 66.1%; 5-year DFS: 27.8% vs. 33.3% vs. 42.3%) [both p < 0.05], as well as higher incidence of overall (45.5% vs. 25.3% vs. 30.9%; p = 0.013) and major complications (18.2% vs. 3.4% vs. 4.5%; p < 0.001) versus individuals with moderate (ALC 500-1000/µL) or no lymphopenia following hepatectomy for HCC. After adjusting for competing risk factors, prolonged lymphopenia was independently associated with higher hazards of death [hazard ratio (HR) 1.38, 95% CI 1.11-1.72] and recurrence (HR 1.22, 95% CI 1.02-1.45). CONCLUSION: Perioperative lymphopenia had short- and long-term prognostic implications among individuals undergoing hepatectomy for HCC.

Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma.

INTRODUCTION: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population. METHODS: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group. RESULTS: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0-67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days. CONCLUSIONS: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.

Preoperative platelet count as an independent predictor of long-term outcomes among patients undergoing resection for intrahepatic cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: An elevated platelet count may reflect neoplastic and inflammatory states, with cytokine-driven overproduction of platelets. The objective of this study was to evaluate the prognostic utility of high platelet count among patients undergoing curative-intent liver surgery for intrahepatic cholangiocarcinoma (ICC). METHODS: An international, multi-institutional cohort was used to identify patients undergoing curative-intent liver resection for ICC (2000-2020). A high platelet count was defined as platelets >300 *109/L. The relationship between preoperative platelet count, cancer-specific survival (CSS), and overall survival (OS) was examined. RESULTS: Among 825 patients undergoing curative-intent resection for ICC, 139 had a high platelet count, which correlated with multifocal disease, lymph nodes metastasis, poor to undifferentiated grade, and microvascular invasion. Patients with high platelet counts had worse 5-year (35.8% vs. 46.7%, p = 0.009) CSS and OS (24.8% vs. 39.8%, p < 0.001), relative to patients with a low platelet count. After controlling for relevant clinicopathologic factors, high platelet count remained an adverse independent predictor of CSS (HR = 1.46, 95% CI 1.02-2.09) and OS (HR = 1.59, 95% CI 1.14-2.22). CONCLUSIONS: High platelet count was associated with worse tumor characteristics and poor long-term CSS and OS. Platelet count represents a readily-available laboratory value that may preoperatively improve risk-stratification of patients undergoing curative-intent liver resection for ICC.

Development and Validation of a Predictive Risk Score for Blood Transfusion in Patients Undergoing Curative-Intent Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Among patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC), perioperative bleeding requiring blood transfusion is a common complication, yet preoperative identification of patients at risk for transfusion remains challenging. The objective of this study was to develop a preoperative risk score for blood transfusion requirement during surgery for ICC. METHODS: Patients undergoing curative-intent liver surgery for ICC (1990-2020) were identified from a multi-institutional database. A predictive model was developed and validated. An easy-to-use risk calculator was made available online. RESULTS: Among 1420 patients, 300 (21.1%) received an intraoperative transfusion. Independent predictors of transfusion included severe preoperative anemia (OR = 1.65, 95% CI 1.10-2.47), T2 category or higher (OR = 2.00, 95% CI 1.36-3.02), positive lymph nodes (OR = 1.75, 95% CI 1.32-2.32) and major resection (OR = 2.56, 95%CI 1.85-3.58). Receipt of blood transfusion significantly correlated with worse outcomes. The model showed good discriminative ability in both training (AUC = 0.68, 95% CI 0.66-0.72) and bootstrapping validation (C-index = 0.67, 95% CI 0.65-0.70) cohorts. An online risk calculator of blood transfusion requirement was developed (https://catalano-giovanni.shinyapps.io/TransfusionRisk). CONCLUSIONS: Intraoperative blood transfusion was significantly associated with poor postoperative outcomes among patients undergoing surgery for ICC. The identification of patients at high risk of transfusion could improve perioperative patient care and blood resources allocation.

Preoperative predictive factors for positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas: a retrospective study.

BACKGROUND: The clinical importance of positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas remains controversial. We evaluated the prognosis of these patients and the predictive preoperative risk factors for positive peritoneal cytology results. METHODS: We retrospectively reviewed patients who underwent curative-intent surgery at our institution between May 2010 and June 2020. Preoperative risk factors for positive peritoneal cytology results were identified using logistic regression analysis. A scoring model was constructed using the total number of significant independent predictors for positive peritoneal cytology results. RESULTS: Of 233 patients, 18 (7.7%) had positive peritoneal cytology results. The recurrence-free survival and cancer-specific survival were markedly worse in patients with positive peritoneal cytology results than in those with negative peritoneal cytology results (recurrence-free survival: 6.0 months vs. 16.6 months, p = 0.050; cancer-specific survival: 19.4 months vs. 47.5 months, p = 0.034). Tumor location (odds ratio: 3.760, 95% confidence interval: 1.099-11.818, p = 0.023), tumor size > 25 mm (odds ratio: 3.410, 95% confidence interval: 1.031-11.277, p = 0.046), preoperative serosal invasion (odds ratio: 5.193, 95% confidence interval: 1.099-24.531, p = 0.038), and preoperative carcinoembryonic antigen level > 5.6 ng/mL (odds ratio: 3.816, 95% confidence interval: 1.248-10.667, p = 0.019) were identified as significant independent predictive factors. Our predictive model's optimal cutoff and positive predictive values for positive peritoneal cytology results were 3 and 27.9%, respectively. CONCLUSIONS: The indications for curative-intent surgery should be considered carefully in patients with high-risk factors for positive peritoneal cytology results.

The shortage of surgeons in Japan: Results of an online survey of qualified teaching hospitals that take part in the surgical training programs for board certification by the Japan Surgical Society.

PURPOSE: A collapse in regional healthcare through the maldistribution of physicians has been a long-debated issue in Japan and amidst this situation, a new system of board certification was initiated. The Japan Surgical Society (JSS) conducted a nation-wide survey to grasp the current distribution of surgeons in Japan, and their roles. METHODS: All 1976 JSS-certified teaching hospitals were invited to respond to a web-based questionnaire. The responses were analyzed to seek a solution to the current issues. RESULTS: Responses to the questionnaire were received from 1335 hospitals. The surgical departments of medical universities serve as an internal labor market and were the source of surgeons for most hospitals. More than 50% of teaching hospitals throughout the country claimed a shortage of surgeons even in well-populated prefectures such as Tokyo and Osaka. Hospitals rely on surgeons to cover the deficits in medical oncology, anesthesiology, and emergency medicine. These additional responsibilities were identified as significant predictors of a shortage of surgeons. CONCLUSIONS: Surgeon shortage is a serious issue throughout Japan. Given the limited number of surgeons and surgical trainees, hospitals should make every effort to recruit specialists in the additional fields where surgeons are filling the gaps and allow surgeons to engage more in surgery.

The aMAP score predicts long-term outcomes after resection of hepatocellular carcinoma: a multi-institutional analysis.

BACKGROUND: The aMAP score is a proposed model to predict the development of hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis. The role of the aMAP score to predict long-term survival among patients following resection of HCC has not been determined. METHODS: Patients undergoing resection for HCC between 2000 and 2020 were identified using a multi-institutional database. The impact of the aMAP score on long-term outcomes following HCC resection was assessed. RESULTS: Among 1377 patients undergoing resection for HCC, a total of 972 (70.6 %) patients had a low aMAP score (≤63), whereas 405 (29.4 %) individuals had a high aMAP score (≥64). aMAP score was associated with 5-year OS in the entire cohort (low vs high aMAP score:66.5 % vs. 54.3 %, p < 0.001). aMAP score predicted 5-year OS following resection among patients with HBV-HCC (low vs. high aMAP:68.8 % vs. 55.6 %, p = 0.01) and NASH/other-HCC (64.7 % vs. 53.7, p = 0.04). aMAP score could sub-stratify 5-year OS among patients undergoing HCC resection within (low vs. high aMAP:81.5 % vs. 67.4 %, p < 0.001) and beyond (55.9 % vs. 38.8 %, p < 0.001) Milan criteria. DISCUSSION: The aMAP score predicted postoperative outcomes following resection of HCC within and beyond Milan criteria. Apart from a surveillance tool, the aMAP score can also be used as a prognostic tool among patients undergoing resection of HCC.

Impact of an artificial intelligence based model to predict non-transplantable recurrence among patients with hepatocellular carcinoma.

OBJECTIVE: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR). METHODS: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors. RESULTS: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001). CONCLUSION: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/).

Machine learning models including preoperative and postoperative albumin-bilirubin score: short-term outcomes among patients with hepatocellular carcinoma.

BACKGROUND: We sought to assess the impact of various perioperative factors on the risk of severe complications and post-surgical mortality using a novel maching learning technique. METHODS: Data on patients undergoing resection for HCC were obtained from an international, multi-institutional database between 2000 and 2020. Gradient boosted trees were utilized to construct predictive models. RESULTS: Among 962 patients who underwent HCC resection, the incidence of severe postoperative complications was 12.7% (n = 122); in-hospital mortality was 2.9% (n = 28). Models that exclusively used preoperative data achieved AUC values of 0.89 (95%CI 0.85 to 0.92) and 0.90 (95%CI 0.84 to 0.96) to predict severe complications and mortality, respectively. Models that combined preoperative and postoperative data achieved AUC values of 0.93 (95%CI 0.91 to 0.96) and 0.92 (95%CI 0.86 to 0.97) for severe morbidity and mortality, respectively. The SHAP algorithm demonstrated that the factor most strongly predictive of severe morbidity and mortality was postoperative day 1 and 3 albumin-bilirubin (ALBI) scores. CONCLUSION: Incorporation of perioperative data including ALBI scores using ML techniques can help risk-stratify patients undergoing resection of HCC.

Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

BACKGROUND: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). METHODS: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. RESULTS: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). CONCLUSION: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

The Impact of a Liver Transplant Program on the Outcomes of Hepatocellular Carcinoma.

OBJECTIVE: We sought to evaluate the impact of liver transplantation (LT) programs on the prognosis of hepatocellular carcinoma (HCC) patients who underwent liver resection (LR) and noncurative intent treatment. BACKGROUND: LT programs have an array of resources and services that would positively affect the prognosis of patients with HCC. METHODS: Patients who underwent LT, LR, radiotherapy (RT), or chemotherapy (CTx) for HCC between 2004 and 2018 were included in the National Cancer Database. Institutions with LT programs were defined as those that performed 1 or more LT for at least 5 years. Centers were stratified by hospital volume. The impact of LT programs was assessed after propensity score matching to achieve covariate balance. RESULTS: A total of 71,735 patients were identified, of which 7997 received LT (11.1%), 12,683 LR (17.7%), 15,675 RT (21.9%), and 35,380 CTx (49.3%). Among a total of 1267 distinct institutions, 94 (7.4%) were categorized as LT programs. Designation as an LT program was also associated with a high volume of LR and noncurative intent treatment (both P <0.001). After propensity score matching, LT programs were associated with better survival among LR and noncurative intent treatment patients. Although hospital volume was also associated with improved prognosis, LT programs were associated with additional survival benefits in noncurative intent treatment. On the other hand, no such benefit was noted in patients who underwent LR. CONCLUSIONS: The presence of an LT program was associated with a higher volume of LR and noncurative intent treatment. Furthermore, designation as an LT program had a "halo effect" on the prognosis of patients undergoing RT/CTx that went beyond the procedure-volume effect.

Standardized upfront Glissonean approach and liver hanging maneuver reduces bile leakage from the hepatic hilum in living donors.

Biliary complications after hepatectomy in living donors have yet to be eradicated. We hypothesized that a standardized upfront Glissonean approach and liver hanging maneuver (GH) would prevent mechanical and thermal injuries to the hilar plate of the remnant liver by determining the point of bile duct division and the final destination of hepatectomy preceding liver parenchymal transection (safety) and facilitate liver transection deep within the parenchyma and allow maximum length of hilar structures (rationality). GH was implemented in 2016 and its incidence of bile leakage was retrospectively compared against the conventional technique. GH comprises six steps: (1) development of the retrohepatic avascular plane between the right hepatic vein (RHV) and the middle hepatic vein (MHV) and isolation of the hepatic vein(s); (2) isolation of the right or left Glissonean pedicle with the corresponding Glissonean pedicles of the caudate lobe; (3) for right liver grafts and left liver grafts with the caudate lobe, passage of the tape for the liver hanging maneuver along the retrohepatic avascular plane and above the hilar plate, and for left liver grafts without the caudate lobe and for left lateral section grafts, passage of the tape from between the RHV and the MHV, along the Arantius ligament, and to the right of the umbilical portion; (4) liver transection; (5) isolation of hilar structures; and (6) graft procurement. Until 2020, 62 consecutive living donors underwent GH (success rate, 100%). The incidence of bile leakage from the hepatic hilum (0%) was significantly lower than that among 59 donors who underwent the conventional technique in 2011-2015 (9%; p = 0.01). In conclusion, GH is highly effective in reducing bile leakage from the hepatic hilum in living donors.

Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments.

BACKGROUND AND AIMS: Immune cells and tumor vessels constitute important elements in tumor tissue; however, their detailed relationship in human tumors, including HCC, is still largely unknown. Consequently, we expanded our previous study on the immune microenvironment of HCC and analyzed the relationship among the immune microenvironment, inflammatory/angiostatic factor expression, angiogenic factor expression, and tumor vessel findings, including vessels encapsulating tumor clusters (VETC) and macrotrabecular-massive (MTM) patterns. APPROACH AND RESULTS: We classified HCC into four distinct immunovascular subtypes (immune-high/angiostatic [IH/AS], immune-mid/angio-mid [IM/AM], immune-low/angiogenic [IL/AG], and immune-low/angio-low [IL/AL]). IH/AS, IM/AM, and IL/AG subtypes were associated with decreasing lymphocytic infiltration and increasing angiogenic factor expression and VETC/MTM positivity, reflecting their reciprocal interaction in the tumor microenvironment of HCC. IL/AG subtype was further characterized by CTNNB1 mutation and activation of Wnt/ß-catenin pathway. IL/AL subtype was not associated with increased lymphocyte infiltration or angiogenic factor expression. Prognostically, IH/AS subtype and VETC/MTM positivity were independently significant in two independent cohorts. Increased angiogenic factor expression was not necessarily associated with VETC/MTM positivity and poor prognosis, especially when inflammatory/angiostatic milieu coexisted around tumor vessels. These results may provide insights on the therapeutic effects of immunotherapy, antiangiogenic therapies, and their combinations. The potential of evaluating the immunovascular microenvironment in predicting the clinical effect of these therapies in nonresectable HCC needs to be analyzed in the future study. CONCLUSIONS: HCC can be classified into four distinct immunovascular subtypes (IH/AS, IM/AM, IL/AG, and IL/AL) that reflect the reciprocal interaction between the antitumor immune microenvironment and tumor angiogenesis. In addition to its clinicopathological significance, immunovascular classification may also provide pathological insights on the therapeutic effect of immunotherapy, antiangiogenic therapy, and their combination.

Higher Tumor Burden Status Dictates the Impact of Surgical Margin Status on Overall Survival in Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma.

BACKGROUND: The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status. METHOD: Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status. RESULTS: Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2-8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1-3 mm 38.5% vs. 3-10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1-3 mm 22.8% vs. 3-10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35-3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58-3.11, p = 0.50). CONCLUSION: R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.

A Novel Online Calculator to Predict Risk of Microvascular Invasion in the Preoperative Setting for Hepatocellular Carcinoma Patients Undergoing Curative-Intent Surgery.

BACKGROUND: The presence of microvascular invasion (MVI) has been highlighted as an important determinant of hepatocellular carcinoma (HCC) prognosis. We sought to build and validate a novel model to predict MVI in the preoperative setting. METHODS: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using a multi-institutional database. Preoperative predictive models for MVI were built, validated, and used to develop a web-based calculator. RESULTS: Among 689 patients, MVI was observed in 323 patients (46.9%). On multivariate analysis in the test cohort, preoperative parameters associated with MVI included α-fetoprotein (AFP; odds ratio [OR] 1.50, 95% confidence interval [CI] 1.23-1.83), imaging tumor burden score (TBS; hazard ratio [HR] 1.11, 95% CI 1.04-1.18), and neutrophil-to-lymphocyte ratio (NLR; OR 1.18, 95% CI 1.03-1.35). An online calculator to predict MVI was developed based on the weighted ß-coefficients of these three variables ( https://yutaka-endo.shinyapps.io/MVIrisk/ ). The c-index of the test and validation cohorts was 0.71 and 0.72, respectively. Patients with a high risk of MVI had worse disease-free survival (DFS) and overall survival (OS) compared with low-risk MVI patients (3-year DFS: 33.0% vs. 51.9%, p < 0.001; 5-year OS: 44.2% vs. 64.8%, p < 0.001). DFS was worse among patients who underwent an R1 versus R0 resection among those patients at high risk of MVI (R0 vs. R1 resection: 3-year DFS, 36.3% vs. 16.1%, p = 0.002). In contrast, DFS was comparable among patients at low risk of MVI regardless of margin status (R0 vs. R1 resection: 3-year DFS, 52.9% vs. 47.3%, p = 0.16). CONCLUSION: Preoperative assessment of MVI using the online tool demonstrated very good accuracy to predict MVI.

TBS-Based Preoperative Score to Predict Non-transplantable Recurrence and Identify Candidates for Upfront Resection Versus Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Recurrence following liver resection (LR) for hepatocellular carcinoma (HCC) can be as high as 50-70%. While salvage liver transplantation may be feasible, patients may develop a non-transplantable recurrence (NTR) (recurrence beyond Milan criteria). We sought to identify preoperative risk factors to predict NTR after resection. PATIENTS AND METHODS: Patients who underwent curative-intent LR for HCC were identified from a multi-institutional database. Preoperative factors associated with NTR were identified and a risk score model (NTR score) was developed and validated. RESULTS: Among 1620 patients, 842 (52.0%) developed recurrence; among patients with recurrence, NTR occurred in 341 (40.5%) with a median recurrence-free survival (RFS) of 30 months (24.7-35.3 months). On multivariable analysis, factors associated with NTR included alpha fetoprotein (AFP) > 400 ng/mL [hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.33-2.19], albumin-bilirubin grade (ALBI) (referent low, medium ALBI: HR 1.41, 95% CI 1.10-1.81, high ALBI: HR 2.47, 95% CI 0.91-6.68), and tumor burden score (TBS) (referent low, high TBS: HR 2.55, 95% CI, 1.99-3.28). A simplified TBS-based NTR score was developed using the ß-coefficients of each factor (C-index 0.68, 95% CI 0.65-0.71). Higher NTR score was associated with incrementally worse 5-year RFS (low 44.8%, medium 37.5%, high 24.5%) [area under the curve (AUC) 0.59] and increased incidence of NTR (low 13.7%, medium 25.4%, high 38.2%) (AUC 0.65) (both p < 0.001). Moreover, higher NTR score was associated with higher risk of extrahepatic recurrence (low 11.3%, medium 28.8%, high 37.5%) (p < 0.001). CONCLUSION: NTR following curative-intent resection of HCC occurred in one in five patients. A simple TBS-based NTR score accurately predicted the risk of NTR and may help identify candidates for upfront resection versus transplantation.

Development and Validation of a Machine-Learning Model to Predict Early Recurrence of Intrahepatic Cholangiocarcinoma.

BACKGROUND: The high incidence of early recurrence after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a detrimental effect on overall survival (OS). Machine-learning models may improve the accuracy of outcome prediction for malignancies. METHODS: Patients who underwent curative-intent hepatectomy for ICC were identified using an international database. Three machine-learning models were trained to predict early recurrence (< 12 months after hepatectomy) using 14 clinicopathologic characteristics. The area under the receiver operating curve (AUC) was used to assess their discrimination ability. RESULTS: In this study, 536 patients were randomly assigned to training (n = 376, 70.1%) and testing (n = 160, 29.9%) cohorts. Overall, 270 (50.4%) patients experienced early recurrence (training: n = 150 [50.3%] vs testing: n = 81 [50.6%]), with a median tumor burden score (TBS) of 5.6 (training: 5.8 [interquartile range {IQR}, 4.1-8.1] vs testing: 5.5 [IQR, 3.7-7.9]) and metastatic/undetermined nodes (N1/NX) in the majority of the patients (training: n = 282 [75.0%] vs testing n = 118 [73.8%]). Among the three different machine-learning algorithms, random forest (RF) demonstrated the highest discrimination in the training/testing cohorts (RF [AUC, 0.904/0.779] vs support vector machine [AUC, 0.671/0.746] vs logistic regression [AUC, 0.668/0.745]). The five most influential variables in the final model were TBS, perineural invasion, microvascular invasion, CA 19-9 lower than 200 U/mL, and N1/NX disease. The RF model successfully stratified OS relative to the risk of early recurrence. CONCLUSIONS: Machine-learning prediction of early recurrence after ICC resection may inform tailored counseling, treatment, and recommendations. An easy-to-use calculator based on the RF model was developed and made available online.