Evaluation of pancreatic chymotrypsin activity for on-site prediction of clinically relevant postoperative pancreatic fistula.

OBJECTIVES: Although the risk of complications due to postoperative pancreatic fistula (POPF) have been evaluated based on the amylase level in drained ascitic fluid, this method has much room for improvement regarding diagnostic accuracy and facility of the measurement. This study aimed to investigate the clinical value of measuring pancreatic chymotrypsin activity for rapid and accurate prediction of POPF after pancreaticoduodenectomy. METHODS: In 52 consecutive patients undergoing pancreaticoduodenectomy, the chymotrypsin activity in pancreatic juice was measured by calculating the increase in fluorescence intensity during the first 5 min after activation with an enzyme-activatable fluorophore. The predictive value for clinically relevant POPF (CR-POPF) was compared between this technique and the conventional method based on the amylase level. RESULTS: According to receiver operating characteristic analyses, pancreatic chymotrypsin activity on postoperative day (POD) 3 measured with a multiplate reader had the highest predictive value for CR-POPF (area under the curve [AUC], 0.752; P < 0.001), yielding 77.8 % sensitivity and 68.8 % specificity. The AUC and sensitivity/specificity of the amylase level in ascitic fluid on POD 3 were 0.695 (P = 0.053) and 77.8 %/41.2 %, respectively. Multivariable analysis identified high pancreatic chymotrypsin activity on POD 3 as an independent risk factor for CR-POPF. Measurement of pancreatic chymotrypsin activity with a prototype portable fluorescence photometer could significantly predict CR-POPF (AUC, 0.731; P = 0.010). CONCLUSION: Measurement of pancreatic chymotrypsin activity enabled accurate and rapid prediction of CR-POPF after pancreaticoduodenectomy. This can help surgeons to implement appropriate drain management at the patient's bedside without delay.

Middle-segment preserving pancreatectomy: a literature review and case report.

PURPOSE: Middle segment-preserving pancreatectomy (MSPP) is a relatively new parenchymal-sparing surgery that has been introduced as an alternative to total pancreatectomy (TP) for multicentric benign and borderline pancreatic diseases. To date, only 36 cases have been reported in English. METHODS: We reviewed 22 published articles on MSPP and reported an additional case. RESULTS: Our patient was a 49-year-old Japanese man diagnosed with Zollinger-Elison syndrome (ZES) caused by duodenal and pancreatic gastrinoma associated with multiple endocrine neoplasia syndrome type 1. We avoided TP and chose MSPP as the operative technique due to his relatively young age. The patient developed a grade B postoperative pancreatic fistula (POPF), which improved with conservative treatment. He was discharged without further treatment. To date, no tumor has recurred, and pancreatic function seems to be maintained. According to a literature review, the morbidity rate of MSPP is as high as 54%, mainly due to the high incidence of POPF (32%). In contrast, there was no perioperative mortality, and postoperative pancreatic function was comparable to that after conventional pancreatectomy. CONCLUSIONS: Despite the high incidence of POPF, MSPP appears to be safe, with low perioperative mortality and good postoperative pancreatic sufficiency.

How to do it: rescue duct-to-duct biliary reconstruction techniques to avoid severe biliary complications of hepatic resection for hepatocellular carcinoma.

There are few reports on duct-to-duct biliary reconstruction for complex liver resection with limited bile duct resection. We performed duct-to-duct biliary reconstruction in two patients undergoing limited bile duct resection where Roux-en-Y hepaticojejunostomy (HJ) was difficult. An external biliary drainage tube was placed routinely at the anastomotic site to prevent stenosis. In case 1, the tumor-infiltrated part of the left hepatic duct (LHD) was resected and the LHD was repaired using duct-to-duct reconstruction with interrupted sutures. In case 2, after the tumor-infiltrated part of the LHD and posterior hepatic duct (PHD) were resected, T-tube reconstruction was performed on the PHD, and the LHD was anastomosed using interrupted sutures for the posterior wall and a round ligament patch for the anterior wall. Our literature review suggests that an external biliary drainage tube with stenting over the anastomosis may reduce the risk of biliary complications.

International survey on opinions and use of robot-assisted and laparoscopic minimally invasive pancreatic surgery: 5-year follow up.

BACKGROUND: Evidence on the value of minimally invasive pancreatic surgery (MIPS) has been increasing but it is unclear how this has influenced the view of pancreatic surgeons on MIPS. METHODS: An anonymous survey was sent to members of eight international Hepato-Pancreato-Biliary Associations. Outcomes were compared with the 2016 international survey. RESULTS: Overall, 315 surgeons from 47 countries participated. The median volume of pancreatic resections per center was 70 (IQR 40-120). Most surgeons considered minimally invasive distal pancreatectomy (MIDP) superior to open (ODP) (94.6%) and open pancreatoduodenectomy (OPD) superior to minimally invasive (MIPD) (67.9%). Since 2016, there has been an increase in the number of surgeons performing both MIDP (79%-85.7%, p = 0.024) and MIPD (29%-45.7%, p < 0.001), and an increase in the use of the robot-assisted approach for both MIDP (16%-45.6%, p < 0.001) and MIPD (23%-47.9%, p < 0.001). The use of laparoscopy remained stable for MIDP (91% vs. 88.1%, p = 0.245) and decreased for MIPD (51%-36.8%, p = 0.024). CONCLUSION: This survey showed considerable changes of MIPS since 2016 with most surgeons considering MIDP superior to ODP and an increased use of robot-assisted MIPS. Surgeons prefer OPD and therefore the value of MIPD remains to be determined in randomized trials.

Liver Resection for Hepatocellular Carcinoma With Tumor Thrombus in the Inferior Vena Cava or Right Atrium: A Large-scale Multicenter Survey Conducted in Japan.

OBJECTIVE: To clarify the short and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA). BACKGROUND: These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease. METHODS: We contacted 211 specialized centers in Japan and collected data on liver resection for hepatocellular carcinoma with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed. RESULTS: A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the 3 groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. Multivariate analysis identified an indocyanine green retention rate at 15 minutes >15% and ≥3 tumors as prognostic factors affecting survival, whereas the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence. CONCLUSIONS: As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.

An International Expert Delphi Consensus on Defining Textbook Outcome in Liver Surgery (TOLS).

OBJECTIVE: To reach global expert consensus on the definition of TOLS in minimally invasive and open liver resection among renowned international expert liver surgeons using a modified Delphi method. BACKGROUND: Textbook outcome is a novel composite measure combining the most desirable postoperative outcomes into one single measure and representing the ideal postoperative course. Despite a recently developed international definition of Textbook Outcome in Liver Surgery (TOLS), a standardized and expert consensus-based definition is lacking. METHODS: This international, consensus-based, qualitative study used a Delphi process to achieve consensus on the definition of TOLS. The survey comprised 6 surgical domains with a total of 26 questions on individual surgical outcome variables. The process included 4 rounds of online questionnaires. Consensus was achieved when a threshold of at least 80% agreement was reached. The results from the Delphi rounds were used to establish an international definition of TOLS. RESULTS: In total, 44 expert liver surgeons from 22 countries and all 3 major international hepato-pancreato-biliary associations completed round 1. Forty-two (96%), 41 (98%), and 41 (98%) of the experts participated in round 2, 3, and 4, respectively. The TOLS definition derived from the consensus process included the absence of intraoperative grade ≥2 incidents, postoperative bile leakage grade B/C, postoperative liver failure grade B/C, 90-day major postoperative complications, 90-day readmission due to surgery-related major complications, 90-day/in-hospital mortality, and the presence of R0 resection margin. CONCLUSIONS: This is the first study providing an international expert consensus-based definition of TOLS for minimally invasive and open liver resections by the use of a formal Delphi consensus approach. TOLS may be useful in assessing patient-level hospital performance and carrying out international comparisons between centers with different clinical practices to further improve patient outcomes.

Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab.

BACKGROUND: Although the standard therapy for advanced-stage hepatocellular carcinoma (HCC) is systemic chemotherapy, the combination of atezolizumab and bevacizumab (atezo + bev) with a high objective response rate may lead to conversion to resection in patients with initially unresectable HCC. This study aims to evaluate the efficacy of atezo + bev in achieving conversion surgery and prolonged progression-free survival (PFS) for initially unresectable HCC. METHODS: The RACB study is a prospective, single-arm, multicenter, phase II trial evaluating the efficacy of combination therapy with atezo + bev for conversion surgery in patients with technically and/or oncologically unresectable HCC. The main eligibility criteria are as follows: (1) unresectable HCC without a history of systemic chemotherapy, (2) at least one target lesion based on RECIST ver. 1.1, and (3) a Child‒Pugh score of 5-6. The definition of unresectable tumors in this study includes macroscopic vascular invasion and/or extrahepatic metastasis and massive distribution of intrahepatic tumors. Patients will be treated with atezolizumab (1200 mg/body weight) and bevacizumab (15 mg/kg) every 3 weeks. If the patient is considered resectable on radiological assessment 12 weeks after initial chemotherapy, the patient will be treated with atezolizumab monotherapy 3 weeks after combination chemotherapy followed by surgery 3 weeks after atezolizumab monotherapy. If the patient is considered unresectable, the patient will continue with atezo + bev and undergo a radiological assessment every 9 weeks until resectable or until disease progression. The primary endpoint is PFS, and the secondary endpoints are the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo + bev therapy. The assessments of safety and quality of life during the treatment course will also be evaluated. The number of patients has been set at 50 based on the threshold and the expected PFS rate at 6 months after enrollment of 40% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods will be 2 and 1.5 years, respectively. DISCUSSION: This study will elucidate the efficacy of conversion surgery with atezo + bev for initially unresectable HCC. In addition, the conversion rate, safety and quality of life during the treatment course will also be demonstrated. TRIAL REGISTRATION: This study is registered in the Japan Registry of Clinical Trials (jRCTs051210148, January 7, 2022).

Reevaluation of Makuuchi's criteria for resecting hepatocellular carcinoma: A Japanese nationwide survey.

AIM: Although Makuuchi's criteria are widely used to determine the cut-off for safe liver resection, there have been few reports of concrete data supporting their validity. Here, we verified the utility of Makuuchi's criteria by comparing the operative mortality rates associated with liver resection between hepatocellular carcinoma (HCC) patients meeting or exceeding the criteria. METHODS: A database was built using data from 15 597 patients treated between 2000 and 2007 for whom values for all three variables included in Makuuchi's criteria for liver resection (clinical ascites, serum bilirubin, and indocyanine green clearance) were available. The patients were divided into those fulfilling (n = 12 175) or exceeding (n = 3422) the criteria. The postoperative mortality (death for any reason within 30 days) and long-term survival were compared between the two groups. RESULTS: The operative mortality rate was significantly lower in patients meeting the criteria than in those exceeding the criteria (1.07% vs. 2.01%, respectively; p < 0.001). On multivariate analysis, exceeded the criteria was significantly associated with the risk for operative mortality (relative risk 2.08; 95% confidence interval (CI), 1.23-3.52; p = 0.007). Surgical indication meeting or exceeding the criteria was an independent factor for overall survival (hazard ratio 1.27; 95% CI, 1.18-1.36; p < 0.001). CONCLUSION: Makuuchi's criteria are suitable for determining the indication for resection of HCC due to the reduction in risk of operative mortality.

Report of the 23rd nationwide follow-up survey of primary liver cancer in Japan (2014-2015).

For the 23rd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 20 889 newly registered patients and 42 274 previously registered follow-up patients were compiled from 516 institutions over a 2-year period from January 1, 2014 to December 31, 2015. Basic statistics compiled for patients newly registered in the 23rd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathological diagnosis, recurrence status, and autopsy findings. Compared with the previous 22nd survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, had more patients with non-B non-C HCC, had smaller tumor diameter, and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2004 and 2015 whose final outcome was survival or death. The median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter, Child-Pugh grade, or albumin-bilirubin grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2015 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer in the world.

Laparoscopic minor liver resection for hepatocellular carcinoma.

BACKGROUND: Previous studies have suggested that laparoscopic liver resection for hepatocellular carcinoma is associated with lower postoperative complications compared with open liver resection. METHODS: We conducted a retrospective analysis of 109 hepatocellular carcinoma patients who underwent minor liver resection at a Japanese tertiary care hospital from November 2010 to December 2022. RESULTS: The laparoscopic liver resection group experienced significantly lower median intraoperative blood loss compared with the open liver resection group (P = 0.0001). Furthermore, the laparoscopic liver resection group had a significantly shorter median hospital stay compared with the open liver resection group (P = 0.0002). However, there was no significant difference in median postoperative survival between the laparoscopic liver resection group and the open liver resection group (P = 0.717). CONCLUSIONS: Laparoscopic minor liver resection for hepatocellular carcinoma resulted in reduced blood loss and hospital stay without compromising long-term survival outcomes.

Percutaneous Transhepatic Gallbladder Intervention as a Bridge to Cholecystectomy: Aspiration or Drainage?

BACKGROUND: Percutaneous transhepatic gallbladder aspiration (PTGBA) and percutaneous transhepatic gallbladder drainage (PTGBD) are often the first-line treatments for acute cholecystitis, instead of surgical cholecystectomy. This retrospective study aimed to compare the treatment outcomes of PTGBA and PTGBD and evaluate the risks of treatment failure among patients undergoing PTGBA before surgical cholecystectomy. METHODS: We retrospectively reviewed 99 patients who underwent PTGBA or PTGBD as the first-line treatment before surgical cholecystectomy, between January 2014 and December 2019. Patient characteristics, computed tomography (CT) findings, and post-treatment outcomes were compared between the PTGBA and PTGBD groups. Additionally, risk factors, including CT findings for PTGBA failure, were assessed using multivariate univariate analysis with a backward selection model. RESULTS: Acute cholecystitis was not controlled in 21 of 47 (44.7%) patients in the PTGBA group and one of 52 patients (1.9%) in the PTGBD group (P < .001). Subsequent multiple logistic regression analysis identified the contrast effect of the gallbladder bed in the arterial phase of contrast-enhanced CT (odds ratio [OR] 9.17, 95% confidence interval [CI] 2.08-40.4, P = 0.003) and onset within 3 days (odds ratio [OR] 6.29, 95% confidence interval [CI] 1.37-29.0, P = 0.018) as independent risk factors for PTGBA failure. CONCLUSIONS: PTGBA is more prone to failure than PTGBD; however, it is a simpler gallbladder drainage treatment method without the need for X-ray fluoroscopy and catheter management after the procedure. Evaluating the risk of PTGBA failure using CT findings and onset date would help us choose a drainage approach more effectively.

Clinical outcomes after tracheostomy in patients with coronavirus disease 2019: a single-center experience in Japan.

PURPOSE: Many patients with coronavirus disease 2019 require mechanical ventilation and tracheostomy. However, the timing and indications for tracheostomy are controversial. This study assessed 11 patients with coronavirus disease 2019 who underwent tracheostomy with clinical information and retrospective analyses. METHODS: A single-center retrospective observational study was performed on patients with coronavirus disease 2019 who underwent tracheostomy between 2020 and 2021. RESULTS: Failure to wean was the most common indication for tracheostomy, followed by extracorporeal membrane oxygenation decannulation and the need for secretion management. After tracheostomy, six patients (54.5%) were liberated from the ventilator. The time from intubation to tracheostomy (21.1 ± 9.14 days) was correlated with the duration of ventilator dependency (36.83 ± 20.45 days, r2 = 0.792, p = 0.018). The mean Acute Physiological and Chronic Health Evaluation II score was significantly lower in the ventilator-liberated group (23 ± 2.77) than in the non-ventilator-liberated group (31 ± 6.13, p = 0.0292). Furthermore, patients with Acute Physiological and Chronic Health Evaluation II scores of < 27 points achieved ventilator liberation and a long-term survival (p = 0.0006). CONCLUSIONS: This study describes the outcomes of a cohort of patients who underwent tracheostomy after intubation for coronavirus disease 2019. The Acute Physiological and Chronic Health Evaluation II score predicted whether or not the patient could achieve ventilator liberation.

Surgical management of appendicitis in patients with human immunodeficiency virus (HIV) positivity: a propensity score-matched analysis in a base hospital for HIV treatment in Japan.

PURPOSE: To investigate the impact of human immunodeficiency virus (HIV) infection on surgical outcomes after appendectomy. METHODS: Data on patients who underwent appendectomy for acute appendicitis between 2010 and 2020 at our hospital were investigated retrospectively. The patients were classified into HIV-positive and HIV-negative groups using propensity score-matching (PSM) analysis, adjusting for the five reported risk factors for postoperative complications: age, sex, Blumberg's sign, C-reactive protein level, and white blood cell count. We compared the postoperative outcomes of the two groups. HIV infection parameters, including the number and proportion of CD4 + lymphocytes and the HIV-RNA levels were also compared before and after appendectomy in the HIV-positive patients. RESULTS: Among 636 patients enrolled, 42 were HIV-positive and 594 were HIV-negative. Postoperative complications occurred in five HIV-positive patients and eight HIV-negative patients, with no significant difference in the incidence (p = 0.405) or severity of any complication (p = 0.655) between the groups. HIV infection was well-controlled preoperatively using antiretroviral therapy (83.3%). There was no deterioration in parameters and no changes in the postoperative treatment in any of the HIV-positive patients. CONCLUSION: Advances in antiviral drugs have made appendectomy a safe and feasible procedure for HIV-positive patients, with similar postoperative complication risks to HIV-negative patients.

Assessment of liver function-related mRNA expression and fluorescence imaging in outflow-obstructed regions in rats.

PURPOSE: The liver function in outflow-obstructed regions is reportedly impaired; however, the functional decrease has not been quantitatively assessed. We therefore evaluated the uptake of indocyanine green (ICG) into hepatocytes and the mRNA expression associated with the liver function in outflow-obstructed regions using rat models. METHODS: A total of 20 rats with the ligation of the right median hepatic vein to induce outflow obstruction were studied. Five rats each were grouped by the time of re-laparotomy, and the fluorescence intensity (FI) values of ICG. The mRNA expression, including that of Albumin, Cytochrome P450 (Cyp) 1a2, Cyp3a1, Cyp7a1, and Gamma-glutamylcysteine synthetase, in outflow-obstructed (mRNAOut-Ob) and non-outflow-obstructed (mRNANon) regions was assessed. RESULTS: Microscopic fluorescence imaging showed that the FI values were significantly lower in outflow-obstructed regions than in non-outflow-obstructed regions at 12 h, 24 h, and 3 days after ligation of the hepatic vein. The mRNAOut-Ob/mRNANon ratios decreased to approximately 30% at 12 h after the outflow obstruction and increased to approximately 70-80% at 7 days. CONCLUSIONS: The liver function in outflow-obstructed regions was impaired in terms of the uptake of ICG and the mRNA expression. Our findings may help estimate the postoperative functional remnant liver volume by considering the decrease in the liver function in outflow-obstructed regions.

The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE.

BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management. METHODS: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSIONS: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis.

BACKGROUND: Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. METHODS: In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). FINDINGS: Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9-9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3-1·4) and median overall survival was 5·2 years (95% CI 5·0-5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0-3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). INTERPRETATION: We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. FUNDING: US National Cancer Institute.

Consensus Conference Statement on the General Use of Near-infrared Fluorescence Imaging and Indocyanine Green Guided Surgery: Results of a Modified Delphi Study.

BACKGROUND: In recent decades, the use of near-infrared light and fluorescence-guidance during open and laparoscopic surgery has exponentially expanded across various clinical settings. However, tremendous variability exists in how it is performed. OBJECTIVE: In this first published survey of international experts on fluorescence-guided surgery, we sought to identify areas of consensus and nonconsensus across 4 areas of practice: fundamentals; patient selection/preparation; technical aspects; and effectiveness and safety. METHODS: A Delphi survey was conducted among 19 international experts in fluorescence-guided surgery attending a 1-day consensus meeting in Frankfurt, Germany on September 8th, 2019. Using mobile phones, experts were asked to anonymously vote over 2 rounds of voting, with 70% and 80% set as a priori thresholds for consensus and vote robustness, respectively. RESULTS: Experts from 5 continents reached consensus on 41 of 44 statements, including strong consensus that near-infrared fluorescence-guided surgery is both effective and safe across a broad variety of clinical settings, including the localization of critical anatomical structures like vessels, detection of tumors and sentinel nodes, assessment of tissue perfusion and anastomotic leaks, delineation of segmented organs, and localization of parathyroid glands. Although the minimum and maximum safe effective dose of ICG were felt to be 1 to 2 mg and >10 mg, respectively, there was strong consensus that determining the optimum dose, concentration, route and timing of ICG administration should be an ongoing research focus. CONCLUSIONS: Although fluorescence imaging was almost unanimously perceived to be both effective and safe across a broad range of clinical settings, considerable further research remains necessary to optimize its use.

Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.

BACKGROUND & AIMS: Although the tumor microenvironment plays an important role in tumor growth, it is not fully understood what role hepatic stellate cells (HSCs) play in the hepatocellular carcinoma (HCC) microenvironment. METHODS: A high-fat diet after streptozotocin was administered to HSC-specific Atg7-deficient (GFAP-Atg7 knockout [KO]) or growth differentiation factor 15 (GDF15)-deficient (GFAP-GDF15KO) mice. LX-2 cells, a human HSC cell line, were cultured with human hepatoma cells. RESULTS: In the steatohepatitis-based tumorigenesis model, GFAP-Atg7KO mice formed fewer and smaller liver tumors than their wild-type littermates. Mixed culture of LX-2 cells and hepatoma cells promoted LX-2 cell autophagy and hepatoma cell proliferation, which were attenuated by Atg7 KO in LX-2 cells. Hepatoma cell xenograft tumors grew rapidly in the presence of LX-2 cells, but Atg7 KO in LX-2 cells abolished this growth. RNA-sequencing revealed that LX-2 cells cultured with HepG2 cells highly expressed GDF15, which was abolished by Atg7 KO in LX-2 cells. GDF15 KO LX-2 cells did not show a growth-promoting effect on hepatoma cells either in vitro or in the xenograft model. GDF15 deficiency in HSCs reduced liver tumor size caused by the steatohepatitis-based tumorigenesis model. GDF15 was highly expressed and GDF15-positive nonparenchymal cells were more abundant in human HCC compared with noncancerous parts. Single-cell RNA sequencing showed that GDF15-positive rates in HSCs were higher in HCC than in background liver. Serum GDF15 levels were high in HCC patients and increased with tumor progression. CONCLUSIONS: In the HCC microenvironment, an increase of HSCs that produces GDF15 in an autophagy-dependent manner may be involved in tumor progression.

Report of the 22nd nationwide follow-up Survey of Primary Liver Cancer in Japan (2012-2013).

In the 22nd Nationwide Follow-up Survey of Primary Liver Cancer in Japan, data from 21 155 newly registered patients and 43 041 previously registered follow-up patients were compiled from 538 institutions over a 2-year period from January 1, 2012 to December 31, 2013. Basic statistics compiled for patients newly registered in the 22nd survey were cause of death, past medical history, clinical diagnosis, imaging diagnosis, treatment-related factors, pathologic diagnosis, recurrence status and autopsy findings. Compared with the previous 21st survey, the population of patients with hepatocellular carcinoma (HCC) was older at the time of clinical diagnosis, had more female patients, more patients with non-B non-C HCC, smaller tumor diameter and was more frequently treated with hepatectomy. Cumulative survival rates were calculated for HCC, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma (combined HCC and intrahepatic cholangiocarcinoma) by treatment type and background characteristics for patients newly registered between 2002 and 2013 whose final outcome was survival or death. Median overall survival and cumulative survival rates for HCC were calculated by dividing patients by combinations of background factors (number of tumors, tumor diameter or Child-Pugh grade) and by treatment type (hepatectomy, radiofrequency ablation therapy, transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy and systemic therapy). The same values were also calculated according to registration date by dividing patients newly registered between 1978 and 2013 into five time period groups. The data obtained from this nationwide follow-up survey are expected to contribute to advancing clinical research and treatment of primary liver cancer worldwide.