Laparoscopic versus open right hepatectomy for colorectal liver metastases after portal vein embolization: international multicentre study.

BACKGROUND: Laparoscopic liver surgery is increasingly used for more challenging procedures. The aim of this study was to assess the feasibility and oncological safety of laparoscopic right hepatectomy for colorectal liver metastases after portal vein embolization. METHODS: This was an international retrospective multicentre study of patients with colorectal liver metastases who underwent open or laparoscopic right and extended right hepatectomy after portal vein embolization between 2004 and 2020. The perioperative and oncological outcomes for patients who underwent laparoscopic and open approaches were compared using propensity score matching. RESULTS: Of 338 patients, 84 patients underwent a laparoscopic procedure and 254 patients underwent an open procedure. Patients in the laparoscopic group less often underwent extended right hepatectomy (18% versus 34.6% (P = 0.004)), procedures in the setting of a two-stage hepatectomy (42% versus 65% (P < 0.001)), and major concurrent procedures (4% versus 16.1% (P = 0.003)). After propensity score matching, 78 patients remained in each group. The laparoscopic approach was associated with longer operating and Pringle times (330 versus 258.5 min (P < 0.001) and 65 versus 30 min (P = 0.001) respectively) and a shorter length of stay (7 versus 8 days (P = 0.011)). The R0 resection rate was not different (71% for the laparoscopic approach versus 60% for the open approach (P = 0.230)). The median disease-free survival was 12 (95% c.i. 10 to 20) months for the laparoscopic approach versus 20 (95% c.i. 13 to 31) months for the open approach (P = 0.145). The median overall survival was 28 (95% c.i. 22 to 48) months for the laparoscopic approach versus 42 (95% c.i. 35 to 52) months for the open approach (P = 0.614). CONCLUSION: The advantages of a laparoscopic over an open approach for (extended) right hepatectomy for colorectal liver metastases after portal vein embolization are limited.

'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer.

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

The differential benefit of laparoscopic over open minor liver resection for lesions situated in the anterolateral or posterosuperior segments.

Background: It is well known that laparoscopic liver surgery can offer advantages over open liver surgery in selected patients. However, what type of procedures can benefit most from a laparoscopic approach has been investigated poorly thus far. The aim of this study is thus to define the extent of advantages of laparoscopic over open liver surgery for lesions in the anterolateral (AL) and posterosuperior (PS) segments. Methods: In this international multicentre retrospective cohort study, laparoscopic and open minor liver resections for lesions in the AL and PS segments were compared after propensity score matching. The differential benefit of laparoscopy over open liver surgery, calculated using bootstrap sampling, was compared between AL and PS resections and expressed as a Delta of the differences. Results: After matching, 3,040 AL and 2,336 PS resections were compared, encompassing open and laparoscopic procedures in a 1:1 ratio. AL and PS laparoscopic liver resections were more advantageous in comparison to open in terms of blood loss, transfusion rate, complications, and length of stay. However, AL resections benefitted more from laparoscopy than PS in terms of overall and severe complications (D-difference were 4.8%, P=0.046 and 3%, P=0.046) and blood loss (D-difference was 195 mL, P<0.001). Similar results were observed in the subset for high-volume centres, while in recent years no significant differences were found in the differential benefit between AL and PS segments. Conclusions: The advantage of laparoscopic over open liver surgery is greater in the AL segments than in the PS segments.

Laparoscopic Versus Open Hemihepatectomy: The ORANGE II PLUS Multicenter Randomized Controlled Trial.

PURPOSE: To compare outcomes after laparoscopic versus open major liver resection (hemihepatectomy) mainly for primary or metastatic cancer. The primary outcome measure was time to functional recovery. Secondary outcomes included morbidity, quality of life (QoL), and for those with cancer, resection margin status and time to adjuvant systemic therapy. PATIENTS AND METHODS: This was a multicenter, randomized controlled, patient-blinded, superiority trial on adult patients undergoing hemihepatectomy. Patients were recruited from 16 hospitals in Europe between November 2013 and December 2018. RESULTS: Of the 352 randomly assigned patients, 332 patients (94.3%) underwent surgery (laparoscopic, n = 166 and open, n = 166) and comprised the analysis population. The median time to functional recovery was 4 days (IQR, 3-5; range, 1-30) for laparoscopic hemihepatectomy versus 5 days (IQR, 4-6; range, 1-33) for open hemihepatectomy (difference, -17.5% [96% CI, -25.6 to -8.4]; P < .001). There was no difference in major complications (laparoscopic 24/166 [14.5%] v open 28/166 [16.9%]; odds ratio [OR], 0.84; P = .58). Regarding QoL, both global health status (difference, 3.2 points; P < .001) and body image (difference, 0.9 points; P < .001) scored significantly higher in the laparoscopic group. For the 281 (84.6%) patients with cancer, R0 resection margin status was similar (laparoscopic 106 [77.9%] v open 122 patients [84.1%], OR, 0.60; P = .14) with a shorter time to adjuvant systemic therapy in the laparoscopic group (46.5 days v 62.8 days, hazard ratio, 2.20; P = .009). CONCLUSION: Among patients undergoing hemihepatectomy, the laparoscopic approach resulted in a shorter time to functional recovery compared with open surgery. In addition, it was associated with a better QoL, and in patients with cancer, a shorter time to adjuvant systemic therapy with no adverse impact on cancer outcomes observed.

National Institute for Health and Care Excellence (NICE) guidance on monitoring and management of Barrett's oesophagus and stage I oesophageal adenocarcinoma.

Barrett's oesophagus is the only known precursor to oesophageal adenocarcinoma, a cancer with very poor prognosis. The main risk factors for Barrett's oesophagus are a history of gastro-oesophageal acid reflux symptoms and obesity. Men, smokers and those with a family history are also at increased risk. Progression from Barrett's oesophagus to cancer occurs via an intermediate stage, known as dysplasia. However, dysplasia and early cancer usually develop without any clinical signs, often in individuals whose symptoms are well controlled by acid suppressant medications; therefore, endoscopic surveillance is recommended to allow for early diagnosis and timely clinical intervention. Individuals with Barrett's oesophagus need to be fully informed about the implications of this diagnosis and the benefits and risks of monitoring strategies. Pharmacological treatments are recommended for control of symptoms, but not for chemoprevention. Dysplasia and stage 1 oesophageal adenocarcinoma have excellent prognoses, since they can be cured with endoscopic or surgical therapies. Endoscopic resection is the most accurate staging technique for early Barrett's-related oesophageal adenocarcinoma. Endoscopic ablation is effective and indicated to eradicate Barrett's oesophagus in patients with dysplasia. Future research should focus on improved accuracy for dysplasia detection via new technologies and providing more robust evidence to support pathways for follow-up and treatment.

Pan-European survey on current treatment strategies in patients with upfront resectable colorectal liver metastases.

BACKGROUND: There is a lack of consensus on the definition of upfront resectability and use of perioperative systemic therapy for colorectal liver metastases (CRLM). This survey aimed to summarize the current treatment strategies for upfront resectable CRLM throughout Europe. METHODS: A survey was sent to all members of the European-African Hepato-Pancreato-Biliary Association to gain insight into the current views on resectability and the use of systemic therapy for upfront resectable CRLM. RESULTS: The survey was completed by 87 surgeons from 24 countries. The resectability of CRLM is mostly based on the volume of the future liver remnant, while considering tumor biology. Thermal ablation was considered as an acceptable adjunct to resection in parenchymal-sparing CRLM surgery by 77 % of the respondents. A total of 40.2 % of the respondents preferred standard perioperative systemic therapy and 24.1 % preferred standard upfront local treatment. CONCLUSION: Among the participating European hepato-pancreato-biliary surgeons, there is a high degree of consensus on the definition of CRLM resectability. However, there is much variety in the use of adjunctive thermal ablation. Major variations persist in the use of perioperative systemic therapy in cases of upfront resectable CRLM, stressing the need for further evidence and a consensus.

Autogenic splenic implantation versus splenectomy in patients undergoing distal pancreatectomy for benign or low-grade malignant lesions of the distal pancreas: study protocol for a multicentre, open-label, randomized controlled trial (RESTORE).

BACKGROUND: The spleen plays a significant role in the clearance of circulating microorganisms. Sequelae of splenectomy, especially immunodeficiency, can have a deleterious effect on a patient's health and even lead to death. Hence, splenectomy should be avoided and spleen preservation during elective surgery has become a treatment goal. However, this cannot be achieved in every patient due to intraoperative technical difficulties or oncological reasons. Autogenic splenic implantation (ASI) is currently the only possible way to preserve splenic function when a splenectomy is necessary. Experience largely stems from trauma patients with a splenic rupture. Splenic immune function can be measured by the body's clearing capacity of encapsulated bacteria. The aim of this study is to assess the splenic immune function after ASI was performed during minimally invasive (laparoscopic or robotic) distal pancreatectomy with splenectomy. METHODS: This is the protocol for a multicentre, randomized, open-labelled trial. Thirty participants with benign or low-grade malignant lesions of the distal pancreas requiring minimally invasive distal pancreatectomy and splenectomy will be allocated to either additional intraoperative ASI (intervention) or no further intervention (control). An additional 15 patients who will undergo spleen-preserving distal pancreatectomy serve as the control group with normal splenic function. Six months postoperatively, after assumed restoration of splenic function, patients will be given a Salmonella typhi (Typhim Vi™) vaccine. The Salmonella typhi vaccine is a polysaccharide vaccine. The specific antibody titres immediately before and 4 to 6 weeks after vaccination will be measured. The ratio between pre- and post-vaccination antibody count is the primary outcome measure and secondary outcome measures include intraoperative details, length of hospital stay, 30-day mortality and morbidity. DISCUSSION: This study will investigate the splenic immune function of patients who undergo ASI during minimally invasive distal pancreatectomy with splenectomy. The splenic immune function will be measured using the surrogate outcome of specific antibody titre after vaccination with a Salmonella typhi vaccine. The results will reveal details about splenic function after ASI and guide further treatment options for patients when a splenectomy cannot be avoided. It might eventually lead to a new standard of care making sometimes more demanding and time-consuming spleen-preserving procedures redundant. TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) ISRCTN10171587. Prospectively registered on 18 February 2019.

The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS).

OBJECTIVE: To develop and update evidence-based and consensus-based guidelines on laparoscopic and robotic pancreatic surgery. SUMMARY BACKGROUND DATA: Minimally invasive pancreatic surgery (MIPS), including laparoscopic and robotic surgery, is complex and technically demanding. Minimizing the risk for patients requires stringent, evidence-based guidelines. Since the International Miami Guidelines on MIPS in 2019, new developments and key publications have been reported, necessitating an update. METHODS: Evidence-based guidelines on 22 topics in 8 domains were proposed: terminology, indications, patients, procedures, surgical techniques and instrumentation, assessment tools, implementation and training, and artificial intelligence. The Brescia Internationally Validated European Guidelines on Minimally Invasive Pancreatic Surgery (EGUMIPS, September 2022) used the Scottish Intercollegiate Guidelines Network (SIGN) methodology to assess the evidence and develop guideline recommendations, the Delphi method to establish consensus on the recommendations among the Expert Committee, and the AGREE II-GRS tool for guideline quality assessment and external validation by a Validation Committee. RESULTS: Overall, 27 European experts, 6 international experts, 22 international Validation Committee members, 11 Jury Committee members, 18 Research Committee members, and 121 registered attendees of the 2-day meeting were involved in the development and validation of the guidelines. In total, 98 recommendations were developed, including 33 on laparoscopic, 34 on robotic, and 31 on general MIPS, covering 22 topics in 8 domains. Out of 98 recommendations, 97 reached at least 80% consensus among the experts and congress attendees, and all recommendations were externally validated by the Validation Committee. CONCLUSIONS: The EGUMIPS evidence-based guidelines on laparoscopic and robotic MIPS can be applied in current clinical practice to provide guidance to patients, surgeons, policy-makers, and medical societies.

Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy.

OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.

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.

A critical appraisal of the potential benefit of post-operative structured follow-up after resection for biliary tract cancer.

BACKGROUND: There is currently no evidence to support structured use of imaging or biomarkers during follow-up of patients after curative resection of biliary tract cancer (BTC). Besides, the influence of early detection of recurrence and subsequent start of palliative chemotherapy on overall survival remains unknown. The aim of this study is to describe and compare the results of two follow-up strategies. METHODS: This retrospective multicenter cohort study compared patients from the Amsterdam UMC undergoing pragmatic clinical follow-up, to patients from the observational cohort of the BILCAP study undergoing structured follow-up. Primary outcome was overall survival. RESULTS: A total of 315 patients were included n=91 pragmatic, n=224 structured follow-up). At median follow-up of 56.9 months, 189 (60%) patients were diagnosed with recurrence. After recurrence, more patients received palliative (chemo) therapy in the structured group (43% vs 75%, P<0.001). Median overall survival was lower in the pragmatic group (27.7 vs 39.1 months, P=0.003). Median overall survival of patients who actually received chemotherapy was comparable (27.2 vs 27.7 months, P=0.574). CONCLUSION: This study describes the results of two follow-up strategies. Although these groups are biased, it is noted that after pragmatic follow-up fewer patients received palliative chemotherapy but that those who actually received chemotherapy had similar overall survival compared to patients undergoing structured follow-up.

Trends in the characteristics and perioperative outcomes of patients undergoing laparoscopic and open resections for benign liver lesions: An international multicenter retrospective cohort study of 845 patients.

BACKGROUND: Solid benign liver lesions (BLL) are increasingly discovered, but clear indications for surgical treatment are often lacking. Concomitantly, laparoscopic liver surgery is increasingly performed. The aim of this study was to assess if the availability of laparoscopic surgery has had an impact on the characteristics and perioperative outcomes of patients with BLL. METHODS: This is a retrospective international multicenter cohort study, including patients undergoing a laparoscopic or open liver resection for BLL from 19 centers in eight countries. Patients were divided according to the time period in which they underwent surgery (2008-2013, 2014-2016, and 2017-2019). Unadjusted and risk-adjusted (using logistic regression) time-trend analyses were performed. The primary outcome was textbook outcome (TOLS), defined as the absence of intraoperative incidents ≥ grade 2, bile leak ≥ grade B, severe complications, readmission and 90-day or in-hospital mortality, with the absence of a prolonged length of stay added to define TOLS+. RESULTS: In the complete dataset comprised of patients that underwent liver surgery for all indications, the proportion of patients undergoing liver surgery for benign disease remained stable (12.6% in the first time period, 11.9% in the second time period and 12.1% in the last time period, p = 0.454). Overall, 845 patients undergoing a liver resection for BLL in the first (n = 374), second (n = 258) or third time period (n = 213) were included. The rates of ASA-scores≥3 (9.9%-16%,p < 0.001), laparoscopic surgery (57.8%-77%,p < 0.001), and Pringle maneuver use (33.2%-47.2%,p = 0.001) increased, whereas the length of stay decreased (5 to 4 days,p < 0.001). There were no significant changes in the TOLS rate (86.6%-81.3%,p = 0.151), while the TOLS + rate increased from 41.7% to 58.7% (p < 0.001). The latter result was confirmed in the risk-adjusted analyses (aOR 1.849,p = 0.004). CONCLUSION: The surgical treatment of BLL has evolved with an increased implementation of the laparoscopic approach and a decreased length of stay. This evolution was paralleled by stable TOLS rates above 80% and an increase in the TOLS + rate.

Cancer cell-derived extracellular vesicles activate hepatic stellate cells in colorectal cancer.

Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths worldwide, primarily due to the development of metastatic disease. The liver is the most frequently affected site. The metastatic cascade relies on a complex interaction between the immune system, tumor, and distant organs. Communication between the tumor and the metastatic site can be mediated by tumor-derived extracellular vesicles (EVs) and their cargo. The mechanisms underlying this process are starting to be understood through research that has rapidly expanded over the past 15 years. One crucial aspect is the remodeling of the microenvironment at the site of metastasis, which is essential for the formation of a premetastatic niche and the subsequent establishment of metastatic deposits. In the evaluated study, the authors use cellular experiments and a mouse model to investigate how tumour derived extracellular vesicles and their microRNA contents interact with hepatic stellate cells (HSCs). They demonstrate how this may lead to remodelling of the microenvironment and the formation of colorectal liver metastasis using their experimental model. In this mini review, we examine the current evidence surrounding tumour derived EVs and their effect on the tumour microenvironment to highlight potential areas for future research in CRC and other malignancies.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial.

Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of -7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI -6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0-30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5-5.5] vs 5 [95% CI 4.7-5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67-1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial.

Importance: Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal. Objective: To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial. Design, Setting, and Participants: This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021. Interventions: Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort. Main Outcomes and Measures: A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS). Results: A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively. Conclusions and Relevance: In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases. Trial Registration: isrctn.org Identifier: ISRCTN22944367.

Laparoscopic Right Hemihepatectomy after Future Liver Remnant Modulation: A Single Surgeon's Experience.

BACKGROUND: Laparoscopic right hemihepatectomy (L-RHH) is still considered a technically complex procedure, which should only be performed by experienced surgeons in specialized centers. Future liver remnant modulation (FLRM) strategies, including portal vein embolization (PVE), and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), might increase the surgical difficulty of L-RHH, due to the distortion of hepatic anatomy, periportal inflammation, and fibrosis. Therefore, this study aims to evaluate the safety and feasibility of L-RHH after FLRM, when compared with ex novo L-RHH. METHODS: All consecutive right hemihepatectomies performed by a single surgeon in the period between October 2007 and March 2023 were retrospectively analyzed. The patient characteristics and perioperative outcomes of L-RHH after FLRM and ex novo L-RHH were compared. RESULTS: A total of 59 patients were included in the analysis, of whom 33 underwent FLRM. Patients undergoing FLRM prior to L-RHH were most often male (93.9% vs. 42.3%, p < 0.001), had an ASA-score >2 (45.5% vs. 9.5%, p = 0.006), and underwent a two-stage hepatectomy (45.5% vs. 3.8% p < 0.001). L-RHH after FLRM was associated with longer operative time (median 360 vs. 300 min, p = 0.008) and Pringle duration (31 vs. 24 min, p = 0.011). Intraoperative blood loss, unfavorable intraoperative incidents, and conversion rates were similar in both groups. There were no significant differences in length of hospital stay and 30-day overall and severe morbidity rates. Radical resection margin (R0) and textbook outcome rates were equal. One patient who underwent an extended RHH in the FLRM group deceased within 90 days of surgery, due to post-hepatectomy liver failure. CONCLUSION: L-RHH after FLRM is more technically complex than L-RHH ex novo, as objectified by longer operative time and Pringle duration. Nevertheless, this procedure appears safe and feasible in experienced hands.

Simultaneous resection of colorectal cancer and synchronous liver metastases: what determines the risk of unfavorable outcomes? An international multicenter retrospective cohort study.

BACKGROUND: The use of a simultaneous resection (SIMR) in patients with synchronous colorectal liver metastases (sCRLM) has increased over the past decades. However, it remains unclear when a SIMR is beneficial and when it should be avoided. The aim of this retrospective cohort study was therefore to compare the outcomes of a SIMR for sCRLM in different settings, and to assess which factors are independently associated with unfavorable outcomes. METHODS: To perform this retrospective cohort study, patients with sCRLM undergoing SIMR (2004-2019) were extracted from an international multicenter database, and their outcomes were compared after stratification according to the type of liver and colorectal resection performed. Factors associated with unfavorable outcomes were identified through multivariable logistic regression. RESULTS: Overall, 766 patients were included, encompassing colorectal resections combined with a major liver resection (n=122), minor liver resection in the anterolateral (n=407), or posterosuperior segments ('Technically major', n=237). Minor and technically major resections, compared to major resections, were more often combined with a rectal resection (29.2 and 36.7 vs. 20.5%, respectively, both P=0.003) and performed fully laparoscopic (22.9 and 23.2 vs. 6.6%, respectively, both P = 0.003). Major and technically major resections, compared to minor resections, were more often associated with intraoperative transfusions (42.9 and 38.8 vs. 20%, respectively, both P = 0.003) and unfavorable incidents (9.6 and 9.8 vs. 3.3%, respectively, both P≤0.063). Major resections were associated, compared to minor and technically major resections, with a higher overall morbidity rate (64.8 vs. 50.4 and 49.4%, respectively, both P≤0.024) and a longer length of stay (12 vs. 10 days, both P≤0.042). American Society of Anesthesiologists grades ≥3 [adjusted odds ratio (aOR): 1.671, P=0.015] and undergoing a major liver resection (aOR: 1.788, P=0.047) were independently associated with an increased risk of severe morbidity, while undergoing a left-sided colectomy was associated with a decreased risk (aOR: 0.574, P=0.013). CONCLUSIONS: SIMR should primarily be reserved for sCRLM patients in whom a minor or technically major liver resection would suffice and those requiring a left-sided colectomy. These findings should be confirmed by randomized studies comparing SIMR with staged resections.

Adjuvant therapy of biliary tract cancers.

Biliary tract cancers (BTCs) are rare and heterogeneous malignant tumours including cholangiocarcinoma and gallbladder cancer. They are very aggressive, often refractory to chemotherapy and associated with an overall poor prognosis. Surgical resection remains the only potentially curative treatment option but less than 35% present with resectable disease. Adjuvant treatments have been widely used but until recently, supportive data were limited to non-randomised, non-controlled retrospective studies. Recent evidence from the BILCAP trial has established adjuvant capecitabine as the standard of care. But there are still unanswered questions as to the role of adjuvant therapy. Further prospective data and translational research with reproducible evidence of clinical benefit are needed. In this review of adjuvant therapy in resectable BTCs, we will summarise the latest evidence setting current treatment standards and highlight future prospects.

Liver resection for metastatic uveal melanoma: experience from a supra-regional centre and review of literature.

Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.