Radiomics of Intrahepatic Cholangiocarcinoma and Peritumoral Tissue Predicts Postoperative Survival: Development of a CT-Based Clinical-Radiomic Model.

BACKGROUND: For many tumors, radiomics provided a relevant prognostic contribution. This study tested whether the computed tomography (CT)-based textural features of intrahepatic cholangiocarcinoma (ICC) and peritumoral tissue improve the prediction of survival after resection compared with the standard clinical indices. METHODS: All consecutive patients affected by ICC who underwent hepatectomy at six high-volume centers (2009-2019) were considered for the study. The arterial and portal phases of CT performed fewer than 60 days before surgery were analyzed. A manual segmentation of the tumor was performed (Tumor-VOI). A 5-mm volume expansion then was applied to identify the peritumoral tissue (Margin-VOI). RESULTS: The study enrolled 215 patients. After a median follow-up period of 28 months, the overall survival (OS) rate was 57.0%, and the progression-free survival (PFS) rate was 34.9% at 3 years. The clinical predictive model of OS had a C-index of 0.681. The addition of radiomic features led to a progressive improvement of performances (C-index of 0.71, including the portal Tumor-VOI, C-index of 0.752 including the portal Tumor- and Margin-VOI, C-index of 0.764, including all VOIs of the portal and arterial phases). The latter model combined clinical variables (CA19-9 and tumor pattern), tumor indices (density, homogeneity), margin data (kurtosis, compacity, shape), and GLRLM indices. The model had performance equivalent to that of the postoperative clinical model including the pathology data (C-index of 0.765). The same results were observed for PFS. CONCLUSIONS: The radiomics of ICC and peritumoral tissue extracted from preoperative CT improves the prediction of survival. Both the portal and arterial phases should be considered. Radiomic and clinical data are complementary and achieve a preoperative estimation of prognosis equivalent to that achieved in the postoperative setting.

Feasibility and operative outcomes of surgery in the liver area in advanced ovarian cancer.

OBJECTIVE: The study aimed to characterize intra-and postoperative complications according to a standardized anatomo-surgical classification for ovarian cancer metastases in the liver area. METHODS: Data from all patients with advanced ovarian cancer undergoing primary or secondary surgery with perihepatic liver involvement (May-2016 to May-2022), were retrospectively retrieved and classified according to a standardized anatomo-surgical classification, and clustered into four Classes: Class I "Peritoneal", Class II "Hepatoceliac-lymph-nodes", Class III "Parenchymal" and Class IV Mixed (≥ 2 classes). RESULTS: Data from 615 patients were collected. Intraoperative complications were observed in 15%, and severe postoperative complications in 17.6% of cases. While surgical complexity scores were similar, Class IV had longer operative times, higher blood loss, and a 30.4% intraoperative transfusion rate. Class II showed a higher prevalence of vascular injuries (8%). Classes II and IV were significantly associated with severe postoperative complications. Specific complications varied among classes, such as perihepatic collection and intrahepatic hematoma/abscess in Class III (p = 0.003, p < 0.001, respectively), and pleuric effusion, sepsis, anemia, and "other complications" in Class IV (p = 0.002, p = 0.004, p = 0.03, p = 0.03, respectively). Multivariable analysis identified Class II and IV (Class II: OR 4.991, p = 0.045; Class IV: OR 5.331, p = 0.030), Surgical Complexity Score group 3 (OR:3.922, p = 0.003), and the presence of residual tumor (OR:1.748, p = 0.048) as independent risk factors for severe postoperative complications. CONCLUSIONS: Liver procedures during advanced ovarian cancer surgery are feasible with acceptable complication rates According to the anatomo-surgical classification, metastatic patterns are related to both different surgical outcomes and postoperative complication profiles.

A multi-national, video-based qualitative study to refine training guidelines for assigning an "unsafe" score in laparoscopic cholecystectomy critical view of safety.

BACKGROUND: The critical view of safety (CVS) was incorporated into a novel 6-item objective procedure-specific assessment for laparoscopic cholecystectomy (LC-CVS OPSA) to enhance focus on safe completion of surgical tasks and advance the American Board of Surgery's entrustable professional activities (EPAs) initiative. To enhance instrument development, a feasibility study was performed to elucidate expert surgeon perspectives regarding "safe" vs. "unsafe" practice. METHODS: A multi-national consortium of 11 expert LC surgeons were asked to apply the LC-CVS OPSA to ten LC videos of varying surgical difficulty using a "safe" vs. "unsafe" scale. Raters were asked to provide written rationale for all "unsafe" ratings and invited to provide additional feedback regarding instrument clarity. A qualitative analysis was performed on written responses to extract major themes. RESULTS: Of the 660 ratings, 238 were scored as "unsafe" with substantial variation in distribution across tasks and raters. Analysis of the comments revealed three major categories of "unsafe" ratings: (a) inability to achieve the critical view of safety (intended outcome), (b) safe task completion but less than optimal surgical technique, and (c) safe task completion but risk for potential future complication. Analysis of reviewer comments also identified the potential for safe surgical practice even when CVS was not achieved, either due to unusual anatomy or severe pathology preventing safe visualization. Based upon findings, modifications to the instructions to raters for the LC-CVS OPSA were incorporated to enhance instrument reliability. CONCLUSIONS: A safety-based LC-CVS OPSA has the potential to significantly improve surgical training by incorporating CVS formally into learner assessment. This study documents the perspectives of expert biliary tract surgeons regarding clear identification and documentation of unsafe surgical practice for LC-CVS and enables the development of training materials to improve instrument reliability. Learnings from the study have been incorporated into rater instructions to enhance instrument reliability.

Laparoscopic cholecystectomy critical view of safety (LC-CVS): a multi-national validation study of an objective, procedure-specific assessment using video-based assessment (VBA).

BACKGROUND: A novel 6-item objective, procedure-specific assessment for laparoscopic cholecystectomy incorporating the critical view of safety (LC-CVS OPSA) was developed to support trainee formative and summative assessments. The LC-CVS OPSA included two retraction items (fundus and infundibulum retraction) and four CVS items (hepatocystic triangle visualization, gallbladder-liver separation, cystic artery identification, and cystic duct identification). The scoring rubric for retraction consisted of poor (frequently outside of defined range), adequate (minimally outside of defined range) and excellent (consistently inside defined range) and for CVS items were "poor-unsafe", "adequate-safe", or "excellent-safe". METHODS: A multi-national consortium of 12 expert LC surgeons applied the OPSA-LC CVS to 35 unique LC videos and one duplicate video. Primary outcome measure was inter-rater reliability as measured by Gwet's AC2, a weighted measure that adjusts for scales with high probability of random agreement. Analysis of the inter-rater reliability was conducted on a collapsed dichotomous scoring rubric of "poor-unsafe" vs. "adequate/excellent-safe". RESULTS: Inter-rater reliability was high for all six items ranging from 0.76 (hepatocystic triangle visualization) to 0.86 (cystic duct identification). Intra-rater reliability for the single duplicate video was substantially higher across the six items ranging from 0.91 to 1.00. CONCLUSIONS: The novel 6-item OPSA LC CVS demonstrated high inter-rater reliability when tested with a multi-national consortium of LC expert surgeons. This brief instrument focused on safe surgical practice was designed to support the implementation of entrustable professional activities into busy surgical training programs. Instrument use coupled with video-based assessments creates novel datasets with the potential for artificial intelligence development including computer vision to drive assessment automation.

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.

Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Lymph-nodal status is an important predictor of survival in intrahepatic cholangiocarcinoma (iCCA), but the need to perform lymphadenectomy in patients with clinically node-negative (cN0) iCCA is still under debate. The aim of this study was to determine whether adequate lymphadenectomy improves long-term outcomes in patients undergoing liver resection for cN0 iCCA. METHODS: We performed a retrospective cohort study on consecutive patients who underwent radical liver resection for cN0 iCCA at five tertiary referral centers. A propensity score based on preoperative data was calculated and used to generate stabilized inverse probability of treatment weight (IPTW). Overall and recurrence-free survival of patients undergoing adequate (≥6 retrieved lymph nodes) vs. inadequate lymphadenectomy were compared. Interactions between adequacy of lymphadenectomy and clinical variables of interest were explored through Cox IPTW regression. RESULTS: The study includes 706 patients who underwent curative surgery for cN0 iCCA. Four-hundred and seventeen (59.1%) received adequate lymphadenectomy. After a median follow-up of 33 months (IQR 18-77), median overall survival was 39 months (IQR 23-109) and median recurrence-free survival was 23 months (IQR 8-74). After stratification according to nodal status at final pathology, node-positive patients had longer overall survival (28 vs. 23 months; hazard ratio 1.82; 95% CI 1.14-2.90; p = 0.023) and disease-free survival (13 vs. 9 months; hazard ratio 1.35; 95% CI 1.14-1.59; p = 0.008) after adequate lymphadenectomy. Adequate lymphadenectomy significantly improved survival outcomes in patients without chronic liver disease, and in patients with less-advanced tumors (solitary tumors, tumor size <5 cm, carbohydrate antigen 19-9 <200 U/ml). CONCLUSIONS: Adequate lymphadenectomy provided better survival outcomes for patients with cN0 iCCA who were found to be node-positive at pathology, supporting the routine use of adequate lymphadenectomy for cN0 iCCA. IMPACT AND IMPLICATIONS: Lymphadenectomy is essential for the surgical staging of intrahepatic cholangiocarcinoma (iCCA). While its role in patients with preoperative suspicion of nodal metastases is implicit, the impact of lymphadenectomy on survival of patients with clinically node-negative (cN0) disease is still under debate. In this large retrospective study on patients who underwent surgical resection for cN0 iCCA, we show that adequate lymphadenectomy (i.e. retrieving ≥6 lymph nodes) significantly improves survival and lowers the risk of tumor recurrence. Lymphadenectomy during surgical resection of iCCA is actually underperformed by the surgical community, resulting in inadequate staging and possibly worse long-term outcomes. The results of this study should empower surgeons and clinicians to push for adequate lymphadenectomy even for cN0 iCCA. Since patients with no chronic liver disease and with less-advanced tumors receive a significant benefit from lymphadenectomy, our results might guide decision making in patients at high-risk of postoperative complications.

The Effect of a Liver Transplant Program on the Outcomes of Resectable Hepatocellular Carcinoma: A Nationwide Multicenter Analysis.

OBJECTIVE: To evaluate the effect of a liver transplantation (LT) program on the outcomes of resectable hepatocellular carcinoma (HCC). BACKGROUND: Surgical treatment of HCC includes both hepatic resection (HR) and LT. However, the presence of cirrhosis and the possibility of recurrence make the management of this disease complex and probably different according to the presence of a LT program. METHODS: Patients undergoing HR for HCC between January 2005 and December 2019 were identified from a national database of HCC. The main study outcomes were major surgical complications according to the Comprehensive Complication Index, posthepatectomy liver failure (PHLF), 90-day mortality, overall survival, and disease-free survival. Secondary outcomes were salvage liver transplantation (SLT) and postrecurrence survival. RESULTS: A total of 3202 patients were included from 25 hospitals over the study period. Three of 25 (12%) had an LT program. The presence of an LT program within a center was associated with a reduced probability of PHLF (odds ratio=0.38) but not with overall survival and disease-free survival. There was an increased probability of SLT when HR was performed in a transplant hospital (odds ratio=12.05). Among transplant-eligible patients, those who underwent LT had a significantly longer postrecurrence survival. CONCLUSIONS: This study showed that the presence of a LT program was associated with decreased PHLF rates and an increased probability to receive SLT in case of recurrence.

Bile duct injury following cholecystectomy: delayed referral to a tertiary care center is strongly associated with malpractice litigation.

BACKGROUND: Bile duct injury (BDI) following cholecystectomy is associated with malpractice litigation. Aim of this study was to evaluate risk factors for litigation in patients with BDI referred in a tertiary care center. METHODS: Patients treated for BDI between 1994 and 2016. Stabilized inverse probability therapy weighting was used and multivariable logistic regression analysis identified risk factors for malpractice litigation. RESULTS: Of the 211 treated patients, 98 met the inclusion criteria: early-referral group (<20 days; 51.0%), late-referral (≥20 days; 49.0%). 36 patients (36.7%) initiated malpractice litigation with verdict in favor of plaintiff in 86.7% of cases (median payment = €90 500, up to €600 000). Attempts at surgical and endoscopic repair before referral were significantly higher in late-referral group. Failed postoperative management (delayed referral, attempts at repair before referral) was one of the strongest predictors for litigation. Risk of litigation progressively increased from 23.8%, when referral time was within 19 days, to 54.5% (61-120 days), to 60.0% (121-210 days) and to 65.1% (211-365 days). DISCUSSION: Litigation rate after BDI was 37%. Delayed referral to tertiary care center was one of the strongest predictors for litigation. Prompt referral to tertiary experienced centers without any attempt at repair may reduce the risk of litigation.

Short and long-term outcomes after minimally invasive liver resection for single small hepatocellular carcinoma: An analysis of 714 patients from the IGoMILS (Italian group of minimally invasive liver surgery) registry.

BACKGROUND: Widespread use of minimally invasive liver surgery (MILS) contributed to the reduction of surgical risk of liver resection for hepatocellular carcinoma (HCC). Aim of this study was to analyze outcomes of MILS for single ≤3 cm HCC. METHODS: Patients who underwent MILS for single ≤3 cm HCC (November 2014 - December 2019) were identified from the Italian Group of Minimally Invasive Liver Surgery (IGoMILS) Registry. RESULTS: Of 714 patients included, 641 (93.0%) were Child-Pugh A; 65.7% were limited resections and 2.2% major resections, with a conversion rate of 5.2%. Ninety-day mortality rate was 0.3%. Overall morbidity rate was 22.4% (3.8% major complications). Mean postoperative stay was 5 days. Robotic resection showed longer operative time (p = 0.004) and a higher overall morbidity rate (p < 0.001), with similar major complications (p = 0.431). Child-Pugh B patients showed worse mortality (p = 0.017) and overall morbidity (p = 0.021), and longer postoperative stay (p = 0.005). Five-year overall survival was 79.5%; cirrhosis, satellite micronodules, and microvascular invasion were independently associated with survival. CONCLUSIONS: MILS for ≤3 cm HCC was associated with low morbidity and mortality rates, showing high safety, and supporting the increasing indications for surgical resection in these patients.

Survival benefit of second line therapies for recurrent hepatocellular carcinoma: repeated hepatectomy, thermoablation and second-line transplant referral in a real life national scenario.

BACKGROUND: Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group). METHODS: Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups. RESULTS: 743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011). CONCLUSION: It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed.

Incidence and predictors of textbook outcome after simultaneous liver and rectal surgeries for Stage IV rectal cancer.

AIM: Textbook outcome (TO) is a new surgical quality measure that combines structure, process and surgical outcomes into a single element. Our study aimed to determine the incidence of TO after simultaneous rectal and liver surgery and to use the achievement of TO as a tool to identify the best candidates for these complex procedures. METHODS: In total, 256 patients who underwent simultaneous liver and rectal surgery for Stage IV rectal cancer between January 2004 and August 2019 at five tertiary centres were enrolled. TO was defined as a lack of complication, prolonged length of stay, readmission and death. RESULTS: Mortality rate at 90 days and major morbidity rate were 2.3% and 15.6%, respectively. An overall TO was achieved in 59% of the patients, which is associated with significantly improved overall (median TO 86.3 months vs. no TO 37.4 months) and disease-free (median TO 70.6 months vs. no TO 24.9 months) survival. On multivariate analysis the presence of multi-comorbidities (OR 3.073) was associated with a reduced likelihood of achieving TO. Left lateral sectionectomy/limited resection was a protective factor (OR 0.416). CONCLUSION: TO was achieved in six of 10 patients undergoing simultaneous resections for rectal cancer and liver metastases. Achieving a TO is strongly associated with improved long-term survival. The best candidates for these procedures were patients without multiple comorbidities and those treated with left lateral sectionectomy/limited resection.

The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.

The largest western experience on salvage hepatectomy for recurrent hepatocellular carcinoma: propensity score-matched analysis on behalf of He.RC.O.Le.Study Group.

BACKGROUND: We aimed to evaluate, in a large Western cohort, perioperative and long-term oncological outcomes of salvage hepatectomy (SH) for recurrent hepatocellular carcinoma (rHCC) after primary hepatectomy (PH) or locoregional treatments. METHODS: Data were collected from the Hepatocarcinoma Recurrence on the Liver Study Group (He.RC.O.Le.S.) Italian Registry. After 1:1 propensity score-matched analysis (PSM), two groups were compared: the PH group (patients submitted to resection for a first HCC) and the SH group (patients resected for intrahepatic rHCC after previous HCC-related treatments). RESULTS: 2689 patients were enrolled. PH included 2339 patients, SH 350. After PSM, 263 patients were selected in each group with major resected nodule median size, intraoperative blood loss and minimally invasive approach significantly lower in the SH group. Long-term outcomes were compared, with no difference in OS and DFS. Univariate and multivariate analyses revealed only microvascular invasion as an independent prognostic factor for OS. CONCLUSION: SH proved to be equivalent to PH in terms of safety, feasibility and long-term outcomes, consistent with data gathered from East Asia. In the awaiting of reliable treatment-allocating algorithms for rHCC, SH appears to be a suitable alternative in patients fit for surgery, regardless of the previous therapeutic modality implemented.

Benchmarking postoperative outcomes after open liver surgery for cirrhotic patients with hepatocellular carcinoma in a national cohort.

BACKGROUND: Benchmark analysis for open liver surgery for cirrhotic patients with hepatocellular carcinoma (HCC) is still undefined. METHODS: Patients were identified from the Italian national registry HE.RC.O.LE.S. The Achievable Benchmark of Care (ABC) method was employed to identify the benchmarks. The outcomes assessed were the rate of complications, major comorbidities, post-operative ascites (POA), post-hepatectomy liver failure (PHLF), 90-day mortality. Benchmarking was stratified for surgical complexity (CP1, CP2 and CP3). RESULTS: A total of 978 of 2698 patients fulfilled the inclusion criteria. 431 (44.1%) patients were treated with CP1 procedures, 239 (24.4%) with CP2 and 308 (31.5%) with CP3 procedures. Patients submitted to CP1 had a worse underlying liver function, while the tumor burden was more severe in CP3 cases. The ABC for complications (13.1%, 19.2% and 28.1% for CP1, CP2 and CP3 respectively), major complications (7.6%, 11.1%, 12.5%) and 90-day mortality (0%, 3.3%, 3.6%) increased with the surgical difficulty, but not POA (4.4%, 3.3% and 2.6% respectively) and PHLF (0% for all groups). CONCLUSION: We propose benchmarks for open liver resections in HCC cirrhotic patients, stratified for surgical complexity. The difference between the benchmark values and the results obtained during everyday practice reflects the room for potential growth, with the aim to encourage constant improvement among liver surgeons.

Liver-First Approach for Synchronous Colorectal Metastases: Analysis of 7360 Patients from the LiverMetSurvey Registry.

BACKGROUND: The liver-first approach in patients with synchronous colorectal liver metastases (CRLM) has gained wide consensus but its role is still to be clarified. We aimed to elucidate the outcome of the liver-first approach and to identify patients who benefit at most from this approach. METHODS: Patients with synchronous CRLM included in the LiverMetSurvey registry between 2000 and 2017 were considered. Three strategies were analyzed, i.e. liver-first approach, colorectal resection followed by liver resection (primary-first), and simultaneous resection, and three groups of patients were analyzed, i.e. solitary metastasis, multiple unilobar CRLM, and multiple bilobar CRLM. In each group, patients from the three strategy groups were matched by propensity score analysis. RESULTS: Overall, 7360 patients were analyzed: 4415 primary-first, 552 liver-first, and 2393 simultaneous resections. Compared with the other groups, the liver-first group had more rectal tumors (58.0% vs. 31.2%) and higher hepatic tumor burden (more than three CRLMs: 34.8% vs. 24.0%; size > 50 mm: 35.6% vs. 22.8%; p < 0.001). In patients with solitary and multiple unilobar CRLM, survival was similar regardless of treatment strategy, whereas in patients with multiple bilobar metastases, the liver-first approach was an independent positive prognostic factor, both in unmatched patients (3-year survival 65.9% vs. primary-first 60.4%: hazard ratio [HR] 1.321, p = 0.031; vs. simultaneous resections 54.4%: HR 1.624, p < 0.001) and after propensity score matching (vs. primary-first: HR 1.667, p = 0.017; vs. simultaneous resections: HR 2.278, p = 0.003). CONCLUSION: In patients with synchronous CRLM, the surgical strategy should be decided according to the hepatic tumor burden. In the presence of multiple bilobar CRLM, the liver-first approach is associated with longer survival than the alternative approaches and should be evaluated as standard.

The Impact of Hospital Volume on Failure to Rescue after Liver Resection for Hepatocellular Carcinoma: Analysis from the HE.RC.O.LE.S. Italian Registry.

OBJECTIVE: The aim of this study was to evaluate correlation between centers' volume and incidence of failure to rescue (FTR) following liver resection for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: FTR, defined as the probability of postoperative death among patients with major complication, has been proposed to assess quality of care during hospitalization. Perioperative management is challenging in cirrhotic patients and the ability to recognize and treat a complication may be fundamental to rescue patients from the risk of death. METHODS: Patients undergoing liver resection for HCC between 2008 and 2018 in 18 Centers enrolled in the He.Rc.O.Le.S. Italian register. Early results included major complications (Clavien ≥3), 90-day mortality, and FTR and were analyzed according to center's volume. RESULTS: Among 1935 included patients, major complication rate was 9.4% (8.6%, 12.3%, and 7.0% for low-, intermediate- and high-volume centers, respectively, P = 0.001). Ninety-day mortality rate was 2.6% (3.7%, 4.2% and 0.9% for low-, intermediate- and high-volume centers, respectively, P < 0.001). FTR was significantly higher at low- and intermediate-volume centers (28.6% and 26.5%, respectively) than at high-volume centers (6.1%, P = 0.002). Independent predictors for major complications were American Society of Anesthesiologists (ASA) >2, portal hypertension, intraoperative blood transfusions, and center's volume. Independent predictors for 90-day mortality were ASA >2, Child-Pugh score B, BCLC stage B-C, and center's volume. Center's volume and BCLC stage were strongly associated with FTR. CONCLUSIONS: Risk of major complications and mortality was related with comorbidities, cirrhosis severity, and complexity of surgery. These factors were not correlated with FTR. Center's volume was the only independent predictor related with severe complications, mortality, and FTR.

RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases.

OBJECTIVE: To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). BACKGROUND: The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. METHODS: Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients. RESULTS: A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. CONCLUSIONS: Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.

Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma.

PURPOSE: To compare liver resection (LR) with single-step, balloon-occluded radiofrequency (RF) ablation plus drug-eluting embolics transarterial chemoembolization in cirrhotic patients with single hepatocellular carcinoma (HCC) ≥ 3 cm. MATERIALS AND METHODS: From 2010 to 2014, 25 patients with compensated cirrhosis and single HCC ≥ 3 cm (median size 4.5 cm; range, 3.0-6.8 cm) not suitable for LR or liver transplantation were treated with RF ablation plus transarterial chemoembolization in a prospective observational single-center pilot study; all patients had complete tumor necrosis after treatment. A retrospective control group included 29 patients (median HCC size 4.0 cm; range, 3.0-7.4 cm) who underwent LR. RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension (65.5% vs 35.0%, P = .017). Primary endpoints were overall survival (OS) and tumor recurrence (TR) rates. RESULTS: One death and 1 major complication (4%) were observed in LR group. No major complications were reported in RF ablation plus transarterial chemoembolization group (P = .463). OS rates at 1 and 3 years were 91.8% and 79.3% in LR group and 89.4% and 48.2% in RF ablation plus transarterial chemoembolization group (P = 0.117). TR rates at 1 and 3 years were 29.5% and 45.0% in LR group and 42.4% and 76.0% in RF ablation plus transarterial chemoembolization group (P = .034). Local tumor progression (LTP) rates at 3 years were significantly lower in LR group (21.8% vs 58.1%, P = .005). Similar results were found in patients with HCC ≤ 5 cm (TR rates 35.4% vs 75.1%, P = .016; LTP 16.0% vs 55.7%, P = .013). CONCLUSIONS: LR achieved lower TR and LTP rates than RF ablation plus transarterial chemoembolization, but 3-years OS rates were not statistically different between the 2 groups. RF ablation plus transarterial chemoembolization is an effective treatment option in patients with compensated cirrhosis and solitary HCC ≥ 3 cm unsuitable for LR.

HepPar1-Positive Circulating Microparticles Are Increased in Subjects with Hepatocellular Carcinoma and Predict Early Recurrence after Liver Resection.

Circulating microparticles (MPs) are novel potential biomarkers in cancer patients. Their role in hepatocellular carcinoma (HCC) is under intensive investigation. In this study, we tested the hypothesis that MPs expressing the antigen HepPar1 are increased in the blood of subjects with HCC and may serve as markers of early recurrence after liver resection (LR). We studied 15 patients affected by HCC undergoing LR, and used flow cytometry to assess the number of circulating HepPar1+ MPs. Ten subjects without HCC (five with liver cirrhosis and five with healthy livers) were used as controls. After LR, HCC patients underwent a follow-up to check for early recurrence, which occurred in seven cases. The number of circulating HepPar1+ MPs was significantly higher in subjects affected by HCC, compared to individuals without cancer (p < 0.01). We also found that, among HCC patients, the number of circulating HepPar1+ MPs, measured before LR, was significantly higher in those who displayed early recurrence compared to those without recurrence (p = 0.02). Of note, other types of circulating MPs, such as those derived from endothelial cells (CD144+) or those produced by the activated endothelium (CD144+/CD62+), were not associated with HCC, nor could they predict HCC recurrence. HepPar1+ MPs deserve further investigation as novel biomarkers of disease and prognosis in HCC patients.