Perioperative Changes in Serum Transaminase Levels: Impact on Postoperative Morbidity Following Liver Resection of Hepatocellular Carcinoma.

OBJECTIVES: To define how dynamic changes in pre- versus post-operative serum aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) levels may impact postoperative morbidity after curative-intent resection of hepatocellular carcinoma (HCC). BACKGROUND: Hepatic ischemia/reperfusion can occur at the time of liver resection and may be associated with adverse outcomes following liver resection. METHODS: Patients who underwent curative resection for HCC between 2010-2020 were identified from an international multi-institutional database. Changes in AST and ALT (CAA) on postoperative day (POD) 3 versus preoperative values () were calculated using the formula: based on a fusion index via Euclidean norm, which was examined relative to the comprehensive complication index (CCI). The impact of CAA on CCI was assessed by the restricted cubic spline regression and Random Forest analyses. RESULTS: A total of 759 patients were included in the analytic cohort. Median CAA was 1.7 (range, 0.9 to 3.25); 431 (56.8%) patients had a CAA<2, 215 (28.3%) patients with CAA 2-5, and 113 (14.9%) patients had CAA ≥5. The incidence of post-operative complications was 65.0% (n=493) with a median CCI of 20.9 (IQR, 20.9-33.5). Spline regression analysis demonstrated a non-linear incremental association between CAA and CCI. The optimal cutoff value of CAA=5 was identified by the recursive partitioning technique. After adjusting for other competing risk factors, CAA≥5 remained strongly associated with risk of post-operative complications (Ref. CAA<5, OR 1.63, 95%CI 1.05-2.55, P=0.03). In fact, the use of CAA to predict post-operative complications was very good in both the derivative (AUC 0.88) and external (ACU 0.86) cohorts (n=1137). CONCLUSIONS: CAA was an independent predictor of CCI after liver resection for HCC. Use of routine labs such as AST and ALT can help identify patients at highest risk of post-operative complications following HCC resection.

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

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

Impact of Surgical Margin Width on Prognosis Following Resection of Hepatocellular Carcinoma Varies on the Basis of Preoperative Alpha-Feto Protein and Tumor Burden Score.

BACKGROUND: We sought to examine the prognostic impact of margin width at time of hepatocellular carcinoma (HCC) resection relative to the alpha-feto protein tumor burden score (ATS). PATIENTS AND METHODS: Patients who underwent curative-intent hepatectomy for HCC between 2000 and 2020 were identified from a multi-institutional database. The impact of margin width on overall survival and recurrence-free survival was examined relative to ATS using univariable and multivariable analyses. RESULTS: Among 782 patients with HCC who underwent resection, median ATS was 6.5 [interquartile range (IQR) 4.3-10.2]. Most patients underwent R0 resection (n = 613, 78.4%); among patients who had an R0 resection, 325 (41.6%) had a margin width > 5 mm while 288 (36.8%) had a 0-5 mm margin width. Among patients with high ATS, an increasing margin width was associated with incrementally better overall and recurrence-free survival. In contrast, among patients with low ATS, margin width was not associated with long-term outcomes. On multivariable Cox regression analysis, each unit increase in ATS was independently associated with a 7% higher risk of death [hazard ratio (HR) 1.07; 95% confidence interval (CI) 1.03-1.11, p < 0.001]. While the incidence of early recurrence was not associated with margin width among patients with low ATS, wider margin width was associated with an incrementally lower incidence of early recurrence among patients with high ATS. CONCLUSION: ATS, an easy-to-use composite tumor-related metric, was able to risk stratify patients following resection of HCC relative to overall survival and recurrence-free survival. The therapeutic impact of resection margin width had a variable impact on long-term outcomes relative to ATS.

Preoperative risk score (PreopScore) to predict overall survival after resection for hepatocellular carcinoma.

BACKGROUND: This study aimed to develop a holistic risk score incorporating preoperative tumor, liver, nutritional, and inflammatory markers to predict overall survival (OS) after hepatectomy for hepatocellular carcinoma (HCC). METHODS: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using an international multi-institutional database. Preoperative predictors associated with OS were selected and a prognostic risk score model (PreopScore) was developed and validated using cross-validation. RESULTS: A total of 1676 patients were included. On multivariable analysis, preoperative parameters associated with OS included α-feto protein (hazard ratio [HR]1.17, 95%CI 1.03-1.34), neutrophil-to-lymphocyte ratio (HR2.62, 95%CI 1.30-5.30), albumin (HR0.49, 95%CI 0.34-0.70), gamma-glutamyl transpeptidase (HR1.00, 95%CI 1.00-1.00), as well as vascular involvement (HR3.52, 95%CI 2.10-5.89) and tumor burden score (medium, HR3.49, 95%CI 1.62-7.58; high, HR3.21, 95%CI 1.40-7.35) on preoperative imaging. A weighted PreopScore was devised and made available online (https://yutaka-endo.shinyapps.io/PrepoScore_Shiny/). Patients with a PreopScore 0-2, 2-3.5, and >3.5 had incrementally worse 5-year OS of 85.8%, 70.7%, and 52.4%, respectively (p < 0.001). The c-index of the test and validation cohort were 0.75 and 0.71, respectively. The PreopScore outperformed individual parameters and previous HCC staging systems. DISCUSSION: The PreopScore can be used as a better guide to preoperatively identify patients and individualize pre-/post-operative strategies.

Postoperative Infectious Complications Worsen Long-Term Survival After Curative-Intent Resection for Hepatocellular Carcinoma.

BACKGROUND: Postoperative infectious complications may be associated with a worse long-term prognosis for patients undergoing surgery for a malignant indication. The current study aimed to characterize the impact of postoperative infectious complications on long-term oncologic outcomes among patients undergoing resection for hepatocellular carcinoma (HCC). METHODS: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The relationship between postoperative infectious complications, overall survival (OS), and recurrence-free survival (RFS) was analyzed. RESULTS: Among 734 patients who underwent HCC resection, 269 (36.6%) experienced a postoperative complication (Clavien-Dindo grade 1 or 2 [n = 197, 73.2%] vs grade 3 and 4 [n = 69, 25.7%]). An infectious complication was noted in 81 patients (11.0%) and 188 patients (25.6%) had non-infectious complications. The patients with infectious complications had worse OS (median: infectious complications [46.5 months] vs no complications [106.4 months] [p < 0.001] and non-infectious complications [85.7 months] [p < 0.05]) and RFS (median: infectious complications [22.1 months] vs no complications [45.5 months] [p < 0.05] and non-infectious complications [38.3 months] [p = 0.139]) than the patients who had no complication or non-infectious complications. In the multivariable analysis, infectious complications remained an independent risk factor for OS (hazard ratio [HR], 1.7; p = 0.016) and RFS (HR, 1.6; p = 0.013). Among the patients with infectious complications, patients with non-surgical-site infection (SSI) had even worse OS and RFS than patients with SSI (median OS: 19.5 vs 70.9 months [p = 0.010]; median RFS: 12.8 vs 33.9 months [p = 0.033]). CONCLUSION: Infectious complications were independently associated with an increased long-term risk of tumor recurrence and death. Patients with non-SSI versus SSI had a particularly worse oncologic outcome.

Prognostic factors of overall survival in patients with recurrent disease following liver resection for colorectal cancer metastases: A multicenter external validation study.

BACKGROUND: The clinical course of patients experiencing recurrence following hepatectomy for colorectal cancer metastases (CRM) is poorly defined. Previous studies associated shorter time to recurrence (TTR) in months, node-positive primary tumor, and more than one site of recurrence with worse outcomes. METHODS: We conducted a retrospective cohort study across four Canadian institutions to externally validate previously established prognostic factors of overall survival (OS). We included consecutive adult patients who had a recurrence following curative-intent liver resection for CRM. Prognostic factors were explored using a multivariable Cox regression model. Risk group cutoffs were identified through recursive partitioning. OS between low- and high-risk groups was compared using the Kaplan-Meier method. RESULTS: This study included 471 patients. Shorter TTR in months (hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.93-0.97), presence of extrahepatic disease at first hepatectomy (HR: 2.54, 95% CI: 1.18-5.50), and larger tumor size in millimetres (HR: 1.01, 95% CI: 1.00-1.02) were associated with worse OS. Median OS in the high- and low-risk groups were 40.5 (95% CI: 34.0-45.7 months) versus 64.7 months (95% CI: 57.9-72.3 months; p < 0.001), respectively. CONCLUSIONS: We externally validated the prognostic significance of shorter TTR (<8.5 months) as a predictor of worse OS in patients who recur the following hepatectomy for CRM.

Serum α-Fetoprotein Levels at Time of Recurrence Predict Post-Recurrence Outcomes Following Resection of Hepatocellular Carcinoma.

INTRODUCTION: Although preoperative α-fetoprotein (AFP) has been recognized as an important tumor marker among patients with hepatocellular carcinoma (HCC), the predictive value of AFP levels at the time of recurrence (rAFP) on post-recurrence outcomes has not been well examined. METHODS: Patients undergoing curative-intent resection of HCC between 2000 and 2017 were identified using a multi-institutional database. The impact of rAFP on post-recurrence survival, as well as the impact of rAFP relative to the timing and treatment of HCC recurrence were examined. RESULTS: Among 852 patients who underwent resection of HCC, 307 (36.0%) individuals developed a recurrence. The median rAFP level was 8 ng/mL (interquartile range 3-100). Among the 307 patients who developed recurrence, 3-year post-recurrence survival was 48.5%. Patients with rAFP > 10 ng/mL had worse 3-year post-recurrence survival compared with individuals with rAFP < 10 ng/mL (28.7% vs. 65.5%, p < 0.001). rAFP correlated with survival among patients who had early (3-year survival; rAFP > 10 vs. < 10 ng/mL: 30.1% vs. 60.2%, p < 0.001) or late (18.0% vs. 78.7%, p = 0.03) recurrence. Furthermore, rAFP levels predicted 3-year post-recurrence survival among patients independent of the therapeutic modality used to treat the recurrent HCC (rAFP > 10 vs. < 10 ng/mL; ablation: 41.1% vs. 76.0%; intra-arterial therapy: 12.9% vs. 46.1%; resection: 37.5% vs. 100%; salvage transplantation: 60% vs. 100%; all p < 0.05). After adjusting for competing risk factors, patients with rAFP > 10 ng/mL had a twofold higher hazard of death in the post-recurrence setting (hazard ratio 1.96, 95% confidence interval 1.26-3.04). CONCLUSION: AFP levels at the time of recurrence following resection of HCC predicted post-recurrence survival independent of the secondary treatment modality used. Evaluating AFP levels at the time of recurrence can help inform post-recurrence risk stratification of patients with recurrent HCC.

Multi-Institutional Development and External Validation of a Nomogram for Prediction of Extrahepatic Recurrence After Curative-Intent Resection for Hepatocellular Carcinoma.

BACKGROUNDS: Extrahepatic recurrence of hepatocellular carcinoma (HCC) after surgical resection is associated with unfavorable prognosis. The objectives of the current study were to identify the risk factors and develop a nomogram for the prediction of extrahepatic recurrence after initial curative surgery. METHODS: A total of 635 patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The clinicopathological characteristics, risk factors, and long-term survival of patients with extrahepatic recurrence were analyzed. A nomogram for the prediction of extrahepatic recurrence was established and validated in 144 patients from an external cohort. RESULTS: Among the 635 patients in the derivative cohort, 283 (44.6%) experienced recurrence. Among patients who recurred, 80 (28.3%) patients had extrahepatic ± intrahepatic recurrence, whereas 203 (71.7%) had intrahepatic recurrence only. Extrahepatic recurrence was associated with more advanced initial tumor characteristics, early recurrence, and worse prognosis versus non-extrahepatic recurrence. A nomogram for the prediction of extrahepatic recurrence was developed using the ß-coefficients from the identified risk factors, including neutrophil-to-lymphocyte ratio, multiple lesions, tumor size, and microvascular invasion. The nomogram demonstrated good ability to predict extrahepatic recurrence (c-index: training cohort 0.786; validation cohort: 0.845). The calibration plots demonstrated good agreement between estimated and observed extrahepatic recurrence (p = 0.658). CONCLUSIONS: An externally validated nomogram was developed with good accuracy to predict extrahepatic recurrence following curative-intent resection of HCC. This nomogram may help identify patients at high risk of extrahepatic recurrence and guide surveillance protocols as well as adjuvant treatments.

Tumor Necrosis Impacts Prognosis of Patients Undergoing Curative-Intent Hepatocellular Carcinoma.

BACKGROUND: The impact of tumor necrosis relative to prognosis among patients undergoing curative-intent resection for hepatocellular carcinoma (HCC) remains ill-defined. METHODS: Patients who underwent curative-intent resection for HCC without any prior treatment between 2000 and 2017 were identified from an international multi-institutional database. Tumor necrosis was graded as absent, moderate (< 50% area), or extensive (≥ 50% area) on histological examination. The relationship between tumor necrosis, clinicopathologic characteristics, and long-term survival were analyzed. RESULTS: Among 919 patients who underwent curative-intent resection for HCC, the median tumor size was 5.0 cm (IQR, 3.0-8.5). Tumor necrosis was present in 367 (39.9%) patients (no necrosis: n = 552, 60.1% vs < 50% necrosis: n = 256, 27.9% vs ≥ 50% necrosis: n = 111, 12.1%). Extent of tumor necrosis was also associated with more advanced tumor characteristics. HCC necrosis was associated with OS (median OS: no necrosis, 84.0 months vs < 50% necrosis, 73.6 months vs ≥ 50% necrosis: 59.3 months; p < 0.001) and RFS (median RFS: no necrosis, 49.6 months vs < 50% necrosis, 38.3 months vs ≥ 50% necrosis: 26.5 months; p < 0.05). Patients with T1 tumors with extensive ≥ 50% necrosis had an OS comparable to patients with T2 tumors (median OS, 62.9 vs 61.8 months; p = 0.645). In addition, patients with T2 disease with necrosis had long-term outcomes comparable to patients with T3 disease (median OS, 61.8 vs 62.4 months; p = 0.713). CONCLUSION: Tumor necrosis was associated with worse OS and RFS, as well as T-category upstaging of patients. A modified AJCC T classification that incorporates tumor necrosis should be considered in prognostic stratification of HCC patients.

Impact of time-to-surgery on outcomes of patients undergoing curative-intent liver resection for BCLC-0, A and B hepatocellular carcinoma.

BACKGROUND: The impact of a prolonged time-to-surgery (TTS) among patients with resectable hepatocellular carcinoma (HCC) is not well defined. METHODS: Patients who underwent curative-intent hepatectomy for BCLC-0, A and B HCC between 2000 and 2017 were identified using a multi-institutional database. The impact of prolonged TTS on overall survival (OS) and disease-free survival (DFS) was examined. RESULTS: Among 775 patients who underwent resection for HCC, 537 (69.3%) had early surgery (TTS < 90 days) and 238 (30.7%) patients had a delayed surgery (TTS ≥ 90 days). Patient- and tumor-related characteristics were similar between the two groups except for a higher proportion of patients undergoing major liver resection in the early surgery group (31.3% vs. 23.8%, p = .04). The percentage of patients with delayed surgery varied from 8.8% to 59.1% among different centers (p < .001). Patients with TTS < 90 days had similar 5-year OS (63.7% vs. 64.9; p = .79) and 5-year DFS (33.5% vs. 42.4; p = .20) with that of patients with TTS ≥ 90 days. On multivariable analysis, delayed surgery was not associated with neither worse OS (BCLC-0/A: adjusted hazards ratio [aHR] = 0.90; 95% confidence interval [CI]: 0.65-1.25 and BCLC-B: aHR = 0.72; 95%CI: 0.30-1.74) nor DFS (BCLC-0/A: aHR = 0.78; 95%CI: 0.60-1.01 and BCLC-B: aHR = 0.67; 95% CI: 0.36-1.25). CONCLUSION: Approximately one in three patients diagnosed with resectable HCC had a prolonged TTS. Delayed surgery was not associated with worse outcomes among patients with resectable HCC.

Impact of Tumor Burden Score on Conditional Survival after Curative-Intent Resection for Hepatocellular Carcinoma: A Multi-Institutional Analysis.

BACKGROUND: The impact of tumor burden score (TBS) on conditional survival (CS) among patients undergoing curative-intent resection of hepatocellular carcinoma (HCC) has not been examined to date. METHODS: Patients who underwent liver resection of HCC between 2000 and 2017 were identified from a multi-institutional database. The impact of TBS and other clinicopathologic factors on 3-year conditional survival (CS3) was examined. RESULTS: Among 1,040 patients, 263 (25.3%) patients had low TBS, 668 (64.2%) had medium TBS and 109 (10.5%) had high TBS. TBS was strongly associated with OS; 5-year OS was 39.0% among patients with high TBS compared with 61.1% and 79.4% among patients with medium and low TBS, respectively (p < 0.001). While actuarial survival decreased as time elapsed from resection, CS increased over time irrespective of TBS. The largest differences between 3-year actuarial survival and CS3 were noted among patients with high TBS (5-years postoperatively; CS3: 78.7% vs. 3-year actuarial survival: 30.7%). The effect of adverse clinicopathologic factors including high TBS, poor/undifferentiated tumor grade, microvascular invasion, liver capsule involvement, and positive margins on prognosis decreased over time. CONCLUSIONS: CS rates among patients who underwent resection for HCC increased as patients survived additional years, irrespective of TBS. CS estimates can be used to provide important dynamic information relative to the changing survival probability after resection of HCC.

Overall Tumor Burden Dictates Outcomes for Patients Undergoing Resection of Multinodular Hepatocellular Carcinoma Beyond the Milan Criteria.

OBJECTIVE: The objective of the current study was to define surgical outcomes after resection of multinodular hepatocellular carcinoma (HCC) beyond the Milan criteria, and develop a prediction tool to identify which patients likely benefit the most from resection. BACKGROUND: Liver resection for multinodular HCC, especially beyond the Milan criteria, remains controversial. Rigorous selection of the best candidates for resection is essential to achieve optimal outcomes after liver resection of advanced tumors. METHODS: Patients who underwent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Patients were categorized according to Milan criteria status. Pre- and postoperative overall survival (OS) prediction models that included HCC tumor burden score (TBS) among patients with multinodular HCC beyond Milan criteria were developed and validated. RESULTS: Among 1037 patients who underwent resection for HCC, 164 (15.8%) had multinodular HCC beyond the Milan criteria. Among patients with multinodular HCC, 25 (15.2%) patients experienced a serious complication and 90-day mortality was 3.7% (n = 6). Five-year OS after resection of multinodular HCC beyond Milan criteria was 52.8%. A preoperative TBS-based model (5-year OS: low-risk, 73.7% vs intermediate-risk, 45.1% vs high-risk, 13.1%), and postoperative TBS-based model (5-year OS: low-risk, 80.1% vs intermediate-risk, 37.2% vs high-risk, not reached) categorized patients into distinct prognostic groups relative to long-term prognosis (both P < 0.001). Pre- and postoperative models could accurately stratify OS in an external validation cohort (5-year OS; low vs medium vs high risk; pre: 66.3% vs 25.2% vs not reached, P = 0.012; post: 61.4% vs 42.5% vs not reached, P = 0.045) Predictive accuracy of the pre- and postoperative models was good in the training (c-index; pre: 0.68; post: 0.71), internal validation (n = 2000 resamples) (c-index, pre: 0.70; post: 0.72) and external validation (c-index, pre: 0.67; post 0.68) datasets. TBS alone could stratify patients relative to 5-year OS after resection of multinodular HCC beyond Milan criteria (c-index: 0.65; 5-year OS; low TBS: 70.2% vs medium TBS: 54.7% vs high TBS: 16.7%; P < 0.001). The vast majority of patients with low and intermediate TBS were deemed low or medium risk based on both the preoperative (98.4%) and postoperative risk scores (95.3%). CONCLUSION: Prognosis of patients with multinodular HCC was largely dependent on overall tumor burden. Liver resection should be considered among patients with multinodular HCC beyond the Milan criteria who have a low- or intermediate-TBS.

Recurrence Patterns and Outcomes after Resection of Hepatocellular Carcinoma within and beyond the Barcelona Clinic Liver Cancer Criteria.

BACKGROUND: Several investigators have advocated for extending the Barcelona Clinic Liver Cancer (BCLC) resection criteria to select patients with BCLC-B and even BCLC-C hepatocellular carcinoma (HCC). The objective of the current study was to define the outcomes and recurrence patterns after resection within and beyond the current resection criteria. PATIENTS AND METHODS: Patients who underwent resection for HCC within (i.e., BCLC 0/A) and beyond (i.e. BCLC B/C) the current resection criteria between 2005 and 2017 were identified from an international multi-institutional database. Overall survival (OS), disease-free survival (DFS), as well as patterns of recurrence of patients undergoing HCC resection within and beyond the BCLC guidelines were examined. RESULTS: Among 756 patients, 602 (79.6%) patients were BCLC 0/A and 154 (20.4%) were BCLC B/C. Recurrences were mostly intrahepatic (within BCLC: 74.3% versus beyond BCLC: 70.8%, p = 0.80), with BCLC B/C patients more often having multiple tumors at relapse (69.6% versus 49.4%, p = 0.001) and higher rates of early (< 2 years) recurrence (88.0% versus 75.5%, p = 0.011). During the first postoperative year, annual recurrence was 38.3% and 21.3% among BCLC B/C and BCLC 0/A patients, respectively; 5-year OS among BCLC 0/A and BCLC B/C patients was 76.9% versus 51.6% (p = 0.003). On multivariable analysis, only a-fetoprotein (AFP) > 400 ng/mL (HR = 1.84, 95% CI 1.07-3.15) and R1 resection (HR = 2.36, 95% CI 1.32-4.23) were associated with higher risk of recurrence among BCLC B/C patients. CONCLUSIONS: Surgery can provide acceptable outcomes among select patients with BCLC B/C HCC. The data emphasize the need to further refine the BCLC treatment algorithm as well as highlight the need for surveillance protocols with a particular focus on the liver, especially for patients undergoing resection outside the BCLC criteria.

Minimally Invasive Versus Open Liver Resection for Hepatocellular Carcinoma in the Setting of Portal Vein Hypertension: Results of an International Multi-institutional Analysis.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and portal vein hypertension assessed with platelet count (PVH-PLT; platelet count < 100,000/mL) are often denied surgery even when the disease is technically resectable. Short- and long-term outcomes of patients undergoing minimally invasive surgery (MIS) versus open resection for HCC and PVH-PLT were compared. METHODS: Propensity score matching (PSM) was used to balance the clinicopathological differences between MIS and non-MIS patents. Univariate comparison and standard survival analyses were utilized. RESULTS: Among 1974 patients who underwent surgery for HCC, 13% had a PVH-PLT and 33% underwent MIS. After 1:1 PSM, 407 MIS and 407 non-MIS patients were analyzed. Incidence of complications and length-of-stay (LoS) were higher among non-MIS versus MIS patients (both p ≤ 0.002). After PSM, among 178 PVH-PLT patients (89 MIS and 89 non-MIS), patients who underwent a non-MIS approach had longer LoS (> 7 days; non-MIS: 55% vs. MIS: 29%), as well as higher morbidity (non-MIS: 42% vs. MIS: 29%) [p <0.001]. In contrast, long-term oncological outcomes were comparable, including 3-year overall survival (non-MIS: 66.2% vs. MIS: 72.9%) and disease-free survival (non-MIS: 47.3% vs. MIS: 50.2%) [both p ≥ 0.08]. CONCLUSION: An MIS approach was associated with improved short-term outcomes, but similar long-term outcomes, compared with open liver resection for patients with HCC and PVH-PLT. An MIS approach for liver resection should be considered for patients with HCC, even those individuals with PVH-PLT.

Assessing Textbook Outcomes Following Liver Surgery for Primary Liver Cancer Over a 12-Year Time Period at Major Hepatobiliary Centers.

INTRODUCTION: The objective of the current study was to comprehensively assess the change of practice in hepatobiliary surgery by determining the rates and the trends of textbook outcomes (TO) among patients undergoing surgery for primary liver cancer over time. METHODS: Patients undergoing curative-intent resection for primary liver malignancies, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) between 2005 and 2017 were analyzed using a large, international multi-institutional dataset. Rates of TO were assessed over time. Factors associated with achieving a TO and the impact of TO on long-term survival were examined. RESULTS: Among 1829 patients, 944 (51.6%) and 885 (48.4%) individuals underwent curative-intent resection for HCC and ICC, respectively. Over time, patients were older, more frequently had ASA class > 2, albumin-bilirubin grade 2/3, major vascular invasion and more frequently underwent major liver resection (all p < 0.05). Overall, a total of 1126 (62.0%) patients achieved a TO. No increasing trends in TO rates were noted over the years (ptrend = 0.90). In addition, there was no increasing trend in the TO rates among patients undergoing either major (ptrend = 0.39) or minor liver resection (ptrend = 0.63) over the study period. Achieving a TO was independently associated with 26% and 37% decreased hazards of death among ICC (HR 0.74, 95%CI 0.56-0.97) and HCC patients (HR 0.63, 95%CI 0.46-0.85), respectively. CONCLUSION: Approximately 6 in 10 patients undergoing surgery for primary liver tumors achieved a TO. While TO rates did not increase over time, TO was associated with better long-term outcomes following liver resection for both HCC and ICC.

Utilizing Machine Learning for Pre- and Postoperative Assessment of Patients Undergoing Resection for BCLC-0, A and B Hepatocellular Carcinoma: Implications for Resection Beyond the BCLC Guidelines.

BACKGROUND: There is an ongoing debate about expanding the resection criteria for hepatocellular carcinoma (HCC) beyond the Barcelona Clinic Liver Cancer (BCLC) guidelines. We sought to determine the factors that held the most prognostic weight in the pre- and postoperative setting for each BCLC stage by applying a machine learning method. METHODS: Patients who underwent resection for BCLC-0, A and B HCC between 2000 and 2017 were identified from an international multi-institutional database. A Classification and Regression Tree (CART) model was used to generate homogeneous groups of patients relative to overall survival (OS) based on pre- and postoperative factors. RESULTS: Among 976 patients, 63 (6.5%) had BCLC-0, 745 (76.3%) had BCLC-A, and 168 (17.2%) had BCLC-B HCC. Five-year OS among BCLC-0/A and BCLC-B patients was 64.2% versus 50.2%, respectively (p = 0.011). The preoperative CART model selected α-fetoprotein (AFP) and Charlson comorbidity score (CCS) as the first and second most important preoperative factors of OS among BCLC-0/A patients, whereas radiologic tumor burden score (TBS) was the best predictor of OS among BCLC-B patients. The postoperative CART model revealed lymphovascular invasion as the best postoperative predictor of OS among BCLC-0/A patients, whereas TBS remained the best predictor of long-term outcomes among BCLC-B patients in the postoperative setting. On multivariable analysis, pathologic TBS independently predicted worse OS among BCLC-0/A (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.02-1.07) and BCLC-B patients (HR 1.13, 95% CI 1.06-1.19) undergoing resection. CONCLUSION: Prognostic stratification of patients undergoing resection for HCC within and beyond the BCLC resection criteria should include assessment of AFP and comorbidities for BCLC-0/A patients, as well as tumor burden for BCLC-B patients.

Barriers and Facilitators to Help-Seeking for Individuals With Posttraumatic Stress Disorder: A Systematic Review.

Posttraumatic stress disorder (PTSD) brings with it diagnostic symptoms that can be debilitating and persist for years. Left untreated, PTSD can have far-reaching and damaging consequences for the individual, families, communities, and society at large. Although early detection and intervention are recognized as key to the effective treatment of PTSD, many individuals who suffer from PTSD do not seek essential health services. The aim of the present study was to identify the barriers and facilitators to help-seeking for individuals with PTSD, based on existing literature. A systematic review, modeled on the Joanna Briggs Institute methodology for systematic reviews, examined studies cited in PsycINFO, Medline, Embase, CINAHL, and PILOTS published from January 1980 to January 2019. Eligible studies measured barriers and facilitators to help-seeking for adults with PTSD. Two reviewers independently screened citations, and double data extraction was exercised. Of 2,391 potentially relevant citations, 21 studies, published between 1989 and 2018 and based in six countries, were included. Seventeen studies focused on military as a target population. We identified 10 principal barrier and facilitator themes: trauma-related; treatment; therapist or provider; knowledge; access; health care system; sociocultural environment; values, beliefs, and priorities; past experiences; and medical care needs and illness burden. In identifying prominent barriers and facilitators to help-seeking for individuals with PTSD, this review highlights opportunities to inform policies and programs that promote PTSD knowledge and recognition, reduce public and personal stigma, improve access and quality of care, and encourage support for patients and families living with PTSD.

The safety and efficacy of hypovolemic phlebotomy on blood loss and transfusion in liver surgery: a systematic review and meta-analysis.

BACKGROUND: Hypovolemic phlebotomy (HP) is a novel intervention that involves intraoperative removal of whole blood (7-10 mL/kg) without volume replacement. The subsequent central venous pressure (CVP) reduction is hypothesized to decrease blood loss and the need for blood transfusion. The objective was to conduct a systematic assessment of the safety and efficacy of HP on blood loss and transfusion in the liver surgery literature. METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched. Outcomes of interest included blood loss, allogenic red blood cell transfusion, postoperative adverse events, and CVP change. A qualitative synthesis and meta-analysis were performed as appropriate. RESULTS: Four cohort studies, one case series, and three randomized controlled trials involving 2255 patients were included. Meta-analysis of studies involving liver resections for any indication (n = 6) found no difference in transfusion (OR 0.38, p = 0.12) or incidence of adverse events with HP compared to non-use. Pooling of studies involving liver resections for an underlying pathology (n = 4) revealed HP was associated with significant reduction in transfusion (OR 0.25, p = 0.03) but no differences in blood loss (-173 mL, p = 0.17). CONCLUSION: This review suggests HP is safe and associated with decreased transfusion in patients undergoing liver surgery. It supports further investigation.

Long-term outcomes after curative resection of HCV-positive versus non-hepatitis related hepatocellular carcinoma: an international multi-institutional analysis.

BACKGROUND: To define the chronological changes of long-term survival among patients with non-hepatitis-related hepatocellular carcinoma (Non-Hep-HCC) versus hepatitis C-related HCC (HCV-HCC) over the last two decades. METHODS: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Overall (OS) and recurrence-free survival (RFS) were analyzed and compared among Non-Hep-HCC versus HCV-HCC patients. Propensity score matching (PSM) was utilized to mitigate residual bias. RESULTS: Among 617 patients, 196 (31.8%) patients had HCV-HCC, whereas 421 (68.2%) patients had Non-Hep-HCC. While patients with HCV-HCC had an improvement in OS over time (5-year OS, 2000-2009 55% vs. 2010-2017 67%, p = 0.034), OS among patients with Non-Hep-HCC remain unchanged (5-year OS, 2000-2009 53% vs. 2010-2017 52%, p = 0.905). In the matched cohort, patients with HCV-HCC had a worse OS versus patients with Non-Hep-HCC during 2000 and 2009 (5-year OS, 12% vs. 63%, p = 0.029), but significantly better OS from 2010 to 2017 than patients with Non-Hep-HCC (5-year OS, 86% vs. 73%, p = 0.035). The recurrence timing, patterns and re-treatments were comparable among Non-Hep-HCC and HCV-HCC patients. CONCLUSION: While OS of patients with HCV-HCC improved over time, the long-term survival of patients with Non-Hep-HCC patients remained unchanged and was more unfavorable.

Hospital variation in Textbook Outcomes following curative-intent resection of hepatocellular carcinoma: an international multi-institutional analysis.

BACKGROUND: Composite measures such as "Textbook Outcome" (TO) may be superior to individual quality metrics to assess surgical care and hospital performance. However, the incidence and factors associated with TO after resection of HCC remain poorly defined. METHODS: Hospital variation in the rates of TO, factors associated with achieving a TO and the impact of TO on long-term survival following resection for HCC were examined using an international multi-institutional database. RESULTS: Among 605 patients who underwent curative-intent resection of HCC, the unadjusted incidence of TO ranged from 50.9% to 77.7%. While achievement of each individual quality metric was relatively high (range, 74.5-98.0%), an overall TO was achieved among only 62.3% (n = 377) of patients. At the hospital level, TO ranged from 54.3% to 72.9%. Patients with BCLC-0 HCC (referent BCLC-B/C; OR: 4.17, 95%CI: 1.62-10.7) and ALBI grade 1 (referent ALBI grade 2/3; OR: 1.49, 95%CI: 1.06-2.11) had higher odds of achieving a TO. On multivariable analysis, TO was associated with improved overall survival (HR: 0.60, 95% CI: 0.42-0.85). CONCLUSION: Roughly 6 in 10 patients achieved a TO following resection for HCC. When achieved, TO was associated with better long-term outcomes. TO is a simple composite measure of both short- and long-term outcomes among patients undergoing resection for HCC.