Using the win ratio to compare laparoscopic versus open liver resection for colorectal cancer liver metastases.

Background: We sought to assess the overall benefit of laparoscopic versus open hepatectomy for treatment of colorectal liver metastases (CRLMs) using the win ratio, a novel methodological approach. Methods: CRLM patients undergoing curative-intent resection in 2001-2018 were identified from an international multi-institutional database. Patients were paired and matched based on age, number and size of lesions, lymph node status and receipt of preoperative chemotherapy. The win ratio was calculated based on margin status, severity of postoperative complications, 90-day mortality, time to recurrence, and time to death. Results: Among 962 patients, the majority underwent open hepatectomy (n=832, 86.5%), while a minority underwent laparoscopic hepatectomy (n=130, 13.5%). Among matched patient-to-patient pairs, the odds of the patient undergoing laparoscopic resection "winning" were 1.77 [WR: 1.77, 95% confidence interval (CI): 1.42-2.34]. The win ratio favored laparoscopic hepatectomy independent of low (WR: 2.94, 95% CI: 1.20-6.39), medium (WR: 1.56, 95% CI: 1.16-2.10) or high (WR: 7.25, 95% CI: 1.13-32.0) tumor burden, as well as unilobar (WR: 1.71, 95% CI: 1.25-2.31) or bilobar (WR: 4.57, 95% CI: 2.36-8.64) disease. The odds of "winning" were particularly pronounced relative to short-term outcomes (i.e., 90-day mortality and severity of postoperative complications) (WR: 4.06, 95% CI: 2.33-7.78). Conclusions: Patients undergoing laparoscopic hepatectomy had 77% increased odds of "winning". Laparoscopic liver resection should be strongly considered as a preferred approach to resection in CRLM patients.

Infectious complications after surgery for perihilar cholangiocarcinoma: A single Western center experience.

BACKGROUND: The aim of this study was to analyze the risk factors for surgical infectious complications and the outcomes of patients undergoing surgery for perihilar cholangiocarcinoma according to the microbiological examinations. METHODS: Patients who underwent surgery for perihilar cholangiocarcinoma in the last decade were enrolled, and all clinical and microbiological data were collected from a retrospective monocentric database. Univariate and multivariate analyses were performed distinguishing patients who developed at least 1 surgical infectious complication (surgical site infections, acute bacterial cholangitis, bacteremia). RESULTS: A total of 98 patients were included. Among patients who developed surgical infectious complications (51%), many preoperative characteristics were significantly more frequent: American Society of Anesthesiologists score ≥3 (P = .026), neutrophil-to-lymphocyte ratio ≥3.4 (P = .001), endoscopic sphincterotomy (P = .032), ≥2 biliary drainage procedures (P = .013), acute cholangitis (P = .012), multidrug resistant (P = .009), and ≥3 microorganisms' detection (P = .042); whereas during the postoperative period, surgical infectious complications were associated to increased incidence of intensive care unit readmission (P = .031), major complications (P < .001), posthepatectomy liver failure (P = .005), ascites (P = .008), biliary leakage (P = .008), 90-day readmission (P = .003), and prolonged length of hospital stay (P < .001). At the multivariate analysis 3 independent preoperative risk factors for surgical infectious complications were identified: neutrophil-to-lymphocyte ratio ≥3.4 (P = .004), endoscopic sphincterotomy (P = .009), and acute cholangitis (P = .013). The presence of multidrug-resistance in the perioperative biliary cultures was related to postoperative multidrug-resistant species from all cultures (P < .001) and organ/space and incisional-surgical site infections (P ≤ .044). CONCLUSION: Infective complications after surgery for perihilar cholangiocarcinoma worsen the short-term outcomes. A careful microbiological surveillance should be carried out in all cases to prevent and promptly treat surgical infectious complications.

A machine learning analysis of difficulty scoring systems for laparoscopic liver surgery.

INTRODUCTION: In the last decade, several difficulty scoring systems (DSS) have been proposed to predict technical difficulty in laparoscopic liver resections (LLR). The present study aimed to investigate the ability of four DSS for LLR to predict operative, short-term, and textbook outcomes. METHODS: Patients who underwent LLR at a single tertiary referral center from January 2014 to June 2020 were included in the present study. Four DSS for LLR (Halls, Hasegawa, Kawaguchi, and Iwate) were investigated to test their ability to predict operative and postoperative complications. Machine learning algorithms were used to identify the most important DSS associated with operative and short-term outcomes. RESULTS: A total of 346 patients were included in the analysis, 28 (8.1%) patients were converted to open surgery. A total of 13 patients (3.7%) had severe (Clavien-Dindo ≥ 3) complications; the incidence of prolonged length of stay (> 5 days) was 39.3% (n = 136). No patients died within 90 days after the surgery. According to Halls, Hasegawa, Kawaguchi, and Iwate scores, 65 (18.8%), 59 (17.1%), 57 (16.5%), and 112 (32.4%) patients underwent high difficulty LLR, respectively. In accordance with a random forest algorithm, the Kawaguchi DSS predicted prolonged length of stay, high blood loss, and conversions and was the best performing DSS in predicting postoperative outcomes. Iwate DSS was the most important variable associated with operative time, while Halls score was the most important DSS predicting textbook outcomes. No one of the DSS investigated was associated with the occurrence of complication. CONCLUSIONS: According to our results DDS are significantly related to surgical complexity and short-term outcomes, Kawaguchi and Iwate DSS showed the best performance in predicting operative outcomes, while Halls score was the most important variable in predicting textbook outcome. Interestingly, none of the DSS showed any correlation with or importance in predicting overall and severe postoperative complications.

Kidney Disease: Improving Global Outcomes Classification of Chronic Kidney Disease and Short-Term Outcomes of Patients Undergoing Liver Resection.

BACKGROUND: The impact of chronic kidney disease (CKD) on surgery is still not well defined. We sought to characterize the association of preoperative CKD with 30-day mortality after hepatic resection. METHODS: Patients included in the American College of Surgeons (ACS) NSQIP who underwent hepatectomy between 2014 and 2018 were identified. Kidney function was stratified according to the "Kidney Disease: Improving Global Outcomes" (KDIGO) Classification: G1, normal/high function (estimated glomerular-filtration-rate ≥ 90 ml/min/1.73m2); G2-3, mild/moderate CKD (89-30 ml/min/1.73m2); G4-5, severe CKD (≤ 29 ml/min/1.73m2). RESULTS: Overall, 18,321 patients were included. Older patients (ie more than 70 years old) and those with serious medical comorbidities (ie American Society of Anesthesiologists [ASA] class 3) had an increased incidence of severe CKD (both p < 0.001). Patients with G2-3 and G4-5 CKD were more likely to have a prolonged length of stay and to experience postoperative complications (both p < 0.001). Adjusted odds of 30-day mortality increased with the worsening CKD (p = 0.03). The degree of CKD was able to stratify patients within the NSQIP risk calculator. Among patients who underwent major hepatectomy for primary cancer, the rate of 30-day mortality was 2-fold higher with G2-3 and G4-5 CKD vs normal kidney function (p = 0.03). CONCLUSIONS: The degree of CKD was related to the risk of complications and 30-day mortality after hepatectomy. CKD classification should be strongly considered in the preoperative risk estimation of these patients.

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.

Non-transplantable Recurrence After Resection for Transplantable Hepatocellular Carcinoma: Implication for Upfront Treatment Choice.

OBJECTIVES: To identify the preoperative risk factors for prediction of non-transplantable recurrence (NTR) after tumor resection for early-stage hepatocellular carcinoma (HCC) to assist in patient selection relative to upfront liver resection (LR) versus liver transplantation (LT). METHODS: Patients who underwent curative resection for transplantable HCC and chronic liver disease were identified from an international multi-institutional database. NTR was defined as recurrence beyond the Milan or UCSF criteria, and the preoperative risk factors of NTR were investigated. RESULTS: Among 293 patients with transplantable HCC within Milan criteria and 320 within UCSF criteria, 113 (38.6%) and 131 (40.9%) patients developed tumor recurrence, respectively. Among patients who recurred, NTR was present in 32 (28.3%) patients within Milan and 35 (26.7%) within UCSF criteria. When either Milan or UCSF criteria was adopted, three preoperative risk factors including liver cirrhosis, tumor size > 3 cm, and multiple lesions were consistently identified as risk factors associated with NTR after curative resection. By summing up the three factors, a scoring model was established and the incidence of NTR among patients with 0, 1 or ≥ 2 risk factors incrementally increased from 4.5%, 13.3% to 20.5% when Milan criteria was used, and from 4.5%, 12.4% to 33.9% when UCSF criteria was adopted. The model demonstrated very good discriminatory power on internal validation (n = 5,000) (c-index 0.689 for Milan criteria, and 0.715 for UCSF criteria). CONCLUSIONS: Whereas surgical resection may be optimal first-line treatment for patients with no or one risk factor, patients with ≥ 2 risk factors should be considered for upfront liver transplantation.

Molecular characterization of extrahepatic cholangiocarcinoma: perihilar and distal tumors display divergent genomic and transcriptomic profiles.

BACKGROUND: Extrahepatic cholangiocarcinoma (ECC) is classified into two subtypes based on anatomic origin: distal extrahepatic (DECC) and perihilar (PHCC) cholangiocarcinoma. This study aimed to shed light on its genomic and transcriptomic profiles. RESEARCH DESIGN AND METHODS: The genomic alterations of 99 ECC (47 PHCC and 52 DECC) were investigated by next-generation sequencing of 96 genes. A subgroup of cases, representative of each subtype, was further investigated using transcriptomic analysis. Bioinformatics tools were applied for clustering and pathway analysis and defining the immune composition of the tumor microenvironment. RESULTS: PHCC had more frequent KRAS mutations (p = 0.0047), whereas TP53 mutations were more common in DECC (p = 0.006). Potentially actionable alterations included high-tumor mutational burden and/or microsatellite instability (7.1%), PI3KCA mutations (8.1%), and MYC (10.1%) and ERBB2 amplification (5.1%). The transcriptomic profiles showed the presence of three distinct clusters, which followed the anatomic origin and differed in immune microenvironment. DECC appeared to contain two distinct tumor subgroups, one enriched for druggable alterations and one lacking actionable opportunities. CONCLUSIONS: This study provides new insights into the molecular landscape and the actionable alterations of ECC. Our findings represent a step toward improved ECC molecular taxonomy and therapeutic strategies for precision oncology.

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.

Role of Inflammatory and Immune-Nutritional Prognostic Markers in Patients Undergoing Surgical Resection for Biliary Tract Cancers.

The relationship between immune-nutritional status and tumor growth; biological aggressiveness and survival, is still debated. Therefore, this study aimed to evaluate the prognostic performance of different inflammatory and immune-nutritional markers in patients who underwent surgery for biliary tract cancer (BTC). The prognostic role of the following inflammatory and immune-nutritional markers were investigated: Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Neutrophil to Lymphocyte ratio (NLR), Platelet to Lymphocyte ratio (PLR), Lymphocyte to Monocyte ratio (LMR), Prognostic Nutritional Index (PNI). A total of 282 patients undergoing surgery for BTC were included. According to Cox regression and ROC curves analysis for survival, LMR had the best prognostic performances, with hazard ratio (HR) of 1.656 (p = 0.005) and AUC of 0.652. Multivariable survival analysis identified the following independent prognostic factors: type of BTC (p = 0.002), T stage (p = 0.014), N stage (p < 0.001), histological grading (p = 0.045), and LMR (p = 0.025). Conversely, PNI was related to higher risk of severe morbidity (p < 0.001) and postoperative mortality (p = 0.005). In conclusion, LMR appears an independent prognostic factor of long-term survival, whilst PNI seems associated with worse short-term outcomes.

Colorectal cancer with microsatellite instability: Right-sided location and signet ring cell histology are associated with nodal metastases, and extranodal extension influences disease-free survival.

Colorectal cancer (CRC) with microsatellite instability (MSI) accounts for 15-18 % of all CRCs and represents the category with the best prognosis. This study aimed at determining any possible clinical/pathological features associated with a higher risk of nodal metastasization in MSI-CRC, and at defining any possible prognostic moderators in this setting. All surgically resected CRCs of the last 20 years (mono-institutional series) with a PCR-based diagnosis of MSI, with and without nodal metastasis, have been retrieved for histological review, which was performed following WHO guidelines. Furthermore, the most important prognostic moderators have been investigated with a survival analysis. The study of 33 cases of MSI-CRCs with nodal metastasis highlighted a high fidelity of histology maintenance between primary tumors and matched nodal metastases. At survival analysis, the strongest prognostic variable in MSI-CRCs with nodal metastasis was the extranodal extension (multivariate analysis, HR: 14.4, 95 %CI: 1.46-140.9, p = 0.022). Furthermore, through a comparison between nodal positive (33 cases) and nodal negative (71 cases) MSI-CRCs, right-sided location (p < 0.0001), pT4 stage (p = 0.0004) and signet-ring histology (p = 0.0089) emerged as parameters more commonly associated with nodal metastasization. These findings shed new light on the biology of MSI-CRC and can be of help for the prognostic stratification of MSI-CRC patients.

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.

Surgery for Bismuth-Corlette Type 4 Perihilar Cholangiocarcinoma: Results from a Western Multicenter Collaborative Group.

BACKGROUND: Although Bismuth-Corlette (BC) type 4 perihilar cholangiocarcinoma (pCCA) is no longer considered a contraindication for curative surgery, few data are available from Western series to indicate the outcomes for these patients. This study aimed to compare the short- and long-term outcomes for patients with BC type 4 versus BC types 2 and 3 pCCA undergoing surgical resection using a multi-institutional international database. METHODS: Uni- and multivariable analyses of patients undergoing surgery at 20 Western centers for BC types 2 and 3 pCCA and BC type 4 pCCA. RESULTS: Among 1138 pCCA patients included in the study, 826 (73%) had BC type 2 or 3 disease and 312 (27%) had type 4 disease. The two groups demonstrated significant differences in terms of clinicopathologic characteristics (i.e., portal vein embolization, extended hepatectomy, and positive margin). The incidence of severe complications was 46% for the BC types 2 and 3 patients and 51% for the BC type 4 patients (p = 0.1). Moreover, the 90-day mortality was 13% for the BC types 2 and 3 patients and 12% for the BC type 4 patients (p = 0.57). Lymph-node metastasis (N1; hazard-ratio [HR], 1.62), positive margins (R1; HR, 1.36), perineural invasion (HR, 1.53), and poor grade of differentiation (HR, 1.25) were predictors of survival (all p ≤0.004), but BC type was not associated with prognosis. Among the N0 and R0 patients, the 5-year overall survival was 43% for the patients with BC types 2 and 3 pCCA and 41% for those with BC type 4 pCCA (p = 0.60). CONCLUSIONS: In this analysis of a large Western multi-institutional cohort, resection was shown to be an acceptable curative treatment option for selected patients with BC type 4 pCCA although a more technically challenging surgical approach was required.

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.

Trends and outcomes of simultaneous versus staged resection of synchronous colorectal cancer and colorectal liver metastases.

BACKGROUND: The objective of this study was to assess trends in the use as well as the outcomes of patients undergoing simultaneous versus staged resection for synchronous colorectal liver metastases. METHODS: Patients undergoing resection for colorectal liver metastases between 2008 and 2018 were identified using a multi-institutional database. Trends in use and outcomes of simultaneous resection of colorectal liver metastases were examined over time and compared with that of staged resection after propensity score matching. RESULTS: Among 1,116 patients undergoing resection for colorectal liver metastases, 690 (61.8%) patients had synchronous disease. Among them, 314 (45.5%) patients underwent simultaneous resection, while 376 (54.5%) had staged resection. The proportion of patients undergoing simultaneous resection for synchronous colorectal liver metastases increased over time (2008: 37.2% vs 2018: 47.4%; ptrend = 0.02). After propensity score matching (n = 201 per group), patients undergoing simultaneous resection for synchronous colorectal liver metastases had a higher incidence of overall (44.8% vs 34.3%; P = .03) and severe complications (Clavien-Dindo ≥III) (16.9% vs 7.0%; P = .002) yet comparable 90-day mortality (3.5% vs 1.0%; P = .09) compared with patients undergoing staged resection. The incidence of severe morbidity decreased over time (2008: 50% vs 2018: 11.1%; ptrend = 0.02). Survival was comparable among patients undergoing simultaneous versus staged resection of colorectal liver metastases (3-year overall survival: 66.1% vs 62.3%; P = .67). Following simultaneous resection, severe morbidity and mortality increased incrementally based on the extent of liver resection and complexity of colectomy. CONCLUSION: While simultaneous resection was associated with increased morbidity, the incidence of severe morbidity decreased over time. Long-term survival was comparable after simultaneous resection versus staged resection of colorectal liver metastases.

Artificial neural networks for multi-omics classifications of hepato-pancreato-biliary cancers: towards the clinical application of genetic data.

PURPOSE: Several multi-omics classifications have been proposed for hepato-pancreato-biliary (HPB) cancers, but these classifications have not proven their role in the clinical practice and been validated in external cohorts. PATIENTS AND METHODS: Data from whole-exome sequencing (WES) of The Cancer Genome Atlas (TCGA) patients were used as an input for the artificial neural network (ANN) to predict the anatomical site, iClusters (cell-of-origin patterns) and molecular subtype classifications. The Ohio State University (OSU) and the International Cancer Genome Consortium (ICGC) patients with HPB cancer were included in external validation cohorts. TCGA, OSU and ICGC data were merged, and survival analyses were performed using both the 'classic' survival analysis and a machine learning algorithm (random survival forest). RESULTS: Although the ANN predicting the anatomical site of the tumour (i.e. cholangiocarcinoma, hepatocellular carcinoma of the liver, pancreatic ductal adenocarcinoma) demonstrated a low accuracy in TCGA test cohort, the ANNs predicting the iClusters (cell-of-origin patterns) and molecular subtype classifications demonstrated a good accuracy of 75% and 82% in TCGA test cohort, respectively. The random survival forest analysis and Cox' multivariable survival models demonstrated that models for HPB cancers that integrated clinical data with molecular classifications (iClusters, molecular subtypes) had an increased prognostic accuracy compared with standard staging systems. CONCLUSION: The analyses of genetic status (i.e. WES, gene panels) of patients with HPB cancers might predict the classifications proposed by TCGA project and help to select patients suitable to targeted therapies. The molecular classifications of HPB cancers when integrated with clinical information could improve the ability to predict the prognosis of patients with HPB cancer.

Synergistic Impact of Alpha-Fetoprotein and Tumor Burden on Long-Term Outcomes Following Curative-Intent Resection of Hepatocellular Carcinoma.

INTRODUCTION: The prognostic role of tumor burden score (TBS) relative to pre-operative α -fetoprotein (AFP) levels among patients undergoing curative-intent resection of HCC has not been examined. METHODS: Patients who underwent curative-intent resection of HCC between 2000 and 2017 were identified from a multi-institutional database. The impact of TBS on overall survival (OS) and cumulative recurrence relative to serum AFP levels was assessed. RESULTS: Among 898 patients, 233 (25.9%) patients had low TBS, 572 (63.7%) had medium TBS and 93 (10.4%) had high TBS. Both TBS (5-year OS; low TBS: 76.9%, medium TBS: 60.9%, high TBS: 39.1%) and AFP (>400 ng/mL vs. <400 ng/mL: 48.5% vs. 66.1%) were strong predictors of outcomes (both p < 0.001). Lower TBS was associated with better OS among patients with both low (5-year OS, low-medium TBS: 68.0% vs. high TBS: 47.7%, p < 0.001) and high AFP levels (5-year OS, low-medium TBS: 53.7% vs. high TBS: not reached, p < 0.001). Patients with low-medium TBS/high AFP had worse OS compared with individuals with low-medium TBS/low AFP (5-year OS, 53.7% vs. 68.0%, p = 0.003). Similarly, patients with high TBS/high AFP had worse outcomes compared with patients with high TBS/low AFP (5-year OS, not reached vs. 47.7%, p = 0.015). Patients with high TBS/low AFP and low TBS/high AFP had comparable outcomes (5-year OS, 47.7% vs. 53.7%, p = 0.24). The positive predictive value of certain TBS groups relative to the risk of early recurrence and 5-year mortality after HCC resection increased with higher AFP levels. CONCLUSION: Both TBS and serum AFP were important predictors of prognosis among patients with resectable HCC. Serum AFP and TBS had a synergistic impact on prognosis following HCC resection with higher serum AFP predicting worse outcomes among patients with HCC of a certain TBS class.

Early Versus Late Recurrence of Hepatocellular Carcinoma After Surgical Resection Based on Post-recurrence Survival: an International Multi-institutional Analysis.

BACKGROUND: To define early versus late recurrence based on post-recurrence survival (PRS) among patients undergoing curative 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 optimal cut-off time point to discriminate early versus late recurrence was determined relative to PRS. RESULTS: Among 1004 patients, 443 (44.1%) patients experienced recurrence with a median recurrence-free survival time of 12 months. A cut-off time point of 8 months was defined as the optimal threshold based on sensitivity analyses relative to PRS for early (n = 165, 37.2%) versus late relapse (n = 278, 62.8%) (p = 0.008). Early recurrence was associated with worse PRS (median PRS, 27.0 vs. 43.0 months, p = 0.019), as well as overall survival (OS) (median OS, 32.0 versus 74.0 months, p < 0.001) versus late recurrence. In addition, patients who recurred early were more likely to recur at extra- ± intrahepatic (35.5% vs. 19.8%, p = 0.003) sites and were less likely to have the recurrence treated with curative intent (33.8% vs. 45.7%, p = 0.08). Patients undergoing curative re-treatment of late recurrence had a comparable OS with patients who had no recurrence (median OS, 139.0 vs. 140.0 months); patients with early recurrence had inferior OS after curative re-treatment versus patients with no recurrence (median OS, 69.0 vs. 140.0 months, p = 0.036), yet still better than patients who received palliative treatment for early recurrence (median OS, 69.0 vs. 21.0 months, p < 0.001). CONCLUSIONS: Eight months was identified as the cut-off value to differentiate early versus late recurrence. Curative-intent treatment for recurrent intrahepatic tumors was associated with reasonable long-term outcomes.

Prediction of tumor recurrence by α-fetoprotein model after curative resection for hepatocellular carcinoma.

BACKGROUND: Preoperative α-fetoprotein (AFP) level levels may help select patients with hepatocellular carcinoma (HCC) for surgery. The objective of the current study was to assess an AFP model to predict tumor recurrence and patient survival after curative resection for HCC. METHODS: Patients undergoing curative-intent resection for HCC between 2000 and 2017 were identified from a multi-institutional database. AFP score was calculated based on the last evaluation before surgery. Probabilities of tumor recurrence and overall survival (OS) were compared according to an AFP model. RESULTS: A total of 825 patients were included. An optimal cut-off AFP score of 2 was identified with an AFP score ≥3 versus ≤2 independently predicting tumor recurrence and OS. Net reclassification improvements indicated the AFP model was superior to the Barcelona Clinic Liver Cancer (BCLC) system to predict recurrence (p < 0.001). Among patients with BCLC B-C, AFP score ≤2 identified a subgroup of patients with AFP levels of ≤100 ng/mL with a low 5-year recurrence risk (≤2 45.2% vs. ≥3 61.8%, p = 0.046) and favorable 5-year OS (≤2 54.5% vs. ≥3 39.4%, p = 0.035). In contrast, among patients within BCLC 0-A, AFP score ≥3 identified a subgroup of patients with AFP values > 1000 ng/mL with a high 5-year recurrence (≥3 47.9% vs. ≤2% 38.4%, p = 0.046) and worse 5-year OS (≥3 47.8% vs. ≤2 65.9%, p < 0.001). In addition, the AFP score independently correlated with vascular invasion, tumor differentiation and capsule invasion. CONCLUSIONS: The AFP model was more accurate than the BCLC system to identify which HCC patients may benefit the most from surgical resection.

Simultaneous approach for patients with synchronous colon and rectal liver metastases: Impact of site of primary on postoperative and oncological outcomes.

BACKGROUND AND AIMS: We aimed to investigate the impact of the site of the primary on postoperative and oncological outcomes in patients undergone simultaneous approach for colon (CC) and rectal cancer (RC) with synchronous liver metastases (SCRLM). PATIENTS AND METHODS: Of the 220 patients with SCRLM operated on between Mar 2006 and Dec 2017, 169 patients (76.8%) were treated by a simultaneous approach and were included in the study. Two groups were considered according to the location of primary tumor RC-Group (n = 47) and CC-group (n = 122). RESULTS: Multiple liver metastases were observed in 70.2% in RC-Group and 77.0% in CC-Group (p = 0.233), whilst median Tumor Burden Score (TBS) was 4.7 in RC-Group and 5.4 CC-Group (p = 0.276). Severe morbidity (p = 0.315) and mortality at 90 days (p = 0.520) were comparable between RC-Group and CC-Group. The 5-year overall survival (OS) rate was similar comparing RC-Group and CC-Group (48.2% vs. 45.3%; p = 0.709), but it was significantly different when considering left-CC, right-CC and RC separately (54.5% vs. 35.2% vs. 48.2%; p = 0.041). Primary tumor location (right-CC, p = 0.001; RC, p = 0.002), microscopic residual (R1) disease at the primary (p < 0.001), TBS ≥6 (p = 0.012), bilobar metastases (p = 0.004), and chemotherapy strategy (preoperative ChT, p = 0.253; postoperative ChT, p = 0.012; and perioperative ChT, p < 0.001) resulted to be independent prognostic factors at multivariable analysis. CONCLUSION: In patients with SCRLM, simultaneous resection of the primary tumor and liver metastases seems feasible and safe and allows satisfactory oncological outcomes both in CC and RC. Right-CC shows a worse prognosis when compared to left-CC and RC.