Spatial and temporal expansion of intrahepatic metastasis by molecularly-defined clonality in multiple liver cancers.

Multiple hepatocellular carcinoma (HCC) is divided into two categories: intrahepatic metastasis (IM), which is a true relapse of HCC, and multicentric origin (MO), which is a second primary tumor. Clinical diagnosis of multiple HCC is usually made based on tumor location and/or time to recurrence; however, it is often difficult to distinguish the two types of multiple HCC. Using 41 matched pairs of multiple HCC specimens, we confirmed the accuracy of clinical diagnoses using exome sequence data and investigated the importance of discriminating the type of multiple HCC. Genomic analysis revealed that 18 (43.9%) patients diagnosed as having genomic IM had common mutations in a pair of HCC tumors with the main tumor of these patients being more progressive compared to those with genomic MO. The accuracy of clinical diagnosis based on lobe (Definition 1) and segment (Definition 2) were 68.3% and 78.0%, respectively. Intriguingly, recurrence ≥2 years after initial surgery for 3 patients was IM. The survival of patients with clinical IM was significantly shorter than for those with clinical MO based on both Definition 1 (P = 0.045) and Definition 2 (P = 0.043). However, mean survival was not different between the patients with genomic IM and those with MO (P = 0.364). Taken together, genomic analysis elucidated that liver cancer may spread more extensively and more slowly than previously thought. In addition, distinguishing multiple HCC as IM or MC may have provided biological information but was not of clinical importance with respect to patient prognosis.

Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan Criteria: a RCT.

BACKGROUND & AIMS: The aim of this randomized comparative trial (RCT) is to compare partial hepatectomy (PH) with transcatheter arterial chemoembolization (TACE) to treat patients with resectable multiple hepatocellular carcinoma (RMHCC) outside of Milan Criteria. METHODS: This RCT was conducted on 173 patients with RMHCC outside of Milan Criteria (a solitary tumor up to 5 cm or multiple tumors up to 3 in number and up to 3 cm for each tumor) who were treated in our centre from November 2008 to September 2010. The patients were randomly assigned to the PH group or the TACE group. The primary outcome measure was overall survival (OS) from the date of treatment. A multivariate Cox proportional hazards regression analysis was performed to assess the prognostic risk factors associated with OS. RESULTS: The 1-, 2-, and 3-year OS rates were 76.1%, 63.5%, and 51.5%, respectively, for the PH group compared with 51.8%, 34.8%, and 18.1%, respectively, for the TACE group (Log-rank test, χ(2)=24.246, p<0.001). Multivariate Cox proportional hazards regression analysis revealed the type of treatment (hazard ratio, 0.434; 95% CI, 0.293 to 0.644, p<0.001), number of tumor (hazard ratio, 1.758; 95% CI, 1.213 to 2.548, p=0.003) and gender (hazard ratio, 0.451; 95% CI, 0.236 to 0.862, p=0.016) were significant independent risk factors associated with OS. CONCLUSIONS: PH provided better OS for patients with RMHCC outside of Milan Criteria than conventional TACE. The number of tumor and gender were also independent risk factors associated with OS for RMHCC.

Development of prognostic models for advanced multiple hepatocellular carcinoma based on Cox regression, deep learning and machine learning algorithms.

Background: Most patients with multiple hepatocellular carcinoma (MHCC) are at advanced stage once diagnosed, so that clinical treatment and decision-making are quite tricky. The AJCC-TNM system cannot accurately determine prognosis, our study aimed to identify prognostic factors for MHCC and to develop a prognostic model to quantify the risk and survival probability of patients. Methods: Eligible patients with HCC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, and then prognostic models were built using Cox regression, machine learning (ML), and deep learning (DL) algorithms. The model's performance was evaluated using C-index, receiver operating characteristic curve, Brier score and decision curve analysis, respectively, and the best model was interpreted using SHapley additive explanations (SHAP) interpretability technique. Results: A total of eight variables were included in the follow-up study, our analysis identified that the gradient boosted machine (GBM) model was the best prognostic model for advanced MHCC. In particular, the GBM model in the training cohort had a C-index of 0.73, a Brier score of 0.124, with area under the curve (AUC) values above 0.78 at the first, third, and fifth year. Importantly, the model also performed well in test cohort. The Kaplan-Meier (K-M) survival analysis demonstrated that the newly developed risk stratification system could well differentiate the prognosis of patients. Conclusion: Of the ML models, GBM model could predict the prognosis of advanced MHCC patients most accurately.

Laparoscopic versus open liver resection for multiple hepatocellular carcinoma within and beyond the Milan criteria: An Eastern-Western propensity score-matched analysis.

BACKGROUND: There is still little knowledge about the outcomes of laparoscopic liver resection (LLR) for multiple hepatocellular carcinomas (HCC). The aim of this study was to assess the short- and long- term outcomes of LLR versus open liver resection (OLR) for patients with multiple HCC within and beyond the Milan criteria, and in both BCLC-A and -B stage. METHODS: Data regarding all consecutive patients undergoing liver resection for multiple HCC were retrospectively collected from Asian (South Korean) and European (Italian) referral HPB centers. The cases were propensity-score matched for age, BMI, center, extent of the resection, postero-superior location of the lesion, underlying liver condition, BCLB staging and the Milan criteria. RESULTS: A total of 203 patients were included in the study: 27% of patients had undergone hemi-hepatectomy, 26.6% atypical resections, 20.6% sectionectomy and 16.2% segmentectomy. After PSM two cohorts of 57 patients were obtained, with no significant differences in all preoperative characteristics. The length of hospital stay was significantly lower after LLR (median 7 vs. 9 days, p < .01), with no statistically significant differences in estimated blood loss, operation time, transfusions, postoperative bile leak, ascites, severe complications and R1 resection rates. After a median follow-up of 61 (±7) months, there were no significant differences between OLR and LLR in both median OS (69 vs. 59 months, p = .74, respectively) and median DFS (12 vs. 10 months, p = .48, respectively). CONCLUSION: LLR for multiple HCC can be safe and effective in selected cases and is able to shorten median hospital stay without affecting perioperative and long-term oncological outcomes.

Construction and validation of a nomogram for patients with multiple hepatocellular carcinoma: A SEER-based study.

BACKGROUND: American Joint Committee on Cancer (AJCC)-TNM system doesn't accurately predict prognosis. Our study was designed to identify prognostic factors in patients with multiple hepatocellular carcinoma (MHCC), establish and validate a nomogram model to predict the risk and overall survival (OS) of MHCC patients. METHODS: We selected eligible HCC patients from the Surveillance, Epidemiology, and End Results (SEER) database, used univariate and multivariate COX regression to determine prognostic factors in MHCC patients, and used these factors to build a nomogram. The accuracy of the prediction was evaluated using the C-index, receiver operating characteristic (ROC) and calibration curve. Decision curve analysis (DCA), net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to compare the nomogram with AJCC-TNM staging system. Finally, the prognosis of different risks was analyzed using Kaplan-Meier (K-M) method. RESULTS: 4950 eligible patients with MHCC were enrolled in our study and randomly assigned to the training cohort and test cohort in a 7:3 ratio. After COX regression analysis, age, sex, histological grade, AJCC-TNM stage, tumor size, alpha-fetoprotein (AFP), surgery, radiotherapy and chemotherapy in total 9 factors could be used to independently determine OS of patients. the above factors were used to construct a nomogram, and the consistency C-index was 0.775. C-index, DCA, NRI and IDI showed that our nomogram was superior to the AJCC-TNM staging system. K-M plots for OS were performed using the log-rank test, the P-value of which was <0.001. CONCLUSIONS: The practical nomogram can provide more accurate prognostic prediction for multiple hepatocellular carcinoma patients.

Selecting the Best Approach for the Treatment of Multiple Non-Metastatic Hepatocellular Carcinoma.

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, the optimal strategy for patients with multiple HCC within the Milan Criteria is liver transplantation (LT). However, LT cannot be offered to all the patients due to organ shortages and long waiting lists, as well as because of the advanced disease carrying a high risk of poor outcomes. For early stages, liver resection (LR) or thermal ablation (TA) can be proposed, while trans-arterial chemoembolization (TACE) still remains the treatment of choice for intermediate stages (BCLC-B). Asian guidelines and the National Comprehensive Cancer Network suggest LR for resectable multinodular HCCs, even beyond Milan criteria. In this scenario, a growing body of evidence shows better outcomes after surgical resection when compared with TACE. Trans-arterial radioembolization (TARE) and stereotaxic body radiation therapy (SBRT) can also play an important role in this setting. Furthermore, the role of minimally invasive liver surgery (MILS) specifically for patients with multiple HCC is still not clear. This review aims to summarize current knowledge about the best therapeutical strategy for multiple HCC while focusing on the role of minimally invasive surgery and on the most attractive future perspectives.

Comparison of the surgical outcomes in patients with synchronous versus metachronous multiple hepatocellular carcinoma.

Multiplicity is one of the characteristics of hepatocellular carcinoma (HCC), and patients with multiple HCC (≤ 3 nodules) are recommended as candidates for liver resection. To confirm the validity of resecting multiple HCC, we compared the surgical outcomes in patients with synchronous and metachronous multiple HCC. Patients who underwent resection for multiple HCC (2 or 3 nodules) were classified into the "synchronous multiple HCC" group, while those undergoing resection for solitary HCC and repeated resection for 1 or 2 recurrent nodules within 2 years after initial operation were classified into the "metachronous multiple HCC" group. After one-to-one matching, longer operation time and more bleeding were seen in the synchronous multiple HCC group (n = 98) than those in the metachronous multiple HCC group (n = 98); however, the complication rates were not different between the two groups. The median overall survival times were 4.0 years (95% CI, 3.0-5.9) and 5.9 years (4.0-NA) for the synchronous and metachronous multiple HCC (after second operation) groups, respectively (P = 0.041). The recurrence-free survival times were shorter in the synchronous multiple HCC group than in the metachronous multiple HCC group (median, 1.5 years [95% CI, 0.9-1.8] versus 1.8 years, [1.3-2.2]) (P = 0.039). On multivariate analysis, independent factors for overall survivals in the synchronous multiple HCC group were older age, cirrhosis, larger tumor, and tumor thrombus. Taken together, resection of metachronous multiple HCC still has good therapeutic effect, even better than synchronous multiple HCC, so resection is suggested for metachronous multiple HCC.

Dissecting the multinodular hepatocellular carcinoma subset: is there a survival benefit after hepatectomy?

Whether hepatic resection for multinodular hepatocellular carcinoma (HCC) is indicated remains to be demonstrated. We investigated the prognostic factors in a large series of patients treated with hepatic resection at a reference cancer center. All consecutive patients resected for multinodular HCC from January 2004 to April 2015 were reviewed. The study endpoints were the survival analysis and the definition of resection criteria. Among 380 patients resected for HCC, 116 (31%) were affected by multinodular HCC without macrovascular invasion. The median tumor number was 2 (range 2-30), while the median tumor size was 3.5 cm (range 1.1-28). The 90-day mortality was 2.6%. Morbidity was 31%. After a median follow-up of 31 months (range 3.1-149.7), the 1-, 3-, and 5-year overall survival rates were 85, 52, and 35%, respectively. At the multivariate analysis, tumor number more than 4 (HR = 2.15; 95% CI 1.8-4.18; P = 0.001), tumor size more than 6 cm (HR = 2.78; 95% CI 2.08-4.91; P = 0.001), esophageal varices (HR = 3.01; 95% CI 1.98-5.61; P = 0.002), and major hepatectomy (HR = 2.91; 95% CI 1.97-4.54; P = 0.001) were independently significant for survival. Median survival shifted from 20 to 52 months based on these factors. Hepatic resection for multinodular HCC may result in survival benefit for patients up to four tumors, none more than 6 cm, without varices, and eventually treated by conservative surgery.

Hepatic resection beyond barcelona clinic liver cancer indication: When and how.

Hepatocellular carcinoma (HCC) is the main common primary tumour of the liver and it is usually associated with cirrhosis. The barcelona clinic liver cancer (BCLC) classification has been approved as guidance for HCC treatment algorithms by the European Association for the Study of Liver and the American Association for the Study of Liver Disease. According to this algorithm, hepatic resection should be performed only in patients with small single tumours of 2-3 cm without signs of portal hypertension (PHT) or hyperbilirubinemia. BCLC classification has been criticised and many studies have shown that multiple tumors and large tumors, as wide as those with macrovascular infiltration and PHT, could benefit from liver resection. Consequently, treatment guidelines should be revised and patients with intermediate/advanced stage HCC, when technically resectable, should receive the opportunity to be treated with radical surgical treatment. Nevertheless, the surgical treatment of HCC on cirrhosis is complex: The goal to be oncologically radical has always to be balanced with the necessity to minimize organ damage. The aim of this review was to analyze when and how liver resection could be indicated beyond BCLC indication. In particular, the role of multidisciplinary approach to assure a proper indication, of the intraoperative ultrasound for intra-operative restaging and resection guidance and of laparoscopy to minimize surgical trauma have been enhanced.

Postoperative adjuvant transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond the Milan criteria: a retrospective analysis.

OBJECTIVE: To clarify the value of postoperative adjuvant transcatheter arterial chemoembolization (TACE) for resectable multiple hepatocellular carcinoma beyond the Milan criteria. BACKGROUND: Patients with multiple HCC have been shown to have a worse survival after a partial hepatectomy (PH) because of the high incidence of intrahepatic tumor recurrence. Postoperative adjuvant TACE is an optional strategy for HCC patients with a high recurrence risk. Its effects and range of applications are debatable. METHODS: This retrospective study enrolled 135 HCC patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria, and those patients underwent a hepatectomy with/without postoperative adjuvant TACE from Jan. 2004 to Dec. 2008. The patients were divided to the PH cohort or the PH+TACE cohort. The prognosis measures were the disease-free survival (DFS) and overall survival (OS) from the date of treatment. Univariate and multivariate analyses were used to assess the prognostic factors associated with DFS and OS, using the Cox proportional hazards model. RESULTS: The 1-, 2-, and 5-year DFS and OS for the PH+TACE group differed significantly from the PH group (p = 0.004, p = 0.002, respectively). Multivariate analysis revealed that the significant independent risk factors associated with the DFS and OS were postoperative TACE treatment (p = 0.002, p = 0.001, respectively) and the number of tumors (p = 0.006, p = 0.037, respectively). CONCLUSIONS: Our results show that postoperative adjuvant treatment resulted in delayed intrahepatic recurrence and better survival for patients with resectable multiple hepatocellular carcinoma beyond the Milan criteria. Postoperative adjuvant TACE should be regarded as a common strategy for patients with resectable multiple HCC beyond the Milan criteria.

Long-term Outcomes after Multiple-site Resection or Combined Resection and Radiofrequency Ablation in Patients with Multiple Hepatocellular Carcinoma

PURPOSE: Hepatic resection is the standard treatment for hepatocellular carcinoma (HCC). In some patients with multiple HCC, one-block resection is not feasible due to either the tumor location or the underlying liver function. In this study, we attempted to compare the outcomes of multiple - site resection or combined resection and radiofrequency ablation with those of one-block resection in patients with multiple HCC. METHODS: We retrospectively reviewed 507 patients who underwent surgical resection. Among 507 patients who received surgical treatment with potentially curative aim from January 1996 to August 2006 in Yonsei University Health System, 58 patients had a radiologically detected multiple HCC. Patients with multiple HCC were divided into: group A, patients treated with one-block resection (n=40) and group B, patients with multiple-site resection or combined resection and RFA (n=18). RESULTS: The 1-, 3- and 5-year overall survival rates for patients with single and multiple HCC were 90.2%, 76.2% and 66.7% and 82.7%, 61.4% and 37.9%, respectively (p 10% were adverse prognostic factors for overall survival. CONCLUSION: Active treatments including multiple-site resection and combined resection and RFA showed similar treatment outcomes compared with one-block resection in patients with multiple HCC.

Long-term Outcomes after Multiple-site Resection or Combined Resection and Radiofrequency Ablation in Patients with Multiple Hepatocellular Carcinoma

PURPOSE: Hepatic resection is the standard treatment for hepatocellular carcinoma (HCC). In some patients with multiple HCC, one-block resection is not feasible due to either the tumor location or the underlying liver function. In this study, we attempted to compare the outcomes of multiple - site resection or combined resection and radiofrequency ablation with those of one-block resection in patients with multiple HCC. METHODS: We retrospectively reviewed 507 patients who underwent surgical resection. Among 507 patients who received surgical treatment with potentially curative aim from January 1996 to August 2006 in Yonsei University Health System, 58 patients had a radiologically detected multiple HCC. Patients with multiple HCC were divided into: group A, patients treated with one-block resection (n=40) and group B, patients with multiple-site resection or combined resection and RFA (n=18). RESULTS: The 1-, 3- and 5-year overall survival rates for patients with single and multiple HCC were 90.2%, 76.2% and 66.7% and 82.7%, 61.4% and 37.9%, respectively (p 10% were adverse prognostic factors for overall survival. CONCLUSION: Active treatments including multiple-site resection and combined resection and RFA showed similar treatment outcomes compared with one-block resection in patients with multiple HCC.