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BackgroundOrthotopic liver transplantation (OLT) is the best available option for early hepatocellular carcinoma (HCC), although its application is limited by stringent selection criteria, costs, and deceased donor graft shortage, particularly in Asia, where living donor liver transplant (LDLT) has been developed.MethodsThis article reviews the present standards for patient selection represented by size-and-number criteria with particular references to Milan Criteria and novel prediction models based on results achieved in patients exceeding those limits, with consideration of the expanded indication represented by the UCSF Criteria.ResultsThe expected outcomes after deceased donor liver transplant (DDLT) or LDLT are favorable if predetermined selection criteria are applied. However, selection bias, difference in waiting time, and ischemia-regeneration injuries of the graft among DDLT vs LDLT may influence long-term results. In the article, the differences between East and West in first-line treatments for HCC (resection vs transplantation), indications, and ethics for the donor, are summarized as well as possible novel predictors of tumor biology (especially DNA mutation and fractional allelic loss, FAI) to be considered for better outcome prediction.ConclusionsLiver transplantation remains the most promising product of modern surgery and represents a cornerstone in the management of patients with HCC.

Background: The purpose of this study was to evaluate the characteristics and prognosis of de novo CRC patients who underwent liver or kidney transplantation. Methods: We retrospectively reviewed the medical records of 66 de novo CRC patients selected from 8,734 liver transplant (LT) or kidney transplant (KT) recipients. We analyzed characteristics and survival outcomes of de novo CRC patients and sporadic CRC patients who underwent radical surgery with stage I-III in Asan Medical Center between 2005 and 2016. Survival outcomes were analyzed via the 1:4 matching method. Results: The standard incidence ratio (SIR) of de novo CRC in KT recipients is 1.67 in men and 2.54 in women. That in LT recipients is 3.10 in men and 2.25 in women. Compared with sporadic CRC patients, de novo CRC patients had more colon cancer than rectal cancer (p=0.041). In 9 patients (13.6%), CRC was diagnosed within one year after transplantation, 21 patients (31.8%) were diagnosed between 1–5 years, and the remaining 36 patients (54.6%) were diagnosed thereafter. There were no significant differences in recurrence-free survival and overall survival between the two groups (p=0.211 and p=0.324, respectively). Conclusions: The risk of developing de novo CRC in transplant recipients was higher than in the general population. The survival outcome of de novo CRC was no different compared with the sporadic CRC. Therefore, regular surveillance is essential for timely diagnosis and treatment for transplantation patients. A large prospective study for an intense CRC surveillance program in transplantation patients is needed. [ABSTRACT FROM AUTHOR]

Introduction: There is no consensus regarding selection criteria on liver transplantation (LT) for hepatocellular carcinoma (HCC), especially for living donor liver transplantation, although emerging evidence has been found for the effectiveness of bridging or downstaging. Objective: We evaluated the long-term outcomes of patients who underwent LT with or without bridging or downstaging for HCC. Methods: This retrospective study included 896 LT recipients with HCC between June 2005 and May 2015. Recurrence-free survival (RFS), overall survival (OS), and their associated factors were evaluated. Results: The 5-year RFS in the full cohort of 896 patients was 82.4%, and the OS was 85.3%. In patients with initial Organ Procurement and Transplantation Network (OPTN) T1 and T2, the 5-year RFS and OS did not significantly differ between LT groups with and without bridging (all p ≥ 0.05). The 5-year RFS and OS of OPTN T3 patients with successful downstaging were not significantly different from those of patients with OPTN T2 with primary LT (p = 0.070 and p = 0.185), but were significantly higher than in patients with OPTN T3 with downstaging failure and initial OPTN T1 or T2 with progression (all p < 0.001). In the multivariate analysis, last alpha-fetoprotein before LT ≥70 ng/mL (hazard ratio [HR]: 1.77, p = 0.001; HR: 1.72, p = 0.004), pretransplant HCC status exceeding the Milan criteria (HR: 5.12, p < 0.001; HR: 3.31, p < 0.001), and positron emission tomography positivity (HR: 2.57, p < 0.001; HR: 2.57, p < 0.001) were independent predictors for worse RFS and OS. Conclusions: The impact of bridging therapy on survival outcomes is limited in patients with early-stage HCC, whereas OPTN T1 or T2 with progression provides worse prognosis. OPTN T3 should undergo LT after successful downstaging, and OPTN T3 with successful downstaging allows for acceptable long-term posttransplant outcomes. [ABSTRACT FROM AUTHOR]

Liver cancer exhibits the fourth most common cause of cancer-associated mortality worldwide. Due to the rapid growth, solid tumors undergo severe hypoxia and produce high levels of extracellular adenosine to maintain homeostasis. A previous study indicated that the hypoxic condition in liver cancer increased hepatic adenosine, which is known to facilitate cancer survival and proliferation. Extracellular adenosine has been revealed to regulate pathological and physiological processes in cells and tissues. However, its pathophysiological role in liver cancer remains undetermined. Emerging evidence has indicated that the adenosine A2B receptor promotes the progression of liver cancer. Therefore, it was hypothesized that HIF-1α is a transcriptional regulator of A2B in human liver cancer. The current study determined A2B expression of a number of liver cancer cell lines and performed functional studies of HIF-1α as a master transcriptional regulator of hepatic A2B signaling during hypoxic conditions. The current study aimed to identify the promoter region of A2B, which has a hypoxia response element, by performing luciferase assays. The present study demonstrated that reduced HIF-1α expression is associated with low expression of A2B, and HIF-1α overexpression is associated with A2B induction. Furthermore, the siRNA-mediated downregulation of A2B inhibited the growth and proliferation of HepG2, which is a liver cancer cell line. The relationship between HIF-1α and A2B expression was also identified in human liver cancer specimens. In conclusion, the current study indicated that A2B is induced by the HIF-1α transcriptional regulator during hypoxia, and it may be a potential pharmacologic and therapeutic target for the treatment of patients with liver cancer. [ABSTRACT FROM AUTHOR]

Background & aim: Hepatocellular carcinoma (HCC) is increasingly being detected at a very early‐stage due to the wide implementation of the surveillance of at‐risk patient populations combined with improved imaging technologies. Whether patients with HCC at a very early stage can be offered local ablation as a first‐line treatment option still remains controversial. We retrospectively compared the effectiveness of surgical resection (SR) and radiofrequency ablation (RFA) for Barcelona Clinic Liver Cancer (BCLC) very early‐stage HCC in patients with long‐term follow‐up. Methods: Propensity score analysis using inverse probability weighting (IPW) from a large‐volume liver centre. We included adult patients who between 2000 and 2013 received a diagnosis of very early‐stage HCC (BCLC stage 0; a single tumour ≤2 cm, Child‐Pugh A class, eastern cooperative oncology group [ECOG] 0) and who were treated with SR or RFA as the first‐line treatment. Results: We identified 1208 patients, 631 in the SR group and 577 in the RFA group. The median follow‐up time was 86.2 months. After propensity score analysis using IPW, the 15‐year overall survival rates were 60.4% and 51.6% in the SR and RFA group respectively. RFA group showed poorer overall survival than SR group (adjusted hazard ratio, 1.29; P = .0378). The 15‐year recurrence‐free survival rates were 37% and 23.6% in the SR and RFA group respectively (P < .001). Conclusion: For patients with very early‐stage HCC, the SR group was associated with better overall and recurrence‐free patient survival compared to the RFA group. Therefore, SR should be considered as the first‐line treatment for these patients. [ABSTRACT FROM AUTHOR]

Background: Liver resection is a potentially curative therapy for hepatocellular carcinoma (HCC). LLR is a newly developed and safe technique associated with shorter hospital stay, less pain, better cosmetic outcomes, and similar complication rates as open surgery; however, data on its long-term outcomes remain scarce.Methods: We retrospectively examined the clinical and follow-up data of 234 patients who underwent LLR (performed by a single surgeon in all cases) for the primary treatment of HCC between July 2007 and December 2015 at Asan Medical Center.Results: The mean patient age was 55.63 (range 31-76) years; 167 were men. The median follow-up duration was 38 (range 6-116) months. A total of 227 patients (97.0%) had Child-Turcotte-Pugh grade A disease. Of them, 167 (71.4%) underwent anatomical resections and 63 (28.6%) underwent non-anatomical partial hepatectomies. Overall survival rates were 98.3, 91.7, and 87.1%, and recurrence-free survival rates were 82.1, 67.5, and 55.3% at 1, 3, and 5 years, respectively. In Cox regression analysis, anatomical resection was a risk factor for recurrence (univariate analysis: hazard ratio [HR] 0.49; 95% confidence interval [CI] 0.31-0.75; p = 0.001; multivariate analysis: HR 0.59; 95% CI 0.38-0.94; p = 0.025).Conclusions: LLR is an acceptable primary treatment for patients with HCC with good hepatic function and with an appropriate anatomical structure, and is associated with improved prognosis. LLR can achieve lower recurrence rates through anatomical resection. [ABSTRACT FROM AUTHOR]

Background: We developed a prognostic prediction model (PPM) using 4 factors for hepatic resection (HR) of large hepatic cellular carcinoma (HCC). Multiplication of α-fetoprotein (AFP), des-γ-carboxy prothrombin, and tumor volume (TV) (ADV score) is a surrogate marker for post-resection prognosis. This study intended to validate the predictive power of 4-factor PPM and to develop new ADV score-based PPM.Methods: A total of 526 patients who underwent HR for solitary HCC ≥ 8 cm were selected from 9 Korean institutions between 2008 and 2014.Results: Median tumor diameter and TV were 11.0 cm and 398 mL, respectively. Tumor recurrence and patient survival rates were 53.0 and 78.4% at 1 year and 70.2 and 49.3% at 5 years, respectively. Independent risk factors for both tumor recurrence and patient survival included AFP ≥ 100 ng/mL, hypermetabolic FDG-positron emission tomography (PET), microvascular invasion and satellite nodules, which comprised 4 factors of the PPM. Five subgroups based on the number of involved risk factors exhibited significant differences in tumor recurrence and patient survival. ADV score cutoff was set at 7log (ADV7log) after cluster prognostic analysis. Patient grouping according to combination of ADV7log and FDG-PET findings (ADV7log-PET) exhibited significant differences in tumor recurrence and patient survival, comparable to those of the 4-factor PPM.Conclusions: Two PPMs using 4 risk factors and ADV7log-PET could reliably predict the risk of early HCC recurrence and long-term survival outcomes in patients who underwent HR for large HCC. We believe that these PPMs can guide surgical treatment for large HCCs from preoperative HR planning to post-resection follow-up. [ABSTRACT FROM AUTHOR]

Background: Combined hepatocellular carcinoma and cholangiocarcinoma (cHC) has wide histological diversity. We intended to investigate the prognostic influence of tumor types of cHC. Methods: We analyzed the clinical and pathological features of cHC along 2010 WHO classification. Study group was 100 cHC patients who underwent primary resection. Control group comprised 200 propensity score-matched patients with intrahepatic cholangiocarcinoma (ICC). Results: In cHC group, tumor diameter was 4.4 ± 2.8 cm and 95 patients had single tumor. They were classified as classical type in 46 and subtypes with stem cell (SC) features in 54. Subtypes with SC features included typical in 16, intermediate cell in 22, and cholangiolocellular in 16. Their 1- and 3-year tumor recurrence rates were 31.7 and 59.8%; and 1- and 3-year patient survival rates were 92.5 and 77.3%, respectively. Tumor recurrence ( p = 0.008) and patient survival ( p = 0.005) rates were different according to tumor types. Further stratification by subtypes with SC features resulted in prognostic stratification in tumor recurrence ( p = 0.045) and patient survival ( p = 0.042). However, tumor stage was the only independent risk factor for tumor recurrence and patient survival. Comparing with ICC control group, cHC group showed no significant difference in rates of tumor recurrence ( p = 0.523), but better survival outcomes ( p = 0.008). Median post-recurrence patient survival period was 20 months in cHC patients and 6 months in ICC patients ( p = 0.001). Conclusions: Our results indicated that there would be close relationship between the post-resection prognosis and histological types according to the 2010 WHO classification, but these histological types did not become an independent prognostic factor. [ABSTRACT FROM AUTHOR]

Background: Simultaneous double primary hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) (dpHCC-ICC) is very rare. This study investigated the clinicopathological features and post-resection prognosis of dpHCC-ICC. Methods: We identified 10 patients with dpHCC-ICC through an institutional database search. Three control groups with HCC, ICC and combined HCC-cholangiocarcinoma (cHCC-CC) were selected (each n = 120) using propensity score matching. Results: The incidence of dpHCC-ICC was 0.23%. The mean age was 57.4 ± 11.7 years, and 8 were male. Hepatitis B virus infection was associated with 8 patients. All dpHCC-ICC were diagnosed incidentally from surgical specimens. Only two patients demonstrated simultaneous elevation of alpha-fetoprotein/des-γ-carboxy prothrombin and carbohydrate antigen 19-9. All patients underwent macroscopic curative resection. The HCC component was classified as stage I in 7 and stage II in 3, and ICC component was classified as stage I in 5, stage II in 2 and stage IV in 3. Tumor recurrence and patient survival rates were 30.0 and 90.0% at 1 year and 52.0 and 77.1% at 3 years, respectively. Tumor recurrence rates were not different between the dpHCC-ICC and the three control groups ( p = 0.505). The overall and post-recurrence patient survival rates were similar between the dpHCC-ICC and cHCC-CC groups ( p > 0.2); however, these were inferior to those in the HCC group but comparable with those in the ICC group. Conclusions: The post-resection prognosis of dpHCC-ICC was more dependent on the tumor stage of the ICC component than that of the HCC component. Therefore, they can be clinically regarded as ICC with concurrent HCC. [ABSTRACT FROM AUTHOR]

Purpose: The study aims to analyze the oncologic outcomes of living donor liver transplantation (LDLT) after combined transarterial chemoembolization (TACE) and radiotherapy for hepatocellular carcinoma (HCC) with major vascular invasion.Methods: We retrospectively reviewed 17 HCC patients with major vascular invasion who underwent LDLT after combined treatment modality between May 2007 and September 2014. The LDLT timing was determined by the surgeons depending on the disease status and liver function. The intrahepatic recurrence-free survival, disease-free survival (DFS), and overall survival (OS) rates were estimated from the date of the LDLT.Results: The median follow-up period was 24.5 months (range, 6.4-66.0 months) after the LDLT. The interval between the combined treatment and the LDLT was a median of 5 months (range, 0.4-65.3 months). On the explanted liver, total necrosis was shown in five patients (29.4 %). The 1- and 3-year DFS rates were 70.6 and 57.8 %, respectively. The 1- and 3-year OS rates were 87.4 and 60.5 %, respectively. The major pattern of failure was distant metastasis (35.3 %), and intrahepatic recurrence occurred in three patients (17.6 %) who experienced distant metastasis.Conclusions: In the selected HCC patients with major vascular invasion, LDLT after combined TACE and radiotherapy showed acceptable oncologic outcomes. [ABSTRACT FROM AUTHOR]

Background: We hypothesized that microvascular invasion (MVI) and post-resection prognosis in patients with solitary hepatocellular carcinoma (HCC) could be predicted using blood tumor markers and tumor volume (TV). We intended to identify a simple surrogate marker of HCC via a combination of clinical variables.Methods: This retrospective study used the strictly selected development cohort (n = 1176) and validation cohort (n = 551) containing patients who underwent curative resection of solitary HCC.Results: In the development cohort study, the median values were 13.7 mL for TV, 24.2 ng/mL for α-fetoprotein (AFP), and 75 mAU/mL for des-γ-carboxy prothrombin (DCP); there was no correlation among these three factors (r 2 ≤ 0.237, p < 0.001). The 1-, 3-, and 5-year rates were 22.4, 41.7, and 46.8 % for tumor recurrence and 93.6, 84.0, and 78.2 % for patient survival, respectively. Independent risk factors for both tumor recurrence and patient survival were tumor diameter >5 cm or TV >50 mL, MVI, satellite nodules, and high DCP. Multiplication of AFP, DCP, and TV (ADV score) resulted in prediction of MVI at a cutoff of 5log with sensitivity of 73.9 % and specificity of 66.7 %. Patient stratifications according to ADV score with cutoffs of 5log alone, 6log and 9log, and its combination with MVI showed significant prognostic differences (all p < 0.001). These prognostic significances were reliably reproduced in the validation cohort study (all p < 0.001).Conclusions: We suggest that ADV score is an integrated surrogate marker of HCC prognosis. We believe that it can be used to predict MVI and post-resection prognosis for solitary HCC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the prognostic impact of preoperative transcatheter arterial chemoembolization (TACE) on long-term survival outcomes in patients undergoing resection of small solitary hepatocellular carcinoma (HCC). Methods: Enrolled patients had undergone macroscopic curative resection of solitary 2-5 cm HCC with ( n = 105) or without ( n = 830; control group) preoperative TACE. Results: TACE group was divided into subgroups A ( n = 68, 1-2 TACEs within 12 months), B ( n = 23, ≥3 TACEs within 12 months), and C ( n = 14, TACE prior to 12 months). The number of TACE sessions was 1.8 ± 1.6. In TACE A-C subgroups, pathological response of tumor necrosis >50 % at median post-TACE period after final TACE was observed in 41 (60.3 %) at 1.9 months, 10 (43.5 %) at 2.1 months, and 2 (14.3 %) at 18.9 months, respectively. The 5-year tumor recurrence and patient survival rates were 62.8 and 70.4 % in TACE group and 51.4 and 83.4 % in control group, respectively ( p ≤ 0.003). Median periods of postoperative tumor recurrence in TACE A-C subgroups and control group were 35, 13, 14, and 55 months, respectively ( p < 0.001); and postoperative survival periods at 75 % survival rate were 51, 38, 51, and 98 months, respectively ( p = 0.003). TACE-induced extensive tumor necrosis did not improve postoperative prognosis in TACE A subgroup ( p ≥ 0.053). Postoperative prognosis after preoperative sequential TACE and portal vein embolization was comparable to that of the control group ( p ≥ 0.052). Conclusions: Preoperative TACE for small solitary HCCs may adversely affect post-resection prognosis, irrespective of pathological responses. Preoperative TACE should be avoided for patients with resectable small HCCs. [ABSTRACT FROM AUTHOR]

Introduction: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) is rare. This study investigated the clinicopathological features of cHCC-CC and compared the postresection survival outcomes of cHCC-CC, hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (IHC).Methods: Between January 2000 and September 2012, 53 patients with cHCC-CC underwent tumor resection, accounting for 1.1 % of surgeries for primary liver malignancies. Control groups included patients with HCC (n = 1452) and IHC (n = 149) who underwent R0 resection of stage I/II tumors ≤5 cm.Results: Mean tumor diameter of cHCC-CC group was 5.5 ± 2.9 cm, and single tumor was identified in 50. Pathological classification included combined (n = 41), mixed (n = 11), and double (n = 1) tumors. The 1-, 3-, 5-, and 10-year tumor recurrence rates were 60.8, 71.8, 80.7, and 80.7 %, respectively. The 1-, 3-, 5-, and 10-year overall survival rates were 73.3, 35.6, 30.5, and 11.1 %, respectively. Tumor recurrence and patient survival did not differ significantly according to AJCC tumor staging and histological type (all p ≥ 0.2). Tumor recurrence rates did not differ significantly between the cHCC-CC, HCC, and IHC groups (p = 0.43), whereas differences in survival rates were significant (p = 0.000), with a median survival after tumor recurrence of 8, 51, and 6 months, respectively (p = 0.000).Conclusions: Patients with cHCC-CC showed similar recurrence rates to those of control patients with HCC and IHC, whereas their survival outcomes were worse than those of control HCC patients because of poor responses to recurrence treatment. Further evaluation of differences in tumor characteristics and tumor biology is necessary to accurately predict the prognosis of patients with cHCC-CC. [ABSTRACT FROM AUTHOR]

Background: Preoperative portal vein embolization (PVE) induces shrinkage of the embolized lobe and compensatory regeneration in the non-embolized lobe, but does not always induce sufficient regeneration of the future remnant liver (FRL). We previously developed preoperative sequential PVE-hepatic vein embolization (HVE), and here we present our experience of treating 42 patients with sequential PVE-HVE. Methods: During 8-year study period, preoperative PVE-HVE was performed on 42 patients with hepatobiliary malignancies. Results: Primary diseases were bile duct cancers [perihilar cholangiocarcinoma ( n = 33) and diffuse bile duct cancer ( n = 1)], hepatocellular carcinomas ( n = 4), and intrahepatic tumors [intrahepatic cholangiocarcinoma ( n = 3) and gallbladder cancer liver invasion ( n = 1)]. These patients demonstrated insufficient FRL regeneration following PVE, thus HVE was performed to induce further regeneration. No PVE-HVE procedure-associated complications occurred. In the bile duct cancer group, FRL volume was 33.9 ± 2.2 % before PVE, 38.4 ± 1.5 % before HVE, 43.7 ± 2.1 % at surgery, and 73.6 ± 8.3 % at 2 weeks after right hepatectomy. The degree of FRL hypertrophy was 13.3 % after PVE, 28.9 % after PHV-HVE, and 117.1 % at 2 weeks after right hepatectomy. All patients except one recovered uneventfully after surgery, and the 3-year patient survival rate was 45.1 %. In the HCC group, transarterial chemoembolization was initially performed and FRL regeneration following PVE-HVE occurred very slowly. Active FRL regeneration occurred in the liver tumor group, but rapid tumor growth was observed in 1 of 4 patients. Conclusion: The sequential application of HVE following PVE safely and effectively induces further FRL regeneration in non-cirrhotic livers. Further validation using larger patient population and multicenter studies is needed to reliably widen the indications. [ABSTRACT FROM AUTHOR]

Background: Tumor recurrence is very common after resection of huge hepatocellular carcinoma (HCC). This study intended to evaluate early recurrence and long-term outcomes in patients with huge HCC ≥ 10 cm after primary resection and treatment of recurrence. Methods: Recurrence and survival outcomes were retrospectively evaluated in 471 patients with huge HCCs who underwent resection between January 2000 and April 2012. Results: Mean tumor diameter was 13.6 ± 3.1 cm, with 93 % of patients having single tumors. Anatomic and R0 resection rates were 91.1 and 89.4 %, respectively. Perioperative mortality rate was 1.7 %. Tumor recurrence and patient survival rates were 62.2 and 69.2 % at 1 year and 76.0 and 35.5 % at 5 years, respectively. Of patients with recurrence, 92.5 % received specific treatment. Median patient survival period after initial intrahepatic recurrence was 16 months. Tumor volume did not affect recurrence or survival outcomes. Independent risk factors for tumor recurrence and patient survival were serum alpha-fetoprotein ≥100 ng/mL, hypermetabolic uptake on positron emission tomography, satellite nodules, and microvascular invasion. These four factors were used to develop a risk prediction model, in which 1-year HCC recurrence rates in patients with 0, 1, 2, 3, and 4 risk factors were 18.7, 30.3, 58.7, 79.0, and 92.1 %, respectively, and their 1-year patient survival rates were 100, 97.0, 75.5, 63.9, and 42.1 %, respectively. Conclusions: In patients with huge HCCs, hepatic resection with active recurrence treatment resulted in improved long-term survival. Our 4-factor risk prediction model appears to contribute to quantitative postoperative risk estimation for early HCC recurrence and patient survival in patients with HCC ≥ 10 cm. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is the evaluation of the surgical and oncological results of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) by comparing laparoscopic and open liver resection (OLR) in the treatment of this disease. Retrospective analysis of laparoscopic and OLR for HCC (<5 cm) performed over a 4-year period was conducted. The LLR was done by a single surgeon. Methods: The study was performed on patients who received liver resection for HCC between July 2007 and August 2011 in our institution. Propensity-based matched analyses were used to account for operative method selection biases. During the 4 years, 1,050 patients with HCC received an operation. Among them patients who never received TACE or RFA before surgery and had HCC (<5 cm) were selected for this study. Results: 174 patients had OLR, and 58 patients underwent LLR. Patients who received LLR had lower operative time, transfusion rate, complication rate, and shorter hospital days. There were significant differences in hospital mortality and morbidity between the two groups. Dietary recovery was relatively fast in the group of LLR. Overall and disease-free survival rates during the 4 years were also not significantly different between the two groups. Conclusions: LLR is a developing and safe technique in a select group of patients including those with malignancies, and use of this procedure is associated with short hospital stays, a rapid return to a normal diet, full mobility, and minimal morbidity, with acceptable oncological parameters. It may be an optimal method of hepatectomy in HCC (<5 cm). Further, long-term follow-up should be acquired for adequate evaluation for survival. [ABSTRACT FROM AUTHOR]

Background: According to the 7th AJCC TNM staging system, solitary hepatocellular carcinoma (HCC) is classified as T1 or T2 based on microvascular invasion (MVI) regardless of tumor size. This study intended to evaluate the prognostic impact of tumor size on survival outcomes after macroscopic curative resection of solitary HCC. Methods: Patients who underwent R0 resection of solitary HCC <10 cm ( n = 2558) were selected for study. Follow-up lasted ≥24 months or until death. Results: HCC was detected during regular health screening or routine follow-up in 2054 cases (80.3 %). Hepatitis B virus (HBV) infection was associated in 2127 (83.2 %). Mean patient age was 54.4 ± 9.9 years. Anatomical resection was performed in 1786 (69.8 %). MVI was identified in 407 (16.0 %) which therefore became stage T2; the other 2150 became stage T1. Tumor recurrence and patient survival rates were 24.9 and 95.0 % after 1 year, 49.6 and 84.1 % after 3 years, 57.7 and 75.0 % after 5 years, and 67.3 and 56.6 % after 10 years, respectively. Multivariate analysis showed that non-anatomical resection, MVI, and tumor size >5 cm were independent risk factors for both tumor recurrence and overall patient survival. Long-term survival correlated negatively with tumor size and MVI. Subgroup analysis with MVI and size cutoff of 5 cm revealed a significant survival difference ( p = 0.000). Tumor size >5 cm was not a significant prognostic factor in non-HBV patients. Conclusions: These results suggest that the prognostic impact of tumor size may be underestimated in the current version of the AJCC staging system and that solitary HCC staging could be improved with inclusion of tumor size cutoff of 5 cm in HBV-associated patients. Further validation is necessary with multicenter studies. [ABSTRACT FROM AUTHOR]

Background: This study analyzed the patient survival outcomes following the resection of hepatocellular carcinoma (HCC) metachronous adrenal metastasis (MAM) in patients who had undergone liver resection or liver transplantation (LT). Methods: Clinical results were analyzed retrospectively in 26 patients with MAM-HCC who underwent adrenalectomy. Results: The mean interval between initial surgery and adrenalectomy was significantly shorter in the resection group than in the LT group (18.3 ± 14.4 vs. 42.6 ± 13.8 months, p < 0.001). Of 19 resected patients, four had adrenal metastases on the right side, 12 on the left side and three bilaterally, with a mean tumor diameter of 3.6 ± 1.5 cm. Ten of these patients underwent open surgery and nine underwent laparoscopic surgery; all patients experienced recurrences within 18 months and 20.3% survived 5 years after adrenalectomy. Of 7 patients who underwent LT, four had adrenal metastases on the right side and three on the left side, with a mean tumor diameter of 3.4 ± 1.8 cm. Six of these patients underwent open surgery and one underwent laparoscopic surgery. Five-year recurrence and patient survival rates after adrenalectomy were 28.6 and 85.7%, respectively. Conclusions: Adrenalectomy is indicated in patients with isolated MAM-HCC. Comparisons with other locoregional treatment modalities and multicenter studies with additional patients are needed to validate the role of adrenalectomy. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background and Aim This study aimed to investigate the prognostic value of expression of hepatocyte nuclear factors ( HNFs) involved in hepatic gene transcription in patients undergoing curative resection for hepatocellular carcinoma ( HCC). Methods We performed immunohistochemical analyses on microarrays of the tumors and matched adjacent tissue using antibodies against HNF1α, HNF1β, HNF4α, and α-fetoprotein ( AFP). We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan- Meier method in a training cohort of 220 patients and conducted an independent validation in 232 patients. We also determined whether measurement of HNFs improved risk prediction beyond the use of established factors, using net reclassification improvement ( NRI). Results Post-surgical recurrence and hepatic death were predicted by intratumoral HNF4α underexpression in both cohorts. In the training cohort they were also predicted by peritumoral HNF1α positivity. A pooled cohort analysis showed that these predictors were independently associated with early but not late-phase recurrence, and resultant mortality. Intratumoral expression levels of HNF4α were correlated with those of HNF1α, HNF1β, and AFP ( P < 0.05). Similarly, HNF1α expression in peritumoral tissue was correlated with that of other markers ( P < 0.05). There was no significant correlation between expression of HNF4α in tumors and HNF1α in peritumoral tissue. Adding combinations of intratumoral HNF4α and peritumoral HNF1α to 2-year recurrence and 5-year mortality models including known clinicopathological prognostic factors significantly improved the NRI indexes (39% and 44%, respectively; P < 0.05). Conclusions Immunohistological activation of intratumoral HNF4α and depletion of peritumoral HNF1α have prognostic significance for delayed recurrence and death after HCC resection. [ABSTRACT FROM AUTHOR]

Background: This study was intended to assess the effect of resection of pulmonary metastasis (PM) of hepatocellular carcinoma (HCC) after liver transplantation (LT). No effective treatment modality exists for PM-HCC, and little is known about the posttransplant outcomes of pulmonary metastasectomy (PMT). Methods: Of 587 adult LT recipients diagnosed with HCC, 43 had PM-HCC. We retrospectively compared outcomes in 23 patients who underwent PMT and 20 who did not. PMT was precluded in ten patients in the non-PMT group by multiple (usually ≥5) lung nodules, in nine by lung nodules with concurrent or residual extrapulmonary metastasis, and in one by comorbidity. Results: Of the 23 patients in the PMT group, 14 underwent a single session of PMT, 7 underwent 2 sessions each, and 2 underwent 3 sessions each, for a total of 34 sessions. There were no surgery-related deaths or complications. After first PMT, 41 nodules, each 0.2-2.5 cm in diameter, were observed: 1-5 nodules per patient. Every available treatment was provided to patients with post-PMT recurrence and those in the non-PMT group to control pulmonary and extrapulmonary metastases. Patient survival rates before PM diagnosis did not differ between the two groups ( p = 0.141). However, 2 year post-PM survival rate was significantly greater in the PMT group (30.6% vs. 0%, p = 0.007), resulting in a significantly greater overall 5 year survival rate (44.7% vs. 12.8%, p = 0.017). Univariate analysis showed no risk factor significantly associated with patient survival after PMT. Conclusions: PMT should be performed for resectable PM-HCC because it may provide a chance of long-term survival. [ABSTRACT FROM AUTHOR]

B Introduction: b Despite technical advancements in liver surgery, resection of liver tumors that involve the hepatic veins adjacent to the vena cava or hepatic hilum remains technically challenging. B Method: b Between September 1999 and March 2016, we encountered 5 patients with conventionally unresectable tumors that were successfully treated by "ex-situ liver resection" and "in-situ & ante -situm hypothermic liver perfusion" under total vascular exclusion and venovenous bypass. B Conclusion: b Hypothermic perfusion hepatectomy is a realistic option for achieving surgical cure or significantly improved survival and quality of life in patients with tumors deemed unresectable using conventional normothermic hepatectomy. [Extracted from the article]

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients. [ABSTRACT FROM AUTHOR]

Background & Aims Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. Methods We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300–375 mg/m 2 /body surface area). Results We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68–1.90; p  = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60–2.00; p  = 0.763). Conclusions These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. Lay summary Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria. [ABSTRACT FROM AUTHOR]

Background:Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment. Materials and Methods:A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT. Results:The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients’ survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%). Conclusions:SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy. [ABSTRACT FROM AUTHOR]

Background & Aims We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT). Methods 271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time-dependent receiver operating characteristic curves (AUC) estimation. Results Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to-seven model. Higher AUC values were observed with the size method only in the up-to-seven model ( p <0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method ( p <0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method ( p = 0.017). Conclusions The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion. [ABSTRACT FROM AUTHOR]

Purpose: We have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). Methods and Materials: A registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy. Results: Median patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21–60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3–4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2–3 gastroduodenal complications were observed in 15 patients (3.6%). Conclusions: Radiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC. [ABSTRACT FROM AUTHOR]