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Background and Aim: Prompt differential diagnosis of liver tumors is clinically important and sometimes difficult. A new diagnostic device that combines probe electrospray ionization-mass spectrometry (PESI-MS) and machine learning may help provide the differential diagnosis of liver tumors., Methods: We evaluated the diagnostic accuracy of this new PESI-MS device using tissues obtained and stored from previous surgically resected specimens. The following cancer tissues (with collection dates): hepatocellular carcinoma (HCC, 2016-2019), intrahepatic cholangiocellular carcinoma (ICC, 2014-2019), and colorectal liver metastasis (CRLM, 2014-2019) from patients who underwent hepatic resection were considered for use in this study. Non-cancerous liver tissues (NL) taken from CRLM cases were also incorporated into the analysis. Each mass spectrum provided by PESI-MS was tested using support vector machine, a type of machine learning, to evaluate the discriminatory ability of the device., Results: In this study, we used samples from 91 of 139 patients with HCC, all 24 ICC samples, and 103 of 202 CRLM samples; 80 NL from CRLM cases were also used. Each mass spectrum was obtained by PESI-MS in a few minutes and was evaluated by machine learning. The sensitivity, specificity, and diagnostic accuracy of the PESI-MS device for discriminating HCC, ICC, and CRLM from among a mix of all three tumors and from NL were 98.9%, 98.1%, and 98.3%; 87.5%, 93.1%, and 92.6%; and 99.0%, 97.9%, and 98.3%, respectively., Conclusion: This study demonstrated that PESI-MS and machine learning could discriminate liver tumors accurately and rapidly., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: According to the American Association for the Study of Liver Diseases guidelines, liver resection is not recommended for multiple hepatocellular carcinomas, although it is performed in Asian countries, including Japan. However, the maximum number, location, and recurrence types of tumors have not been reported in detail., Methods: This retrospective study analyzed data for 1,170 patients who underwent surgical resection for hepatocellular carcinoma between October 2002 and December 2020 in a Japanese tertiary care hospital. Statistical analysis was performed to compare the surgical short-term and long-term outcomes among patients with >3 tumors and those with ≤3 tumors., Results: This study of patients who underwent liver resection identified 775 who had a single tumor and compared overall survival rates with 477 who had multiple hepatocellular carcinomas: 242 had 2 hepatocellular carcinomas, 79 had 3 hepatocellular carcinomas, and 74 had >3 hepatocellular carcinomas. The median survival times based on the number of tumors were 9.74 years for a single tumor, 6.36 years for 2 tumors, 7.21 years for 3 tumors, 3.31 years for 4 tumors, and 3.48 years for 5 tumors. The median survival time was significantly worse in patients with >3 tumors than in those with 3 tumors (P < .0001). Concerning the type of treatments for recurrence, the patients who underwent surgical treatment had significantly better survival after recurrence than patients who underwent other treatments (8.32 vs 3.19 years; P < .001)., Conclusion: The overall survival after liver resection was significantly worse for patients with >3 tumors than for those with <3 tumors. However, liver resection can be recommended for patients with 2 or 3 hepatocellular carcinomas because an acceptable median survival (>5 years) can be expected., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: We assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection., Methods: Among 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay., Results: HBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P < 0.001., Conclusion: HBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Optimal strategies for advanced hepatocellular carcinoma (HCC) tumors, such as those with vascular tumor thrombus and those with extrahepatic metastases are unclear., Methods: A literature review was conducted focusing on conversion surgery for HCC after molecular targeted therapy and therapy using immune checkpoint inhibitors., Results: Upfront surgical resection of advanced HCC tumors has been challenged at some institutions because of lack of promising therapeutic options. Preoperative transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, and radiotherapy in patients with unresectable HCC were developed to improve long-term outcome, but the results were not promising. Nonetheless, the recent advent of molecular targeted therapies and immune check-point inhibitors, enabling frequent tumor responses, has accelerated the use of conversion surgery after these therapies in patients with initially unresectable HCC. Increasing numbers of conversion surgeries after lenvatinib therapy has been reported, and the first prospective clinical trial assessing conversion surgery after lenvatinib therapy in initially unresectable HCC has been commenced. Furthermore, the superiority of combination therapy using atezolizumab and bevacizumab over sorafenib, a conventional first-line drug for unresectable HCC, in terms of overall survival and tumor response has been demonstrated, and the use of this regimen alongside conversion surgery is expected in addition to lenvatinib., Conclusion: The literature demonstrated the feasibility of conversion surgery after systemic therapy. Further clinical investigation of surgery after systemic therapy for advanced HCC may be undertaken by clearly distinguishing the tumor status as technically unresectable or oncologically unresectable but technically resectable., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan., Methods: The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications., Results: The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients., Conclusions: As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background/aim: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is one of the main causes of death after LT, and patient prognosis is reportedly poor. Herein, we report two cases of unresectable HCC recurrences after living donor LT that were treated effectively and safely with lenvatinib., Case Report: Both cases underwent LT for HCC beyond the Milan criteria. About 2 years following LT, HCC recurrences were found and resected. However, unresectable 2 nd -recurrences were found several months after surgery. In the first case, a complete response was maintained for 12 months with transarterial chemoembolization and lenvatinib. In the second case, a partial response was maintained for 5 months with lenvatinib. Severe adverse events were not observed in either case., Conclusion: The presently reported cases suggest that lenvatinib might be effective for the treatment of unresectable HCC recurrence after LT., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The factors associated with hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) have not been fully clarified. The aim of this study was to determine the risk factors associated with HBV recurrence after LDLT. From January 1996 to December 2018, a total of 609 LDLT operations were performed at our center. A retrospective review was performed of 70 patients (male, n = 59; female, n = 11; median age = 54 years) who underwent LDLT for HBV-related liver disease. The virologic and biochemical data, tumor burden, antiviral and immunosuppressive therapy were evaluated and compared between the HBV recurrence and non-recurrence groups. Eleven of 70 patients (16%) developed post-LDLT HBV recurrence. The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 13%, 16.7%, 18.8%, and 18.8%, respectively. The median interval between LDLT and HBV recurrence was 57 months (range, 18-124 months). Based on the univariate and multivariate analyses, a serum HBV DNA level of ≥ 4 log copies/mL (hazard ratio [HR], 4.861; 95% confidence interval [95% CI], 1.172-20.165; P = 0.029), and hepatocellular carcinoma (HCC) beyond the Milan criteria (HR, 10.083; 95% CI, 2.749-36.982; P < 0.001) were independent risk factors for HBV recurrence after LDLT. In LDLT patients, high pre-LT HBV DNA levels and HCC beyond the Milan criteria were risk factors for HBV recurrence. With the current expansion of the LT criteria for HCC, we should remain cautious regarding the risk of HBV recurrence, particularly in these groups.

Background: Indications for hepatectomy in patients with hepatocellular carcinoma (HCC) who have portal hypertension (PH) have been controversial. Some studies have concluded that PH is a contraindication to hepatectomy, whereas others have suggested that perioperative prophylactic management (PPM) can help overcome complications after hepatectomy associated with PH. The objective of this retrospective study was to assess the short- and long-term outcomes after hepatectomy for HCC in patients with PH, with or without PPM., Methods: Records were reviewed of consecutive patients who underwent hepatectomy for HCC, with or without PPM of PH, in a single institution from 1994 to 2015. Patients were divided into three groups: those who received PPM for PH (PPM group), patients who had PH but did not receive PPM (no-PPM group) and those without PH (no-PH group)., Results: A total of 1259 patients were enrolled, including 123 in the PPM group, 181 in the no-PPM group and 955 in the no-PH group. Three- and 5-year overall survival rates were 74·3 and 53·1 per cent respectively in the PPM group, 69·2 and 54·9 per cent in the no-PPM group, and 78·1 and 64·2 per cent in the no-PH group (P = 0·520 for PPM versus no PPM, P = 0·027 for PPM versus no PH, and P < 0·001 for no PPM versus no PH). Postoperative morbidity and mortality rates were 26·0 and 0·8 per cent respectively in the PPM group, 29·8 and 1·1 per cent in the no-PPM group, and 20·3 and 0 per cent in the no-PH group., Conclusion: The present study has demonstrated acceptable outcomes among patients with HCC who received appropriate management for PH in an Asian population. Enhancement of the safety of hepatic resection through use of PPM may provide a rationale for expansion of indications for hepatectomy in patients with PH., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Indocyanine green (ICG) accumulates only in hepatocytes and their malignant counterpart, hepatocellular carcinoma (HCC). We have developed ICG-conjugated anti-cancer drugs and noted their significant accumulation in HCC cells both in vitro and in vivo. ICG-conjugated gemcitabine was less toxic to normal cells and it had superior anti-tumor action compared to gemcitabine alone in a subcutaneous tumor xenograft. ICG conjugation can provide a novel fluorescent drug delivery system for treatment of liver cancer and this system can be used to both diagnose and treat HCC.

Background: The aim of this study was to evaluate the feasibility of liver resection in hepatocellular carcinoma (HCC) patients with preoperative renal dysfunction (RD)., Methods: Data from 735 patients undergoing primary liver resection for HCC between 2002 and 2014 were analyzed. Short- and long-term outcomes were compared between the RD group, defined by a preoperative estimated glomerular filtration rate of <45 mL/min/1.73 m 2 , and the non-RD group., Results: Sixty-two patients had RD. The incidence of postoperative pleural effusion (24 vs. 11%; P = 0.007) and major complications (Clavien-Dindo III-V; 31 vs. 15%; P = 0.003) were significantly higher in RD patients. In RD patients with Child-Pugh A, 90-day mortality rate (1.9%) and median survival time (6.11 years) were comparable to that of non-RD patients. In contrast, RD patients with Child-Pugh B had a very high 90-day mortality rate (22.2%), and a significant shorter median survival time compared to non-RD patients (1.19 vs. 4.84 years; P = 0.001)., Conclusions: Liver resection for Child-Pugh A patients with RD is safe and has comparable oncological outcomes compared to non-RD patients. However, selection of liver resection candidates from Child-Pugh B patients with RD should be stricter.

Introduction: Repeated resection is known to prolong survival, with an acceptable morbidity rate, in patients with hepatocellular carcinoma. However, little is known about the effect of repeated liver resection on postoperative liver regeneration and liver function. The aim of this study is to determine the impact of repeated liver resections on the postoperative liver regeneration rate and liver function., Methods: A total of 71 patients, who had undergone more than three liver resections for hepatocellular carcinoma between May 2001 and December 2013 at a tertiary care hospital in Japan, were included in the analysis. Among them, CT-volumetric data for the first, second, third, and fourth or more resections were available for 36, 49, 53, and 24 patients. We analyzed the regeneration index (RI) defined as the postoperative TLV/preoperative TLV × 100 was calculated after each operation to measure the degree of regeneration. Liver function was evaluated using the indocyanine green retention rate at 15 min (ICG-R15)., Results: No significant differences in RI were observed among the first, second, and third or more liver resection groups. No significant difference in the ICG R15 value was seen between the first liver resection group and the second or more liver resection group (P = 0.75). However, a significant difference in the RI was observed when the 1 segmentectomy or less liver resection group (median [range] RI 98.1 [72.9-119.9]) was compared with the 2 or more segmentectomy group (median [range] RI 90.5 [62.6-113.6]) (P = 0.005)., Conclusion: The regeneration process is maintained after as many as four repeated resections. Patients with sustained liver function can safely undergo repeated liver resections for recurrences of HCC.

Background: Left lateral sectionectomy (LLS) is frequently performed for surgical treatment of hepatocellular carcinoma (HCC) located in the left lateral section. However, no reports have described liver resection for such HCCs using a parenchyma-sparing strategy involving anatomic resection (AR) of segment II (S2 AR) or segment III (S3 AR)., Methods: From 1994 to 2014, patients who underwent LLS and S2 AR or S3 AR for HCC were included in the analysis. Short- and long-term outcomes and pre- and postoperative LV were assessed., Results: Of the 89 patients selected, 49 underwent LLS (LLS group) and 40 underwent S2 AR and S3 AR (S2/S3 AR group). The postoperative LV was not significantly smaller than the preoperative LV in the S2/S3 AR group (p = 0.114), whereas the postoperative LV was significantly smaller in the LLS group (p = 0.019). The overall survival (OS) and recurrence free survival (RFS) rates were not significantly different between the groups (OS, p = 0.056; RFS, p = 0.102)., Conclusions: Parenchyma-sparing liver resection for HCC in the left lateral section is associated with better postoperative LV recovery than LLS with similar oncological outcomes. S2/S3 AR can be a reasonable therapeutic option when LLS results in the removal of more parenchyma than necessary., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

A 68-year-old male who had undergone low anterior resection for primary rectal cancer 19 months ago presented with multiple CLM at Couinaud's segments IV, V, and VIII. There was no apparent macroscopic intrabiliary growth on preoperative computed tomography and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI). However, the hepatobiliary phase of EOB-MRI revealed peritumoral low signal intensity in lesions in segments V and VIII, which indicates vascular invasion around hepatocellular carcinoma. Contrast-enhanced intraoperative ultrasound (CE-IOUS) clearly determined the extent of macroscopic glissonean growth from lesions in segments V and VIII, and more extensive resection was performed than was planned. Analysis of the resected specimens from segments V and VIII confirmed the presence of macroscopic intrabiliary growth with microscopic portal vein invasion. All three CLM were histopathologically diagnosed as well-to-moderately differentiated adenocarcinoma, and R0 resection was verified. Postoperative recovery was uneventful, and the patient was alive without evidence of recurrence 12 months after hepatic resection. CE-IOUS should be considered at the time of CLM resection, as it might enable more accurate detection of macroscopic intrabiliary growth of CLM, and enable resection with safer margins.

Objective: To assess how virtual hepatectomy (VH), conducted using surgical planning software, influences the outcomes of liver surgery., Background: Imaging technology visualizes the territories of the liver vessels, which were previously impossible. However, the clinical impact of VH has not been evaluated., Methods: From 2004 to 2013, we performed 1194 VHs preoperatively. Outcomes of living donor liver transplantation (LDLT) and hepatectomy for hepatocellular carcinoma (HCC)/colorectal liver metastases (CRLM) were compared between patients in whom VH was performed (VH) and those without VH evaluation (non-VH)., Results: In LDLT, the rate of right liver graft use was higher in the VH (62.1%) than in the non-VH (46.5%) (P < 0.01), which did not increase morbidity of donor surgery. Duration of recipient surgery in the VH in which middle hepatic vein branch reconstruction was skipped was shorter than that in the VH with venous reconstruction. Among HCC patients with impaired liver function, portal territory-oriented resection was conducted more often in the VH than in the non-VH. The 5-year disease-free survival rate for localized HCC was higher in the VH than in the non-VH (37.2% vs 23.9%; P = 0.04). In CRLM, long-term outcomes were similar in the VH and non-VH despite the larger tumor load in the VH., Conclusions: VH in LDLT allows double equipoise for the recipient and donor by optimizing decision-making on graft selection and venous reconstruction. VH offers a chance for radical hepatectomy even in HCC patients with impaired liver function and CRLM patients with advanced tumors, without compromising survival.

Aims: To clarify the clinical impact, risk factors, and preventive methods for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC)., Methods: We included 879 consecutive patients who underwent hepatectomy for HCC between 2002 and 2011. Univariate and multivariate analyses were conducted to identify the risk factors for incisional and organ/space SSIs. ORs and 95% CIs are reported., Results: The incidences of incisional and organ/space SSIs were 24 (2.7%) and 73 (8.3%), respectively. High body mass index, multiple resections, and organ/space SSI were associated with incisional SSIs, while repeat hepatectomy (OR 2.14, 95% CI 1.27-3.60), ascites (OR 2.97, 95% CI 1.55-5.48), and bile leakage (OR 4.77, 95% CI 2.77-8.11) were independent risk factors for organ/space SSI. Among the cases with bile leakage, lower rates of organ/space SSIs tended to be observed in patients with cystic duct tubes than in patients without such tubes (13.2 vs. 26.5%, p = 0.157). Retrograde drain infections increased when drain placement was prolonged for more than 4 postoperative days., Conclusion: Bile leakage was associated with the greatest risk of organ/space SSI after hepatectomy for HCC. Cystic duct tubes might be useful for preventing bile leakage and subsequent organ/space SSI after procedures that extensively expose Glissonean pedicles., (© 2017 S. Karger AG, Basel.)

Background: Real-time tissue elastography during open hepatectomy facilitates the differential diagnosis of liver tumors by providing information on elasticity. This study investigated the utility of intraoperative real-time tissue elastography (IORTE) during laparoscopic hepatectomy (LH)., Methods: Between 2012 and 2014, IORTE was performed during LH for 21 hepatocellular carcinomas (HCCs), 16 adenocarcinomas and 5 other tumors in 32 patients. The elasticity images were classified into six categories according to the modified criteria on the elasticity type of liver tumors, in which type 1 tumors show more strain than the surrounding liver and type 6 tumors no strain. The concordance of the IORTE findings with those of the pathological examination of the tumors was assessed (The registration no. 1418)., Results: Among the 21 HCCs, 20 were classified as "HCC pattern" (type 3, 4, or 5), resulting in a sensitivity of 95.2%, a specificity of 66.7% and an accuracy of 81.0%. Ten out of the 16 adenocarcinomas were classified as "adenocarcinoma pattern" (type 6), resulting in a sensitivity of 62.5%, a specificity of 92.3% and an accuracy of 81.0%., Conclusion: IORTE is feasible and provides useful information on the elasticity of liver tumors in LH, in which conventional tumor palpation is difficult., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Effective adjuvant therapies have not been established for hepatocellular carcinoma (HCC). The study aimed to determine prognostic influence of statin against HCC recurrence after initial resection. From 2003 to 2013, 734 patients underwent initial HCC resection. Exposure to statins was defined as the use at the recommended daily dosage for > 90 days after surgery. Outcomes were compared between patients who did and did not receive statins. Of 734 patients, 31 (4.2%) received statins for dyslipidemia (statin group) and 703 (95.8%) did not (non-statin group). The proportions of hepatitis B (6.5% vs. 22.8%, P = 0.032), C (19.4% vs. 45.0%, P = 0.005), and a fibrosis score of F3-4 (16.1 % vs. 39.8%, P = 0.008) were significantly lower in the statin than non-statin group. The recurrence-free survival rate was significantly higher in the statin than non-statin group (P < 0.001), without significant difference of the overall survival rate (P = 0.142). A multivariable Cox proportional hazards model revealed that the use of statins (hazard ratio, 0.34; P = 0.005) was associated with a significantly lower risk of HCC recurrence. After one-to-two propensity score matching, the RFS rate was also significantly higher in the statin group (n = 31) than in the non-statin group (n = 62) (P = 0.008)., In Conclusion: The statins use reduced the risk of HCC recurrence after initial resection. Statins may have protective influences on HCC recurrence in patients who undergo initial liver resection.

Indocyanine green (ICG) is a photothermal agent, photosensitizer, and fluorescence imaging probe which shows specific accumulation in hepatocellular carcinoma (HCC) cells. We recently developed a photodynamic therapy (PDT) using ICG and near-infrared (NIR) laser as a new anti-cancer treatment for HCC. However, the molecular mechanism underlying this effect needs to be elucidated. HuH-7 cells, a well-differentiated human HCC cell line, were transplanted subcutaneously into BALB/c-nu/nu mice for in vivo experiment. ICG was administered 24 h before NIR irradiation. The irradiation was performed at three tumor locations by 823-nm NIR laser on days 1 and 7. The temperature of HuH-7 xenografts increased to 48.5 °C 3 minutes after ICG-NIR irradiation start. Reactive oxygen species (ROS) production was detected after ICG-NIR irradiation both in vitro and in vivo. There was certain anti-tumor effect and ROS production even under cooling conditions. Repeated NIR irradiation increased the cell toxicity of ICG-NIR therapy; the mean tumor volume on day 9 was significantly smaller after ICG-NIR irradiation compared to tumor without irradiation (87 mm 3 vs. 1332 mm 3 ; p = 0.01) in HCC mice xenografts model. ICG-NIR therapy induced apoptosis in HCC cells via a photothermal effect and oxidative stress. Repeated ICG-NIR irradiation enhanced the anti-tumor effect.

Background: Although achieving a sustained virological response (SVR) in hepatitis C virus (HCV) infection is recognized as improving liver function and reducing hepatocellular carcinoma (HCC) development, its impact on HCC recurrence is unclear. This study investigated how preoperative SVR achievement by interferon treatment affects HCC recurrence in patients undergoing hepatic resection., Methods: The study subjects were 521 patients with HCV infection who underwent initial and curative hepatic resection for HCC. To adjust for confounding factors between the SVR and non-SVR groups, propensity score-matching analysis was performed., Results: After propensity score matching, 45 of the 49 patients in the SVR group, and an equal number of the 472 patients in the non-SVR group, were matched. The two groups had similar distributions of clinicopathological characteristics. In the matched cohort, the 3-, 5-, and 7-year recurrence-free survival rates after surgery were 56, 45, and 37%, respectively, in the SVR group, and 34, 23, and 7.2%, respectively, in the non-SVR group (p = 0.033). Additionally, the 3-, 5-, and 7-year overall survival rates after surgery were 82, 80, and 75%, respectively, in the SVR group, and 78, 64, and 44%, respectively, in the non-SVR group (p = 0.065). The 1- and 2-year cumulative recurrence rates in the early phase showed no significant difference between the SVR and non-SVR groups (p = 0.27). however, the 3-, 5-, and 7-year cumulative recurrence rates in the late phase were 14, 32, and 43%, respectively, in the SVR group, and 33, 55, and 86%, respectively, in the non-SVR group (p = 0.037)., Conclusion: Achievement of SVR may reduce postoperative recurrence after hepatic resection.

Background: Efficacy of preoperative portal vein embolization (PVE) has been established; however, differences of outcomes among diseases, including hepatocellular carcinoma (HCC), biliary tract cancer (BTC), and colorectal liver metastases (CLM), are unclear., Methods: Subjects included patients in a prospectively collected database undergoing PVE (from 1995 to 2013). A future liver remnant (FLR) volume ≥40% is the minimal requirement for patients with an indocyanine green retention rate at 15 min (ICGR15) <10%, and stricter criteria (FLR volume ≥50%) have been applied for patients with 20% > ICGR15 ≥ 10%. Patient characteristics and survivals were compared among those three diseases, and predictors of dropout and better FLR hypertrophy were determined., Results: In 319 consecutive patients undergoing PVE for HCC (n = 70), BTC (n = 172), and CLM (n = 77), the degree of hypertrophy did not significantly differ by cancer types (median 10, 9.6, and 10%, respectively). Eighty percent (256 of 319) of patients completed subsequent hepatectomy after a median waiting interval of 24 days (range 5-90), while dropout after PVE was more common in BTC or CLM (odds ratio 2.75, p = 0.018), mainly because of disease progression. Ninety-day liver-related mortality after hepatectomy was 0% in the entire cohort, and 5-year overall survival of patients with HCC, BTC, and CLM was 56, 50, and 51%, respectively (p = 0.948). No patients who dropped out survived more than 2.5 years after PVE., Conclusion: PVE produced equivalent FLR hypertrophy among the three diseases as long as liver function was fulfilling the preset criteria; however, the completion rate of subsequent hepatectomy was highest in HCC. PVE followed by hepatectomy was a safe and feasible strategy for otherwise unresectable disease irrespective of cancer types.

Background: Most patients with hepatocellular carcinoma (HCC) have underlying liver disease, therefore, precise preoperative evaluation of the patient's liver function is essential for surgical decision making., Methods: We developed a grading system incorporating only two variables, namely, the serum albumin level and the indocyanine green retention rate at 15 minutes (ICG R15), to assess the preoperative liver function, based on the overall survival of 1868 patients with HCC who underwent liver resection. We then tested the model in a European cohort (n = 70) and analyzed the predictive power for the postoperative short-term outcome., Results: The Albumin-Indocyanine Green Evaluation (ALICE) grading system was developed in a randomly assigned training cohort: linear predictor = 0.663 × log10ICG R15 (%)-0.0718 × albumin (g/L) (cut-off value: -2.20 and -1.39). This new grading system showed a predictive power for the overall survival similar to the Child-Pugh grading system in the validation cohort. Determination of the ALICE grade in Child-Pugh A patients allowed further stratification of the postoperative prognosis. This result was reproducible in the European cohort. Determination of the ALICE grade allowed better prediction of the risk of postoperative liver failure and mortality (ascites: grade 1, 2.1%; grade 2, 6.5%; grade 3, 16.0%; mortality: grade 1, 0%; grade 2, 1.3%; grade 3, 5.3%) than the previously reported model based on the presence/absence of portal hypertension., Conclusions: This new grading system is a simple method for prediction of the postoperative long-term and short-term outcomes.

Background: Hepatocellular carcinoma (HCC) not associated with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, termed non-B non-C HCC (nBnC-HCC), is reportedly correlated with better survival outcomes than HBV- or HCV-related HCC. However, the nBnC-HCC population includes patients with a history of HBV infection possessing anti-hepatitis B core antibodies (HBcAb), and the oncologic significance of this finding remains unclear., Methods: A retrospective review of the data for 562 patients who underwent curative resection for primary HCC was performed. The clinical outcomes were compared among the following four groups: HBV group (HBsAg-positive), HCV group (HCVAb-positive), HBcAb-positive nBnC-HCC group, and pure nBnC-HCC group (negative for these viral markers)., Results: The HBcAb-positive nBnC-HCC group showed better overall survival (OS) and recurrence-free survival (RFS) rates than the HBV, HCV, and pure nBnC-HCC groups (5-year OS 89.4 vs 68.4, 62.0, and 66.2 %; P = 0.003; 5-year RFS 53.8 vs 31.4, 28.1, and 33.6 %; P = 0.01). A multivariate analysis confirmed that a history of HBV is associated with a lower risk of OS (hazard ratio [HR] 0.23; 95 % confidence interval [CI] 0.09-0.56; P = 0.001) and RFS (HR 0.45; 95 % CI 0.27-0.73; P = 0.001). The HBcAb-positive nBnC-HCC group was associated with a higher incidence of well-differentiated HCC (33 vs 15 %; P = 0.03) and lower plasma des-gamma-carboxyprothrombin concentration (72 vs 357 mAu/mL; P = 0.047) than the pure nBnC group., Conclusion: The subgroup of patients with a history of HBV infection may have better survival outcomes after resection of HCC than the HBV/HCV-related or pure nBnC-HCC patients.

This chapter covers recent important topics relevant to ensuring safe liver resection. In particular, preoperative and intraoperative techniques, such as 3-dimensional CT, intraoperative ultrasonography with contrast agent and fluorescence imaging using indocyanine green are reportedly useful and have been applied to liver resection and liver transplantation. We, herein, describe the performance of liver resection under the guidance of these techniques and present tips for more accurate intraoperative tumor detection and safer surgical procedures., (© 2015 S. Karger AG, Basel.)

Background: Although radiofrequency ablation (RFA) is an effective local ablative technique for the treatment of hepatocellular carcinoma (HCC), the optimal treatment for recurrence after RFA has not been established., Methods: Between September 2002 and December 2011, 46 hepatectomies (salvage group) were performed for intrahepatic (local or multifocal) recurrent HCC after RFA. The difference between the imaging findings before RFA and at the time of salvage resection, especially in the Local recurrent group, and the short-term and long-term outcomes after salvage surgery were analyzed retrospectively by comparing them with those for a matched control group (n = 46) and with those of patients who underwent a second hepatic resection for HCC recurrence after an initial hepatic resection during the same period (n = 155)., Results: The tumor-occupying region was more distributed widely before the salvage resection compared with that before RFA, and a more extensive operation would have been required (rather than the RFA) in the local group. An evaluation of the short-term outcomes revealed that salvage resection required a longer operative time and was associated with a greater frequency of morbidity. The long-term outcomes of the salvage group were poorer than those of patients who underwent repeat hepatic resection for HCC recurrence after an initial hepatic resection., Conclusion: The indications for RFA should be determined carefully, because recurrence after RFA may be associated with a more aggressive pattern of recurrence, and the long-term results after salvage resection are unsatisfactory., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There seems to be a consensus in regard to the initial treatment of small hepatocellular carcinomas (HCCs): either percutaneous ablation or liver resection should be selected. Liver resection provides for excellent local control, which is one of the most important factors to be considered in the treatment of HCC. However, percutaneous ablation has the advantage of less invasiveness, which allows for repeated sessions of ablation. However, there has been a longstanding debate on which of the two therapeutic modalities might be superior in individual cases with various tumor-related and liver function factors. Although it is practically difficult to conduct randomized controlled trials (RCTs) to compare these two therapeutic modalities, there have been four RCTs published in English, which we focus on in this review article. We discuss the aforementioned unsolved problem according to the results of these RCTs, in addition to the results of a large-scale cohort study and the recommendations of clinical practice guidelines.

Background: Liver resection is the mainstay of curative treatment for localized hepatocellular carcinoma (HCC). However, the impact of surgery for HCC on quality of life (QOL) has not been well assessed., Methods: Health-related QOL was assessed using the Short Form-36 questionnaire in 108 patients who underwent a liver resection for HCC between January 2004 and January 2008. The QOL assessment was scheduled before and every 3 months after the operation. Patients were divided into two groups based on patient-, tumor-, and surgery-related variables. The physical component summary (PCS) and mental component summary (MCS) were compared between the two groups., Results: Altogether, 69 patients (64 %) completed the consecutive QOL assessments until 6 months after surgery. At 3 months, the PCS scores were significantly lower for women and for patients who had undergone thoracotomy than among men (p = 0.010) and patients who had not undergone thoracotomy (p = 0.048), respectively. No significant differences in any of the PCS scores were observed at 6 months. No significant differences in the MCS scores were observed between the groups throughout the investigation, and improvement relative to the preoperative status was observed at 6 months., Conclusions: Physical impairments in the QOL after surgery had returned to the baseline at 6 months, and the postoperative mental QOL improved relative to the preoperative state. The surgical candidates were expected to have a satisfactory QOL regardless of the preoperative status and surgical outcomes. A thoracoabdominal approach had a transient negative impact on the physical health status.

Tumor markers [alpha-fetoprotein (AFP) or des-gamma-carboxyprothrombin (DCP)] and neutrophil/lymphocyte ratio (NLR) reportedly correlate with long-term outcomes for hepatocellular carcinoma (HCC). However, no standardized method has been established for evaluating the pretransplant data. One hundred and twenty-four patients who underwent living donor liver transplantation (LDLT) were retrospectively reviewed. The best predictive parameters for tumor recurrence were maximum values for AFP or DCP and 90-day mean values for NLR, respectively, and multivariate analysis confirmed these values were correlated with tumor recurrence. However, receiver operating characteristic analysis revealed that discriminative powers were sufficient only in maximum AFP [area under the curve (AUC) 0.88, P < 0.001] and maximum DCP (AUC 0.76, P < 0.001), while mean NLR was less predictive (AUC 0.62, P = 0.20). When incorporating AFP and DCP to the Tokyo criteria (≤5 tumors with each tumor ≤ 5 cm), the presence of at least two of the following factors: (i) beyond the Tokyo criteria, (ii) AFP>250 ng/ml, and (iii) DCP > 450 mAu/ml (>450 ng/ml), was correlated with a worse 5-year disease-free survival rate (20.0% vs. 96.8%, P < 0.001) and 5-year overall survival rate (20.0% vs. 84.0%, P < 0.001). The prognosis of patients undergoing LDLT for HCC strongly relies on maximum AFP or DCP values before transplantation, while the prognostic impact of NLR is limited., (© 2014 Steunstichting ESOT.)

Background: Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear., Methods: In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence)., Results: ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P < 0.001). Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence., Conclusions: Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

Spontaneous intrahepatic hematoma caused by hepatocellular carcinoma is a rare condition since usually the circumference shows liver cirrhosis. We report a case of hepatocellular carcinoma with an intrahepatic hematoma. A 79-year-old man was admitted to our hospital with sudden onset upper abdominal pain and high fever. Laboratory data showed that the patient had liver dysfunction but was not anemic. Abdominal computed tomography( CT) revealed an intrahepatic tumor with a hematoma measuring 8.5 cm in diameter in the right lobe of the liver. An enhancing lesion and pooling of contrast media inside the tumor was observed. Angiography also revealed a microaneurysm in the tumor. The patient underwent right hepatic lobectomy, and histopathological examination showed hepatocellular carcinoma.

Background: Indocyanine green (ICG) fluorescent imaging has been used effectively to identify hepatocellular carcinoma (HCC) in intraoperative setting. However, whether extrahepatic metastatic lesions from HCC can also be detected by this imaging is unknown., Methods: This study was conducted on 17 patients with suspected extrahepatic HCC metastases in the lung (n = 3), adrenal gland (n = 1), lymph node (n = 7), peritoneum (n = 5) and both lymph node and peritoneum (n = 1). ICG was administered intravenously at a dose of 0.5 mg/kg prior to operation for liver function evaluation. Intraoperative ICG fluorescent imaging was performed with a near-infrared light camera system. The surgical specimens were also examined in all cases for the presence of ICG fluorescence., Results: Of 28 lesions for which ICG fluorescence was examined intraoperatively, 24 lesions exhibited fluorescence and were proved to be HCC metastases pathologically. Five of them were newly identified by ICG fluorescent imaging. The other four lesions included two HCC metastases and two benign tumors. Of 33 suspicious metastatic lesions extirpated, 26 lesions emitting fluorescence from the specimen were all metastatic HCC. The other 7 lesions consisted of 6 benign tumors and one HCC metastasis. Accordingly, the positive predictive value of in vivo and ex vivo ICG fluorescent imaging were both 100 %, while the negative predictive value of those methods were 50 and 86 %, respectively., Conclusions: Extrahepatic metastases from HCC exhibited ICG fluorescence when illuminated by near-infrared light, indicating their capability to transport ICG. This imaging can be a useful tool for intraoperative detection of metastasis in HCC patients.

Background: Anatomical resection of segment VIII (SVIII) is technically demanding. Only two small studies have published short-term outcomes. The aim of the present study was to evaluate short- and long-term outcomes after anatomical resection involving SVIII for hepatocellular carcinoma (HCC), and to compare long-term outcomes with those after non-anatomical resection of SVIII., Methods: Outcomes after anatomical resection of SVIII or its subsegments for HCC were compared with those in patients who underwent primary non-anatomical resection of SVIII during the same period., Results: A total of 154 patients underwent anatomical resection involving SVIII and 122 had non-anatomical resection. In patients undergoing anatomical resection, the preoperative indocyanine green retention rate at 15 min ranged from 2·9 to 32·2 (median 13·6) per cent, and was 10 per cent or more in 109 patients (70·8 per cent). Median duration of operation and blood loss were 378 min and 705 ml respectively. There were no postoperative deaths, but major adverse events occurred in ten patients (6·5 per cent). The cumulative 5-year recurrence-free and overall survival rates were 28·5 and 79·6 per cent, which were significantly better than rates of 19·4 and 64·8 per cent respectively after non-anatomical resection (P = 0·036 and P < 0·001)., Conclusion: Complete resection of SVIII or its subsegments can be performed safely and the long-term outcomes seem acceptable. This can be a curative procedure for HCC, especially in patients with limited liver function reserve, in whom right hepatectomy or right paramedian sectorectomy might otherwise be needed., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Hepatocellular carcinoma (HCC) recurrence after liver transplantation is associated with a poor prognosis; nonetheless, we report two cases of long-term survival after resection of pulmonary metastatic lesions following living donor liver transplantation (LDLT). The intervals between LDLT and pulmonary resection for the metastatic lesion were 24 months and 30 months, respectively. Regular checking of tumor markers and prompt workup for early detection may contribute to the resectability of such metastatic lesions. These cases suggest that resection of a solitary metastatic lesion in the lung from HCC after liver transplantation may be a feasible treatment for selected patients.

In a 53-year-old male who received a right liver graft from his son, computed tomography 1 week before living donor liver transplantation (LDLT) revealed three hepatocellular carcinoma (HCC) tumors in the liver that met the Milan criteria. Resected specimen revealed four tumors and microscopically, one of four HCC tumors in the resected whole liver comprised a glandular structure with spindle-like cells indicative of a sarcomatous change in HCC. Two hundred and sixty days after LDLT, the patient complained of left meralgia, which was diagnosed as iliac bone metastasis from HCC. Over a period of 3 months, the iliac bone metastasis rapidly enlarged. The tumor aggressively extended into the patient's bone marrow, causing severe pancytopenia. The patient died 371 days after LDLT. This tumor was detected preoperatively by computed tomography but lack of enhancement. These findings indicate that pathologic evaluation of each tumor is a key to predicting an accurate prognosis.

Hepatocellular carcinoma (HCC) nodules newly found in the explant liver have been observed, but the impact on patient prognosis is not known. Sixty HCC patients who underwent living donor liver transplantation were the subjects of the study. Radiologic findings prior to transplantation and pathologic findings of the explant liver were compared. Histologic characteristics of preoperatively overlooked tumors were examined. The influence of the discrepancy between these findings on tumor recurrence was evaluated. A total of 227 HCC nodules were found in the explant livers. Of these, 91 nodules (40%) were newly found by pathologic examination. They were smaller and more likely to be well differentiated than the others. The number and size of the tumors were underestimated in 50% (30/60) and 32% (19/60), respectively. There was no significant difference in the recurrence-free survival rate between patients who met the Milan criteria both in the pre- and post-transplant evaluation (n = 29) and those who met the Milan criteria preoperatively, but exceeded the criteria in the explant (n = 19). Nodules newly found in the explant liver had little impact on recurrence-free survival. A decision for liver transplantation according to the Milan criteria based on preoperative evaluation is valuable for securing an excellent outcome.

Milan criteria are standards for considering the indications of liver transplantation for hepatocellular carcinoma. A 57-year-old man underwent living donor liver transplantation for hepatitis B-related liver cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma had been treated with percutaneous microwave coagulation therapy and transarterial chemoembolization. Resected specimens revealed a solitary necrotic tumor 5 cm in diameter, which satisfied the Milan criteria. Although the patient survived the operation, he suffered from tumor recurrence in the graft and lung 2 months afterward. Adjuvant chemotherapy had no effect and the patient expired 7 months after transplantation. The present results indicate that a tumor satisfying the Milan criteria does not necessarily guarantee long-term survival after transplantation.

We describe here a case of living-related liver transplantation with a spontaneous splenorenal shunt. On the third postoperative day, Doppler ultrasound follow-up revealed impairment of intrahepatic portal vein flow and reoperation was performed. Intraoperatively, simple compression of the collateral veins forming the splenorenal shunt resulted in an immediate change in the portal flow pattern, which suggested the absence of a portal thrombus. Splenectomy and ligature of the more dilated collateral veins were carried out and satisfactory portal flow was restored. Although the role of splenectomy was controversial, splenectomy provided an increased portal vein flow in the present case. The uneventful postoperative course validated our decision.