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There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust., (© 2024 UICC.)

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study., (© 2024. The Author(s).)

Background: During systemic therapy, the management of portal hypertension (PH)-related complications is vital. This study aimed to clarify factors associated with the incidence and exacerbation of PH-related complications, including the usefulness of contrast-enhanced computed tomography (CECT) in the management of PH-related complications during systemic therapy., Methods: A total of 669 patients who received systemic therapy as first-line treatment (443 patients for sorafenib, 131 for lenvatinib, and 90 for atezolizumab/bevacizumab [ATZ/BEV]) were enrolled in this retrospective study. Additionally, the lower esophageal intramural vessel diameters (EIV) on CECT and endoscopic findings in 358 patients were compared., Results: The cutoff values of the EIV diameter on CECT were 3.1 mm for small, 5.1 mm for medium, and 7.6 mm for large varices, demonstrating high concordance with the endoscopic findings. esophageal varices (EV) bleeding predictors include EIV ≥ 3.1 mm and portal vein tumor thrombosis (PVTT). In patients without EV before systemic therapy, factors associated with EV exacerbation after 3 months were EIV ≥ 1.9 mm and ATZ/BEV use. Predictors of hepatic encephalopathy (HE) include the ammonia level or portosystemic shunt diameter ≥ 6.8 mm. The incidence of HE within 2 weeks was significantly higher (18%) in patients with an ammonia level ≥ 73 μmol/L and a portosystemic shunt ≥ 6.8 mm. The exacerbating factors for ascites after 3 months were PVTT and low albumin levels., Conclusions: Careful management is warranted for patients with risk factors for exacerbation of PH-related complications; moreover, the effective use of CECT is clinically important., (© 2024. The Author(s).)

Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child-Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child-Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44-2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3-5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes., (© 2024. The Author(s).)

Background/purpose: The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy., Methods: We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group., Results: SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group., Conclusions: There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group., (© 2023 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Introduction: The albumin-bilirubin (ALBI) score evaluates liver dysfunction severity. However, this score had prognostic effects in patients with hepatocellular, pancreatic, and gastric carcinomas. We aimed to assess the predictive value of the ALBI score in patients with esophageal squamous cell carcinoma (ESCC)., Methods: Data from 154 patients with ESCC who consecutively underwent neoadjuvant chemotherapy (NAC) and subtotal esophagectomy were retrospectively investigated. The ALBI score was calculated as pre-NAC ALBI and categorized into grades 1, 2a, 2b, and 3; low-ALBI group (n = 134) was assigned with ALBI grade 1 and the other grades were assigned to the high-ALBI group (n = 20)., Results: The pre-NAC ALBI was significantly associated with relapse-free survival (RFS) and overall survival (P = 0.003 and P = 0.014, respectively). Based on multivariate analysis, pre-NAC ALBI, pathological T factor, and N factor were identified as independent prognostic factors for poor RFS. Multivariate and univariate analyses limited to factors were obtained before treatment, indicating high pre-NAC ALBI as an independent prognostic factor of poor overall survival (P = 0.039) and RFS (P = 0.008). With respect to pathological response to NAC, patients in the high pre-NAC ALBI group had a significantly lower response than patients in the low pre-NAC ALBI group (P = 0.010)., Conclusions: Our results suggested that the pre-NAC ALBI marker predicts the long-term outcome and pathological response to NAC in patients with ESCC consecutively undergoing NAC and a subtotal esophagectomy., (Copyright © 2023. Published by Elsevier Inc.)

Several studies have investigated the association between the use of anti-cholesterol drugs and cancer risks, of which results have been inconsistent. This study included 67,768 participants from the Japan Public Health Center-based Prospective Study. The data on anti-cholesterol drug use was collected using three questionnaires of the survey conducted every five years. We divided the participants into three groups according to the duration of the anti-cholesterol drug use. Multivariable-adjusted Cox proportional hazard regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). During the 893,009 person-years of follow-up from the 10-year follow-up survey, 8,775 participants (5,387 men and 3,388 women) were newly diagnosed with cancers. The duration of anti-cholesterol drug use was significantly associated with a decreased risk of liver cancer (HR:0.26, 95% CI 0.11-0.64 in > 5 y group) and with an increased risk of pancreatic cancer (HR:1.59, 95% CI 1.03-2.47 in > 5 y group). Moreover, a different trend was observed between men and women in the association with the risk of lung cancer. This study suggested that long-term use of anti-cholesterol drugs may have associations with a decreased incidence of liver cancer and with an increased incidence of pancreatic cancers., (© 2024. The Author(s).)

Purpose: This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial, a phase III trial that compared lenvatinib with sorafenib., Patients and Methods: This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced hepatocellular carcinoma (HCC) and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab., Results: From December 2019 to September 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in the high-burden group. No other significant ad verse events (AE) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AE (100.0%) and high discontinuation rates caused by AE (33.3%) compared with patients with Child-Pugh A (80.9% and 17.0%, respectively). Median progression-free survival was 6.4 and 2.5 months and median overall survival was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in patients with Child-Pugh B on days 8 and 15 and correlated with dose modifications and lower relative dose intensity., Conclusions: Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AE and may not provide adequate efficacy for patients with Child-Pugh B status., (©2023 American Association for Cancer Research.)

Purpose: Factors affecting the prognosis of repeat hepatectomy for transplantable hepatocellular carcinoma (HCC) recurrence after hepatectomy remain unclear. We aimed to clarify the prognostic factors for transplantable hepatocellular carcinoma recurrence after hepatectomy., Methods: We included 1758 primary and 486 repeat hepatectomies out of 2244 for HCC performed between 2006 and 2017 using the Hiroshima Study Group for Clinical Oncology and Surgery database. We first compared survival rates of primary and repeat hepatectomy patients. Subsequently, prognostic factors were analyzed in patients who underwent a repeat hepatectomy for transplantable hepatocellular carcinoma recurrence after hepatectomy (defined as age < 70 years at the time of recurrence and recurrent tumor morphology that meets the Milan criteria)., Results: The 5-year overall survival rate (OS) after repeat hepatectomy was 63.2%, while the 5-year recurrence-free survival rate (RFS) was 23.7%. RFS demonstrated significant inferiority in the repeat hepatectomy group than in the primary hepatectomy group; however, OS did not present a notable difference between the two cohorts. In the transplantable recurrence group, mALBI grade 2b, max tumor size > 20 mm, and multiple tumors were independent prognostic risk factors for overall survival. Patients with two or more risk factors had a significantly lower survival rate (only 30.6% at 5 years) compared to those with one or fewer risk factors (81.8% at 5 years)., Conclusions: We identified the risk factors involved in post-hepatectomy survival for patients with transplantable recurrence after hepatectomy. The results are a potential indicator of whether salvage liver transplantation should be considered during repeat hepatectomy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The effect of the combination of atezolizumab and bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC) on pulmonary arterial hypertension (PAH) is unknown. Estimation of PAH by using computed tomography (CT) has recently been proposed. Thus, we aimed to estimate the effect of Atez/Bev on PAH using CT. Altogether, 113 patients who received Atez/Bev for HCC were enrolled. Probable PAH was defined as the diameter of the main pulmonary artery (mPA-D) ≥ 33 mm, whereas suspicious PAH was defined as mPA-D ≥ 29 mm or mPA-D/the diameter of the ascending aorta (aAo-D) ≥ 1.0. Before treatment, probable/suspicious PAH were diagnosed in 7 (6.7%)/22 (21.0%) patients, respectively. mPA-D and mPA-D/aAo-D significantly increased after induction of Atez/Bev. The increment of mPA-D was correlated with the occurrence of post-treatment respiratory/heart failure. In analysis of 55 patients who underwent CT at 3 months after the last dose of Atez/Bev, mPA-D and mPA-D/aAo-D significantly decreased. However, in the group with continuous treatment of other molecular-targeted drugs after Atez/Bev, mPA-D and mPA-D/aAo-D showed no significant change. In conclusion, PAH may not be a rare complication in patients with HCC and should be managed carefully because of the possible negative effect of Atez/Bev on PAH., (© 2023. The Author(s).)

Background and Aim: This study aimed to investigate whether telephone follow-up by clinical pharmacists for unresectable hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN) contributes to improved adherence and treatment duration for LEN., Methods: This retrospective study enrolled 132 patients with HCC who were treated with LEN. The patients were classified into non-telephone follow-up (n = 32) or telephone follow-up groups (n = 100) [the latter group was further classified into family-pharmacist (FP) telephone follow-up (n = 18), or hospital family-pharmacist (HFP) telephone follow-up (n = 82) groups]., Results: The progression-free survival (PFS) in the telephone follow-up group was significantly higher than that in the non-telephone follow-up group (PFS 6.1 months vs 3.7 months, P = 0.001, respectively). Although treatment duration was significantly longer in the telephone follow-up group than in the non-telephone follow-up group [median treatment duration: 10.4 months vs 4.1 months, P = 0.001, respectively.], no significant differences were noted between the HFP telephone follow-up group and FP telephone follow-up groups (10.3 months vs 13.3 months, P = 0.543). Self-interruption and adverse-event discontinuation in the HFP-telephone follow-up group were significantly lower than those in the FP-telephone and non-telephone groups (0% vs 11.1% vs 18.8%; P < 0.001, 25.6% vs 33.3% vs 53.1%; P = 0.022, respectively)., Conclusions: Telephone follow-up contributes to prolonged treatment duration for LEN in patients with HCC treated. Moreover, telephone follow-up with an HFP may further improve treatment adherence., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: The importance of a nutrition scoring system, including the geriatric nutritional risk index (GNRI), was reported as an objective tool widely used to assess nutritional status in patients with inflammatory disease, chronic heart failure, and chronic liver disease. However, studies on the relationship between GNRI and the prognosis in patients who have undergone initial hepatectomy have been limited. Thus, we conducted a multi-institutional cohort study to clarify the relationship between GNRI and long-term outcomes for hepatocellular carcinoma (HCC) patients after such a procedure., Methods: Data from 1,494 patients who underwent initial hepatectomy for HCC between 2009 and 2018 was retrospectively collected from a multi-institutional database. The patients were divided into two groups according to GNRI grade (cutoff: 92), and their clinicopathological characteristics and long-term results were compared., Results: Of the 1,494 patients, the low-risk group (≥ 92; N = 1,270) was defined as having a normal nutritional status. Meanwhile, low GNRI (< 92; N = 224) were divided into malnutrition as the high-risk group. Multivariate analysis identified seven prognostic factors of poor overall survival (higher tumor markers; α-fetoprotein (AFP) and des-γ-carboxy protein [DCP], higher ICG-R15 levels, larger tumor size, multiple tumors, vascular invasion, and lower GNRI and eight prognostic factors of high recurrence (HCV antibody positive, higher ICG-R15 levels, higher tumor markers such as AFP and DCP, greater bleeding, multiple tumors, vascular invasion, and lower GNRI)., Conclusions: In patients with HCC, preoperative GNRI predicts poorer overall survival and high recurrence., (© 2023. The Society for Surgery of the Alimentary Tract.)

Cases of adult liver transplant recipients with a postoperative right-side acquired diaphragmatic hernia are extremely rare. In this report, we describe an adult case of right-side acquired diaphragmatic hernia 15 years after living donor liver transplant. A 27-year-old woman was diagnosed with pancreatic insulinoma with multiple metastases in the liver. To treat the liver failure, she underwent left lobe living donor liver transplant and distal pancreatectomy with splenectomy 3 years after the transcatheter arterial chemoembolization. As a result of the liver abscesses that reached the diaphragm, the delicate diaphragm was injured, which required repair during the transplant surgery. At the age of 46 years, she developed a cough and intermittent abdominal pain. One month later, she went to another hospital's emergency room with complaints of epigastric pain. The computed tomography scan revealed colon and small intestine prolapse into the right thoracic cavity. She was referred to our hospital and underwent surgery the next day. Two adjacent right diaphragm defects were successfully sutured with nonabsorbable sutures. The patient was discharged on postoperative day 11.

Background: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics., Methods: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGK R ) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed., Results: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGK R , 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGK R . No significant difference was observed in the baseline characteristics between HPD and non-HPD., Conclusion: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated., (© 2023. The Author(s).)

Purpose: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies., Methods: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events., Results: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3)., Conclusion: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial., (© 2023. The Author(s).)

In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence., (© 2023. The Author(s).)

Background: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long-term efficacy and association with adverse events in real-world practice are unknown. This study was designed to shed light on these issues., Methods: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition., Results: A total of 123 patients were enrolled in this study. The median progression-free survival (PFS) for the first-line treatment group was 8.0 months (95% confidence interval [CI], 6.1-9.9), whereas the median PFS for the second- or later-line treatment group was 4.1 months (95% CI, 2.6-5.7), which was significantly worse than that of the first-line treatment group (p = .005). Twenty-seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013)., Conclusions: The PFS of atezolizumab plus bevacizumab as first-line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long-term PFS., Plain Language Summary: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma., (© 2022 American Cancer Society.)

Background/aim: Conversion surgery (CS) following atezolizumab plus bevacizumab (Atez+Bev) is a treatment strategy for unresectable hepatocellular carcinoma (UR-HCC). Herein, we report a case of CS after transcatheter arterial embolization (TAE) and Atez+Bev for primary HCC with peritoneal metastases and multiple liver metastasis after HCC rupture., Case Report: A 75-year-old man with a suspected ruptured HCC in segment 4b was referred to the National Hospital Organization Kumamoto Medical Center. TAE was performed to stop the bleeding. Subsequently, 15 courses of Atez+Bev were administered for UR-HCC with primary tumor, peritoneal metastasis, and multiple liver metastases. Multiple liver metastases and peritoneal metastasis resolved 7 months after initiation of Atez+Bev. The primary HCC had shrunk, but the patient decided not to continue treatment because of severe numbness in his fingers. Six months after stopping Atez+Bev, CS was performed because no new lesions were observed, and the patient wished to become cancer-free by resection of the remaining tumor. HCC was successfully resected, and he was discharged without any complications. The pathological findings demonstrated that there was no remnant viable HCC., Conclusion: We herein present a case of CS following TAE and Atez+Bev for unresectable and ruptured HCC. The patient did not require chemotherapy after CS and is alive and recurrence-free for 7 months., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: This study aimed to evaluate the prognostic impact of conversion hepatectomy in patients with initially unresectable colorectal liver metastasis (CRLM) and to identify prognostic factors after conversion hepatectomy., Methods: Correlations of conversion hepatectomy with relapse-free survival (RFS) and overall survival (OS) were retrospectively investigated in 554 consecutive patients who underwent hepatectomy for CRLM in 2000-2017. Prognostic factors after conversion hepatectomy were examined in multivariable analysis., Results: Five hundred and nine patients (92%) had initially resectable CRLM at diagnosis and underwent hepatectomy (primary resection group) and 45 (8%) underwent conversion hepatectomy following chemotherapy (conversion group). The 5-year RFS was 30.0% in the primary resection group and 19.8% in the conversion group (p = 0.042); the respective 5-year OS rates were 62.0% and 52.4% (p = 0.253). Multivariable analysis did not identify conversion hepatectomy as a significant prognostic factor for RFS (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.64-1.37, p = 0.796) or OS (HR 1.12, 95% CI 0.67-1.79, p = 0.667). In the conversion group, multivariable analysis identified the following independent prognostic factors: timing of liver metastases for RFS (synchronous: HR 3.14, 95% CI 1.20-8.24, p = 0.020) and preoperative CEA level for RFS (> 5 ng/ml: HR 3.10, 95% CI 1.45-6.61, p = 0.003) and OS (> 5 ng/ml: HR 3.29, 95% CI 1.18-9.17, p = 0.023)., Conclusions: RFS and OS rates after conversion hepatectomy were not inferior to those after primary resection in patients with CRLM. Patients with a normal CEA level before hepatectomy can be expected to have good long-term prognosis after conversion hepatectomy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

It is unclear whether prediagnostic iron-related biomarkers in circulation are associated with cancer risk. We constructed a case-cohort of participants who had plasma samples available from the Japan Public Health Center-based Prospective Study and determined the incidence of cancer in these participants. We measured plasma concentrations of iron, ferritin, and hepcidin, and assessed the association between each biomarker and cancer incidence using a weighted Cox regression model. There were 4,253 participants in the sub-cohort (the randomly selected participants from an eligible, at-risk population) and 3,596 incident cancer cases (499 cases occurred in the sub-cohort). Median follow-up was for 16.5 years. In the multivariable adjusted analysis, iron deficiency (plasma ferritin <30 ng/mL) was associated with a higher risk of total cancer [adjusted HR, 1.23; 95% confidence interval (CI), 1.07-1.42] and the association was weaker after excluding those followed-up for <3 years. Iron overload was not significantly associated with total cancer (HR, 1.04; 95% CI, 0.82-1.33), but was associated with liver cancer (HR, 4.49; 95% CI, 2.71-7.43). Lower plasma levels of hepcidin and ferritin are associated with an increased gastrointestinal cancer risk. Meanwhile, lower plasma hepcidin and higher plasma ferritin levels were associated with an increased liver cancer risk. In conclusion, there was no association between iron overload and cancer risk, besides liver cancer., Prevention Relevance: High ferritin and low hepcidin levels in the plasma were associated with increased liver cancer risk. Evaluating iron metabolism including hepcidin levels may help identify people with high liver cancer risk., (©2022 American Association for Cancer Research.)

Purpose: We previously reported that polyphyllin D, a main component of the traditional Chinese medicinal herb Paris polyphylla, exhibited anticancer effects in vitro against human neuroblastoma cells. The aims of this investigation was to examine the presence or absence of in vivo anti-metastasis effects of polyphyllin D were to establish a liver metastasis model of neuroblastoma and to evaluate the anti-metastasis effects of polyphyllin D., Methods: Subcutaneous and intraperitoneal tumors, and metastasis models were established in immune-deficient BALB/c nude and BALB/c Rag-2/Jak3 double-deficient (BRJ) mice using the human neuroblastoma cell lines IMR-32, LA-N-2, or NB-69. For evaluating polyphyllin D activity, we used a mouse model of liver metastasis with the IMR-32 cells line injected through the tail vein. We analyzed the livers number and area of liver tumors in of the phosphate buffer solution- and polyphyllin D-treated groups., Results: Liver metastasis and intraperitoneal dissemination models were successfully established in immune-deficient BRJ mice using the three human neuroblastoma cell lines. In the liver metastasis, the model of IMR-32 cells, we found that polyphyllin D suppressed both the number and total area of metastatic foci the average number of metastatic foci, average focus areas, and number of cleaved caspase-3-positive cells were significantly lower in the polyphyllin D group (p = 0.016, 0.020, 0.043, respectively)., Conclusions: We developed a mouse models of neuroblastoma metastasis and demonstrated for the first time that polyphyllin D has an antitumor effect on neuroblastoma liver metastases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial., Methods: Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses., Results: Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups., Conclusion: Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Liver transplantation (LTx) is indicated for unresectable hepatoblastoma (HB) without distal metastasis. However, to our knowledge, there is no consensus on the management of unresectable HB with pulmonary metastases, or on the treatment of recurrent HB. We report a successful case of metastatic HB treated with repeated lung resection, chemotherapy, and LTx. This study strictly complied with the Helsinki Congress and the Istanbul Declaration regarding donor source., Case Report: Our case was a 1-year-old boy who developed pre-treatment extent of disease (PRETEXT) Ⅲ HB with multiple pulmonary metastases. The liver tumor was unresectable because it involved all hepatic veins. After 3 cycles of chemotherapy (cisplatin/carboplatin plus doxorubicin), the remaining 2 pulmonary metastases were resected and living donor liver transplantation (LDLT) was performed. Five months after LDLT, a tumor recurrence was detected in the right lung. Repeat lung resection was performed followed by 1 cycle of chemotherapy (carboplatin plus doxorubicin). There has been no recurrence for 18 months since the last lung resection., Discussion: Previous reports revealed that 14 patients, including the present case, underwent LTx after resection of metastatic HB pulmonary lesions. Of these patients, the 2-year survival rate after LTx was 91%. Recurrence was reported in 5 patients, 2 of whom were successfully treated with repeated resection of the metastatic lesions. LTx after resection of lung recurrence may be a potential treatment for unresectable HB with pulmonary metastases., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: In this study, we evaluated the association between working hours and cancer risk in the Japanese population, which has not been evaluated., Methods: Using a cohort database from a Japan Public Health Center-based Prospective Study, we evaluated 26 738 participants (16 351 men and 10 387 women), who responded to a questionnaire about working hours and followed these participants from 1993-1994 to 2013. Participants were divided into four groups according to working hours (≤6, 7-8, 9-10, ≥11 h/day). The hazard ratio (HR) and 95% confidence interval (CI) of each cancer incidence were calculated using a multivariable-adjusted Cox proportional hazard model., Results: During 488 383 person-years of follow-up, 481 patients with newly diagnosed cancers were identified. There was no clear association between long working hours and overall cancer, lung cancer, and stomach cancer risks. Long working hours tended to increase prostate cancer risk in men and breast cancer risk in women, although the difference was not statistically significant. Increased liver cancer risk with short working hours (HR [95% CI]; 3.15 [1.44-6.88] in the ≤6 h/day group vs. 7-8 h/day) was observed. Colorectal cancer also tended to increase risk in short working hours, however, there were not statistically significance., Conclusions: In this population, long working hours were not associated with cancer risk with statistically significance. The association between short working hours and liver cancer risk was observed, probably due to the reverse causation of liver cancer., (© 2022 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Duodenal gastrointestinal stromal tumors (dGISTs) are rare, and a lack of consensus exists regarding their treatment, particularly for recurrent disease. We herein report a rare case of liver metastasis 7 years after resection of a low-risk duodenal gastrointestinal stromal tumor. A 45-year-old woman revealed positive fecal occult blood. Upper gastrointestinal endoscopy revealed a submucosal duodenal tumor with ulceration and oozing on the apex. Endoscopic ultrasound showed a hypoechoic mass originating in the submucosa. Contrast-enhanced abdominal computed tomography (CT) revealed a 30-mm hyper-vascular tumor in the duodenal bulb. The patient underwent partial resection of the duodenal bulb with distal gastrectomy, followed by Roux-en-Y reconstruction. Histopathological evaluation revealed a tumor comprised of spindle-shaped cells including 5 mitotic figures per 50 high-power fields. Immunohistochemical evaluation indicated that the tumor cells were positive for c-Kit and CD34 expression. The tumor was diagnosed as low-risk dGIST. Postoperative follow-up was continued, and 7 years later, CT revealed a 39-mm enhanced tumor in liver segment 4. The tumor was diagnosed as a metastatic liver tumor, and the patient underwent S4 partial hepatectomy. As a result of histological and immunohistochemical analysis, the tumor was diagnosed as a liver metastasis from dGIST. The patient has been receiving oral imatinib 400 mg daily and remains free of disease 5 years after her last surgery. Low-risk dGIST can metastasize relatively long after surgery. However, an excellent long-term prognosis may be achieved by combining complete resection and imatinib therapy in patients with recurrent liver metastases., (© 2021. Japanese Society of Gastroenterology.)

Introduction: Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities., Methods: The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients' body mass index (BMI) and visceral fat area (VFA)., Results: Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups ( P = .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR ( P = .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR ( P = .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR ( P = .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups ( P = .017, < .001, and < .001, respectively)., Conclusion: LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.

Purpose: The aim of this study was to compare the impact of fermented and unfermented soy intake, based on the following soy-derived products: tofu, soymilk, natto, and miso, on the risk of liver cancer among Japanese adults., Methods: 75,089 Participants of the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from the time of the 5-year follow-up questionnaire until the end of 2012-2013. Subjects with available data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection status from blood samples (n = 14,016) and those who were anti-HCV antibody (anti-HCV) or hepatitis B virus antigen (HBsAg) positive (n = 1033) were also analyzed separately. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs)., Results: During 1,145,453 person-years, 534 newly diagnosed cases of liver cancer were identified in the JPHC Study. For miso intake among men, the multivariate-adjusted highest versus lowest quartile HR was 0.65 (95% CI, 0.48-0.89); p for trend = 0.006. Results were similar in those who were anti-HCV or HBsAg positive, 0.24 (0.08-0.70); p for trend = 0.004 highest versus lowest tertile. For the sub-analysis among only participants with known hepatitis infection status and HCV and HBsAg adjustment, a similar association was observed. In the multivariate complete cohort analysis, among women, the highest intake of fried tofu was inversely associated with the risk of liver cancer, HR = 0.45 (0.26-0.80); p for trend = 0.014., Conclusions: We observed no association between total soy intake, fermented and unfermented, and risk of liver cancer, and only an inverse association between miso intake and liver cancer among men.

Hepatocellular carcinoma (HCC) is the fifth most common primary tumor and the third leading cause of cancer-related deaths worldwide. Rodent models of HCC have contributed to the advancement of studies investigating liver carcinogenesis, tumor-host interactions, and drug screening. However, their small size renders them unsuitable for surgical or clinical imaging studies, necessitating the development of larger-size HCC models. Here, we developed a xenograft model of human HCC in X-linked interleukin-2 receptor gamma chain gene (Il2rg)-targeted severe combined immunodeficient (SCID) pigs. HepG2 cell suspension in serum-free medium containing 50% membrane matrix was directly injected into the liver parenchyma of eight X-linked Il2rg-targeted SCID pigs (6.6-15.6 kg) via ultrasonography-guided percutaneous puncture. Tumor engraftment was evaluated weekly using ultrasonography, and cone-beam computed tomography was performed during arterial portography (CTAP) and hepatic arteriography (CTHA) to evaluate the hemodynamics of engrafted tumors. The engrafted tumors were histologically analyzed following necropsy and assessed for pathological similarities to human HCCs. Macroscopic tumor formation was observed in seven of the eight pigs (simple nodular tumors in three and multinodular tumors in four). Engrafted tumors were identified as low-echoic upon ultrasonography and as perfusion-defect nodules on the CTAP images. Meanwhile, CTHA showed that the tumors were hyperattenuating. Further, histopathological findings of the engrafted tumors were consistent with those of human HCC. In conclusion, the porcine model of human HCC, successfully generated herein, might help develop more effective therapeutic strategies for HCC., Competing Interests: The authors have declared that no competing interests exist.

A 42-year-old man complaining of left back pain was admitted to our hospital. The hepatis B and C surface antigens were negative. The serum levels of tumor markers were within the reference ranges. Abdominal ultrasound revealed an 8 cm-sized, primarily round and hyperechoic mass in the left lateral segment. Contrast-echo showed non-uniform enhancement in the arterial phase and uniform enhancement in the portal phase. This mass did not indicate"wash-out"on contrast- enhanced CT. It showed hypointensity in the hepatobiliary phase on MRI. The definitive diagnosis could not be obtained, and the patient was suspected with malignancy, such as hepatocellular carcinoma(HCC). Therefore, left hemi-hepatectomy was performed for the diagnostic treatment. Based on the immunochemical staining results, he was diagnosed with angiomyolipoma( AML). AML is composed of fat, blood vessels, and smooth muscles. It is regarded as a tumor of perivascular epithelioid cell tumor(PEComa). Early venous return and adipose tissues in the tumor were the distinctive features of this tumor. The preoperative diagnosis of AML without any fatty component as in this case is very difficult.

A 69-year-old woman with a hepatocellular carcinoma(HCC)was followed-up for type B chronic hepatitis and underwent partial hepatectomy(S6)at our hospital. Afterwards, she underwent radiofrequency ablation(RFA)therapy twice because of intrahepatic recurrence. Seven months after the first hepatectomy, a left adrenalectomy was performed for a left adrenal metastasis. Seventeen months after the first hepatectomy, a splenectomy was performed for a splenic metastasis. Forty-three months after the first hepatectomy, a second hepatectomy was performed for intrahepatic recurrence, and a right adrenalectomy was performed for an adrenal metastasis. Sixty-eight months after the first hepatectomy, an abdominal CT revealed a growing solitary lesion in the ascending colon, which was diagnosed as a peritoneal metastasis. The peritoneal dissemination was removed because there were no other extrahepatic or intrahepatic recurrences. Histologically, the resected specimen was diagnosed as a peritoneal metastasis from a HCC. The patient survived, and there were no recurrences for 6 months after the operation. We report this case of a peritoneal metastasis from a HCC after surgery with a review of the literature.

Neoadjuvant chemoradiotherapy is a standard mode of therapy for rectal cancer but not colon cancer. A 74-year-old man undergoing treatment for prostate cancer was found to have a tumor in both the sigmoid colon and liver. Colonoscopy showed a type 2 tumor of the sigmoid colon, with a biopsy confirming a diagnosis of well differentiated tubular adenocarcinoma. Computed tomography demonstrated a tumor of the sigmoid colon with metastasis to the liver. As there was a high suspicion of invasion of the left ureter, we decided to administer mFOLFOX6 as neoadjuvant chemotherapy prior to tumor resection. After 8 courses of mFOLFOX6, both the primary lesion and liver metastasis significantly decreased in size. Subsequently, the patient underwent a sigmoidectomy and partial hepatectomy. Histopathological examination revealed pathological complete response(Grade 3). It is important to reveal effective cases of neoadjuvant chemotherapy, the appropriate treatment regime and timing of surgical intervention so as to advance therapeutic strategies for the treatment of colon cancer.

Background: Previous studies investigating the impact of tumor location on colorectal cancer prognosis only compared two groups by location, e.g., 'right-sided colon vs. left-sided colon,' 'colon vs. rectum,' and 'right-sided (right-sided colon) vs. left-sided (left-sided colon and rectum).' This nationwide multicenter retrospective study aimed to clarify the prognostic impact of tumor location in patients with stage III colorectal cancer by classifying tumors into three groups: right-sided colon, left-sided colon, and rectum., Methods: Subjects were 9194 patients with stage III colorectal cancer who underwent curative surgery from 1997 to 2012. Relapse-free survival (RFS) after primary surgery and overall survival (OS) after recurrence were examined., Results: Rectal cancer (n = 2922) was associated with worse RFS compared to right-sided colon cancer (n = 2362) (hazard ratio (HR) 0.65; 95% CI 0.59-0.72; p < 0.001) and left-sided colon cancer (n = 3910) (HR 0.72; 95% CI 0.66-0.78; p < 0.001) after adjusting for key clinical factors (i.e., sex, age, histological type, CEA, adjuvant therapy, T category, and N category). Among patients with recurrence (n = 2823), rectal cancer was associated with better OS compared to right-sided colon cancer (HR 1.23; 95% CI 1.08-1.40; p = 0.002) and worse OS compared to left-sided colon cancer (HR 0.88; 95% CI 0.79-0.99; p = 0.029). Twenty percent of right-sided colon cancer recurrences exhibited peritoneal dissemination, 42% of left-sided colon cancer recurrences were liver metastases, and 33% of rectal cancer recurrences were local recurrences., Conclusions: The three tumor locations (right-sided colon, left-sided colon, rectum) had different prognostic implications for recurrence after curative resection and overall mortality, suggesting that tumor location serves as a prognostic biomarker in stage III colorectal cancer.

Background: Repeat liver resection is an effective treatment approach for patients with recurrent hepatocellular cell carcinoma (HCC). However, the surgical feasibility and oncological significance of repeat laparoscopic liver resection (r-LLR) remain unproven. This study evaluates and compares the clinical outcomes of non-anatomic r-LLR applied towards recurrent HCC, with those of primary LLR (p-LLR) for primary HCC., Methods: This retrospective study reports 104 patients with HCC, treated with LLR between 2014 and 2018. Twenty eight of these patients underwent r-LLR for recurrent HCC. The clinical and surgical variables were reviewed for all cases., Results: The analysis was limited to non-anatomic resection across both groups (r-LLR: 89% (25/28) vs. p-LLR: 80% (61/76)). There were no statistically significant differences about patient background between the two groups, with the exception of Child-Pugh classification. r-LLR surgical techniques included single-site laparoscopic adhesiolysis (32%, 8/25), Pringle maneuver (8%, 2/25), and crush-clamp method using BiClamp for hepatic parenchymal transection (72%, 18/25). No severe postoperative complications were observed in the r-LLR group. Postoperative hospital stays and procedure-related postoperative survival were similar for both groups., Conclusions: Non-anatomical r-LLR renders comparable surgical and oncological outcomes. Our data suggest that non-anatomical r-LLR is a safe and feasible therapeutic approach to recurrent HCC.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

Background: Coffee and green tea, two popular drinks in the Japanese, have recently drawn much attention as potential protective factors against the occurrence of liver cancer., Methods: We systematically reviewed epidemiologic studies on coffee, green tea and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence ('convincing', 'probable', 'possible', or 'insufficient'), together with biological plausibility., Results: We identified four cohort and four case-control studies on coffee and liver cancer and six cohort and one case-control studies on green tea and liver cancer. All cohort and case-control studies on coffee reported a weak to strong inverse association, with a summary relative risk (RR) for one cup increase being 0.72 (95% confidence interval [CI] 0.66-0.79). Conversely, all studies but two cohort studies on green tea reported no association, with a corresponding summary RR of 0.99 (95% CI 0.97-1.01, P = 0.37)., Conclusion: Coffee drinking 'probably' decreases the risk of primary liver cancer among the Japanese population whereas the evidence on an association between green tea and liver cancer is 'insufficient' in this population., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: We reviewed the available literature on observational studies, meta-analyses, expert reports, and umbrella reviews. Here, we summarize the latest findings on the association between coffee intake and liver cancer risk., Recent Findings: Most observational studies and meta-analyses show a protective effect of coffee intake on liver cancer risk, with dose-responsiveness and across different populations, and regardless of hepatitis virus infection status. Risk reduction by coffee consumption has also been observed for chronic liver diseases. Potential mechanisms include the effect of a number of bioactive compounds such as caffeine, chlorogenic acids, phenolic compounds and diterpenes; antioxidant properties; induction of defense mechanisms; and anti-inflammatory properties. Other potential mechanisms include improvement in insulin sensitivity and prevention of metabolic syndrome and diabetes. Accumulated evidence, with consistency across study designs and populations, suggests that coffee intake probably reduces the risk of liver cancer. Future research should aim to elucidate the mechanism of this preventive effect with establishing the causality of an association.

Background: THUNDERBEAT® (TB) (Olympus Medical Systems Corp., Tokyo, Japan) is a dynamic energy system device that simultaneously delivers ultrasonically generated frictional heat energy and electrically generated bipolar energy. TB is being routinely used in various operative procedures, however, less is known about its utility in liver resection. We, herein, report our early experience of using TB in open liver resection particularly in patients with normal or near-normal liver parenchyma., Methods: We retrospectively reviewed the clinical characteristics, and evaluated the perioperative outcome of twenty-eight patients who underwent liver resection with TB, and twenty-four patients who underwent liver resection with basic procedure in our institution. The resection type was stratified into: major hepatectomy; resection of 3 or more than 3 Couinauds segments, and minor hepatectomy; resection of less than 3 Couinauds segments., Results: Liver resection time (mean ± SD) in TB group with major hepatectomy was significantly shorter: 16.7 ± 8.8 compared to 62.8 ± 39.4 min in basic procedure group (P < 0.0001). Accordingly, the liver resection time (mean ± SD) in TB group with minor hepatectomy was also significantly shorter, 8.3 ± 2.9 min compared to 45.2 ± 23.9 min in liver resection with basic procedure (P < 0.001). No significant difference was observed between the groups in terms of intraoperative blood transfusion ratio, postoperative complication and postoperative liver dysfunction., Conclusion: TB as a new energy device can offer a safe, reliable and substantially rapid liver resection particularly in patients with normal or near-normal liver parenchyma.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

Although Henoch-Schönlein purpura (HSP) is known to be accompanied by malignancies, cases with hepatobiliary cancer are extremely rare. A 62-year-old man with palpable purpura rapidly extending to both lower legs was admitted to our hospital. He was undergoing follow-up for cirrhosis caused by chronic hepatitis B virus infection and hepatocellular carcinoma (HCC). He had renal dysfunction with hematuria and proteinuria and abdominal pain. Based on the clinical presentation and skin biopsy findings, he was diagnosed with HSP. The administration of steroids resulted in the rapid improvement of the patient's symptoms and he was discharged 12 days after admission.

Background and Aims: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) performed before curative therapy for hepatocellular carcinoma (HCC) can distinguish between intrahepatic distant recurrence and hypervascularization. This study aimed to retrospectively evaluate the presence of non-hypervascular hypointense nodules on hepatobiliary phase images from Gd-EOB-DTPA-enhanced MRI as a risk factor of the intrahepatic distant recurrence of early stage HCC following radiofrequency ablation (RFA)., Methods: A total of 132 patients who underwent preprocedural Gd-EOB-DTPA-enhanced MRI followed by initial RFA were retrospectively analyzed. Post-RFA intrahepatic distant recurrence, which excluded the hypervascularization of non-hypervascular hypointense nodules detected by preprocedural Gd-EOB-DTPA-enhanced MRI, was evaluated according to the presence of non-hypervascular hypointense nodules on preprocedural Gd-EOB-DTPA-enhanced MRI., Results: Intrahepatic distant recurrence rates following RFA were higher in patients with non-hypervascular hypointense nodules (1-year: 22.5%, 2-year: 52.1%, 5-year: 89.1%) compared with in patients without non-hypervascular hypointense nodules (1-year: 7.0%, 2-year: 28.8%, 5-year: 48.7%). The presence of non-hypervascular hypointense nodules was associated with markedly increased cumulative recurrence rates of both identical and different subsegment intrahepatic distant recurrence, being an independent risk factor for post-RFA identical and different subsegment intrahepatic distant recurrence (identical: HR = 2.365, P = 0.027; different: HR = 3.276, P < 0.001)., Conclusion: The presence of non-hypervascular hypointense nodules on hepatobiliary phase images from Gd-EOB-DTPA-enhanced MRI obtained prior to RFA is an important predictive factor of intrahepatic distant recurrence following RFA of HCC., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor β1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown. Combined analyses of chromatin immunoprecipitation followed by sequencing and RNA-sequencing led to successful identification of 96 candidate epigenetic targets of G9a. Pharmacological inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. Intraperitoneal administration of BIX-01294 suppressed the growth of xenograft tumors generated by implantation of HCC cells in non-obese diabetic/severe combined immunodeficient mice. Immunohistochemical analyses revealed high levels of G9a and H3K9me2 in 36 (66.7%) and 35 (64.8%) primary HCC tissues, respectively. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues. In contrast, in non-tumor tissues, G9a and H3K9me2 were only observed in biliary epithelial cells and periportal hepatocytes. In conclusion, G9a inhibition impairs anchorage-dependent and -independent cell growth, but not EMT in HCC cells. Our data indicate that pharmacological interference of G9a might be a novel epigenetic approach for the treatment of HCC.

Background: Radiofrequency ablation (RFA) is commonly used to locally treat hepatocellular carcinoma (HCC). However, when tumors are close to the Glisson's capsule, RFA may induce injury in this region, complicating therapeutic efforts. We investigated the impact of RFA-induced Glisson's capsule-associated complications on liver function and prognosis of HCC patients., Methods: We retrospectively reviewed our patient database and found 170 early-stage HCC patients treated via RFA from April 2004 to December 2012. We defined RFA-induced Glisson's capsule-associated complication as lasting hepatic arterioportal (AP) fistula, major intrahepatic bile-duct dilatation (affecting two or more subsegments), or hepatic infarction. We also defined liver failure as initial occurrence of either total bilirubin increase (>3.0 mg/dL), uncontrolled ascites, or encephalopathy., Results: In our cohort, 15 patients had RFA-induced Glisson's capsule-associated complications (incidence of related complications, with some overlap: lasting AP fistula, n = 9; major intrahepatic bile-duct dilatation, n = 7; and hepatic infarction, n = 2). The cumulative incidence of liver failure before stage progression was significantly higher and the median overall survival (OS) was significantly lower (52.3 months) in HCC patients with Glisson's capsule-associated complications than in those without Glisson's capsule-associated complications (95.0 months). In addition, multivariate analysis demonstrated that Glisson's capsule-associated complication was a significant independent factor associated with OS., Conclusions: In this study, we have shown that early-stage HCC patients with RFA-induced Glisson's capsule-associated complications may have higher risks in poor prognosis., Competing Interests: All authors who took part in this study indicated that they did not have anything to declare regarding funding or conflict of interest with respect to this study.

Background: Treatment outcomes of sorafenib therapy may greatly vary depending not only on tumor spread but also on past clinical processes prior to sorafenib therapy and timing of sorafenib administration in the past clinical course of hepatocellular carcinoma (HCC). We evaluated the efficacy of sorafenib in patients with HCC, taking into account of their past clinical courses., Methods: Patients with HCC treated with sorafenib as a first-line systemic therapy, whose courses documented from the time of the initial diagnosis, were retrospectively analyzed., Results: Of the 123 patients receiving sorafenib therapy at an advanced-stage, baseline characteristics differed including the rate of hepatitis C virus, Child-Pugh class, and status of intrahepatic lesions according to stage progression processes. Overall survival (OS) in patients progressed directly from the early-stage (15.3 months) was significantly longer than that in patients diagnosed at the advanced-stage (5.3 months, P = 0.022) and progressed from the intermediate-stages (6.0 months, P = 0.041). Of 105 patients diagnosed at the intermediate-stage on past clinical courses, OS of starting sorafenib therapy before progression to the advanced-stage (67 patients) was significantly longer than for patients starting sorafenib therapy only after progression to the advanced-stage (38 patients) (P = 0.015)., Conclusion: Characteristic differences between past stage progression processes might affect prognosis in advanced-stage HCC patients receiving sorafenib. Switching to sorafenib therapy before progression to the advanced-stage appears more effective than that after progression to the advanced-stage in patients diagnosed in the intermediate-stage on past clinical courses prior to sorafenib administration.

Background: Liver regeneration (LR) involves an early inductive phase characterized by the proliferation of hepatocytes, and a delayed angiogenic phase distinguished by the expansion of non-parenchymal compartment. The interest in understanding the mechanism of LR has lately shifted from the proliferation and growth of parenchymal cells to vascular remodeling during LR. Angiogenesis accompanied by LR exerts a pivotal role to accomplish the process. Vascular endothelial growth factor (VEGF) has been elucidated as the most dynamic regulator of angiogenesis. From this perspective, platelet derived/Intra-platelet (IP) VEGF-A should be associated with LR., Material and Methods: Thirty-seven patients diagnosed with hepatocellular carcinoma and undergoing partial hepatectomy (PH) were enrolled in the study. Serum and IP VEGF-A was monitored preoperatively and at four weeks of PH. Liver volumetry was determined on computer models derived from computed tomography (CT) scan., Results: Serum and IP VEGF-A was significantly elevated at four weeks of PH. Preoperative IP VEGF-A was higher in patients with advanced cancer and vascular invasion. Postoperative IP VEGF-A was higher after major liver resection. There was a statistically significant correlation between postoperative IP VEGF-A and the future remnant liver volume. Moreover, the soluble vascular endothelial growth factor receptor-1 (sVEGFR1) was distinctly down-regulated suggesting a fine-tuned angiogenesis at the later phase of LR., Conclusion: IP VEGF-A is overexpressed during later phase of LR suggesting its implications in inducing angiogenesis during LR.

We report a case of radical resection of rectal cancer with multiple liver and lung metastases after preoperative chemotherapy. A 54-year-old woman presented with abdominal pain and loss of body weight due to rectal cancer with multiple liver and lung metastases. Therefore, the patient received 14 courses of bevacizumab+mFOLFOX6, and 7 courses of panitumumab+FOLFIRI. After the chemotherapy, the size of the distant metastases reduced by 62% on computed tomography, according to RECIST. Due to the reduction in size, a conversion surgery was attempted. First, an abdominal operation with laparoscopy was performed, and 2 months later an operation to resect the lung metastases via thoracoscopy was performed. Currently, 3 months after surgery, the patient is alive, without recurrence.

Background: Small hepatocellular carcinomas (HCC) with poorly differentiated components (PDC) are reportedly at risk of dissemination and needle tract seeding after percutaneous radiofrequency ablation, although it is the preferred treatment for HCC ≤ 2 cm because of the low rate of vascular invasion. On the other hand, the clinical outcomes after hepatectomy for these tumors are still unclear because of their rarity., Methods: A total of 233 cases of solitary HCC ≤ 2 cm were retrospectively reviewed and divided into two groups according to the presence of PDC: 199 without PDC (NP-HCCs) and 34 with PDC (P-HCCs). The clinicopathological characteristics and prognosis were compared., Results: A comparison of clinicopathological characteristics showed that the elevation of the tumor markers alpha-fetoprotein (AFP) (>20 ng/mL) and des-gamma-carboxyprothrombin (DCP) (>40 AU/L) was significantly frequent in P-HCCs. The 3- and 5-year recurrence-free survival rates for P-HCCS were 39 and 29 %, respectively, which were significantly worse than those for NP-HCCs (64 and 50 %, respectively) (p < 0.01). Initial recurrence of P-HCCs was significantly more frequent, as well as extrahepatic recurrence and advanced recurrence in the early period after the operation. Recurrences with tumor dissemination were observed in 15 % of P-HCCs and 4 % of NP-HCCs (p = 0.03)., Conclusion: PDC is present in 15 % of HCC < 2 cm and should be suspected when the both tumor markers are elevated. Moreover, significantly worse post-hepatectomy outcomes such as early advanced recurrence or recurrence with dissemination should be taken into account if PDC is present even in HCCs ≤ 2 cm.

Background: Evidence suggests that estrogen plays a preventive role in primary liver cancer development, and it might be thought that isoflavones, which are structurally similar to estrogens and bind to estrogen receptors, are associated with the risk of liver cancer. We investigated this suspected association by measuring plasma concentrations of isoflavones in a nested case-control study of a population-based prospective cohort in Japan., Methods: From 18,628 target participants ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or hepatitis C virus infection at baseline (n = 1,544). Among these, 90 (28 women and 62 men) were newly diagnosed with primary liver cancer from 1993 through 2006; they were matched with 175 controls (54 women and 121 men). Plasma concentrations of isoflavones (genistein, daidzein, glycitein, and equol) were measured using triple quadrupole tandem liquid chromatography-mass spectrometry. The ORs of liver cancer development based on plasma concentrations were estimated with a conditional logistic regression model., Results: Basically, distributions of plasma isoflavone concentrations did not differ between the cases and controls. No statistically significant associations of genistein, daidzein, glycitein, and equol with primary liver cancer risk were found in either women or men., Conclusions: In middle-aged Japanese women and men with hepatitis virus infection, plasma isoflavones were unassociated with the occurrence of primary liver cancer., Impact: The role of isoflavones in liver carcinogenesis merits further study using both biomarkers and data on dietary intake of isoflavones. Cancer Epidemiol Biomarkers Prev; 24(3); 532-7. ©2014 AACR., (©2014 American Association for Cancer Research.)

Background: The implication of extremely high preoperative alpha-fetoprotein (AFP) values for the long-term outcomes of hepatectomy for resectable hepatocellular carcinoma (HCC) remains uncertain., Methods: A total of 762 hepatectomized HCC patients were divided into 3 groups according to preoperative AFP serum concentrations: 578 patients with AFP <100 ng/mL (low [LAP]), 147 patients with AFP 100-4,000 ng/mL (high [HAP]), and 37 patients with AFP ≥4,000 ng/mL (extremely high [EAP]). The clinicopathologic features and prognosis of the EAP group were compared with those of the other 2 groups to investigate their characteristics and whether the choice of hepatectomy was valid., Results: The EAP group had a greater proportion of younger patients and those with hepatitis B compared with the other 2 groups. Large tumor size, poor histologic differentiation, and microscopic vascular invasion were also more common in the EAP group. The recurrence-free and overall survival rates of the EAP group were worse than those of the LAP group (both P < .01) but were not greatly different from those of the HAP group (P = .65 and P = .80, respectively). When the analysis was limited to solitary HCC cases, both recurrence-free and overall survival rates of EAP were not significantly different from those of LAP (P = .79 and P = .99, respectively)., Conclusion: An extremely high AFP level does not provide additional postoperative prognostic implications beyond those provided by a high AFP level. Hepatectomy should be performed without reservation for cases of HCC associated with an extremely high AFP value., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To investigate the significance of downregulation of liver fatty acid-binding protein (L-FABP) expression in hepatocellular carcinoma (HCC)., Methods: Tissue microarrays of 146 cases of HCC were used to perform immunohistochemical staining for L-FABP. For each L-FABP-negative HCC, further immunohistochemical staining was performed using a representative whole-tissue section to confirm the downregulation of L-FABP expression and to assess the intratumoral heterogeneity of the staining pattern. Clinical data were retrieved from the clinical files, and histological slides were reviewed. Immunohistochemical staining for cytokeratin (CK) 7, CK 19, β-catenin, glutamine synthetase (GS), and serum amyloid A were also performed on the tissue microarrays. Clinicopathological features of the L-FABP-negative and L-FABP-positive HCC cases were compared. Furthermore, L-FABP and GS gene expression in HCC and cholangiocarcinoma cell lines were analyzed using real-time reverse transcription polymerase chain reaction. Mutation analysis of HNF1A [encoding hepatocyte nuclear factor 1 (HNF1)α] was performed for L-FABP-negative HCC cases., Results: Sixteen (10.9%) of the 146 cases of HCC stained negative for L-FABP. When we examined the correlation between the downregulation pattern of L-FABP and tumor size, most cases of smaller HCC (≤ 2 cm in diameter) exhibited focal downregulation, while most cases of larger HCC (> 2 cm in diameter) exhibited diffuse downregulation. The correlation was statistically significant (P = 0.036). When the HCC was smaller, the L-FABP-negative area often corresponded to a "nodule-in-nodule" appearance. Among the small HCC cases, tumor differentiation was significantly lower, and the frequency of intratumoral inflammation was significantly lower in L-FABP-negative cases than in L-FABP-positive cases (P = 0.032 and P = 0.009, respectively). The frequency of positivity for β-catenin and GS staining was significantly higher in L-FABP-negative cases of small HCC than in L-FABP-positive cases of small HCC (P = 0.009 and P = 0.000, respectively). Among six HCC cell lines examined, four showed higher expression of L-FABP, and the remaining two cell lines showed lower or no expression of L-FABP. Two of the 16 L-FABP-negative HCC cases possessed a mutation in exon 4 of HNF1A., Conclusion: In smaller HCC, L-FABP downregulation probably occurs because of phenotypic changes during tumor progression. Moreover, this downregulation correlated with tumor differentiation and intratumoral inflammation.

Purpose: This paper describes the technical details of the new indwelling catheter system, which we refer to as System-i, and provides an overview of our experience with this system at our institution., Materials and Methods: The system is implanted via the left brachial artery. The feeding artery of the tumor is catheterized at each treatment, and the system can be used for multiple treatments via more than one feeding artery. Between January 2004 and January 2013, System-i was used to administer 398 treatments in 30 patients with hepatocellular carcinoma (HCC). The technical aspects and outcomes of treatment procedures were evaluated., Results: Implantation was successful in all cases. System-i was used for a median number of 11 treatments per patient over a median period of 5.7 months, and 71.6 % of all treatments were administered on an outpatient basis., Conclusion: System-i provides an effective and safe method for selective catheterization of feeding arteries for administration of transcatheter arterial chemoembolization or infusion in patients with HCC. Treatment regimens can be individualized without limiting the number of treatments or treatment locations, and patients can be treated on an outpatient basis.