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Background and Aim: The outcomes of immune checkpoint blockade for colorectal cancer (CRC) treatment are unsatisfactory. Furthermore, the efficacy of immune checkpoint blockade for liver metastasis of various cancer is poor. Here, we investigated the relationship between stromal programmed death-ligand 1 (PD-L1) expression and the prognosis of patients with colorectal cancer liver metastasis (CRLM)., Methods: The present study enrolled 84 CRLM patients who underwent surgery (R0) for CRC. Immunohistochemistry was performed to analyze stromal PD-L1 expression in CRLM., Results: Stromal PD-L1 was expressed in 52.3% of CRLM samples, which was associated with fewer not optimally resectable metastases (p = 0.04). Stromal PD-L1 also tended to associate with a lower tumor grade (p = 0.08). Stromal PD-L1-positive patients had longer overall survival (p = 0.003). Multivariate analysis identified stromal PD-L1 expression (p = 0.008) and poorer differentiation (p < 0.001) as independent prognostic indicators. Furthermore, stromal PD-L1 expression was correlated to a high number of tumor-infiltrating lymphocytes (TILs). Stromal PD-L1- and low TIL groups had shorter OS than stromal PD-L1 + and high TIL groups (46.6% vs. 81.8%, p = 0.05) Stromal PD-L1-positive patients had longer disease-free survival (DFS) (p = 0.03) and time to surgical failure (p = 0.001). Interestingly, stromal PD-L1 expression was positively related to the desmoplastic subtype (p = 0.0002) and inversely related to the replacement subtype of the histological growth pattern (p = 0.008)., Conclusions: Stromal PD-L1 expression may be a significant prognostic marker for CRLM., (© 2024. The Author(s).)

Background/aim: Indocyanine green (ICG) fluorescence is useful in laparoscopic hepatectomy (LH) for tumor identification and staining, as well as determination of resection margins. At our Institution, patient-specific, three-dimensional simulations and rehearsal of surgical strategies are carried out preoperatively. We describe cases in which ICG administered preoperatively became stagnated and fluoresced in an area similar to the preoperatively established resection area and the pathological findings in these cases., Patients and Methods: Four patients who underwent LH at our hospital between 2020 and 2023 (due to hepatocellular carcinoma in two and colorectal liver metastasis in two) were enrolled in the present study. The ICG-fluorescing liver segments were resected laparoscopically and their pathological characteristics were examined using a fluorescence microscope., Results: In four cases, the areas of ICG fluorescence seen intraoperatively were due to stasis of preoperatively administered ICG, which fortuitously was equivalent to the planned resection area in the preoperative patient-specific simulation. The fluorescent areas were resected; there were no cases of bile leakage or recurrence. Fluorescence microscopy revealed areas with diffuse ICG fluorescence in normal hepatocytes on the tumor's peripheral side., Conclusion: It was suggested that resection of the liver area that was fluorescent due to stagnation of preoperatively administered ICG was rational and justified both anatomically and oncologically. This resection may also contribute to the prevention of bile leakage and recurrence., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2',4'-BNA-based VASH2-ASO. When systemically administered, naked 2',4'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2',4'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2',4'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.

Reports on pleomorphic type of undifferentiated sarcoma (PUS) originating from the gastrointestinal tract, especially the stomach, are extremely rare. We herein report a case of pleomorphic type undifferentiated gastric sarcoma. The patient was a 67-year-old woman. The chief complaint was upper abdominal pain. Upper gastrointestinal endoscopy, ultrasonography, and contrast-enhanced computed tomography showed two submucosal tumors at the greater curvature of the fundus and the lesser curvature of the gastric angle. Endoscopic ultrasound-guided fine-needle aspiration revealed a c-kit-negative spindle cell tumor at the greater curvature of the fundus. Total gastrectomy, splenectomy, and partial resection of the diaphragm and liver were performed. One lesion had invaded the lateral segment of the liver, left diaphragm and spleen. The postoperative course was uneventful. Histopathological and immunohistochemical examinations of the resected specimen revealed PUS. Peritoneal dissemination was detected at 8 months after surgery. However, no effective therapeutic agents were adopted for chemotherapy. The patient had poor performance status due to disease progression and underwent best supportive care. The patient died 10 months after surgery. This case highlights the imaging, histological diagnosis, and treatment strategy for PUS originating from the stomach. Surgeons should be aware of PUS as a differential diagnosis in cases with submucosal tumor of the stomach., (© 2022. Japanese Society of Gastroenterology.)

Background: A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear., Objective: This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC., Patients and Methods: This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed., Results: After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007)., Conclusions: ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN., (© 2022. The Author(s).)

Background: Triple-phase CT and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI have been used to differentiate hepatocellular carcinomas (HCCs) in dogs., Methods: This retrospective case series aimed to compare the CT findings with MRI findings of 20 canine hepatocellular lesions, including eight poorly/moderately-differentiated HCCs, eight well-differentiated HCCs and four hyperplasias. CT data were analysed, and the following parameters were noted: vessel enhancement, enhancement pattern in the equilibrium phase, maximal transverse diameter, the lowest enhancement, and the attenuation values of each hepatocellular lesion in the precontrast and triple-phase series, including the arterial phase, portal phase and equilibrium phase. MRI data were analysed, and the following parameters were noted: signal intensities of each hepatocellular lesion on T2-weighted images and T1-weighted images, and signal intensity ratio of the hepatocellular lesions in the hepatobiliary phase., Results: In 62.5% of poorly/moderately-differentiated HCC and 75% of well-differentiated HCC, presumptive necrosis was detected on CT and MRI. In the hepatobiliary phase on MRI, the median signal intensity ratio of poorly/moderately-differentiated HCC (0.54 [range: 0.3-0.71]) was significantly lower than that of well-differentiated HCC (0.75 [range: 0.6-0.96]) and hyperplasia (0.79 [range: 071-0.98]; p = 0.02 and p = 0.02, respectively)., Conclusion: Gd-EOB-DTPA-enhanced MRI may be a superior modality for differentiating hepatocellular origin lesions., (© 2021 British Veterinary Association.)

Background: Few clinical studies concerning the efficacy of microwave ablation for intermediate stage hepatocellular carcinoma have been published. Our purpose was to examine perioperative and long-term outcomes after operative microwave ablation for intermediate stage hepatocellular carcinoma., Methods: This retrospective study included 246 patients who had undergone operative microwave ablation for intermediate stage hepatocellular carcinoma in our institute between January 2001 and December 2017. We analyzed overall and recurrence-free survival and used the Cox proportional hazard model to evaluate potential prognostic factors., Results: The overall median follow-up time was 51 months. The 1-, 3-, 5-, and 10-year overall survival rates were 98%, 74%, 51%, and 28%, respectively, whereas the 1-, 3-, 5-, and 10-year recurrence-free survival rates were 80%, 32%, 18%, and 10%, respectively. The major complication rate (Clavien-Dindo classification IIIa or above) after operative microwave ablation was 7%, with no procedure-related mortality. Multivariate analysis identified beyond up-to-7 criteria (the sum of the largest tumor's diameter in cm and the total number of tumors), Child-Pugh grade B, and serum alpha-fetoprotein concentration ≥ 100 ng/mL as independent risk factors for overall survival after operative microwave ablation. The overall survival of patients within up-to-7 and Child-Pugh grade A was better than that of the remaining patients, 5-year overall survivals being 67% and 37%, respectively (P < 0.001)., Conclusions: Operative microwave ablation is safe and effective in patients with intermediate stage hepatocellular carcinoma. In particular, patients within up-to-7 and Child-Pugh grade A can be expected to have better long-term outcomes after operative microwave ablation., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Cancer recurrence is an important predictor of survival outcomes in patients with colorectal cancer-associated liver metastasis (CRLM), who undergo radical hepatectomy. Therefore, identification of patients with the greatest risk of recurrence is critical for developing a precision oncology strategy that might include frequent surveillance (in low-risk patients) or a more aggressive treatment approach (in high-risk patients). We performed genome-wide expression profiling, to identify and develop a transcriptomic signature for predicting recurrence in patients with CRLM., Methods: We analysed a total of 383 patients with CRLM, including 63 patients from a publicly available data set (the NCBI's Gene Expression Omnibus with accession number GSE81423). and 320 patients from whom surgical specimens were collected for independent training (n = 169) and validation (n = 151) of identified biomarkers. Using Cox's proportional hazard regression analysis, we evaluated the clinical significance of the identified gene signature by comparing its performance with several key clinical factors., Results: We identified a six-gene panel that robustly categorised patients with recurrence in the discovery (area under the curve (AUC) = 0.90). We showed that the panel was a significant predictor of recurrence in the clinical training (AUC = 0.83) and validation cohorts (AUC = 0.81). By combining our panel with key clinical factors, we established a risk-stratification model that emerged as an independent predictor of recurrence (AUC = 0.85; univariate: hazard ratio (HR) = 4.34, 95% confidence interval (CI) = 2.71-6.93, P < 0.001; multivariate: HR = 3.40, 95% CI = 1.76-6.56, P < 0.001). The stratification model revealed recurrence prediction in 89% of high-risk group and non-recurrence in 62% of low-risk group., Conclusions: We established a novel transcriptomic signature that robustly predicts recurrence, which has significant implications for the management of patients with CRLM., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background/aim: Radiofrequency ablation (RFA) is used to treat primary and metastatic tumors in the liver. However, local recurrence after RFA is frequent and subsequent salvage hepatectomy is often ineffective due to difficulty in visualization of tumor margins., Patients and Methods: In the present retrospective clinical trial, seven patients from the Department of General and Gastro-enterological Surgery, Showa University School of Medicine underwent salvage hepatectomy for recurrent hepatocellular carcinoma (HCC) (n=2), colorectal liver metastasis (n=4) and lung-carcinoid liver metastasis (n=1), after RFA, between 2011 and 2020. Tumors were labeled with indocyanine green (ICG) and resected under fluorescence guidance. Resected specimens were evaluated under fluorescence microscopy as well as by standard histopathological techniques., Results: Pathological findings revealed negative tumor margins in all patients after fluorescence-guided surgery. Six of seven resected tumors had a fluorescent rim, including both HCC and liver metastasis. Fluorescence microscopy demonstrated that viable cancer tumor cells were located only on the inside of the fluorescent rim, and no malignant cells were detected within the fluorescent rim surrounding the tumor. Fluorescence microscopy showed that the tumor margin was secured if the fluorescence signal was completely resected., Conclusion: The present results demonstrate that ICG labeling of liver tumors recurring after RFA enabled complete resection under fluorescence guidance. The present study is the first clinical study to demonstrate that tumor types that generally cannot be completely resected with bright light are fully resectable under fluorescence guidance., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: There are few published data regarding long-term outcome survival after microwave ablation (MWA) for hepatocellular carcinoma (HCC) within 3 cm and 3 nodules. The aim of this study was to examine long-term outcomes after operative MWA for HCC within 3 cm and 3 nodules., Methods: This cohort of this retrospective study comprised 559 patients who underwent operative MWA for HCC within 3 cm and 3 nodules in our institute between 1996 and 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis., Results: Median follow-up time was 69 months for the entire cohort. OS rates were 1-year: 98%, 3-year: 87%, 5-year: 73%, and 10-year:39%; RFS rates were 1-year: 91%, 3-year: 60%, 5-year: 42%, and 10-year: 21%. Multivariate analysis revealed that hepatitis C virus (HCV)-positive status, ALBI grade 2 or 3, maximum tumor diameter ≥ 20 mm, and multiple nodules were independent risk factors for both OS and RFS. A prognostic staging model using one point for each risk factor provided a well-categorized predictive model. The 5-year OS rates were 93%, 81%, and 57% for scores of 0, 1 or 2, and 3 or 4, respectively (P < 0.001). The 5-year RFS rates were 70%, 48%, and 28% for scores of 0, 1 or 2, and 3 or 4, respectively (P < 0.001)., Conclusions: Our results revealed good long-term outcomes after operative MWA for HCC within 3 cm and 3 nodules., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: The prognostic nutritional index (PNI) is used to assess immune and nutritional status, and is a prognostic factor for several malignant tumors. However, little evidence exists regarding the predictive impact of prognostic nutritional index (PNI) after local ablation therapy for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the value of PNI to predict recurrence and survival after operative microwave ablation in patients with early-stage HCC., Methods: This retrospective study included 341 patients who underwent operative microwave ablation for HCC in Barcelona Clinic Liver Cancer (BCLC) stage 0-A at our institute between 2007 and 2015. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis in multivariate Cox regression analyses., Results: The OS rates at 1, 3, 5, and 10 years after microwave ablation were 100%, 92.7%, 85.1%, and 57.5% in patients with high-PNI levels, and 96.5%, 78.2%, 59.7%, and 20.7% in patients with low-PNI levels, respectively (P < 0.001). The RFS rates at 1, 3, 5, and 10 years after microwave ablation were 96.3%, 75.2%, 55.4%, and 30.4% in patients with high-PNI levels, and 94.4%, 48.8%, 36.4%, and 13.1% in patients with low-PNI levels, respectively (P < 0.001). In multivariate analyses, preoperative PNI level was an independent prognostic factor for both OS and RFS., Conclusion: Our results revealed the preoperative PNI level was a simple and novel predictive marker of survival and recurrence after microwave ablation in patients with early-stage HCC., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Background: Ultrasonography (US) is widely used for pre-operative detection of liver tumors. However, US does not have high resolution and very small tumors, tumors located near the liver surface, or those in cirrhotic livers are often not detected., Case Report: A 47-year-old woman with a previous surgery for sigmoid colon cancer (T3N1bM0 Stage3b) showed a liver tumor on the surface of segment 2 by contrast-enhanced computed tomography (CT) and gadoliniumethoxybenzyldiethlenetriaminepen-taacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI). However, preoperative US could not identify a tumor lesion at the same site. The most likely preoperative diagnosis was metastasis from her sigmoid colon cancer and laparoscopic liver resection was performed. Intraoperative ultrasonography (IOUS) did not identify the tumor, but it was visualized with indocyanine green (ICG) fluorescence at the surface of segment 2. Laparoscopic liver resection was performed under fluorescence guidance. Pathological examination showed a pseudotumor with negative margins., Conclusion: ICG fluorescence imaging can allow visualization of liver tumors that are undetectable on US., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Recently, virtual navigation system has been applied to hepatic surgery, enabling better visualization of intrahepatic vascular branches and location of tumor. Intraoperative ultrasonography (IOUS) is the most common form of image guidance during liver surgery. However, during laparoscopic hepatectomies (LH), IOUS has several limitations and its reliability has been poorly evaluated. The objective of this work is to evaluate VRCT (virtual real-time CT-guided volume navigation) during LH. This system aims to provide accurate anatomical orientation for surgeons enhancing the safety of LH., Methods: Twenty-seven hepatic neoplasms were resected laparoscopically at our institution under reference guidance of VRCT. During operation, electromagnetic tracking of the surgical instrument was used for navigating the direction of accurate liver transection., Results: Twenty-six (96.3%) of the 27 lesions (mean diameter 11 mm) were successfully performed under VRCT guidance. Average registration time was < 2 min. Average setup time was approximately 7 min per procedure. VRCT allows the surgeon to navigate liver transection with acceptable accuracy. The mean error was 12 mm. All surgical margins were negative and the mean histologic resection margin was 9 mm., Conclusions: VRCT-guided LH is feasible and provides valuable real-time anatomical feedback during hepatic resections. Advancement of such systems to improve accuracy might greatly compensate for the limitation of laparoscopic IOUS., (© 2020. The Society for Surgery of the Alimentary Tract.)

Background: It remains to be clarified whether combined hepatectomy and microwave ablation for multifocal hepatocellular carcinoma (HCC) is feasible. This aim of this study was to examine the perioperative and oncological outcomes after combined hepatectomy and microwave ablation for multifocal HCC., Methods: This retrospective study included 81 patients who underwent combined hepatectomy and microwave ablation for multifocal HCC in our institute between June 1998 and December 2017. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis., Results: Median follow-up time was 45.6 months for the entire cohort. OS rates were 1-year: 96%, 3-year: 72%, and 5-year: 54%; RFS rates were 1-year: 77%, 3-year: 37%, and 5-year: 22%. The major complication rate (Clavien-Dindo classification IIIa or above) after surgery was 10%, with one patient of in-hospital mortality. Multivariate analysis revealed that des-γ-carboxy prothrombin level >200 mAU/mL and >5 tumors were independent risk factors for OS, and des-γ-carboxy prothrombin level >200 mAU/mL, > 5 tumors, and maximum tumor size >5 cm were independent risk factors for RFS., Conclusions: Our results indicate that combined hepatectomy and microwave ablation is safe and feasible for selected patients with multifocal HCC., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier Taiwan LLC.)

Background/aim: To evaluate the complication rates and risk factors associated with transumbilical wounds and investigate the usefulness of an incision for organ removal in laparoscopic hepatectomy (Lap-H)., Patients and Methods: We enrolled 42 patients who underwent Lap-H excluding a small partial resection in our hospital between 2013 and 2018. The occurrences of superficial surgical site infection (SSI) and transumbilical port-site incisional hernia were recorded., Results: SSI was not observed, and hernia occurred in 3 patients (7.14%). Univariate analysis revealed that body mass index (BMI) (p=0.004) was significantly associated with the risk of hernia formation., Conclusion: High BMI is a risk factor for hernia formation in patients undergoing Lap-H with transumbilical incision; hence, wound closure should be performed carefully. The construction of the transumbilical wound for organ removal was feasible with rationality, with no need to create a new wound., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear. The aim of this study was to investigate HIF-1α expression and its association with prognosis in patients with CRLM with a focus on hepatic stellate cells (HSCs)., Methods: Colon cancer cells were cultured in HSC-conditioned medium (CM), and HIF-1α expression and cell migration were analyzed. Seventy-five patients with CRLM who underwent an initial curative hepatectomy were enrolled. We examined HIF-1α expressions and patient prognosis between primary CRCs and the matched liver metastatic specimens., Results: Activated HSCs induced HIF-1α mRNA and protein expression in colon cancer cells (p < 0.01) and promoted cell migration (p < 0.01). The positive rates of HIF-1α expression in primary CRCs and liver metastases were 68.0 and 72.0%, respectively. There were no differences in overall (OS) and disease-free survival (DFS) of HIF-1α expression in primary CRC. However, HIF-1α expression in liver metastasis correlated to poor prognosis in both OS and DFS. Furthermore, patients with HIF-1α positive expression in liver metastasis had poor prognosis., Conclusion: HIF-1α expression in liver metastasis determines poor prognosis of CRLM patients. HSCs might play a key role in aggressive phenotypes of tumor cells.

The feasibility and safety of microwave ablation in elderly hepatocellular carcinoma (HCC) patients remains unknown. The aim of this study was to evaluate the feasibility and safety of surgical microwave ablation for HCC in patients older than 80 years of age. This retrospective study enrolled consecutive 114 patients older than 80 years of age who underwent surgical microwave ablation for HCC between July 1994 and December 2017. We analyzed perioperative outcomes and long-term outcomes to clarify the prognostic factors. The 1-, 3-, 5-year overall survival and recurrence-free survival rates were 97.3%, 76.0%, 49.2% and 84.2%, 44.7%, and 32.5%, respectively. The overall major morbidity rates (Clavien-Dindo grade IIIA or above) were 2.6%. There were no cases of mortality. Multivariate analysis showed that hepatitis C virus antibody (HCV-Ab) positivity and the presence of multiple tumors were independent prognostic factors for long-term outcomes. The overall survival rate of patients with HCV-Ab negative and single tumor was better than that of other patients (p = 0.026). Surgical microwave ablation was feasible and safe for elderly patients with HCC. Elderly patients with HCV-Ab negative and single tumor would be expected to have better long-term outcomes after surgical microwave ablation.

Objective: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE., Design: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing., Results: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities., Conclusion: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials., Trial Registration Number: NCT01217034., Competing Interests: Competing interests: KM: Honoraria from Bayer, Eisai, MSD, Ajinomoto. Consulting or advisory role for Kowa, MSD, BMS, Bayer, Chugai, Taiho. Research funding from Chugai, Otuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie. IM: Honoraria from Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Taiho Pharmaceutical, Eli Lilly Japan, Daiichi-Sankyo, Yakult, Otsuka Pharmaceutical, Nobelpharma, EA Pharma, Teijin Pharma. Consulting or advisory role for Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD, Bristol Myers Sqiibb, Eli Lilly Japan, Sumitomo Dainippon, Daiichi-Sankyo, Teijin Pharma, Takara Bio. Research funding from Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Chugai, Bristol Myers Sqiibb, Merck Serono, Kowa, Nano Carrier, ASLAN, Daiichi-Sankyo., Sumitomo Dainippon, Novartis Pharma, Baxalta, Boehringer Ingelheim, Takara Bio. Board membership: ASLAN, Chugai. IN: Honoraria from Bayer, Gilead, Abbvie, Otuka. IN: Research funding from Abbvie GK. HK: Honoraria from MSD, Abbvie, Bristrol-Myers Squibb, Dainippon Sumitomo and Otsuka, Research funding from Gilead, Bristrol-Myers Squibb, MSD. IA: Honoraria from AbbVie GK, Bristol Myers Squibb, Gilead, Eisai. Research funding from AbbVie GK, Otsuka, MSD, Chugai, Eisai, Astellas, Takeda. KN: Research funding from Abbvie GK.Nakao K: Honoraria from Gilead. YO: Research funding from AstraZeneca, Asteras, Ajinomoto, AsahiKasei-Kurare Medical, Bayer Yakuhin, Bristol Myers Sqiibb, Chugai, Daiichi-Sankyo, Eisai, Kyowa Hakko Kirin, Kowa, Nihon Kayaku, MSD, Otsuka, Ono, Taiho, Tanabe-Mitsubishi, Takeda, Torii, Tsumura, Zeria. YK: Honoraria from Chugai, Eli Lilly, Taiho, Nippon Shinyaku. OT: Honoraria from Novartis, Taiho, Eli Lilly, Dainippon Sumitomo, Bayer, Yakult, FUJIFILM, AstraZeneca, Ono Pharmaceutical, EA Pharma, Nippon Chemiphar, Celgene, Chugai, Bristol Myers, Eisai, Pfizer, Teijin, Daiichi Sankyo, MSD, Shire, AbbVie, Takeda. Consulting or advisory role for Eli Lilly, Dainippon Sumitomo, Taiho, Zeria Pharmaceutical, Daiichi Sankyo, Bristol Myers. Research Funding from Eli Lilly, Eisai, Novartis, Yakult Honsha, Taiho, Kowa, Kyowa Hakko Kirin, Merck Serono, Ono Pharmaceutical, Bayer, Pfizer Japan, AstraZeneca, Dainippon Sumitomo, Chugai, Bristol Myers, Zeria Pharmaceutical. KN: Honoraria from Eisai. AY: Royalties from Sumitomo Bakelite. Research funding from Canon Medical Systems, Taiho Pharmaceutical, Eisai. Honoraria from Merit Medical Systems., Fuji Pharma, Terumo International Systems, Nippon Kayaku, Canon Medical Systems, Bristol Meyer Squibb, Sumitomo Bakelite, Bayer Pharmaceuticals, Boston Scientific Japan, Taiho Pharmaceutical, Guerbet Japan, Guerbet Asia Pacific., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aim: This study investigated the use of near-infrared fluorescent imaging for securing safe margins during liver resection., Patients and Methods: This study included 125 patients who underwent liver tumor resection in 2014-2018. Indocyanine green testing was performed 2-14 days before surgery. Histopathological specimens of hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) were evaluated using fluorescent microscopy., Results: Fluorescence microscopy identified signals in 26/53 (49.0%) and 36/72 (50%) cases of HCC and CRLM, respectively. HCC demonstrated total, partial, rim, and combined fluorescence patterns; CRLM uniformly demonstrated rim fluorescence. Although rim fluorescence was seen in both HCC and CRLM, no malignancy was confirmed pathologically in the peritumoral area demonstrating fluorescence. The median widths of fluorescence from the tumor edge in HCC and CRLM were 1227.5 μm and 1608 μm, respectively, with no significant difference., Conclusion: Near-infrared fluorescent imaging can reliably detect safe surgical margins intraoperatively during liver resection., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study., Methods: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL., Results: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%)., Conclusions: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.

Background: Little evidence exists regarding postrecurrence survival after microwave ablation for recurrent hepatocellular carcinoma (HCC) after curative hepatectomy; we aimed to evaluate the feasibility of surgical microwave ablation., Methods: In this retrospective review, we enrolled patients who underwent curative hepatectomy for primary HCC in our department and had intrahepatic recurrence. We analyzed overall survival according to treatment modality to clarify the prognostic factors for survival., Results: Of 257 patients, 119 had intrahepatic recurrence. Three patients underwent repeat hepatectomy; 75 patients underwent surgical microwave ablation, and 34 patients underwent transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy. The median postrecurrence survival time and 5-year postrecurrence survival after surgical microwave ablation were 37.4 months and 55.4%, respectively. The major complication rate (Clavien-Dindo classification IIIa or above) after surgical microwave ablation was 5.3% with no mortality. Multivariate analysis showed that microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for overall survival after surgical microwave ablation for recurrent HCC., Conclusion: Our results suggested that surgical microwave ablation is safe and feasible for recurrent intrahepatic HCC after curative hepatectomy. Close follow-up and further curative treatment could be important for improving postrecurrence survival., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported., Methods: The intent-to-treat population enrolled in Japan was analyzed., Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm., Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC., Trial Registration Id: ClinicalTrials.gov. No. NCT01761266.

A nomogram is a statistical tool that can provide the specific outcomes of individual patients. In this study, we used a nomogram developed by Beppu et al to evaluate the prognoses of 38 patients who underwent hepaticresec tion at our hospital. This nomogram predicts disease-free survival(DFS)after hepatic resection for colorectal liver metastasis based on 6 clinical and oncological factors. Using this nomogram, we divided the 38 patients into 3 groups: Group N, actual DFS was almost similar to the estimated median DFS(EMDFS)provided by the nomogram; Group A, DFS was longer than EMDFS; and Group B, DFS was shorter than EMDFS. Then, we compared and analyzed clinical and oncological factors between Groups A and B. Group B patients tended to have single metastasis and non-normal levels of CA19-9. Besides, Group B patients had DFS shorter than approximately 2 years. These results suggest that if CA19-9 levels are not normalized after hepaticresec tion for single metastasis, we should consider careful observation and adjuvant chemotherapy for potential micrometastasis.

Background/aim: Carbohydrate antigen 19-9 (CA19-9) is a poor prognostic marker in intrahepatic cholangiocarcinoma (IHCC). Previous studies have shown a link between hypoxia and CA19-9 in cancer, and we have previously demonstrated a correlation between HDAC1 and HIF-1α in IHCC. Here, we evaluated the expression and correlation of CA19-9 with HIF-1 and HDAC in IHCC., Patients and Methods: This study included 62 patients with IHCC who underwent primary hepatectomy at our department. Clinicopathological characteristics were examined. Immunohistochemical expression of HIF-1 and HDAC1 in specimens was quantitatively evaluated., Results: Patients with high preoperative serum CA19-9 levels showed clinicopathological characteristics associated with tumour progression. High CA19-9 levels were associated with worse overall and recurrence-free survival. Univariate and multivariate analysis detected high CA19-9 levels as an independent poor prognostic factor for IHCC. Serum CA19-9 was significantly correlated with both HIF-1α and HDAC1 expression., Conclusion: High serum CA19-9 level is a poor prognostic factor for overall survival in IHCC and correlates with HIF-1α and HDAC1 expression., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Little evidence exists regarding long-term survival after microwave ablation for hepatocellular carcinoma (HCC). The aim of this study is to determine actual 10-year survival and clarify the clinicopathological features of patients surviving ≥ 10 years after surgical microwave ablation., Patients and Methods: This retrospective study identified 459 patients who underwent surgical microwave ablation for HCC with curative intent between 2001 and 2008. We compared 100 patients who survived ≥ 10 years with 321 patients who died within 10 years., Results: Median overall survival and recurrence-free survival rates were 5.5 and 2.4 years, respectively. The actual 10-year overall survival rate was 23.8%, and the actual 10-year recurrence-free survival rate was 8.1%. Multivariate analysis showed that age > 70 years [odds ratio 1.87, P = 0.029], hepatitis C virus positivity (OR 2.30, P = 0.004), Child-Pugh class B (OR 3.28, P = 0.003), and platelet count < 10 × 10 4 /µL (OR 1.93, P = 0.033) were independent risk factors for actual 10-year survival. During 10-year follow-up, 66% of the ≥ 10-year survivors developed recurrence, and 91% of these patients underwent further curative treatment, including hepatic resection or local ablation, for HCC recurrence., Conclusion: Ten-year survival after surgical microwave ablation for HCC can be expected in approximately 24% of patients, even though nearly 2/3 of our 10-year survival patients experienced recurrence. Close postoperative follow-up and further curative treatment for recurrence are important for improving long-term survival.

Background: Little evidence exists regarding the perioperative and oncologic benefits of microwave ablation for hepatocellular carcinoma. The aim of this study was to compare the efficacy of hepatic resection and operative microwave ablation (microwave coagulo-necrotic therapy) for single hepatocellular carcinoma ≤5 cm., Methods: Between 1994 and 2015, a total of 551 patients with a single hepatocellular carcinoma ≤5 cm were treated in our institution (hepatic resection: n = 128; microwave coagulo-necrotic therapy: n = 423). We compared overall survival and recurrence-free survival between hepatic resection and microwave coagulo-necrotic therapy. Propensity score matching analysis identified 94 matched pairs of patients to compare outcomes., Results: After propensity score matching, baseline variables, including liver function and tumor size, were well-balanced between the 2 groups. The 5- and 10-year overall survival rates were 76% and 47% for hepatic resection and 77% and 48% for microwave coagulo-necrotic therapy, respectively (P = .865). The 5- and 10-year recurrence-free survival rates were 55% and 41% for hepatic resection and 47% and 32% for microwave coagulo-necrotic therapy, respectively (P = .377). In the subgroup analysis, the hepatic resection group had better recurrence-free survival than the microwave coagulo-necrotic therapy group in patients with tumor size >3 cm, with 5-year recurrence-free survival rates of 56.5% and 32.4% in the hepatic resection and microwave coagulo-necrotic therapy group, respectively (P = .029)., Conclusion: Our propensity score matching study confirmed no statistically significant differences in both overall survival and recurrence-free survival between hepatic resection and microwave coagulo-necrotic therapy for single hepatocellular carcinoma ≤5 cm; however, hepatic resection is recommended for hepatocellular carcinoma with tumor size >3 cm when patients have good liver function., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Microvascular invasion (MVI) is recognized as a risk factor for early recurrence of hepatocellular carcinoma (HCC) within the Milan criteria after curative treatment., Methods: One hundred eleven consecutive patients with HCC within the Milan criteria who underwent hepatic resection were retrospectively reviewed. Independent preoperative predictors of MVI were identified, and a scoring system was developed using significant predictors., Results: MVI was identified in 51 of 111 patients (46%). Multivariate analysis identified the following independent predictors of MVI: alpha-fetoprotein (AFP) of > 95 ng/mL (odds ratio [OR], 9.87; 95% confidence interval [95% CI], 2.24-56.8; P = 0.002), des-γ-carboxy prothrombin (DCP) of > 55 mAU/mL (OR, 5.50; 95% CI, 2.09-15.4; P < 0.001), tumor size of > 2.8 cm (OR, 6.10; 95% CI, 2.07-20.0; P < 0.001), and non-smooth tumor margin in the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) (OR, 5.34; 95% CI, 1.84-16.9; P = 0.002). A clinical scoring system was developed using these four variables. Within a total possible score of 0 to 4, the prevalence of MVI with a score of 0, 1, 2, 3, and 4 was 4.5%, 24.0%, 45.5%, 91.7%, and 100%, respectively (P < 0.001). The area under the curve of the scoring system was 0.865 based on the receiver operating characteristic curve analysis of the prediction score., Conclusions: Our clinical scoring system, consisting of AFP, DCP, tumor size, and tumor margin in Gd-EOB-DTPA-enhanced MRI, can be valuable for predicting MVI in HCC within the Milan criteria before curative treatment.

Background: Indications and efficacy of surgical treatment for liver metastases from gastric cancer (LMGCs) remain controversial. This retrospective study was designed to clarify the benefits of surgical treatment and identify prognostic factors., Methods: Between December 1997 and December 2015, 34 consecutive patients underwent hepatic resection and surgical microwave ablation for synchronous or metachronous LMGCs at our institution. We analyzed their cumulative overall survival (OS) and recurrence-free survival (RFS) rates and clinical parameters to identify predictors of prognosis., Results: Of the 34 patients, 14 underwent hepatic resection, 13 underwent surgical microwave ablation, and 7 underwent hepatic resection combined with surgical microwave ablation. Their OS rates were 1-year: 84.4%, 3-year: 38.6%, and 5-year: 34.7%; and their RFS rates were 1-year: 38.5%, 3-year: 28.0%, and 5-year: 28.0%. OS did not significantly vary among the surgical procedures. In multivariable analysis, positive of both CEA and CA19-9 were independent predictors of poor survival (hazard ratio [HR] 4.51; P = 0.049) and early recurrence (HR 5.70; P = 0.047)., Conclusions: Both hepatic resection and surgical microwave ablation for LMGCs are effective and can improve survival in selected patients., (Copyright © 2017. Published by Elsevier Taiwan LLC.)

Hepatobiliary and pancreatic surgery is recognized as technically demanding due to the complicated local anatomy and diverse anatomical variation that require precise techniques. Therefore, preoperative simulation to understand the detailed local anatomy and intraoperative navigation methods for surgical guidance are needed. Intraoperative navigation for anatomical hepatectomy originated with dye injection into the dominant portal pedicle under intraoperative ultrasound guidance to identify hepatic segments, which was reported by Makuuchi et al in 1985. In recent years, with advancing medical technology, newer medical devices that promote the safety and reliability of various surgical procedures have been developed. In this article, we will discuss the current state and future prospects of intraoperative navigation in hepatobiliary and pancreatic surgery.

Background/aims: Some patients experience very late recurrence of HCC more than 5 years after initial therapy. We aimed to clarify the predictive factors for very late recurrence of HCC in such cases., Methods: Among 807 HCC patients undergoing surgical resection or ablative therapy with curative intent, the patients who survived for 5 years without any recurrence were reviewed. The prognosis and possible predictive factors for late recurrence were analyzed retrospectively., Results: A total of 184 patients survived for more than 5 years without recurrence. Among them, 61 patients experienced recurrence, at a median of 6 years after initial therapy. In univariate analysis, the pre-treatment aspartate aminotransferase, alanine aminotransferase, Child-Pugh class, and ALBI grade were not related to recurrence, but those at 5 years after treatment were significantly related to recurrence. By multivariate analysis, an ALBI grade of 2-3 at 5 years was an independent risk factor for recurrence (P < 0.0001). Moreover, variation of the ALBI grade over the 5 years after the initial treatment was significantly related to recurrence-free survival., Conclusions: The ALBI grade is an effective index of the variation in liver function after curative therapy and may be a useful prognostic factor for the long-term recurrence-free survival of HCC patients.

Objective Sorafenib is a standard therapy for advanced hepatocellular carcinoma (HCC), whereas radiotherapy is effective for local control of extrahepatic spread (EHS) or macrovascular invasion (MVI). This study investigated the safety and efficacy of this combined therapy to treat advanced HCC. Methods This retrospective study reviewed 62 patients with advanced-stage HCC with EHS or MVI who received sorafenib therapy, excluding the patients with only lung metastases. Results Of the 62 patients, 15 were treated using the combined therapy of sorafenib and radiotherapy (group RS), and 47 were treated with sorafenib monotherapy (group S). In group RS, patients were treated using three-dimensional conformal radiotherapy with a total irradiation dose of 30-60 Gy (median, 50 Gy). Irradiation was targeted at the bone, lymph nodes, adrenal gland, and MVI in 6, 5, 1, and 4 patients, respectively. The overall incidence of adverse events was 93.3% in group RS and 91.5% in group S (p=N.S.). Incidences of thrombocytopenia, leukopenia, and skin reaction were significantly higher in group RS (73.3%, 40.0%, and 66.7%, respectively) than in group S (36.2%, 10.6%, and 27.7%, respectively, p=0.02, 0.02, and <0.01, respectively). The incidence of severe adverse events, however, was comparable in the 2 groups: 20% in group RS and 19.2% in group S. The median progression-free survival (PFS) of EHS or MVI, PFS of whole lesions, and overall survival were longer in group RS (13.5, 10.6, and 31.2 months, respectively) than in group S (3.3, 3.5, and 12.1 months, respectively) (p<0.01 for all). Conclusion Sorafenib in combination with radiotherapy is a feasible and tolerable treatment option for advanced HCC.

Background and Aim: The effects of achieving sustained virological response (SVR) on recurrence and survival after curative treatment in patients with hepatitis virus C (HCV)-related hepatocellular carcinoma (HCC) is unclear. This study examined the influence of SVR achievement by interferon therapy before HCC occurrence on recurrence and survival., Methods: This retrospective study included 518 patients who underwent surgical microwave ablation for initial HCV-related HCC between January 2001 and December 2015. Thirty-four patients had achieved SVR (SVR group) and 484 patients had not (control group). Clinical characteristics and long-term outcomes were compared between the two groups., Results: Overall survival rates at 5 and 10 years after curative ablation were 95.8 and 80.4% in the SVR group, and 50.7 and 23.4% in the control, respectively (p < 0.0001). Recurrence-free survival rates at 5 and 10 years were 68.7 and 26.4% in the SVR group, and 24.5 and 7.8% in the control group, respectively (p < 0.0001). Multivariate analyses revealed that achieving SVR as an independent prognostic factor for both overall and recurrence-free survival. In the SVR group, the 5-year recurrence-free survival rates for patients with an interval of 5 years or fewer (n = 24) vs. more than 5 years (n = 10) between achieving SVR and curative ablation were 58.7 and 88.9%, respectively (p = 0.03)., Conclusions: Achieving SVR before HCC occurrence allowed a favorable clinical outcome after curative ablation in HCV-related HCC patients. Patients with HCC that occurred more than 5 years after achieving SVR had longer recurrence-free survival.

Background: Surgical indication for hepatic resection is controversial in gastric cancer liver metastasis (GLM). The aim of this study is to clarify the effect of hepatic resection for GLM., Methodology: Ten patients who underwent hepatic resection for GLM between 2001 and 2013 were enrolled in this study. Six patients underwent synchronous hepatic resection and gastrectomy, and the remaining four patients underwent metachronous hepatic resection. Six patients had solitary liver metastasis, and 4 patients had multiple liver metastasis. The median follow-up period was 12.4 months (the range being 0.5 months to 50 months)., Result: The actual 1- year and 3-year overall survival rates for the patients who underwent hepatic resection are 88.9% and 17.8%, respectively. The median survival time was 21.5 months. And the 1-year recurrence free survival time was 20.0%. The median recurrence free survival rate was 4.7 months. Regarding post-operative recurrence, synchronous hepatic resection tended to be a recurrence factor (p=0.08)., Conclusion: Hepatic resection for GLM has an acceptable outcome. Metachronous hepatic resection tends to have a better outcome than synchronous hepatic resection for the treatment of GLM. J. Med. Invest. 65:27-31, February, 2018.

The prognostic implications of the expression patterns of three tumor markers, alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γ-carboxy prothrombin (DCP), have been evaluated in patients with hepatocellular carcinoma (HCC). From January 1994 to December 2014, 1182 consecutive patients underwent hepatic resection and surgical microwave ablation for HCC at our institution. This study analyzed 475 patients within the Milan criteria and Child-Pugh class A. Cumulative overall survival (OS) and disease-free survival (DFS) rates were analyzed relative to the number of positive tumor markers. OS and DFS at 5 years postoperatively were 85.3 and 44.2% in triple-negative patients, 79.4 and 48.0% in single-positive patients, 56.2 and 32.9% in double-positive patients, and 61.7 and 35.7% in triple-positive patients with statistical significance. OS in triple-negative or single-positive patients was 85.3%, and that in all double- or triple-positive patients was 58.0% (P < 0.0001); DFS at 5 years postoperatively in these two groups was 45.9 and 34.0%, respectively (P < 0.0013). Both double- and triple-positive tumor markers are associated with early recurrence and poor survival in HCC patients within the Milan criteria and Child-Pugh class A.

Purpose: To establish the efficacy and safety of simultaneous microwave coagulo-necrotic therapy (MCN) and laparoscopic splenectomy (Lap-Sp) for the treatment of hepatocellular carcinoma (HCC) with cirrhotic hypersplenism., Methods: Seventeen patients with HCC and cirrhotic hypersplenism underwent simultaneous MCN and Lap-Sp at our institution between January, 2010 and July, 2015. Eight and nine patients had Child-Pugh class A and B liver cirrhosis, respectively. The median number of tumors ablated was 1 (range 1-7) and the median largest dimension of the resected lesions was 1.7 cm (range 1.1-3.6 cm). We analyzed postoperative complications and long-term outcomes retrospectively., Results: The median operating time was 283 min (range 197-418 min) and the median blood loss was 125 mL (range 5-1312 mL). Postoperative morbidity and mortality rates were 29 and 0 %, respectively. The median follow-up time after surgery was 22.5 months (range 4.3-70.9 months). The 1-, 3-, and 5-year disease-free survival rates were 68.8, 10.7, and 10.7 %, respectively, and the 1-, 3-, and 5-year overall survival rates were 88.2, 75.6, and 63.0 %, respectively., Conclusions: The findings of this study suggest that simultaneous MCN and Lap-Sp is safe and effective for treating HCC with cirrhotic hypersplenism.

Background: REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline α-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed., Methods: An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93)., Results: The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263]., Conclusions: In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients. ClinicalTrials.gov identifier NCT01140347.

We developed a reliable prediction model for colorectal cancer(CRC)patients after surgically curative resection. Using clinicopathological factors, prediction models were constructed for liver metastasis-free survival(LMFS). Between January 2004 and December 2010, 528 CRC patients were investigated. On univariate analysis of clinicopathological factors, the following factors associated with LMFS: pathological tumor invasion, lymph node metastasis, lymphatic invasion, venous invasion, and preoperative serum CEA. Using these factors, a prediction model was constructed using a Cox regression model with a concordance index of 0.824 for LMFS. These individualized prediction models could help clinicians in the treatment of postoperative CRC patients.

Background: Because the recurrence rate of hepatocellular carcinoma (HCC) is high, even after curative treatments such as hepatic resection and microwave ablation, chemopreventive agents that can effectively suppress HCC recurrence are required. Cyclooxygenase-2 (Cox-2) was recently found to be overexpressed in HCC. Therefore, Cox-2 inhibitors may offer a chemopreventive therapy for HCC. This randomised controlled trial (RCT) investigated the potential for meloxicam, a clinically used Cox-2 inhibitor, to prevent HCC recurrence after initial curative treatment., Methods: A total of 232 consecutive patients underwent hepatic resection and/or microwave ablation as initial therapy for HCC at our institute between July 2008 and April 2011. Eight patients were excluded because of poor renal function, history of non-steroidal anti-inflammatory drug-related ulceration, or multiple cancers. The remaining 224 patients were randomised to a control group (n = 113) or a meloxicam group (n = 111). To patients in the meloxicam group, meloxicam was administered at 15 mg daily (5 mg three times a day) as long as possible. The overall survival (OS) and disease-free survival (DFS) rates were determined., Results: The 1-, 3-, and 5-year OS rates of the meloxicam group were 95.4, 82.4, and 70.1 %, respectively. Those of the control group were 98.2, 85.1, and 71.5 %, respectively (p = 0.9549). The corresponding DFS rates of the meloxicam group were 89.2, 53.9, and 44.0 % and those of control group were 86.5, 57.0, and 43.4 %, respectively (p = 0.6722). In the OS and DFS of subsets including patients with hepatitis B or C virus infection, we could not find significant differences between the meloxicam and control groups. However, in the subgroup of analysis of patients without viral hepatitis (NBNC-HCC), significant differences were observed in the DFS between the meloxicam group (1-year DFS, 92.3 %; 3-year DFS, 75.8 %; 5-year DFS, 70.4 %) and control group (1-year DFS, 83.3 %; 3-year DFS, 48.1 %; 5-year DFS, not obtained) (p = 0.0211)., Conclusion: Administration of the Cox-2 inhibitor meloxicam may have a possibility to suppress HCC recurrence after initial curative treatments in patients with NBNC-HCC., Competing Interests: Yuko Takami, Susumu Eguchi, Masaki Tateishi, Tomoki Ryu, Kazuhiro Mikagi, Yoshiyuki Wada, and Hideki Saitsu declare that they have no conflicts of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Purpose: Laparoscopic and thoracoscopic/laparoscopic hepatectomy is a safe procedure that has potential advantages over open surgery. However, deeply positioned liver tumors require expert laparoscopic and thoracoscopic/laparoscopic hepatectomy techniques. Using simulated preoperative three-dimensional virtual endoscopy (P3DVE) guidance, we demonstrate herein that a thoracoscopic approach (TA), thoracoscopic-laparoscopic approach (TLA), and laparoscopic approach (LA) are all feasible and safe routes for performing pure laparoscopic and thoracoscopic/laparoscopic resection of liver tumors located in the 4a, 7, and 8 liver subdiaphragmatic areas., Methods: Thirty-eight patients underwent laparoscopic and thoracoscopic/laparoscopic partial liver resection (TA 13 cases, TLA two cases, and LA 23 cases) of the subdiaphragmatic area at Showa University Hospital. All surgical approaches were preoperatively determined based on preoperative 3D virtual endoscopic simulation (P3DVES) visualization and findings using the image processing software SYNAPSE VINCENT(®)., Results: Laparoscopic and thoracoscopic/laparoscopic liver resection was successfully performed for all cases under P3DVE instruction. The mean operative times using TA, TLA, and LA approaches were 193, 185, and 190 min, respectively. Mean blood loss during TA, TLA, and LA was 179, 138, and 73 g, respectively. No patients required conversion to open surgery, and there were no deaths, although there were three cases of Clavien-Dindo grade I in TA along with three cases of grade I and one case of grade II in LA., Conclusions: TA, TLA, and LA routes performed under P3DVE instruction are feasible and safe to perform for pure laparoscopic and thoracoscopic/laparoscopic liver resection in selected patients with lesions located in the hepatic subdiaphragmatic area.

Background: Whether radiologically detected progressive disease (PD) is an accurate metric for discontinuing sorafenib treatment in patients with hepatocellular carcinoma (HCC) is unclear. We investigated the efficacy of sorafenib treatment after radiologic confirmation of PD in patients with advanced HCC., Methods: We retrospectively analyzed HCC patients treated with sorafenib at Kyushu Medical Center. Six of the 92 patients with radiologically confirmed PD were excluded because they were classified as Child-Pugh C or had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3; 86 patients were ultimately enrolled., Results: Among the 86 patients, 47 continued sorafenib treatment after radiologic confirmation of PD (the continuous group), whereas 39 did not (the discontinuous group). The median survival time (MST) in the continuous group after confirmation was 12.9 months compared with 4.5 months in the discontinuous group (p <0.01). The time to progression in the continuous group after confirmation was 2.6 months compared with 1.4 months in the discontinuous group (p <0.01); it was 4.2 months and 2.1 months in patients who had received sorafenib ≥4 months and <4 months, respectively, before confirmation (p = 0.03). In these subgroups, the post-PD MST was 16.7 months and 9.6 months, respectively (p < 0.01). Independent predictors of overall survival after radiologic detection of PD were (hazard ratio, confidence interval): ECOG PS <2 (0.290, 0.107-0.880), Barcelona Clinical Liver Cancer stage B (0.146, 0.047-0.457), serum α-fetoprotein level ≥400 ng/mL (2.801, 1.355-5.691), and post-PD sorafenib administration (0.279, 0.150-0.510)., Conclusion: Continuing sorafenib treatment after radiologic confirmation of PD increased survival in patients with advanced HCC. Therefore, radiologically detected PD is not a metric for discontinuation of sorafenib treatment in such patients.

An 84-year-old Japanese man was admitted with hepatocellular carcinoma (HCC). He underwent transcatheter arterial chemoembolization and percutaneous radiofrequency ablation (RFA). Three weeks later, he developed sudden-onset right pleural effusion mixed with bile. Drip infusion cholangiography-computed tomography revealed leakage of the contrast agent, which passed from the HCC to the pleural cavity through a perforation in the diaphragm. The patient's condition improved after thoracic and endoscopic nasobiliary drainage. The occurrence of pleural effusion mixed with bile is a rare complication of RFA. This case provides important information about the morbidity, prevention, and treatment of this complication.

Purpose: To evaluate the effectiveness and safety of radiofrequency ablation(RFA)for liver metastases from colorectal cancer after chemotherapy., Patients: From January 2006 to June 2012, 27 tumors in 17 patients with liver metastases from colorectal cancer were treated using RFA after systemic chemotherapy., Results: The median tumor diameter after chemotherapy was 12(range: 3-35)mm, and the mean number of tumors was 1.6(range: 1-4).The median time without local recurrence was 21.3(range: 2.2-61.9)months, and the median overall survival time was 38.0(range: 5.9-66.3)months. One patient had a complication(liver abscess).Of the 27 tumors, 9 were larger than 20 mm in diameter, and 4 of these 9 tumors showed local recurrence after RFA. In tumors smaller than 20 mm in diameter, only 1 showed local recurrence. The local recurrence rate was significantly higher for tumors larger than 20 mm than for tumors smaller than 20 mm(44.4% vs 5.6%,p=0.030)., Conclusion: RFA was an effective and safe method for treating liver metastases from colorectal cancer, especially for tumors smaller than 20 mm and in cases of less than 3 tumors after systemic chemotherapy.

A 73-year-old man was found to have an intestinal tumor, approximately 10 cm in diameter, on computed tomography (CT). In September 2001, he underwent partial resection of the jejunum with partial colectomy and left nephrectomy. Pathological examination showed 2 mitoses per 50 high-power fields, and immunohistochemical analysis showed positive staining for c-kit. Based on the above findings, the tumor was diagnosed as a high-risk malignant gastrointestinal stromal tumor( GIST) of the small intestine; the patient was followed up and no adjuvant therapy was administered. In October 2005, an abdominal CT scan revealed 2 tumors with diameters of 21 and 28 mm in the S8 and S7 region of the liver, respectively, and the patient was diagnosed with liver metastases from GIST. After obtaining adequate informed consent, chemotherapy with imatinib (400 mg/day) was initiated. Although the patient experienced partial response (PR) 2 months after the treatment, grade 3 neutropenia and general fatigue were observed. Therefore, the treatment schedule was changed to 1 week of therapy, followed by 1 week of rest. At present, at 91 months after the diagnosis of liver metastases, the patient shows no signs of recurrence. Therefore, it is important that adjuvant chemotherapy should be considered for the treatment of patients with high-risk malignant GIST.

Background: Hepatic resection (HRx) or radiofrequency ablation may be carried out as the first-line treatment of hepatocellular carcinoma (HCC). However, we have used intraoperative microwave ablation, named microwave coagulo-necrotic therapy (MCN) as part of our strategy for the treatment of HCCs for more than 15 years. Here we describe the treatment outcomes achieved at our institution as a high-volume center for microwave ablation., Methods: Between July 1994 and December 2010, 719 consecutive patients received MCN as their initial therapy for HCC (mean tumor size 26.9 mm, mean number of lesions 2.51) at our institute. The therapeutic survival effect, local tumor progression, and overall recurrence were prospectively evaluated and statistically analyzed., Results: The 1-, 3-, 5-, 7-, and 10-year overall survival rates of all 719 patients were 97.7, 79.8, 62.1, 45.3, and 34.1 %, respectively. Thirty percent of the patients had Child-Pugh class B cirrhosis and the 5-year survival rate of these patients was 46.6 %. The 5-year survival of patients with ≥4 lesions (n = 168) was 49.6 % and that of patients meeting the Milan criteria (n = 470) was 70.9 %. The 1-, 3-, 5-, 7-, and 10-year overall survival rates for 390 patients treated with MCN who had ≤3 lesions with diameter ≤3 cm were 97.9, 85.1, 70.0, 57.1, and 43.0 %. No significant differences were found between the overall survival rates after MCN and the overall survival rates in 34 patients treated with HRx during the same period at our institute and under the same (P = 0.3592), nor were there any differences in disease-free survival (P = 0.3496) and local recurrence rates between the MCN and HRx groups (P = 0.5926)., Conclusion: MCN is effective for the locoregional control of HCC, with results comparable to those of HRx. MCN should be considered as one of the first-choice treatments for HCC, even for patients with poor liver function or multiple lesions.