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Various locoregional treatments for localized hepatocellular carcinoma (HCC) have been developed. This retrospective study investigated the safety and feasibility of combining on-demand selective locoregional treatment for residual lesions after tumor shrinkage (complete response [CR] oriented) or for solitary or few drug-resistant lesions (progressive disease (PD) salvage) with first-line atezolizumab plus bevacizumab (atezo/bev) for unresectable HCC. Twenty-nine patients with unresectable HCC were included. Fourteen locoregional treatments were performed (CR oriented, 7; PD salvage, 7) in ten patients in the combination-therapy group. All patients in the combination-therapy group successfully achieved a CR or PD salvage status after the planned locoregional treatment. The objective response rate of the combination-therapy group (80.0%) was higher than that of the atezo/bev alone group (21.1%; p = 0.005). Progression-free survival (PFS) and overall survival (OS) were longer in the combination group (medians for PFS and OS not reached) than in the atezo/bev alone group (median PFS, 7.4 months; median OS, 19.8 months) (PFS, p = 0.004; OS, p < 0.001). The albumin-bilirubin score did not change, and no severe complications occurred after locoregional treatment. When performed in a minimally invasive manner, on-demand selective locoregional treatment combined with first-line atezo/bev could be safe and feasible for unresectable HCC.

Background: Although hepatocellular carcinoma (HCC) is frequently associated with thrombosis, it is also associated with liver cirrhosis (LC) which causes hemostatic abnormalities. Therefore, hemostatic abnormalities in patients with HCC were examined using a clot waveform analysis (CWA). Methods: Hemostatic abnormalities in 88 samples from HCC patients, 48 samples from LC patients and 153 samples from patients with chronic liver diseases (CH) were examined using a CWA-activated partial thromboplastin time (APTT) and small amount of tissue factor induced FIX activation (sTF/FIXa) assay. Results: There were no significant differences in the peak time on CWA-APTT among HCC, LC, and CH, and the peak heights of CWA-APTT were significantly higher in HCC and CH than in HVs and LC. The peak heights of the CWA-sTF/FIXa were significantly higher in HCC than in LC. The peak times of the CWA-APTT were significantly longer in stages B, C, and D than in stage A or cases of response. In the receiver operating characteristic (ROC) curve, the fibrin formation height (FFH) of the CWA-APTT and CWA-sTF/FIXa showed the highest diagnostic ability for HCC and LC, respectively. Thrombosis was observed in 13 HCC patients, and arterial thrombosis and portal vein thrombosis were frequently associated with HCC without LC and HCC with LC, respectively. In ROC, the peak time×peak height of the first derivative on the CWA-sTF/FIXa showed the highest diagnostic ability for thrombosis. Conclusion: The CWA-APTT and CWA-sTF/FIXa can increase the evaluability of HCC including the association with LC and thrombotic complications.

Tumor endothelial cells (TECs) promote tumor angiogenesis and regulate cytotoxic T cells in the tumor microenvironment. However, the roles of TECs for tumor-infiltrating T-cell in hepatocellular carcinoma (HCC) is still unknown. Here, we aimed to investigate how TECs influenced tumor growth and immune responses of HCC focusing on CD8 + T-cell infiltration and exhaustion. First, TECs were isolated from subcutaneous HCC tumors with murine HCC cell lines (BNL-T) with magnetic selection of CD31 + cells, and normal endothelial cells (NECs) were isolated from normal liver. Second, immunocompetent mice were injected with BNL-T alone, BNL-T + NECs, or BNL-T + TECs for tumor formation, and the functions and exhaustion of tumor-infiltrating CD8 + T cells were evaluated. The mice injected with BNL-T + TEC showed rapid tumorigenesis and a decrease in the number of infiltrating CD8 + T cells. In addition, the percentage of CD8 + T-cell exhaustion was significantly higher in tumors from the administration of BNL-T + TEC. Third, the next-generation sequencing on TECs was performed to identify mRNAs that might be a novel treatment target. The molecule of glycoprotein nonmetastatic melanoma protein B (GPNMB) was identified and the functions of GPNMB was analyzed by silencing of GPNMB expression using small interfering RNAs. The silencing of GPNMB expression in TECs induced the suppression of tumor growth and T-cell exhaustion. In conclusion, TECs induced tumor-infiltrating T-cell exhaustion via GPNMB expression and GPNMB might be a novel therapeutic target in HCC., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Gastric cancer with portal vein tumor thrombus (PVTT) is poor prognosis, and the treatment remains challenging. Regarding surgery, there are only reports of highly invasive laparotomy. We report some techniques of the completely robotic total gastrectomy with thrombectomy and portal vein reconstruction for the patient with gastric cancer and PVTT for the first time., Case Presentation: A 79-year-old man was diagnosed with a 5-cm gastric cancer on the side of the lesser curvature from the middle of the gastric body to the cardia. Computed tomography revealed a massive PVTT extending from the left gastric vein to the portal trunk (28 x 16 mm). There were no other distant metastases. After 3 cycles of the chemotherapy, the PVTT shrank to 19 x 12 mm. After obtaining informed consent from the patient, robotic total gastrectomy with regional lymphadenectomy and thrombectomy were performed. We used the da Vinci Xi Surgical System. A 3-cm incision was made at the umbilicus, and a wound retractor was placed. Five additional ports were placed. The right side suprapancreatic lymph nodes were performed at the time of the thrombectomy. It was important to identify the precise extent of the PVTT with intraoperative ultrasonography before the thrombectomy. After PVTT identification, the portal trunk was clamped above and below the tumor thrombus with vascular clips. The membrane on the anterior wall of the portal trunk around the PVTT was carefully incised with da Vinci Scissors. The tumor thrombus was completely enucleated without separation. The incised part of the portal trunk was reconstructed with continuous 5-0 synthetic monofilament nonabsorbable polypropylene sutures. After removing the vascular clamps, we made sure there was no leakage from the portal vein and no tumor thrombus remnants with intraoperative ultrasonography. Robotic total gastrectomy with lymphadenectomy and Roux-en-Y reconstruction were performed. The patient was discharged without complications. The patient has remained alive for 30 months after surgery., Conclusions: Robotic total gastrectomy with thrombectomy and portal vein reconstruction is a safe, minimally invasive, and precise surgery. It may contribute to improved prognosis of gastric cancer with PVTT when combined with chemotherapy., (© 2022. The Author(s).)

Purpose: To investigate the impact of different setup methods, vertebral body matching (VM), diaphragm matching (DM), and marker matching (MM), on the dose distribution in proton therapy (PT) for hepatocellular carcinoma (HCC)., Materials and Methods: Thirty-eight HCC lesions were studied retrospectively to assess changes in the dose distribution on two computed tomography (CT) scans. One was for treatment planning (1st-CT), and the other was for dose confirmation acquired during the course of PT (2nd-CT). The dose coverage of the clinical target volume (CTV-D 98 ) and normal liver volume that received 30 Gy relative biological effectiveness (RBE) (liver-V 30 ) were evaluated under each condition. Initial treatment planning on the 1st-CT was defined as reference, and three dose distributions recalculated using VM, DM, and MM on the 2nd-CT, were compared to it, respectively. In addition, the relationship between the CTV-D 98 of each method and the distance between the center of mass (COM) of the CTV and the right diaphragm top was evaluated., Results: For CTV-D 98 , significant differences were observed between the reference and VM and DM, respectively (P = 0.013, P = 0.015). There were also significant differences between MM and VM and DM, respectively (P = 0.018, P = 0.036). Regarding liver-V 30 , there was no significant difference in any of the methods, and there were no discernable difference due to the different setup methods. In DM, only two out of 34 cases with a distance from right diaphragm top to COM of CTV of 90 mm or less that CTV-D 98 difference was 5% or more and CTV-D 98 was worse than VM were confirmed., Conclusion: Although MM is obviously the most effective method, it is suggested that DM may be particularly effective in cases where the distance from right diaphragm top to COM of CTV of 90 mm or less., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Portal vein tumor thrombosis (PVTT) is an extremely locally advanced form of hepatocellular carcinoma. The natural median survival time of patients with hepatocellular carcinoma with PVTT is 2.7 to 4.0 months. A 63-year-old woman visited our clinic complaining of abdominal distention and appetite loss, which she had had for 3 weeks prior to admission. A contrast-enhanced computed tomography scan showed double hepatocellular carcinomas with Type III PVTT and massive ascites caused by arterio-portal shunts within the PVTT. The ascites could not be treated by concentrated ascites reinfusion therapy or diuretics. Transarterial embolization using microspheres followed by radiation therapy against PVTT and five courses of transarterial chemoembolization using microspheres and cisplatin led to the maintaining of complete remission of both ascites and tumors for over 12 months after treatment. Fluoroglucose accumulation of PVTT showed 11.2 as a maximum standard uptake value on positron emission tomography before treatment. No fluoroglucose accumulation within PVTT was observed for over 12 months following treatment. Transarterial chemoembolization using microspheres followed by radiation therapy against Type III PVTT may result in drastic anti-cancer effects and improvement of both serum albumin and intractable ascites after treatment of arterio-portal shunts within the PVTT causing portal hypertension.

Objective: The purpose of this cross-sectional study was to evaluate the efficacy and safety of proton beam therapy for liver metastatic recurrence in gastric cancer patients., Methods: Consecutive patients who underwent proton beam therapy from 2010 to 2015 were isolated from our institutional database. Patients with extrahepatic metastatic lesions were excluded. Seven patients were enrolled. The median diameter of target lesions was 31 mm (13-68 mm). The most frequent dosage was 72.6 Gy equivalent in 22 fractions. The effectiveness was assessed based on the local control, overall survival and progression-free survival rates. The local control, overall survival and progression-free survival rates were calculated using the Kaplan-Meier method. Adverse events were described according to the patients' medical records., Results: The median follow-up period was 41.7 months (20.7-66.3 months). The 3-year local control, overall survival and progression-free survival rates were 85.7, 68.6 and 43%, respectively. All patients completed proton beam therapy without interruption. No grade ≥3 adverse events were observed., Conclusions: Proton beam therapy might be a treatment option for patients with liver metastasis of gastric cancer., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hepatocellular carcinoma (HCC) with tumour thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is a rare advanced disease state with a poor prognosis. The aim of this study was to examine survival after surgical resection., Methods: Patients with HCC and TT of either the IVC or RA, who underwent liver resection between February 1997 and July 2017, were included. Their short- and long-term outcomes and surgical details were analysed retrospectively., Results: Thirty-seven patients were included; 16 patients had TT in the IVC below the diaphragm, eight had TT in the IVC above the diaphragm, and 13 had TT entering the RA. Twelve patients had advanced portal vein TT (portal vein invasion (Vp) greater than Vp3 and Vp4), ten had bilobar disease, and 12 had extrahepatic disease. There were no in-hospital deaths, although two patients died within 90 days. Median survival did not differ between patients who had resection with curative intent (18·7 months) and those with residual tumour in the lung only (20·7 months), but survival was poor for patients with residual tumour in the liver (8·3 months)., Conclusion: Liver resection with thrombectomy for advanced HCC with TT in the IVC or RA is safe and feasible, leading to moderate survival., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

The prognosis of hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. We conducted a prospective study to evaluate the efficacy and safety of tri-modality therapy, including preoperative stereotactic body radiotherapy (SBRT) and surgery, followed by hepatic arterial infusion chemotherapy (HAIC) in HCC patients with PVTT. In this report, we investigated the pathology of the irradiated PVTT specimen in resected cases and SBRT-related acute toxicity. A total of 8 HCC patients with PVTT received preoperative SBRT targeting the PVTT at a dose of 48 Gy in 4 fractions at our institute from 2012 to 2016. Of the eight patients, six underwent surgery, while the remaining two did not because of disease progression. At the pathological examination, all patients' irradiated PVTT specimens showed necrotic tissue, and three of six patients showed complete pathological response. Two patients showed 30% necrosis with high degeneration and one patient, with 30% necrosis without degeneration, was the only recurrent case found during the follow-up period (median: 22.5, range: 5.9-49.6 months). No SBRT-related acute toxicity worse than grade 2 was observed from SBRT to surgery. In conclusion, the preoperative SBRT for HCC was pathologically effective and the acute toxicities were tolerable.

The optimal type of surgery (e.g., anatomic or non-anatomic resection) or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is still under debate despite numerous comparative studies based on overall survival. This debate continues not only because these endpoints are influenced by non-surgical factors, such as liver function, but because the definition of non-anatomic resection for HCC has remained unclear. The optimal surgery could be logically determined based on the mechanism of local intrahepatic metastasis, that is, the drainage of tumour blood flow (TBF), because HCC spreads locally through tumour blood flowing to the peri-tumourous liver parenchyma. Since TBF is clearly demonstrated by CT scan under hepatic arteriography, the surgical margin can be determined individually based on the drainage of TBF without deteriorating local curability. Controversy regarding RFA and surgery does not result from the curability of treatment itself but from the lack of scientific evidence on safety margins. Based on proper concepts and self-evident truths, an algorithm of loco-regional treatment for HCC is proposed., (© 2020 S. Karger AG, Basel.)

Objectives: Surgical indications for pulmonary metastasis from hepatopancreatobiliary (HPB) carcinomas remain controversial., Methods: Between 2000 and 2015, 25 patients with pulmonary metastasis from HPB carcinomas and 145 with that from colorectal carcinomas underwent metastasectomies in our institution. The primary diseases were hepatocellular carcinoma (HCC) in 8 patients, pancreatic carcinoma (PC) in 12 and biliary tract carcinoma (BTC) in 5. All patients had a sufficient pulmonary reserve, controlled primary disease and no evidence of other metastatic disease. Perioperative factors were investigated retrospectively to analyze the overall survival (OS), pulmonary metastasis-free survival (PmFS) after pulmonary metastasectomy and disease-free interval between surgery for primary disease and the development of pulmonary metastasis (DFI)., Results: Complete resection was performed in all patients with lobectomy in 3, segmentectomy in 5 and partial resection in 17. The respective 1-, 2- and 5-year OS rates after metastasectomy were 82.6%, 69.8% and 69.8% in HPB patients and 98.3%, 92.4% and 78.0% in colorectal carcinoma patients (p = 0.351). The 2-year PmFS of HPB patients was 80.0%, versus 60.6% for colorectal carcinoma patients (p = 0.265). The DFI was 41.4 months for HPB patients and 34.5 months for colorectal carcinoma patients (p = 0.273)., Conclusions: Metastasectomy for pulmonary metastasis from HPB may be performed in carefully selected patients.

Purpose: In this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells., Methods: Exosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC ® , and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC., Results: Exosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence., Conclusion: These results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC.

Background/aim: Inferior vena cava (IVC) resection and reconstruction with concomitant liver resection sometimes represent the only chance for patients with liver tumors involving the IVC to get cured. However, surgical outcomes of liver resection with IVC resection and reconstruction using an artificial vascular graft have not been well investigated., Methods: Out of a total of 1,179 cases, only 12 involving liver resection between 1998 and 2016 at our institution included IVC resection and reconstruction using an artificial vascular graft. An expanded polytetrafluoroethylene graft was used for the IVC reconstruction in all 12 cases. We investigated the surgical outcomes of these combined surgeries., Results: The median operative time was 650 min and the median blood loss was 2,600 mL. Postoperative complications (≥ grade III in the Clavien-Dindo classification) developed in 2 patients - 1 case of bleeding and one of bile leakage. There were no cases of operative mortality. No complications associated with the vascular graft were observed throughout the postoperative follow-up period, and the grafts remained patent in all cases., Conclusions: These results indicate favorable surgical outcomes of liver resection combined with IVC resection and reconstruction., (© 2018 S. Karger AG, Basel.)

Purpose: The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients., Methods: We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score., Results: Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients., Conclusions: In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

Background & Aims: To improve prognosis in patients with hepatocellular carcinoma (HCC), the molecular mechanisms of tumor thrombus formation and metastasis must be clarified. The epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles in tumor invasion and metastasis. This study aimed to reveal the clinical significance of the expression of the functional CSC marker, CD13, and investigate the correlation between CD13 expression and two EMT markers, E-cadherin and vimentin., Methods: We acquired clinical samples from 86 patients with HCC that underwent radical liver resections. We performed immunohistochemistry to evaluate CD13, E-cadherin and vimentin expression. We investigated the relationships among protein expression levels, clinicopathological factors and prognosis., Results: Based on CD13 expression, patients were categorized into CD13high (n = 30, 34.9%) and CD13low (n = 56, 65.1%) groups. The mean tumor size was significantly larger in the CD13high group than in the CD13low group (P = 0.049). Compared with the CD13low group, the CD13high group showed significantly earlier recurrences and shorter survival times. In the multivariate analysis, CD13high was an independent prognostic factor for overall survival (hazard ratio, 1.98; P = 0.044). The disease-free survival time was shorter in the vimentin-positive group than that in the vimentin-negative group (P = 0.014). In an analysis of the relationship between CD13 and EMT, there was no significant correlation between CD13 and EMT markers., Conclusions: Our findings suggested that CD13 enrichment was correlated with early recurrences, and poor prognosis in patients with HCC and that vimentin was associated with early recurrences. CD13 represents a potential therapeutic target for HCC, because CSC regulation and EMT suppression are essential in cancer therapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Repeat liver resection is an effective treatment, with long-term surgical outcomes for recurrent hepatocellular carcinoma and colorectal liver metastasis. However, the efficacy of a minimally invasive surgical approach for recurrent liver cancer is not yet confirmed. The purpose of this study is to examine the efficacy of minimally invasive repeat liver resection (MISRLR) compared with open repeat liver resection (ORLR) for primary and metastatic liver cancer. Here, we retrospectively analyzed the clinicopathological features and short-term surgical outcomes of patients undergoing MISRLR and ORLR., Methods: From 2005 to 2016, 97 patients with liver cancer underwent repeat hepatectomy. Of these patients, 68 patients receiving macroscopically curative resection and only hepatectomy, without other additional operations, were selected. Twenty patients underwent MISRLR and 48 patients underwent ORLR. We compared the clinicopathological and surgical parameters in the MISRLR group with those in the ORLR group., Results: There were no statistically significant differences in patients' gender, age, viral infection status, Child-Pugh classification, tumor size, tumor number, tumor location, or the presence of liver cirrhosis in the two groups. The operative times were similar, but blood loss was significantly lower in MISRLR group (159 vs. 502 ml, P = 0.0035). The length of the postoperative hospital stay was significantly shorter in the MISRLR group (14.2 vs. 19.2 days, P = 0.0275). Postoperative complications were observed only in the ORLR group, with a complication rate of 19%., Conclusions: We demonstrate that MISRLR for primary and metastatic liver cancer reduces blood loss and postoperative complications compared with ORLR. MISRLR might be a feasible and effective procedure for the selected patients.

The prognosis for hepatocellular carcinoma(HCC)with right atrium tumor thrombus(RATT)is dismal and necessary to be treated on as oncologic emergency. We report a case of HCC with RATT which was treated with multidisciplinary therapy including surgery. After repeated transarterial chemoembolization(TACE)and radiofrequency ablation(RFA), a 71-year-old man consulted to our hospital with multiple HCC, lung metastasis, and RATT. Left hemihepatectomy, thrombectomy of RATT, and 3 months of hepatic arterial infusion chemotherapy(HAIC)was performed, and intrahepatic HCCs were controlled. However, during treatment of lung metastasis by sorafenib, the patient died of brain metastasis, 3 years after the first treatment. Although surgery and HAIC may give a chance of further treatment by control of intrahepatic HCCs, stronger regimen for systemic HCC would be necessary.

Carbonic anhydrase 9 (CA9) is a plasma membrane-associated isoenzyme that catalyzes pH regulation under hypoxic conditions. CA9 is transcriptionally regulated by hypoxia-inducible factor 1. Recent studies reported that hypoxia also promoted the epithelial-mesenchymal transition (EMT) in various cancers. In the present study, we evaluated the relationship between CA9 expression and EMT in vitro with two hepatoma cell lines. We also examined the clinical significance of CA9 expression in 117 consecutive patients that underwent hepatectomies for hepatocellular carcinoma (HCC). We evaluated CA9 expression and EMT induction under hypoxia with quantitative RT-PCR, western blot analysis and immunofluorescence staining, in HuH7 and HepG2 cells. We knocked down CA9 expression with small interfering RNA to evaluate the relationship between CA9 and EMT. We found that hypoxia induced CA9 expression in HCC cells and promoted EMT, evidenced by a loss of E-cadherin and an increase in N-cadherin. Twist, a transcriptional regulator of EMT, was also upregulated with hypoxia. The CA9 deficiency attenuated hypoxia-induced changes in E-cadherin and N-cadherin. Immunohistochemical evaluations of patient samples showed that CA9 was expressed in 50.4% of patients (59/117). However, patients with and without CA9 expression were not significantly different in clinicopathological factors. Nevertheless, a multivariate analysis showed that CA9 expression was an independent factor for both recurrence and prognosis among patients that underwent curative surgery for HCC. In conclusion, this study revealed that CA9 expression was a pivotal predictive factor for poor prognosis after radical surgery for HCC. Moreover, the CA9 regulation of the expression of EMT-related molecules represented a mechanism that enhanced malignant potential.

Background: In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT)., Methods: From 16 Japanese LT centers, data were collected on 182 recipients with HCC who underwent living donor liver transplantation (LDLT) between February 2005 and November 2013. PET-positive status was defined as increased uptake of FDG in the tumor compared to the surrounding non-tumor liver tissue. The median follow-up after LDLT was 54.5 months (range 1-125 months)., Results: Postoperative HCC recurrence occurred in 23 patients. Multivariate analysis revealed that exceeding the Milan criteria (MC), alpha-fetoprotein (AFP) level ≥115 ng/ml, and PET-positive status were significant and independent risk factors for recurrence. In the over-MC group, a subgroup of patients with AFP level <115 ng/ml and PET-negative status (n = 22) had a significantly lower 5-year recurrence rate than the other patients (n = 27, 19% vs. 53%, P = 0.019)., Conclusions: These results suggest that preoperative FDG-PET status offers additional information on HCC recurrence risk after LT. Over-MC patients with PET-negative status and lower AFP level may achieve successful outcome comparable to that of within-MC patients., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: While spontaneously ruptured hepatocellular carcinoma (HCC) has a poor prognosis, the true impact of a rupture on survival after hepatic resection is unclear., Methods: Fifty-eight patients with ruptured HCC and 1922 with non-ruptured HCC underwent hepatic resection between 2000 and 2013. To correct the difference in the clinicopathological factors between the two groups, propensity score matching (PSM) was used at a 1:1 ratio, resulting in a comparison of 42 patients/group. We investigated outcomes in all patients with ruptured HCC and compared outcomes between the two matched groups., Results: Of the 58 patients with ruptured HCC, 7 patients (13 %) died postoperatively. Overall survival (OS) rate at 5 years after hepatic resection was 37 %. Emergency hepatic resection was an independent risk factor for in-hospital death and Child-Pugh class B for unfavorable OS in multivariate analysis. Clinicopathological variables were well-balanced between the two groups after PSM. No significant differences were noted in incidence of in-hospital death (ruptured HCC 12 % vs non-ruptured HCC 2 %, p = 0.202) or OS rate (5/10-year; 42 %/38 % vs 67 %/30 %, p = 0.115)., Conclusion: Emergency hepatic resection should be avoided for ruptured HCC in Child-Pugh class B patients. Rupture itself was not a risk for unfavorable surgical outcomes.

Background: Several reports have suggested that hepatic resection provides a survival benefit in patients with hepatocellular carcinoma (HCC) at the intermediate stage of the Barcelona Clinic Liver Cancer classification (BCLC-B). The operative indications for multiple BCLC-B have not been established, however. The aim of this study was to clarify the survival benefit of hepatic resection for multinodular BCLC-B HCC., Methods: We retrospectively analyzed 85 patients with BCLC-B HCC who underwent liver resection. To evaluate clinicopathologic factors and survival, we divided the patients into 3 types based on radiologic findings regarding tumor number and maximum tumor diameter: type 1, up to 3 lesions <5 cm; type 2, up to 3 lesions ≥5 cm or 4 nodules of any size; type 3, >4 nodules., Results: Thirty-four patients were classified as type 1, 32 as type 2, and 19 as type 3. The 1-, 3-, and 5-year survival in type 1 were 97.1%, 87.4%, and 75.2%, respectively. Those in type 2 were 84.0%, 74.0%, and 63.0%, and those in type 3 were 64.9%, 55.7%, and 37.1%, respectively. The overall survival of type 1 patients was significantly better than that of type 3 patients. The prognosis of type 2 patients was worse than that of type 1 patients and better than that of type 3. Multivariate analysis identified radiologic tumor size and tumor number as independent prognostic factors., Conclusion: Our findings suggest that hepatic resection should be considered a radical treatment for multinodular BCLC-B HCC. Our subclassification can be applied to select the initial treatment and when making decisions regarding hepatic resection of BCLC-B HCC with multiple nodules., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Local recurrence is a specific problem after radiofrequency ablation of small hepatocellular carcinoma, and additional treatment is an important issue. We aimed to investigate the outcome of salvage hepatectomy in patients who develop local, recurrent hepatocellular carcinoma after treatment with radiofrequency ablation., Methods: From 2001-2013, we reviewed 58 patients from 6 university hospitals with local, recurrent hepatocellular carcinoma who underwent salvage hepatectomy after their initial radiofrequency ablation treatment. Pathologic characteristics and prognostic factors influencing overall survival were analyzed., Results: Noncurative resection, des-gamma carboxy prothrombin levels >40 mAU/mL, and multiple preceding treatments before salvage hepatectomy were negative prognostic factors for overall survival. The 5-year survivals for the prognostic factors were 0%, 24%, and 30%, respectively, after salvage hepatectomy, and 0%, 54%, and 54% after initial radiofrequency ablation treatment, respectively. As for the pathologic finding of local, recurrent hepatocellular carcinoma after radiofrequency ablation, vascular invasion was observed frequently in patients with increases in des-gamma carboxy prothrombin levels and with multiple preceding treatments before salvage hepatectomy with a frequency of 59% and 53%, respectively (P < .01 and .05)., Conclusion: Noncurative resection, increases in serum des-gamma carboxy prothrombin, and multiple preceding treatments were prognostic factors for subsequent salvage hepatectomy; nevertheless, survival outcomes were still acceptable when a curative salvage hepatectomy was performed. Increases in serum des-gamma carboxy prothrombin and multiple preceding treatments were positive predictors for pathologic vascular invasion. These factors should be taken into consideration when selecting treatment modalities for locally recurrent hepatocellular carcinoma following radiofrequency ablation. Repetition of unsuccessful, loco-regional treatment would appear to decrease the potential survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification., Competing Interests: None of the authors have any potential conflicts of interest to report.

Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in HCC. In the present study, we explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs, fluorouracil (5-FU), cisplatin (CDDP), doxorubicin (DXR) and sorafenib (SOR), and we elucidated the mechanism of these combination therapies. We evaluated changes in the expression of CD13 before and after treatment with anticancer drugs and with or without ubenimex in the human HCC cell lines HuH7 and PLC/PRF/5. The interactions between the anticancer drugs and ubenimex were determined with isobologram analyses. We analyzed cell cycle, apoptosis, and intracellular reactive oxygen species (ROS) levels to explore the mechanisms of the combination therapies. In both cell lines, the expression of CD13 increased after a 72-h exposure to each anticancer drug alone (p<0.05), and the expression of CD13 decreased with ubenimex administration (p<0.05). Isobologram analyses indicated that ubenimex had synergistic effects with 5-FU, CDDP and DXR, and an additive effect with SOR. Cell cycle analyses showed that ubenimex decreased the proportion of cells in G0/G1. Ubenimex enhanced the effects of 5-FU, CDDP and DXR by increasing apoptosis and intracellular ROS levels. In combination therapies, ubenimex synergistically enhanced the antitumor effects of 5-FU, CDDP and DXR on cell cycle regulation and apoptosis induction in HCC cell lines. The effects of ubenimex were due to increased intracellular ROS levels.

Background: Transcatheter arterial chemoembolization (TACE) is a widely used and well-established treatment for hepatocellular carcinoma (HCC). However, TACE loses its therapeutic efficacy when performed repeatedly, a phenomenon termed TACE refractoriness. c-Met is associated with malignant potential and with resistance to anti-tumor therapies in some kinds of cancers., Aims: The aim of this study is to investigate the clinical impact of TACE on c-Met expression with the aim of understanding the mechanism underlying TACE refractoriness., Methods: The effect of TACE on the c-Met expression level was investigated in vitro in HCC cell lines, and it was shown that c-Met expression is upregulated in HCC cell lines cultured under hypoxia and/or exposed to chemotherapeutic agents. The in vitro results were validated using 82 clinical samples of HCC with and without preoperative TACE treatment., Results: c-Met upregulation was observed significantly more frequently in clinical samples of HCC that were treated with preoperative TACE than in samples with no TACE treatment. Increased c-Met expression was significantly associated with poor prognosis. Furthermore, the incidence of c-Met-positive expression was significantly higher in TACE-refractory HCC samples., Conclusions: TACE treatment upregulates c-Met expression in HCC and the upregulated c-Met expression may be responsible for TACE refractoriness.

Background and Objectives: Preoperatively evaluating reserved liver function is critical in preventing posthepatectomy liver failure (PHLF) in patients undergoing liver resection. The commonly used indocyanine green (ICG) clearance test has several drawbacks. Patients would benefit from a more reliable and straightforward means of assessing the risk of PHLF., Methods: This study included 277 patients with hepatocellular carcinoma (HCC) undergoing liver resection. The predictive value of known risk factors for PHLF was compared to that of ICG., Results: PHLF was identified in 25 out of 277 patients (9.0%). Multivariate logistic regression analysis for identifying predictors for the PHLF development revealed platelet count and resected liver volume as significant independent predictors. In a subgroup analysis based on resected liver volume, platelet count was significantly correlated with PHLF in both larger volume (≥100 g) and smaller volume resection groups (<100 g), although ICG R15 level was associated with PHLF only in larger volume group., Conclusions: Platelet count is superior to ICG R15 level in predicting PHLF development in HCC patients. J. Surg. Oncol. 2016;113:565-569. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

A 65-year-old woman underwent sigmoidectomy for colon cancer in January 2002. She had multiple liver metastases and received systemic chemotherapy (UFT-E plus CPT-11) for 6 months. She underwent partial hepatectomy of S7 and S3 and cholecystectomy in July 2003. After 4 years without recurrence, right adrenal and para-aortic lymph nodes metastases were detected and she underwent right adrenalectomy and para-aortic lymphadenectomy in July 2007. In July 2008, local recurrence (1 cm in size) was identified in the cavity of the right adrenal gland. She received chemotherapy (mFOLFOX6 plus bevacizumab) for 5 years. In May 2013, PET-CT showed abnormal accumulation of FDG in S7 of the liver (SUVmax 6.7). The enhanced EOB-MRI showed a mass lesion in S7 (3 cm in size) and 2 nodules (1 cm in size) in S3 and S4. We scheduled for liver surgery with reconstruction of the inferior vena cava (IVC) after systemic chemotherapy (FOLFIRI plus cetuximab). The patient underwent partial hepatectomy of the tumor in S7 combined with resection of the diaphragm and IVC. Reconstruction of the IVC was performed using a ringed Gore-Tex tube graft in February 2014. The patient is still alive without recurrence 18 months after surgery.

We report a case of locally advanced huge hepatocellular carcinoma (HCC) invading the diaphragm and the right lung, which was controlled by sorafenib, thereby allowing curative resection. A 72-year-old man was diagnosed with advanced HCC invading the diaphragm and the right lung. At the time of diagnosis, his tumor was considered unresectable and he underwent transarterial embolization (TAE)/transcatheter arterial chemoembolization (TACE) 3 times. Assessment with enhanced CT after TAE/TACE showed that a viable lesion remained. Subsequently, he was treated with sorafenib for 15 months. Reassessment showed that the main tumor remained stable in size, and he was admitted to our hospital for surgery. Preoperative evaluation by enhanced CT and MRI detected an intrahepatic metastasis in segment 4 of the liver. After TACE was performed for this nodule, extended right hemihepatectomy with right diaphragmatic and right lung partial resection was performed. He had no postoperative complications and was discharged 27 days after surgery. He remains alive without recurrence 10 months after surgery.

The patient was a 65-year-old man. In July 2014, he was diagnosed with rectal cancer in a different hospital and underwent high anterior resection(type 2, T3N0M0, StageⅡ [TMN classification, 7th edition]). During the operation, a small nodule was detected in segment 4 of the liver. Contrast-enhanced abdominal CT revealed a tumor measuring 5 cm in diameter located in segment 4/8 of the liver with a tumor thrombus in the main trunk of the portal vein. In August 2014, the patient was referred to our hospital for further examination and treatment. MR imaging showed a lobulated tumor located in segment 4/8 of the liver. Gadoxeticac id-enhanced hepatobiliary phase MR imaging showed that the tumor was less enhanced than was the adjacent liver parenchyma. 18F-FDG-PET/CT demonstrated abnormal accumulation of 18F-FDG in the main tumor(SUVmax=18.3). There was no obvious abnormal accumulation in the other organs. In September 2014, he underwent extended left hepatectomy and portal vein tumor thrombectomy. The resected specimen showed a well-differentiated adenocarcinoma. Immunohistochemical staining results were CK7/CK20 (-/+) and CDX2 (+), which suggested that the tumor was derived from the gastrointestinal tract rather than the liver. The pathological diagnosis was a liver metastasis from rectal cancer. In the 6 months after the operation, intrahepatic recurrence was detected, and the patient was treated with systemicchemotherapy.

Purpose: The clinical significance of the surgical resection of metastatic lymph nodes (LN) from patients with hepatocellular carcinoma (HCC) remains controversial. The aim of this study was to evaluate the significance of the surgical resection of LN metastasis of HCC., Methods: Among 961 patients who underwent surgical resection for HCC in our hospital, LN metastasis was identified in 38 patients. In these patients, the metastatic LN were removed completely in 22 patients (complete removal group), and incompletely or not removed in 16 patients (control group). The long-term prognosis after LN metastasis was compared between the two groups., Results: The overall survival rate after LN metastasis was significantly better in the complete removal group (1-, 3- and 5-year: 71.2, 58.0 and 49.7%, respectively) than in the control group (45.9, 23.0 and 15.3%, respectively, p = 0.0477). LN metastasis was not the cause of death in any of the patients in the complete removal group, whereas it was a cause in some patients in the control group. No local LN recurrence was identified in the complete removal group., Conclusions: The present results suggest that the complete removal of metastatic LN from HCC is clinically beneficial in selected patients.

Background: Glomus tumors typically occur in the subcutaneous tissue of distal extremities, but rarely in visceral organs. Most glomus tumors are benign, while others have been reported to have malignant potential. Herein, a unique case of a liver glomus tumor with atypical histological features is reported., Case Presentation: A 39-year-old man felt fullness in the epigastrium, and an enhanced computed tomography (CT) scan of the abdomen and pelvis revealed a 21-cm solid and cystic mass in the left liver lobe. The patient underwent a left hepatic lobectomy, and the tumor was pathologically identified as a glomus tumor with atypical histological features in the liver. This case is unique for three reasons. First, cases of glomus tumors in the liver are extremely rare. Second, this is the first report of a hepatic glomus tumor with histologically atypical features. Third, immunohistochemical staining showed focal positivity for synaptophysin. A literature review revealed that glomus tumors in visceral organs positive for synaptophysin show histological atypical features in most cases., Conclusions: This is the first case of a glomus tumor with atypical histological features arising in the liver. This unique case and literature review yielded interesting findings and enabled us to postulate that synaptophysin positivity may be indicative of atypical histological features in glomus tumors arising in visceral organs.

The anti-Hu antibody is one of the most famous onco-neural antibodies related to paraneoplastic neurological syndrome, and is associated with small cell lung carcinoma in most cases. Here, we report a case of poorly differentiated hepatocellular carcinoma accompanied by paraneoplastic peripheral neuropathy positive for the anti-Hu antibody. Image inspection before operation revealed that no tumors were found in organs other than the liver, including lung, and that the liver tumor had no metastatic lesion. The liver tumor showed histological appearance of poorly differentiated carcinoma with cartilaginous metaplasia and partial blastoid cell appearance. Most tumor cells presented trabecular-like structure lined by sinusoidal vessels. Immunohistochemically, the tumor cells were positive for low molecular weight cytokeratin and vimentin, partially positive for cytokeratin 19 and CD56, but negative for synaptophysin, chromogranin A and alpha-fetoprotein. Based on the trabecular-like morphology and the results of immunohistochemical staining, we concluded that the tumor was diagnosed as poorly differentiated hepatocellular carcinoma. Anti-Hu antibody-positive paraneoplastic peripheral neuropathy accompanied with liver tumor is extremely rare as far as is known. The presented case indicates that poorly differentiated carcinoma has the potential to be the responsible lesion of anti-Hu antibody-positive paraneoplastic neurological syndrome and systemic work-up is important for the management of this neurological disorder., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: The benefits of anatomic resection in patients with small (<5 cm), solitary hepatocellular carcinomas remain unclear. Outcomes were therefore evaluated in patients who underwent anatomic resection or nonanatomic resection of small solitary hepatocellular carcinomas., Methods: Factors affecting overall survival and disease-free survival were investigated in 330 patients who underwent curative hepatectomy for solitary (≤5 cm) hepatocellular carcinomas without macroscopic vascular invasion. In addition, a propensity score matching model with 330 patients was constructed to overcome bias, with subgroups analyzed by tumor diameter (<3 cm and 3-5 cm)., Results: ICG-R15 ≥25% was confirmed as being independently associated with poorer overall survival and disease-free survival. One-to-one matching of preoperative characteristics yielded 72 pairs of patients receiving anatomic resection and nonanatomic resection, with long-term outcomes, including overall survival and disease-free survival, being similar in these 2 groups. Subgroup analysis showed that, in patients with tumors <3 cm in diameter, short-term outcomes were better in the nonanatomic resection group than in the anatomic resection group, including significantly reduced operation time (P = .02), blood loss (P = .01), blood transfusion (P < .01), complications (particularly bile leakage and abdominal abscess) (P = .04), and postoperative hospital stay (P < .01)., Conclusion: Anatomic resection was not superior to nonanatomic resection in survival outcomes in patients with solitary small hepatocellular carcinomas without macroscopic vascular invasion. Rather, postoperative short-term outcomes were more favorable with nonanatomic resection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Although studies have shown that Oct4, Sox2, Klf4, and c-Myc (OKSM)-mediated induced pluripotent stem cell (iPSC) technology sensitizes cancer cells to drugs, the potential risk of inserting c-Myc and random insertions of exogenous sequences into the genome persists. Several authors, including us, have presented microRNA (miRNA)-mediated reprogramming as an alternative approach. Herein, we evaluated the efficacy of miRNA-mediated reprogramming on hepatocellular carcinoma (HCC) cells., Methods: Among three miRNAs (miR-200c, miR-302s, and miR-369s) that were previously presented for miRNA-mediated reprogramming, miR-302 was expressed at low levels in HCC cells. After transfecting three times with miR-302, the cells were incubated in ES medium for 3 weeks and then characterized., Results: iPSC-like spheres were obtained after the 3-week incubation. Spheres presented high NANOG and OCT4 expression, low proliferation, high apoptosis, low epithelial-mesenchymal transition marker expression (N-cadherin, TGFBR2), and sensitization to drugs. Several miRNAs were changed (e.g., low oncomiR miR-21, high miR-29b). cMyc was decreased, and methylation was elevated on histone 3 at lysine 4 (H3K4). Differentiated cells expressed markers of each germ layer (GFAP, FABP4, and ALB). AOF2 (also known as LSD1 or KDM1), one of the targets for miR-302, was repressed in iPSC-like-spheres. Silencing of AOF2 resulted in similar features of iPSC-like-spheres, including cMyc down-regulation and H3K4 methylation. In drug-resistant cells, sensitization was achieved through miR-302-mediated reprogramming., Conclusions: miR-302-mediated iPSC technology reprogrammed HCC cells and improved drug sensitivity through AOF2 down-regulation, which caused H3K4 methylation and c-Myc repression.

A 58-year-old man presented with anorexia and weight loss in April 2010. Endoscopic examination revealed a type 3 tumor extending from the gastric cardia to the antrum. Preoperative imaging showed liver metastasis (S8; 2 cm) and direct invasion of the cancer into the pancreas. We administered 4 courses of chemotherapy (DCS) for the unresectable tumor; the impact of the therapy was partial response (PR). We performed total gastrectomy, D2 dissection, splenectomy, distal pancreatectomy, and partial hepatectomy (S8) in April 2011. The patient was treated with 8 courses of adjuvant chemotherapy with S-1. In April 2012, abdominal computed tomography (CT) revealed a solitary recurrent lesion in the liver (S2). After 7 courses of chemotherapy(weekly paclitaxel), abdominal CT and magnetic resonance imaging (MRI) revealed a tumor thrombus in the portal vein extending from P2 to the umbilical portion (UP). We performed left hepatectomy and cholecystectomy due to the absence of new lesions. Histopathological findings revealed that the poorly differentiated adenocarcinoma had metastasized to the liver. Abdominal CT revealed the presence of multiple recurrent metastases in the liver, 4 months after the surgery. The patient died 27 months after the initial surgery and 7 months after the last operation.

The prognosis for hepatocellular carcinoma (HCC) with severe vascular invasion is dismal. Surgery alone is not enough to control recurrence. Here, we report long-term survival in a case of HCC with tumor thrombus in the portal vein and right atrium, which was successfully treated through multidisciplinary therapies including surgery. The patient, a 74-year-old man, had undergone several rounds of local ablation and transarterial chemoembolization for HCC recurrence, in another hospital. He was referred to us for recurrent HCC with vascular invasion in July 2011. An abdominal computed tomography (CT) revealed a mass lesion(4 cm in diameter)in the left hepatic lobe. It also detected a tumor thrombus in the main trunk of the portal vein (Vp4), and in the right atrium (Vv3). Consequently, the patient underwent an extended left lobectomy and removal of the tumor thrombus in the portal vein and right atrium. Subsequently, fluorouracil (FU) arterial infusion and interferon therapy (FAIT) was initiated, and followed with sorafenib administration. However, multiple recurrent lesions were found in the liver, lungs, and lymph nodes. The dose of sorafenib was increased and maintained for 10 months. So far, the patient has been alive for 35 months after the operation.

A 61-year-old man presented with lower abdominal pain. Further examination revealed descending colon cancer and multiple liver metastases (S1, S2, and S5). The largest metastatic lesion in S1 showed massive invasion to the inferior vena cava (IVC) and was considered unresectable. Resection of the primary colon cancer was performed in January 2011, followed by several types of systemic chemotherapy(12 courses of capecitabine plus oxaliplatin [XELOX] + bevacizumab[Response Evaluation Criteria In Solid Tumors{RECIST}: PD], 5 courses of folinic acid, fluorouracil, and irinotecan [FOLFIRI] + bevacizumab[RECIST: SD], and 13 courses of FOLFIRI+ panitumumab). After these regimens, the lesions in S1 and S2 substantially decreased in size (RECIST: PR), and the lesion in S5 was no longer visible. The extent of invasion to the IVC significantly reduced, and liver resection(extended left lobectomy)and partial IVC resection were performed in November 2013 without reconstruction of the IVC by using a vascular prosthesis. The patient was discharged uneventfully on postoperative day 16, and administration of tegafur-uracil-Leucovorin (UFT/UZEL) was initiated. After 4 months, a recurrent lesion was found in S5, and partial liver resection was performed. In addition, FOLFIRI+panitumumab was reinitiated for the multiple lung metastases. The patient is alive without progression of disease 3 years and 4 months after colectomy.

The patient was a 66-year-old woman who had undergone low anterior resection for rectal cancer. Although she received adjuvant chemotherapy after the surgery, a 1.5 cm hepatic metastasis was observed in segments 4/8. Radiofrequency ablation ( RFA) was performed for the metastatic tumor. Approximately 1 month after RFA, a local recurrence was identified together with intrahepatic bile duct dilation in the right lobe of the liver. Extended right hepatic lobectomy and left intrahepatic cholangiojejunostomy were performed to remove the tumor. Histopathological examination of the resected specimen showed a liver metastasis from the rectal cancer with stricture of the bile duct although the bile duct was not involved in the tumor. This suggested that the bile duct stricture was caused by RFA and not by the recurrent tumor. Currently, the patient is alive with no recurrence 14 months after the surgery. This case suggests the importance of salvage surgery for recurrent tumors after RFA therapy, especially in the case of RFA-related complications in conjunction with the tumor.

A 51-year-old female patient was admitted to our hospital with a diagnosis of sigmoid colon cancer, and a sigmoidectomy and D3 lymphadenectomy was performed. The tumor was a moderately differentiated tubular adenocarcinoma (pT3N0M0, pStage II). No adjuvant therapy was administered. An abdominal computed tomography (CT) performed 11 months after the sigmoidectomy revealed a hepatic metastasis. The patient chose to undergo carbon ion radiotherapy (53.0 GyE/1 Fr). However, a second CT performed 10 months later indicated regrowth of the hepatic metastasis. A partial liver resection was performed, and severe deformity was observed in the irradiated region of the liver. The borderline between the tumor and surrounding tissue was not clearly discriminated. Histopathological examinations indicated increased numbers of fibrous cells in the irradiated region. To perform hepatic resection safely for liver metastasis of colorectal cancer following heavy particle radiotherapy, it is necessary to accurately determine the resection line before and during surgery. When feasible, resection of the whole irradiated area should be considered.

A 65-year-old woman presented to our department with a liver tumor. She had undergone subtotal colectomy and total hysterectomy for hereditary nonpolyposis colorectal cancer and uterine cancer 14 years prior to diagnosis. An abdominal CT scan revealed a ring-enhancing tumor with portal vein tumor thrombus on the left lobe. With a preoperative diagnosis of intrahepatic cholangiocarcinoma, combined hepatocellular and cholangiocarcinoma, or metastatic liver cancer; we performed an extended left hepatic lobectomy. The histopathological examination showed adenocarcinoma of the liver. The histopathological findings of the liver tumor resembled that of the previous uterine cancer. Immunohistochemical testing was positive for CK7 and negative for CK20, CDX2, PgR, vimentin, and CA125. However, PgR, vimentin, and CA125 were positively stained in the uterine cancer. Based on these findings, the final diagnosis of the liver tumor was primary intrahepatic cholangiocarcinoma.

We report a case of gastric carcinoma with metastasis to the liver responding to surgery and chemotherapy.The patient was a 74-year-old man with gastric cancer, clinically diagnosed as P0H0M0T3N0.We initially planned to perform an open distal gastrectomy.However, intraoperative findings revealed metastatic tumors in the liver.Therefore, the patient underwent a D1 distal gastrectomy.After surgery, the patient received the following chemotherapy regimens: 1 course of S-1 and 8 courses of a S-1 and cisplatin (CDDP) combination.After 8 courses of S-1 plus CDDP treatment, liver metastases could not be detected by computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET). The patient was assessed to have a clinical complete response.Fifty months after surgery, the patient is alive without recurrence.

Aims: We performed a retrospective analysis to evaluate the short and long-term impact of simultaneous prophylactic cholecystectomy with hepatectomy in these patients., Methods: We identified 642 patients who underwent curative hepatocellular carcinoma resection between 2001 and 2005 at five university hospitals. One hundred and twenty-five hepatocellular carcinoma patients who received left lateral sectionectomy or partial resection in the left lateral and Spiegel lobes were identified and followed. They were divided into two groups, 74 with and 51 without simultaneous cholecystectomy. None of these patients had gallbladder stones or polyps at preoperative diagnosis., Results: Although not statistically significant, the operating time was longer and blood loss was greater in the cholecystectomy group. Patients in the cholecystectomy group had a significantly higher postoperative morbidity rate. Surgical complications according to the Clavien classification differed significantly between the two groups. Variables significantly associated with complications in the univariate and multivariate analyses were simultaneous cholecystectomy and operative blood loss ≥ 1000 ml., Conclusion: Simultaneous cholecystectomy of the asymptomatic gallbladder with curative resection of hepatocellular carcinoma in the left lateral section or Spiegel lobe resulted in higher postoperative complications. Consequently, the gallbladder should be preserved except in cases of gallbladder stones or polyps.

Background: Although several studies have reported the outcomes of surgery for the treatment of liver metastases of gastric cancer (GLM), indications for liver resection for gastric metastases remain controversial. This study was designed to identify prognostic determinants that identify operable hepatic metastases from gastric cancer and to evaluate the actual targets of surgical therapy., Methods: Retrospective analysis was performed on outcomes for 24 consecutive patients at five institutions who underwent gastrectomy for gastric cancer followed by curative hepatectomy for GLM between 2000 and June 2012., Results: Overall 5-year survival and median survival were 40.1 % and 22.3 months, respectively. Uni- and multivariate analyses showed that liver metastatic tumour size less than 5 cm was the most important predictor of overall survival (OS, p = 0.03). Four patients survived >5 years. Repeat hepatectomy was performed in three patients. Two of these patients have remained disease-free since the repeat hepatectomy., Conclusions: GLM patients with metastatic tumour diameter less than 5 cm maximum are the best candidates for hepatectomy. Hepatic resection should be considered as an option for gastric cancer patients with liver metastases.

Hypoxia regulates the expression of genes that promote tumor growth, angiogenesis and invasion. We previously studied hypoxic tumor cells in vitro and from hepatic metastases of colorectal cancer and determined several potential prognostic factors for hepatocellular carcinoma (HCC). In this study, we evaluated the prognostic impact of the expression of ephrin-A1 (EFNA1) and its receptor, EPHA2, in patients with HCC after curative resection. Samples from a total of 139 HCC patients were analyzed by either microarray alone (n=86) or by microarray and quantitative PCR (n=53). There was no correlation between EFNA1 expression and clinicopathological factors. EPHA2 expression was not significantly correlated with any clinicopathological factors, except for microscopic portal invasion. EFNA1 was an independent prognostic factor for HCC (p=0.0277). These findings suggest that EFNA1 expression may be a useful marker for predicting high risk of recurrence in patients who have undergone curative resection for HCC.

Interferon-α (IFN-α) is used clinically to treat hepatocellular carcinoma (HCC), although the detailed therapeutic mechanisms remain elusive. In particular, IFN-α has long been implicated in control of the cell cycle, but its actual point of action has not been clarified. Here, using time lapse imaging analyses of the human HCC cell line HuH7 carrying a fluorescence ubiquitination-based cell cycle indicator (Fucci), we found that IFN-α induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-α type-2 receptor (IFNAR2)-dependent signaling pathway. Detailed analyses by time lapse imaging and biochemical assays demonstrated that the IFN-α/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for cell death in the G0/G1 phases. In summary, this study is the first to demonstrate the detailed mechanism of IFN-α as an anticancer drug, using Fucci-based time lapse imaging, which will be informative for treating HCC with IFN-α in clinical practice., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Although simultaneous resection of primary colorectal cancer and synchronous liver metastases is reported to be safe and effective, the feasibility of a laparoscopic approach remains controversial. This study evaluated the safety, feasibility, and short-term outcomes of simultaneous laparoscopic surgery for primary colorectal cancer with synchronous liver metastases. From September 2008 to December 2013, 10 patients underwent simultaneous laparoscopic resection of primary colorectal cancer and synchronous liver metastases with curative intent at our institute. The median operative time was 452 minutes, and the median estimated blood loss was 245 mL. Median times to discharge from the hospital and adjuvant chemotherapy were 13.5 and 44 postoperative days, respectively. Negative resection margins were achieved in all cases, with no postoperative mortality or major morbidity. Simultaneous laparoscopic colectomy and hepatectomy for primary colorectal cancer with synchronous liver metastases appears feasible with low morbidity and favorable outcomes.

Background and Objectives: It remains unclear what kinds of patients undergoing hepatectomy for hepatocellular carcinoma (HCC) actually need autologous blood storage/transfusion., Methods: Prior to surgery, autologous blood storage was prospectively performed in 245 patients with HCC, whereas it was not performed in 40 patients. Based on the use of the deposited autologous blood and the estimated postoperative hemoglobin (Hb) level when blood was not deposited, they were divided into necessary group and unnecessary group. By comparing the two groups, a scoring system to predict the need for autologous blood was established., Results: The 245 patients from whom blood was collected and stored were categorized into necessary group (32 patients with homologous blood transfusion and 11 with estimated postoperative Hb of <8.0 g/dl) and unnecessary group (30 patients with autologous blood discarded and 172 with estimated Hb ≥ 8.0 g/dl). Using factors that were significantly different between the two groups, a scoring system to predict the need for autologous blood was developed; preoperative Hb level, tumor size, and tumor thrombus. The area under the receiver-operator characteristic curve of the score was 0.836., Conclusions: The established scoring system was found useful in identifying those HCC patients who need autologous blood storage/transfusion during hepatectomy., (© 2013 Wiley Periodicals, Inc.)

Purpose: Because of the recurrence of hepatocellular carcinoma (HCC) at the graft after liver transplantation, circulating HCC cells may be present during the anhepatic period. Intravenous doxorubicin (DOX) is used during the anhepatic period to combat these cells; however, pharmacokinetics data have been poorly analyzed. This study aims to investigate DOX administration during the anhepatic period., Patients and Methods: We administered 5 mg/m(2) DOX immediately after liver removal and compared serum DOX concentrations at several intervals during the anhepatic period in patients who underwent liver transplantation because of liver cirrhosis and HCC (n = 3) and patients who underwent liver resection owing to HCC with portal vein tumor thrombi (n = 5). We also measured serum DOX concentrations and pharmacokinetic parameters in transplant patients that received 3-15 mg/m(2) DOX (n = 3 per dose level). We evaluated transplant patients' adverse drug reactions and survival., Results: At 10 and 30 min after DOX administration, serum DOX concentrations were elevated two- to threefold in transplant patients versus resection patients. Dose escalation in transplant patients exhibited a prolonged T½ in the one-compartment model and T½ β in the two-compartment model, as well as a dose-dependent elevation of the area under the curve. No obvious adverse drug reactions were noted at 3-15 mg/m(2) DOX. In transplant patients, 5-year recurrence-free survival was 68.8 %; overall survival was 100.0 %., Conclusion: During the anhepatic period, serum DOX concentrations were elevated two- to threefold, T½ was prolonged dose dependently, and up to 15 mg/m(2) DOX could be safely administered

A 62-year-old man had been previously diagnosed as having a 7-cm liver tumor in segment 4 at another hospital, but did not pursue treatment. Twenty-nine months later, he was referred to our hospital suffering from jaundice. Abdominal computed tomography( CT) revealed a 13.5-cm tumor in the liver( S4) with early staining and isodensity in the portal and equilibrium phases. Because magnetic resonance imaging (MRI) of this tumor showed central scarring in T2WI and uptake of EOB in the hepatocyte phase, focal nodular hyperplasia (FNH) was included as a differential diagnosis. Alternatively, the signal decreased out of phase, suggesting a possibility of hepatocellular carcinoma( HCC). We performed extended left lobe resection because of tumor growth and exclusion of the bile duct. Histopathological examination revealed well and moderately differentiated hepatocellular carcinoma with various types of pathological patterns, including necrosis, fat, and scarring. The patient remains well at 12 months after this surgery with no signs of recurrence.

A 59-year-old man was diagnosed as having hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) from the left branch to the main trunk and multiple liver tumors in the right lobe. He first underwent 8 courses of fluorouracil arterial infusion and interferon therapy( FAIT).The PVTT shrunk following combination therapy; however, the liver tumors were enlarged and metastasis was noted in the right adrenal gland. Treatment with sorafenib was initiated. Ten months later, additional reduction of PVTT was noted with no changes in the multiple liver tumors. After confirmation of sufficient portal flow, we performed transcatheter arterial chemoembolization (TACE).After having undergone, in total, 4 rounds of TACE with sorafenib, the patient underwent radiofrequency ablation( RFA) for the right adrenal gland metastasis. The patient is still alive, in good health. Our findings from this case suggest that, in some patients having advanced HCC with PVTT, long- term survival can be achieved when the intrahepatic lesions are controlled by various adequate therapies.