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We herein report a 63-year-old man who presented with left lower jaw pain and was diagnosed with hepatocellular carcinoma with bone metastases post-examination. All tumors grew after immunotherapy with atezolizumab and bevacizumab, and his jaw pain worsened. After palliative radiation therapy, however, the tumors shrank markedly, with no recurrence seen after stopping immunotherapy. To our knowledge, this is the first case in which a radiotherapy- and immunotherapy-mediated abscopal effect facilitated tumor shrinkage and immunotherapy discontinuation.

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment., (© 2023. The Author(s).)

Purpose: Selected patients with initially unresectable colorectal cancer (CRC) and liver metastases undergo conversion surgery after appropriate chemotherapy. The prognosis of these patients is good, with some even cured of the disease. This retrospective, single-institution study analyzes the clinical importance of patient characteristics on the outcomes of conversion hepatectomy., Methods: We evaluated 229 consecutive patients with initially unresectable CRC and liver metastasis, who underwent systemic chemotherapy. The patients were assigned to groups depending on conversion hepatectomy., Results: Conversion hepatectomy was performed in 30 patients (13.1%). The proportion of patients with extrahepatic metastasis was significantly lower in the conversion group than in the unresectable group (30.0 vs. 66.8%; P < 0.01). The rate of left-sided primary colorectal tumors was significantly higher in the conversion group than in the unresectable group (96.7 vs. 65.8%; P < 0.01). Multivariate analyses identified that left-sided tumors, no extrahepatic metastasis, H1 or H2 grade CLM, and treatment with molecular-targeted agents were associated with conversion hepatectomy (odds ratios: 16.314, 4.216, 7.631, and 4.070; P < 0.01). Overall survival was significantly longer in the conversion group than in the unresectable group (MST: 50.0 versus 14.7 months; P < 0.01)., Conclusion: Left-sided primary tumors, absence of extrahepatic metastases, H1 or H2 grade, and use of molecular-targeted agents were associated with successful conversion hepatectomy; thus, patients with these characteristics may be candidates for conversion therapy., (© 2021. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Patients with liver metastasis of head-and-neck carcinoma and esophageal carcinoma are generally not treated with hepatic resection, but there are no established standard treatment methods. We report 11 cases of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma performed at 5 Japanese institutions., Methods: The subjects of this retrospective analysis were 11 patients who underwent hepatic resection for metastatic liver tumors, originating from head-and-neck carcinoma in 5 and from esophageal cancer in 6, between January, 2010 and March, 2020 RESULTS: There were nine men and two women (median age, 64 years; range 40-72 years). The primary disease was esophageal carcinoma in six patients and pharyngeal carcinoma in five patients. All cancers were squamous cell carcinoma. The time from the initial treatment to the diagnosis of liver metastasis was 15.3 months and the 1-year and 3-year overall survival rates after hepatic resection were 72% and 32%, respectively. The overall and disease-free survival rates after hepatic resection were significantly higher for patients who underwent hepatic resection more than 12 months after the initial treatment than for those who underwent hepatic resection within 12 months after the initial treatment (p = 0.0172 and p = 0.0120, respectively)., Conclusions: Liver resection may prolong the survival of patients with liver metastases controlled for more than 12 months after the initial treatment of head and neck or esophageal carcinoma., (© 2021. Springer Nature Singapore Pte Ltd.)

The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group ( n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group ( n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.

Developments in image fusion technology made it possible to visualize the ablative margin on ultrasound (US). The purpose of the present study was to assess the ablative area of radiofrequency ablation for hepatocellular carcinoma and compare it with the ablative hyperechoic zone with a non-enhanced area on contrast-enhanced US/contrast-enhanced computed tomography (CEUS/CECT) in the same cross-section. This retrospective study included 25 patients with 27 hepatocellular carcinomas. The long and short dimensions of the ablative hyperechoic zone were measured using B-mode US, and those of the non-enhanced area were assessed with CEUS/CECT on the same cross-section measured with B-mode US, using image fusion techniques. The technical effectiveness of ablation with an adequate ablative margin in a single session was determined in all patients. The long and short dimensions of the ablative hyperechoic zone ranged between 15.0 and 40.7 mm (mean: 27.3 ± 6.9 mm) and between 14.0 and 33.0 mm (mean: 23.3 ± 5.8 mm), respectively. R values for the long and short dimensions were 0.99 and 0.98, respectively, between B-mode US and CEUS, and 0.96 and 0.92, respectively, between B-mode US and CECT. The ablative hyperechoic zone may be regarded as a necrotic lesion after radiofrequency ablation., (Copyright © 2021. Published by Elsevier Inc.)

Background/aim: The Geriatric Nutritional Risk Index (GNRI) is a prognostic indicator for several cancers; however, the association between the GNRI and colorectal liver metastasis (CRLM) remains unknown., Patients and Methods: Eighty patients who underwent hepatectomy for synchronous CRLM were divided into two groups based on the GNRI., Results: The preoperative CA19-9 levels were significantly higher in the low (GNRI ≤98; n=30) than the normal GNRI group (GNRI >98; n=50). Patients in the low GNRI group had poorer outcomes than those in the normal GNRI group. A low GNRI was an independent prognostic factor for recurrence-free survival and overall survival. Among 50 patients who experienced recurrence, only 16 of 22 patients (72.7%) in the low GNRI group could receive intensive treatment and 27 of 28 patients (96.4%) in the normal GNRI group., Conclusion: The GNRI is a simplified prognostic factor for patients with CRLM., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Aim: To develop a scoring method using with common clinical data for predicting hepatocellular carcinoma (HCC) development after sustained virological response at 24 weeks (SVR24) after treatment with direct acting antivirals (DAAs), we retrospectively evaluated clinical features of patients who obtained SVR24., Methods: From October 2014 to December 2017, 1069 hepatitis C virus patients without a past history of HCC, who obtained SVR24 by DAAs at two different areas, were enrolled (the training [n = 484, ChuShikoku-group] and validation [n = 585, Chubu-group] sets). All were examined by ultrasonography as surveillance for HCC at the time of starting DAAs and twice a year after SVR24. We identified three parameters at SVR24, male gender, FIB-4 index > 3.25, and α-fetoprotein level > 5.0 ng/mL, as risk factors for HCC development and gave them point values, with the sum used as After DAAs Recommendation for Surveillance (ADRES) score., Results: In the ChuShikoku-group, the respective 1-/2-year rates for HCC incidence rates ADRES score 0 were 0.0%/0.0%, for a score 1 were 1.1%/2.1%, score 2 were 8.8%/15.9%, and score 3 were 17.1%/28.1%. On the other hand, those respective scores for the Chubu-group were 0.0%/0.0%, 0.0%/0.7%, 7.9%/10.6%, and 19.5%/not available. The c-index of the predictive value for HCC development in the training set after SVR24 was 0.835 while 0.899 in the validation set. Finally, those of the entire cohort were 0.0%/0.0%, 0.5%/1.6%, 8.4%/13.4%, and 18.0%/32.8%., Conclusion: The present ADRES score was simple and easy to use and may be useful for predicting risk of HCC development in short term after reaching SVR24 by DAAs., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin recombinant fusion protein, is an immunosuppressive agent indicated for rheumatoid arthritis. Although no significant increase in malignancy has been reported in abatacept-treated patients, whether or not abatacept accelerates tumor progression in specific cancer types remains unclear. We herein report a 66-year-old woman who showed unusually rapid progression of hepatocellular carcinoma following abatacept therapy for rheumatoid arthritis. Abatacept was speculated to have accelerated her hepatocellular carcinoma progression in the setting of her preexisting risk factors: autoimmune hepatitis and long-term methotrexate use. We propose close tumor surveillance be performed during abatacept therapy, especially for high-risk patients.

Overall survival of patients with hepatocellular carcinoma (HCC) refractory to locoregional therapy is dismal, even following treatment with sorafenib, a multikinase inhibitor. To develop a more efficacious treatment, we undertook a feasibility study of personalized peptide vaccination (PPV) for HCC, in which the peptides were selected from 31 peptide candidates based on the pre-existing immunity. Twenty-six HCC patients refractory to locoregional therapies (cohort 1) and 30 patients refractory to both locoregional and systemic therapies (cohort 2) were entered into the study. There were no severe adverse events related to PPV except for one injection site reaction. At the end of the first cycle of six vaccinations, successful CTL or IgG boosting was observed in 57% or 46% of patients in cohort 1 and in 54% or 52% of patients in cohort 2, respectively. Successful IgG boosting at the end of the second cycle was observed in the majority of patients tested. Median overall survival was 18.7 months (95% confidence interval, 12.2-22.5 months) in cohort 1, and 8.5 months (95% confidence interval, 5.9-12.2 months) in cohort 2. Based on the higher rates of immune boosting and the safety profile of PPV, further clinical studies of PPV would be warranted for patients with HCC refractory to not only locoregional therapy but also both locoregional and systemic therapies. The protocol of this study was registered with the UMIN Clinical Trials Registry (UMIN000001882 and UMIN000003590)., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

Background: Molecular profiling in gastric cancer (GC) is important for diagnosis and treatment. In this study, we investigated signal transduction pathways that might induce chromosomal instability in GC., Methods: Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and p-AKT expression were analyzed using immunohistochemistry, and chromosomal instability was assessed by DNA aneuploidy using laser scanning cytometry, in a total of 202 GC cases., Results: The rate of EGFR expression and p-AKT expression was 70.3 and 34.2 %, respectively, in GC patients. In total, 57.5 % of GC patients exhibited DNA aneuploidy, and p-AKT positively correlated with EGFR and HER2 (p = 0.0127 and p = 0.00031, respectively). Patients with EGFR overexpressing GC showed shorter disease-specific survival than the other cases (hazard ratio 2.00, 95 % confidence interval 1.19-3.53; p = 0.0104). Moreover, EGFR and p-AKT expression was significantly correlated with DNA aneuploidy (p = 0.0002 and p = 0.0302, respectively)., Conclusions: Our data showed that both EGFR and p-AKT overexpression were clearly associated with DNA aneuploidy. Aneuploidy could be a useful marker for therapies that target EGFR.

Purpose: Transcatheter arterial chemoembolization (TACE) is one of the most effective therapeutic options for hepatocellular carcinoma (HCC) and it is important to protect residual liver function after treatment as well as the effect. To reduce the liver function deterioration, we evaluated the automatic software to predict the embolization area of TACE in 3 dimensions., Materials and Methods: Automatic prediction software of embolization area was used in chemoembolization of 7 HCCs. Embolization area of chemoembolization was evaluated within 1 week CT findings after TACE and compared simulated area using automatic prediction software., Results: The maximal diameter of these tumors is in the range 12-42 mm (24.6 ± 9.5 mm). The average time for detecting tumor-feeding branches was 242 s. The total time to detect tumor-feeding branches and simulate the embolization area was 384 s. All cases could detect all tumor-feeding branches of HCC, and the expected embolization area of simulation with automatic prediction software was almost the same as the actual areas, as shown by CT after TACE., Conclusion: This new technology has possibilities to reduce the amount of contrast medium used, protect kidney function, decrease radiation exposure, and improve the therapeutic effect of TACE., (© 2016 S. Karger AG, Basel.)

Background/aims: Interferon (IFN) therapy improves the prognosis of the patients with HCV-related hepatocellular carcinoma (HCC). However, the effects of IFN therapy for hepatectomy (Hx) for primary HCC have not been established. Several published reports investigating the effects of IFN therapy on survival and tumor recurrence after curative resection of HCC have been inconclusive., Methodology: Subjects included 470 patients who underwent Hx for HCV related primary HCC. One hundred and fifty nine patients received IFN therapy past or postoperatively of the first Hx. Seventy-four of those patients attained a sustained viral response (SVR group). The other 396 patients, including 85 were no responders (NR) and 311 patients who had not received IFN therapy (non-IFN) were classified as the control group., Results: Overall survival (SVR group vs. control group: 5-yr, 93.2 vs. 61.9%; p<0.0001) and disease-free survival (SVR group vs. control group: 5-yr, 56.0 vs. 27.4%; p<0.0001) rates were significantly different. By multivariate analysis, NR/non-IFN was the independent risk factor for overall survival (p=0.0002) and disease-free survival (p=0.0053) after Hx., Conclusions: SVR achieved past or postoperatively to the Hx of HCV-related HCC significantly inhibits recurrence and consequently improves patient survival after Hx for HCC.

A 57-year-old woman with a complaint of a right upper quadrant mass was referred to our hospital. Multimodal studies such as PET-CT revealed large hepatic tumors and swollen para-aortic lymph nodes, the origin of which was unclear. Pathological analysis of a biopsy specimen obtained from the liver tumor led to a diagnosis of neuroendocrine carcinoma. After 4 CDDP/CPT-11 chemotherapy treatment courses, remarkable shrinkage of liver tumors and disappearance of the swollen lymph nodes were achieved. Subsequently, liver tumor and extrahepatic bile duct resection and lymphatic dissection were performed. Pathological analysis of the resected specimens revealed that the liver tumors and metastatic lymph nodes originated from the gallbladder, leading to a diagnosis of mixed adenoneuroendocrine carcinoma. After 5 courses of adjuvant chemotherapy using the same regimen, the patient has remained disease free for 24 months since the initialdiagnosis.

Background: The CXCL12/CXCR4 axis plays a pivotal role in cancer progression and metastases in various epithelial cancer cells. The aim of the present study was to evaluate the localization and correlation between CXCL12/CXCR4 expression and clinicopathological features in gastric cancers., Materials and Methods: This study included 111 Japanese patients with primary gastric cancers, which invade submucosa or more, all of whom underwent gastrectomy between 1992 and 1996. Immunohistochemical analysis was performed., Results: A significant correlation was found in the immunoreactivity of nuclear CXCR4 and poor differentiation (p=0.0026), infiltrated pattern (p<0.0001), larger size (p<0.0001), advanced stage (p=0.0342) and reduced 5-year survival rate (30% vs. 61%, p=0.0012). Multivariate analysis revealed that high nuclear CXCR4 immunoreactivity (RR: 3.077, p=0.0329) retained its strength as an independent prognostic factor for overall survival., Conclusion: High immunoreactivity of nuclear CXCR4 in gastric cancer suggests that CXCL12 binds to its unique receptor CXCR4 at the membrane, translocates to the nucleus and then becomes more invasive, and thus can be considered a prognostic factor., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery.

Carcinosarcoma of the hepatobiliary tract is highly aggressive and has a poor prognosis even after curative resection. The purpose of this study was to collate and analyze published data to clarify the surgical outcome of carcinosarcoma of the hepatobiliary tract and the relationships between potential prognostic factors and survival after surgery. We surveyed worldwide literature from 1970 to 2012 and obtained clinicopathological data for 131 patients who had undergone surgical resection for carcinosarcoma of the hepatobiliary tract, including one patient from our clinic. The relationships between potential prognostic factors and survival rates were examined using the Kaplan-Meier method and the log-rank test. The overall 1-, 3-, and 5-year survival rates for patients with carcinosarcoma of the hepatobiliary tract after surgery were 44.0, 29.3, and 27.0 %, respectively. In univariate analyses, age and gender were not significant prognostic factors; however, advanced stage according to the classification of the Union for International Cancer Control in resected specimens was significantly associated with a shorter survival time after surgery. Although carcinosarcoma of the hepatobiliary tract remains a rare disease worldwide, its poor prognosis, even after curative resection, demands further epidemiological and pathological study that could lead to the development of new management strategies.

Introduction: Simultaneous resection for colorectal cancer and synchronous colorectal liver metastases (SCRLM) has been found to be safe and effective. However, pure laparoscopic simultaneous resection (PULSAR) for primary colorectal cancer and SCRLM is usually difficult, especially in the right lobe of the liver. The purpose of this study was to assess the feasibility of PULSAR for patients with primary colorectal cancer and SCRLM., Methods: From January 2008 to December 2012, a total of 10 patients (9 men and 1woman; mean age, 64 years) underwent PULSAR for a primary tumor and SCRLM., Results: Seven patients (70%) with lesions in the right lobe (segments 6, 7, and 8) successfully underwent resection with a pure laparoscopic procedure while in the left semi-prone position. No patient was converted to conventional open surgery. The mean operative duration, volume of bleeding, and postoperative hospital stay were 606 ± 46 min, 585 ± 145 mL, and 18 ± 3.5 days, respectively. Although a liver abscess developed in one patient, no colonic complications or perioperative death occurred., Conclusion: PULSAR for primary colorectal cancer and SCRLM is a feasible multidisciplinary treatment. Moreover, PULSAR can be safely and effectively performed with the patient in the semi-prone position, even when SCRLM exists in the right lobe of the liver., (© 2014 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.)

Background: Mortalin is a heat-non-inducible member of the heat shock protein 70 family. Mortalin binds to p53 and prevents p53 from entering the nucleus. To understand the significance of mortalin in gastric cancer, we investigated the expression of mortalin and p53., Methods: Expression of mortalin and p53 was examined by immunohistochemical staining of 182 clinical samples of gastric cancer., Results: Mortalin-positive and aberrant p53-positive tumors were found in 75.2 and 49.5 % of cases, respectively. Mortalin-positive tumors were deeper in invasion and had more lymph node and liver metastases compared with mortalin-negative tumors (P < 0.01, P < 0.05, respectively). Mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.035). Moreover, in tumors with normal p53 function, mortalin-positive tumors had worse prognosis compared with mortalin-negative tumors (P = 0.017)., Conclusions: Mortalin has a great impact on gastric cancer with normal p53. Therefore, mortalin is a target molecule for treatment of gastric cancer, as well as a promising prognostic factor, especially in tumors with normal p53.

We report a case of 90-year-old patient who underwent preoperative 3-dimensional (3D) computed tomography (CT) volumetric analysis using SYNAPSE VINCENT imaging software and anatomical resection of segment VIII using ultrasound-guided vessel compression. Preoperative abdominal CT revealed a liver mass measuring 5.0 cm in diameter, and the patient was diagnosed with hepatocellular carcinoma. Liver function was preserved. Preoperative 3D volumetry using SYNAPSE VINCENT revealed the volume of the entire liver to be 1,339 mL and the volume of segment VIII to be 327 mL. Anatomical hepatic resection of segment VIII was performed using ultrasound-guided vessel compression. Operative duration was 372 min and estimated blood loss was 760 mL. Resected liver volume was 290 g. The patient's postoperative course was uneventful, and there has been no evidence of recurrence since the surgery.

Background: Hepatectomy in a patient with situs inversus patient is technically challenging because of its complete mirror image anatomy, especially for a tumor located deep in the liver. Incorrectly identifying intrahepatic vessels and biliary system would lead to serious complications. We experienced a hepatectomy for a tumor in a patient with situs inversus totalis with referring to computer-generated mirror images., Methods: A 66-year-old female patient with situs inversus totalis was diagnosed with hepatocellular carcinoma, 5 cm in diameter, centrally located just above the hepatic hilum compressing the right and left hepatic duct. The liver infected with hepatitis C was cirrhotic with a moderate amount of ascites. We preoperatively created several diagrams of the mirror image anatomy and made plans for how to resect this tumor, presupposing the patient had an ordinary anatomy. The tumor was successfully enucleated with referring to these diagrams., Results: The operation time was 454 minutes. Five units of fresh frozen plasma was transfused intraoperatively. Although she suffered refractory ascites which needed repeated paracentesis, she managed to leave the hospital two months after the operation., Conclusion: Creating a mirror image anatomy enables surgeons to safely perform a complex hepatectomy in a patient with situs inversus totalis.

Liver transplantation (LT) is currently one of the best available strategies for treating multiple hepatocellular carcinoma (HCC) and decompensated liver cirrhosis. However, patients often undergo HCC recurrence after LT, with most HCC recurrences detected at 1-2 years. CD133 was the first identified member of the prominin family of pentaspan membrane proteins and is a marker of hepatic stem cells. Here, we report a unique case of seven repeated recurrences of HCC in the lungs after LT, with all HCC recurrences resected curatively by a thoracoscopic approach. Pathological examination revealed moderately differentiated HCC identical to that in the original histology of the liver tumor. Interestingly, no CD133 immunoreactivity was observed in cancerous lesions of the primary HCC and the 1st to 2nd recurrences, as indicated by immunohistochemistry. However, CD133 was strongly stained in the cancerous lesions from the 3rd to 7th recurrences. The patient survived and had no recurrence after 9 years of the initial living donor LT. In conclusion, we investigated an evocative case of seven repeated recurrences of HCC in the lungs to elucidate the significance of circulating CD133-positive hepatic stem cells. This case illustrates the need for further research to clarify the mutual effect of CD133-positive hepatic stem cells for the development of new therapeutic strategies.

Insulin-like Growth Factor 1 (IGF-1) antigen was immunohistochemically examined in 28 patients of the primary hepatocellular carcinoma with hepatectomy. IGF-1 was expressed in 93% (26/28) of the primary lesion and 100% (28/28) of the normal liver. Compared with expression in normal liver, decreased expressions in primary lesions were noted in 36% (10/28) for IGF-1. Histological examination revealed that there were significant correlations between patients with decreased expressions of IGF-1 in primary lesions and poor differentiated hepatocellular carcinoma, and portal vein infiltration. These results indicate that expression of IGF-1 has the relationship with the differentiation in human primary hepatocellular carcinoma.

Hepatitis B virus (HBV) recurrence after liver transplantation for HBV-associated liver diseases results in decreased patient and graft survival. Herein we have reported two cases of HBV recurrence following relapse of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT). Both cases had LDLT for end-stage liver disease secondary to HBV infection with nodules of HCC exceeding the Milan criteria. HBV prophylaxis using hepatitis B immunoglobulin with nucleos (t) ide analogues were given and HBV DNA levels were consistently undetectable after LDLT. HCC recurred at 5 months and 13 months posttransplant respectively, and chemotherapy and radiation therapy were performed. HBV recurrence occurred during the treatment of HCC. HBV DNA levels increased despite the treatment with anti-HBV agents after HBV recurrence. In hepatitis B surface antigen positive recipients, HBV prophylaxis should be intensified during the treatment of recurrent HCC.

Unlabelled: Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-α, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-α expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups., Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Recent studies have shown that the tumor microenvironment plays an important role in cancer progression. Tumor-associated macrophages (TAMs), in particular, have been found to be associated with tumor progression. Macrophages have multiple biological roles, including antigen presentation, target cell cytotoxicity, removal of foreign bodies, tissue remodeling, regulation of inflammation, induction of immunity, thrombosis, and endocytosis. Recent immunological studies have identified two distinct states of polarized macrophage activation: the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes. Bacterial moieties such as lipopolysaccharides and the Th1 cytokine interferon-γ polarize macrophages toward the M1 phenotype. The M2 polarization was discovered as a response to the Th2 cytokine interleukin-4. In general, M2 macrophages exert immunoregulatory activity, participate in polarized Th2 responses, and aid tumor progression. TAMs have recently been found to play an important role in hepatocellular carcinoma (HCC) progression. Based on the properties of TAMs, obtained from pathological examination of resected specimens, we have identified new therapeutic approaches, involving the targeting of TAMs with adjuvant therapy after hepatic resection for HCC. This review discusses the roles of TAM in HCC progression and the possibility of new therapies targeting TAMs.

Purpose: Although laparoscopic liver resection has been widely adopted, performing a pure laparoscopic right hepatectomy remains a challenging procedure. The aim of this report is to evaluate the efficiency of a pure laparoscopic right hepatectomy (PLRH) in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver., Methods: Pure laparoscopic right hepatectomy was performed in the semi-prone position with the use of an intrahepatic Glissonian approach and modified hanging maneuver for patients with primary liver cancer (n = 3) and metastatic liver cancer (n = 1)., Results: The intraoperative total blood loss was only 95-140 g (mean: 126.2 g). None of the patients required a blood transfusion, and no serious complications were encountered. The durations of the surgeries ranged from were 308 to 445 min (mean: 394.8 min). The postoperative hospital stay was 8-11 days (mean 9.5 days)., Conclusion: Pure laparoscopic right hepatectomy in the semi-prone position using the intrahepatic Glissonian approach and a modified hanging maneuver is thus considered to be a safe modality, which minimizes intraoperative bleeding.

This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases.

Aim: Periodontitis induces overproduction of reactive oxygen species (ROS). This state increases circulating ROS levels and may affect hepatocellular carcinoma (HCC). The Japan Integrated Stage (JIS) score is a novel staging system for HCC. The objective of the present study was to compare JIS scores in HCC patients with and without periodontitis., Material and Methods: We recruited 64 HCC patients comprising 31 chronic periodontitis subjects (HCC + P) and 33 periodontally healthy controls (HCC + H). Their JIS scores were recorded. Serum levels of reactive oxygen metabolites (ROM) from HCC + P, HCC + H and healthy age- and gender-matched subjects with healthy gingiva (control, n = 15) were also assessed for circulating ROS levels., Results: The HCC + P and HCC + H groups had similar body mass index, habitual drinking and tobacco exposure data. The HCC + P group showed higher JIS scores than the HCC + H group (p = 0.027). Both the HCC + P and HCC + H groups had higher serum levels of ROM than controls (p < 0.001), while serum levels of ROM in the HCC + P group were a further 25.8% higher than those in the HCC + H group (p < 0.001)., Conclusion: HCC patients with periodontitis had higher JIS score and circulating ROS level than HCC patients without periodontitis., (© 2011 John Wiley & Sons A/S.)

The prognosis of patients with liver metastasis from gastric cancer is dismal. This article reviews the characteristics of gastric cancer metastasizing to the liver, and multimodality of treatments. Differentiated adenocarcinoma, poorly differentiated adenocarcinoma with a medullary growth pattern, and special types, including endocrine carcinoma and hepatoid carcinoma, are likely to metastasize to the liver. The overexpression of growth factors or adhesion molecules is clinically significant for liver metastasis. Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if a complete resection seems feasible after careful preoperative staging. A hepatic resection should always be considered as an option for gastric cancer patients with hepatic metastases. Newer generation cytotoxic agents such as S-1, irinotecan, and taxanes show promising activity for patients with metastases. Adjuvant chemotherapy or molecular targeted therapy will provide significant benefits to patients in the future.

Nowadays, the advancements of systemic chemotherapy for colorectal carcinoma improve a clinical response rate, and expand the possibility of resection which couldn't operable at the initial visit. In addition, the prognoses of the patients, who had a radical operation for metastasis, are clearly longer than the non-operable patients. Bevacizumab, anti-human VEGF monoclonal antibody, is significantly effective when used in combination with one of the systemic multi-agent chemotherapy such as FOLFOX regimen or FOLFIRI regimen. We report here two cases with colon carcinoma, which had initially unresectable liver metastases, were respond to the treatment of systemic multi-agent chemotherapy with bevacizumab. Then, both cases were able to undergo radical resections of primary tumor and liver metastases safely.

Recently, standard therapies for either gastric cancer or colorectal cancer have been established through the development of multidrug systemic chemotherapy and the appearance of molecular targeting drugs. For example, either FOLFIRI or FOLFOX therapy is normally chosen for the treatment of unresectable liver metastasis from colorectal cancer. On the other hand, hepatic artery infusion (HAI) chemotherapy is generally used as only a second-line therapy. There are, however, some cases in which systemic chemotherapy is not indicated due to age and/or the risk of side effects. We herein report three cases that were treated by HAI after initially performing systemic chemotherapy in order to treat liver metastasis from either gastric cancer or colorectal cancer.

Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in hepatocellular carcinoma (HCC), but the significance of AI analysis in focal nodular hyperplasia (FNH) has not been fully clarified. We hypothesized, therefore, that comprehensive allelotyping of FNH could be a useful tool for differentiating FNH from HCC. A 27-year-old man was admitted to the hospital because of general fatigue. A computed tomography (CT) scan disclosed a hepatic nodule 8 cm in diameter. No definite diagnosis was made after imaging or by biopsy before surgery. Macroscopically and microscopically, the surgical specimen showed typical features of FNH. Comprehensive microsatellite analysis was carried out with 382 microsatellite markers distributed throughout all chromosomes. To detect AI effectively, the cutoff value of the AI index was set at 0.70. Among the 382 microsatellite markers, 212 loci were informative, but no AI was detected. The absence of gross chromosomal alterations strongly suggested that the large nodule was FNH rather than HCC, in terms of its genetic background. The patient's subsequent clinical course revealed the nodule to be benign. The results suggest that this genome-wide microsatellite analysis is a useful tool for the differential diagnosis of non-neoplastic liver nodules from HCC.

A 44-year-old male presented to our hospital with abdominal pain. The upper endoscopy revealed advanced gastric cancer. On the abdominal CT, there was evidence of multiple, massive liver metastases. After total gastrectomy, the patient was treated with daily oral administration of 120 mg TS-1 for 4 weeks followed by 2 weeks' rest and 6 weekly infusions of 10 mg CDDP in an intra-hepatic artery as 1 cycle. On the follow-up CT, the liver metastases had decreased significantly both in size and number after 2 cycles. The current case suggests that TS-1 and CDDP may have a potent therapeutic efficacy in cases of advanced gastric cancer with multiple liver metastases.

Purpose and Experimental Design: We previously reported that an increased expression of cystatin-like metastasis-associated protein (CMAP) mRNA is involved in liver-specific metastasis in a mouse model. We also identified its human homologue and showed that the expression of CMAP in various human cancer cell lines correlated with the description of malignancy in these cell lines. However, there is still no information available on the clinical significance of CMAP expression in human cancer specimens. Thus, we studied the CMAP expression levels using a real-time quantitative reverse transcription-PCR for 79 patients with colorectal cancer, including 17 cases with liver metastasis., Results: The mean expression level of CMAP in tumor tissue specimens was significantly higher than in the corresponding normal tissue specimens (P < 0.05). A higher expression of CMAP was significantly correlated with liver metastasis (P < 0.01) as well as with a less differentiated histological type (P < 0.05) of colorectal cancer. An increased expression of CMAP was also identified as the strongest independent factor for liver metastasis based on a multivariate analysis (P < 0.001). Furthermore, the prognosis of the patients with a higher expression of CMAP was significantly worse than those with a lower expression (5-year survival rate; 49.7% and 75.0%, respectively, P = 0.038)., Conclusions: These findings imply that the expression level of CMAP in human cancer may be a new biomarker for both liver metastasis and the patient's outcome.

A novel metastasis-associated gene was identified with a differential display system in murine carcinoma cells showing a high rate of metastasis to the liver. A human homologue was also identified using a PCR-based strategy. The protein coded by this gene was named cystatin-like metastasis-associated protein (CMAP) and showed 22.1-28.1% homology to human family 2 cystatins. CMAP mRNA was selectively overexpressed in all murine liver metastatic tumors but not in any pulmonary metastatic tumors examined. Transfection of CMAP antisense DNA into highly metastatic liver cells greatly decreased their metastatic potential and CMAP expression, indicating that CMAP is involved in liver metastatic ability after intravasation of malignant cells. The human homologue of CMAP was found to be expressed in various human cancer cell lines established from malignant tumors. Our discovery of this novel liver metastasis-related gene indicates a new approach to the diagnosis and/or prevention of liver metastasis of human cancer.

We compared the segmental SMANCS/Lip-TAI and the segmental SMANCS/Lip-TAE and studied the effectiveness of both treatments and the influence and/or the side effects on liver function. In resected cases, we studied histopathologic examination. The response rate of the group treated by TAI was 28.6%, and that of the group treated by TAE was 76.5%. In the group treated by TAE, the therapeutic effects were good in nodular type HCC, using small doses of SMANCS. In both groups, the incidence and degree of side effects showed no significant difference. Hepatic insufficiency occurred in a few cases of the group treated by TAI. In resected cases, viable areas remained below the tumor capsule. In conclusion, segmental SMANCS/Lip-TAE seemed to be an effective treatment without any serious complications.

Infantile and maternal choriocarcinoma is a very rare disease. We report a case with the characteristic clinical features of infantile choriocarcinoma: developing anemia, hemorrhagic liver tumors, rapid progression to death and maternal choriocarcinoma. Bone scintigraphy showed increased uptake by the liver tumors. In this case there were two possible primary sites: the placenta of this pregnancy and a hydatidiform mole that had been present 2 years previously.

Seven patients with unresectable liver metastases from colorectal carcinoma were treated with low-dose CDDP plus 5-FU continuous hepatic arterial infusion chemotherapy. A hepatic artery catheter was placed into the gastroduodenal artery at laparotomy or percutaneously placed into the proper hepatic artery via left subclavian artery. Through an injection port placed beneath the skin, 5-FU (300 mg/m2/day) was continuously infused for 5 days; CDDP (6 mg/m2/day) was infused for 5 successive days a week. One cycle consisted of 4 weeks. The response rate was 71% (1 CR, 4 PR, 2 NC). The CEA level decreased in all cases. The median survival was 17 months. Major toxicities were abdominal pain and appetite loss due to extrahepatic perfusion of the drugs. Failure in maintaining the catheter was a problem in most cases. The pharmacokinetic study demonstrated high hepatic extraction of CDDP and 5-FU (40% and 90%, respectively). These results suggest that continuous hepatic arterial infusion chemotherapy with low-dose CDDP plus 5-FU is effective for patients with unresectable liver metastases from colorectal carcinoma.

IMC-HM cells were isolated from spontaneously induced ascitic IMC carcinoma cells that had been maintained intraperitoneally in CDF1 mice. Metastasis to the liver of subcutaneously implanted IMC-HM cells was detected 10 days after implantation into the flanks of mice (day 10), but metastasis to other organs was limited. Thereafter, however, tumor cells spread rapidly to lymph nodes, lung, spleen, ovary and other organs, and the mice died on day 13 to 18. We report here, together with the properties of IMC-HM cells, the effects of adriamycin, cisplatin, etoposide and a new indolocarbazole antitumor compound (NB-506) on this model of metastasis. Although these anticancer agents all inhibited the growth of the subcutaneous tumors, their effects on the life span of the tumor-bearing mice varied. Treatment with NB-506, started on day 1, more than doubled the survival period at doses 30 mg/m2 to 900 mg/m2. Further, treatment with NB-506, started on day 4 after resection of the primary tumor, inhibited growth of the metastasized tumor in the liver and other organs. Etoposide also increased the life span at a limited range of doses. However, the life-prolonging effects of adriamycin and cisplatin were marginal. These results demonstrate that IMC-HM carcinoma is a good model for spontaneous metastasis to the liver followed by lethal spread to many organs. Moreover, NB-506 was found to be highly effective against the growth not only of subcutaneous tumors, but also of tumors metastasized to the liver.

Hepatocellular carcinomas (HCC) of various differentiation, Edmondson (Edm) grade I-IV, often based upon viral infectious hepatitis transformed through regeneration, nodular and/or dysplastic adenomatous hyperplasia. Aspiration cytology, even needle biopsy for such lesions, is very difficult to interpret. We have been studying multiparametric cytologic analysis using DAPI/Hematoporphyrin (HP) staining for the cece samples provided from exactly trimmed 50-microns thick paraffin sections, employing a new software program which we developed, combining DNA ploidy and cell protein content analysis with morphometry. DAPI indicates DNA content and nuclear size and HP indicates cell protein content and cell size. From 21 cases of HCC, 43 nodules or masses including multiple lesions and nodule in nodule were analyzed. Surrounding non-neoplastic hepatic tissues were examined as the control specimens. On DNA histogram, cases with the peak over 2.4 c are identified as aneuploid (Aneupl). Cases of Edm I, or II, 6 of 8 samples showed Aneupl., all of 11 cases of Edm II, 11 cases of Edm III, and one of Edm IV showed Aneupl. Multinodular foci in the same cases and also nodule in nodule often showed different modes of Aneupl. This suggested heterogenetic carcinogeneity. Noncarcinomatous foci often showed Aneupl. modes, which may indicate malignant transformation or malignant potential.

An ongoing analysis of 762 patients with esophageal cancer revealed 4 (0.52%) male patients with synchronous hepatocellular carcinoma (HCC). A long history of habitual alcohol intake and heavy cigarette smoking was recognized in all four patients and, therefore, the possibility of these two factors being independent risk factors for this double cancer was suggested. Palliative treatment was undertaken since either one or both cancers were too far advanced, or because liver function was poor even in those patients with resectable cancers. The prognosis correlated more closely to the TNM stage of esophageal cancer rather than the HCC and the causes of death were related to the esophageal cancer in all four patients. These findings suggest that, in patients with this combination of double cancer, the state of the esophageal cancer may be a more reliable prognostic factor than that of the HCC and thus, the curability of esophageal cancer is of primary importance.