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Background and Aims: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants., Methods: Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined., Results: The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis., Conclusion: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Deregulation of the Wnt/β-catenin pathway is associated with the development of human cancer including colorectal and liver cancer. Although we previously showed that histidine ammonia lyase (HAL) was transcriptionally reduced by the β-catenin/TCF complex in liver cancer cells, the mechanism(s) of its down-regulation by the complex remain to be clarified. In this study, we search for the transcription factor(s) regulating HAL, and identify CEBPA and FOXA1, two factors whose expression is suppressed by the knockdown of β-catenin or TCF7L2. In addition, RNA-seq analysis coupled with genome-wide mapping of CEBPA- and FOXA1-binding regions reveals that these two factors also increase the expression of arginase 1 (ARG1) that catalyzes the hydrolysis of arginine. Metabolome analysis discloses that activated Wnt signaling augments intracellular concentrations of histidine and arginine, and that the signal also increases the level of lactic acid suggesting the induction of the Warburg effect in liver cancer cells. Further analysis reveals that the levels of metabolites of the urea cycle and genes coding its related enzymes are also modulated by the Wnt signaling. These findings shed light on the altered cellular metabolism in the liver by the Wnt/β-catenin pathway through the suppression of liver-enriched transcription factors including CEBPA and FOXA1., (© 2024. The Author(s).)

Introduction: This study aimed to extract prognostic factors in patients undergoing neoadjuvant chemotherapy (NAC) for borderline resectable colorectal liver metastasis (BR-CRLM) (tumor size ≥5 cm, number of tumors ≥4, or resectable extrahepatic diseases) and assess validity of this strategy., Materials and Methods: Since 2010, patients with BR-CRLM were treated with hepatectomy after six cycles of NAC. Prognostic factors of these patients were evaluated using clinicopathological data., Results: Of 650 patients who underwent initial hepatectomy for CRLM from 2010 to 2018, 246 BR-CRLM cases underwent hepatectomy after NAC (BR-NAC). The 5-year recurrence-free survival rate was 16.7% and the 5-year overall survival rate (5y-OS) was 52.9%. Number of tumors ≥6, carcinoembryonic antigen (CEA) level ≥25 ng/mL, tumor diameter ≥5 cm, and progressive disease (PD) after NAC were identified as independent poor prognostic factors for OS. Patients were divided into four groups according to the number of risk factors, and prognoses of the four groups were well stratified., Conclusion: In patients with BR-NAC, number of tumors ≥6, CEA ≥25 ng/mL, tumor diameter ≥5 cm, and PD after NAC were independent poor prognostic factors. Patients with three or four risk factors showed poor prognosis and may need to switch chemotherapy., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Although patients with resectable colorectal liver metastasis (CLM), a population with good prognosis, have been treated with upfront surgery, some patients have had a poor prognosis. This study aimed to investigate biologic prognostic factors in patients with resectable CLMs., Methods: This single-center retrospective study enrolled consecutive patients who underwent liver resection for initial CLMs at the Cancer Institute Hospital between 2010 and 2020. The study defined CLMs as resectable (tumor size < 5 cm; < 4 tumors; no extrahepatic metastasis) or borderline resectable (BR). Preoperative chemotherapy was administered to patients with BR CLMs., Results: During the study period, 309 CLMs were classified as resectable without preoperative chemotherapy and 345 as BR with preoperative chemotherapy. For the 309 patients with resectable CLMs, the independent poor prognostic factors associated with overall survival in the multivariable analysis were high tumor marker levels (CEA ≥ 25 ng/mL and/or CA19-9 ≥ 50 U/mL; (hazard ratio [HR], 2.45; p = 0.0007), no adjuvant chemotherapy (HR, 1.69; p = 0.043), and age of 75 years or older (HR, 2.09; p = 0.012). The 5-year survival rates for the patients with high tumor marker (TM) levels (CEA ≥25 ng/mL and/or CA19-9 ≥50 U/mL) were significantly worse than for those with low TM levels (CEA < 25 ng/mL and CA19-9 < 50 U/mL) (55.3% vs. 81.1%; p <0.0001) and similar to the rate for those with BR CLMs (52.1%; p = 0.864). Postoperative adjuvant chemotherapy had an impact on prognosis only in the high-TM group (HR, 2.65; p = 0.007)., Conclusions: High TM levels have a prognostic impact on patients with resectable CLMs stratified by tumor number and size. Perioperative chemotherapy improves long-term outcomes for patients with CLM and high TM levels., (© 2023. Society of Surgical Oncology.)

Background: Morphologic response (MR) is a novel chemotherapeutic efficacy predictor of solid tumors, especially those treated with anti-vascular endothelial growth factor antibodies. Nevertheless, the importance of systemic chemotherapy MR for colorectal liver metastases (CLM) remains unclear. We aimed to evaluate the usefulness of MR as a factor associated with the therapeutic effects of chemotherapy plus bevacizumab for initially unresectable CLM cases., Methods: We retrospectively evaluated the associations between MR and/or Response Evaluation Criteria in Solid Tumors (RECIST), progression-free survival (PFS), and overall survival (OS) in patients who received first-line capecitabine, oxaliplatin, and bevacizumab treatment for initially unresectable CLM using multivariate analysis. Patients who showed a complete or partial response based on the RECIST, or an optimal response based on MR, were defined as "responders.", Results: Ninety-two patients were examined, including 31 (33%) patients who responded optimally. PFS and OS estimates were comparable in MR responders and non-responders (13.6 vs. 11.6 months, p = 0.47; 26.6 vs. 24.6 months, p = 0.21, respectively). RECIST responders showed better PFS and OS than non-responders (14.8 vs. 8.6 months, p < 0.01; 30.7 vs. 17.8 months, p < 0.01, respectively). The median PFS and OS estimates of MR and RECIST responders were better than those of single responders or non-responders (p < 0.01). Histological type and RECIST response were independently associated with PFS and OS., Conclusion: MR predicts neither PFS nor OS; nevertheless, it may be useful when combined with the RECIST. The Ethics Committee of The Cancer Institute Hospital of JFCR approved this study in 2017 (No. 2017-GA-1123): retrospectively registered., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was developed to predict disease-free survival in patients with colorectal liver metastases (CRLM) undergoing upfront hepatectomy. However, the utility of the nomogram in patients with resected CRLM remains unknown in the current situation in which treatment strategies are changing with advances in drugs., Methods: Patients in the initial nomogram cohort (n = 727) and validation cohort (n = 2225) were divided into the upfront hepatectomy and preoperative chemotherapy groups. The nomogram was validated by measuring calibration and discrimination in the two cohorts. Calibration curves were plotted, and survival probabilities were compared. Finally, to quantify the discrimination power, we estimated the concordance index (C-index)., Results: In the upfront hepatectomy group, the C-index was 0.63, the suitable cutoff value of the Beppu score was 7, and adjuvant chemotherapy was significantly effective limited to high-risk patients (Beppu score ≥7). The C-index was 0.56 in the preoperative chemotherapy group., Conclusions: The JSHBPS nomogram remains beneficial for patients undergoing upfront hepatectomy in the recent era but is less effective for patients undergoing hepatectomy after chemotherapy. Patients with a Beppu score ≥7 showed high-risk recurrence, and adjuvant chemotherapy should be recommended for these patients., (© 2022 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Myxofibrosarcoma (MFS) and undifferentiated sarcoma (US) have been considered as tumors of the same lineage based on genetic/epigenetic profiling. Although MFS shows a notably better prognosis than US, there are no clear criteria for distinguishing between them. Here, we examined 85 patients with MFS/US and found that tumors with infiltrative growth patterns tended to have more myxoid areas and higher local recurrence rates but fewer distant metastases and better overall survival. Morphologically characteristic sickle-shaped blood vessels, which tended to have fewer αSMA-positive cells, were also observed in these tumors, compared with normal vessels. Based on the incidence of these sickle-shaped blood vessels, we subdivided conventionally diagnosed US into two groups. This stratification was significantly correlated with metastasis and prognosis. RNA sequencing of 24 tumors (9 MFS and 15 US tumors) demonstrated that the proteasome, NF-kB, and VEGF pathways were differentially regulated among these tumors. Expression levels of KDR and NFATC4, which encode a transcription factor responsible for the neuritin-insulin receptor angiogenic signaling, were elevated in the sickle-shaped blood vessel-rich US tumors. These findings indicate that further analyses may help elucidate the malignant potential of MFS/US tumors as well as the development of therapeutic strategies for such tumors., (© 2023. The Author(s).)

The Wnt/β-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Primary liver cancer (PLC) is classified into hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular and intrahepatic cholangiocarcinoma (CHC). We investigated the genomic landscape of PLC according to the histological classification and established a cross-histological molecular subtyping for PLC by a multi-omics analysis., Methods: We analyzed 265 PLC cases with whole-exome sequencing and DNA copy number analyses and 251 cases with gene expression profiling., Results: The cohort included HCC (n = 223, 84%), ICC (n = 34, 13%), and CHC (n = 8, 3%). Mutation analyses identified histological type-specific driver genes, such as CTNNB1 in HCC and KRAS, IDH1, and PIK3CA in ICC, and ARID1A and KMT2C in CHC. The tumor suppressor gene TP53 mutation was detected in 21.1% of HCC, 16.1% of ICC, and 25.0% of CHC cases. Other well-characterized tumor suppressor genes included RB1, which was mutated in 2.8% of HCC and 3.2% of ICC; and PTEN, which was mutated in 1.4% of HCC, 3.2% of ICC, and 12.5% of CHC cases. DNA copy number analyses identified focal amplifications, with NUF2 (1q23.3) the most frequently detected as an amplified gene in all 3 types (HCC, 3.8%; CHC, 12.5%, ICC, 3.2%). Molecular subtyping for PLC based on the multi-omics analysis identified three subtypes, one of which was associated with recurrence after resection and amplified genes located at chromosome 8q., Conclusions: Our dataset serves as a fundamental resource for genomic medicine for PLC in Japan and identified amplified genes located at chromosome 8q as promising therapeutic targets for the subgroup with a poor prognosis., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM., Methods: This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated., Results: Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level > 5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p < 0.01) and shorter time until recurrence (4.4 versus 36.9 months, p < 0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level > 5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p < 0.01) for recurrence-free survival (RFS) and 3.18 (p < 0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level > 5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group., Conclusions: The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level > 5 ng/ml group may be predictors of RFS and OS., (© 2022. Society of Surgical Oncology.)

Background: Multiple mutation (MM) within a single gene has recently been reported as a mechanism involved in carcinogenesis. The present study investigated the clinical significance of MMs in hepatocellular carcinoma (HCC)., Methods: Two hundred twenty-three surgically resected HCCs were subjected to gene expression profiling and whole-exome sequencing., Results: MMs in individual genes were detected in 178 samples (MM tumors: 79.8%). The remaining samples all carried a single mutation (SM tumors: 20.2%). Recurrence-free survival in the MM group was significantly worse in comparison to the SM group (P = 0.012). A Cox proportional hazard analysis revealed that MM tumor was an independent predictor for worse a prognosis (hazard ratio, 1.72; 95% confidence interval, 1.01-3.17; P = 0.045). MMs were frequently observed across in various genes, especially MUC16 (15% of samples had at least one mutation in the gene) and CTNNB1 (14%). Although the MUC16 mRNA expression of MUC16 wild-type and MUC16 SM tumors did not differ to a statistically significant extent, the expression in MUC16 MM tumors was significantly enhanced in comparison to MUC16 SM tumors (P < 0.001). In MUC16, MMs were associated with viral hepatitis, higher tumor marker levels and vascular invasion. The MUC16 MMs group showed significantly worse recurrence-free survival in comparison to the MUC16 SM group (P = 0.022), while no significant difference was observed between the MUC16 SM group and the MUC16 wild-type group (P = 0.324)., Conclusions: MM was a relatively common event that may occur selectively in specific oncogenes and is involved in aggressive malignant behavior., (© 2022. The Author(s).)

A 72-year-old woman with rheumatoid arthritis was treated with methotrexate (MTX) and iguratimod. Upon examination of a liver tumor, blisters due to varicella-zoster virus (VZV) infection were observed. Despite oral administration of valacyclovir, she developed varicella pneumonia and meningoencephalitis. A VZV antibody test revealed reinfection. The liver tumor shrank after discontinuance of MTX, and polymerase chain reaction revealed the reactivation of the Epstein-Barr virus (EBV). Therefore, we were unable to deny MTX-associated lymphoproliferative disorder (MTX-LPD). This is the first case of a complication of pneumonia and meningoencephalitis due to VZV reinfection and EBV reactivation.

Purpose: To clarify the efficacy of perioperative chemotherapy for the patients with resectable colorectal liver metastases (CLM), we conducted a multicenter randomized phase III trial to compare surgery followed by postoperative FOLFOX regimen with perioperative FOLFOX regimen plus cetuximab in patients with KRAS wild-type resectable CLM., Methods: Patients who had KRAS wild-type resectable CLM having one to eight liver nodules without extrahepatic disease were randomly assigned to the postoperative chemotherapy group, wherein up-front hepatectomy was performed followed by 12 cycles of postoperative modified FOLFOX6, and the perioperative chemotherapy group (experimental), wherein six cycles of preoperative modified FOLFOX6 plus cetuximab were performed followed by hepatectomy and six cycles of postoperative modified FOLFOX6 plus cetuximab. The primary endpoint was progression-free survival (PFS)., Results: There were 37 patients in postoperative chemotherapy group and 40 patients in the perioperative chemotherapy group who were analyzed. Baseline characteristics were well-balanced between groups. The PFS and overall survival (OS) showed no significant difference (PFS, hazard ratio 1.18 [95% confidence interval 0.69-2.01], P = 0.539: OS, 1.03 [0.46-2.29], P = 0.950). In the postoperative chemotherapy group, 35.1% had a 3-year PFS, and 86.5% had a 3-year OS. Meanwhile, in the perioperative chemotherapy group, 30.0% had a 3-year PFS, and 74.4% had a 3-year OS., Conclusion: There was no difference in survival found between the group of the perioperative chemotherapy plus cetuximab and that of the postoperative chemotherapy in the cohort of our study. The study was registered in the University Hospital Medical Information Network (UMIN000007787)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The genomic characteristics of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) and its differences according to whether an SVR was achieved by treatment with direct-acting antivirals (DAA) or interferon (IFN) are still not fully understood., Methods: Sixty-nine surgically resected HCCs from patients with hepatitis C virus infection were analyzed by gene expression profiling and whole-exome sequencing., Results: Among the 69 HCC patients, 34 HCCs in which an SVR was not achieved at the time of surgery were classified as HCV-positive, and 35 HCCs in which an SVR was achieved at the time of surgery were classified as HCV-SVR. According to the HCV treatment, 35 HCV-SVR HCCs were classified into two groups: eight tumors with DAA (HCV-SVR-DAA) and 24 tumors with interferon (HCV-SVR-IFN). The frequency of samples with ARID2 mutations was significantly lower in HCV-SVR than in HCV-positive tumors (p = 0.048). In contrast, the frequency of samples with PREX2 mutations was significantly higher in HCV-SVR samples than in HCV-positive samples (p = 0.048). Among the patients with HCV-SVR, the frequency of samples with TP53 mutations was significantly higher in HCV-SVR-DAA tumors than in HCV-SVR-IFN tumors (p = 0.030). TP53 inactivation scores in HCV-SVR-DAA tumors were found to be significantly enhanced in comparison to HCV-SVR-IFN tumors (p = 0.022). In addition, chromosomal instability and PI3K/AKT/mTOR pathway signatures were enhanced in HCV-SVR-DAA tumors. HCV-SVR-DAA was significantly associated with portal vein invasion (p = 0.003) in comparison to HCV-SVR-IFN., Conclusion: Our dataset potentially serves as a fundamental resource for the genomic characteristics of HCV-SVR-DAA tumors. Our comprehensive genetic profiling by WES revealed significant differences in the mutation rate of several driver genes between HCV-positive tumors and HCV-SVR tumors. Furthermore, it was revealed that the frequency of samples with mutations in TP53 was significantly higher in HCV-SVR-DAA tumors than in HCV-SVR-IFN tumors., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs)., Methods: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared., Results: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008)., Conclusions: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients., (© 2021. Japanese Society of Gastroenterology.)

Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain-expressed X-linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2 high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM ≥5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm., Methods: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (≤ 5 vs >5 cm) and lesion number (1, 2-4, and ≥5)., Results: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size ≤5 cm; lesions other than nH1 or nH3; and ≥5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable., Conclusion: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Resection for hepatic recurrence after gastrectomy in patients with gastric cancer may be curative; however, the prediction of hepatic recurrence remains intractable. Therefore, we aimed to explore predictive markers for hepatic recurrence in gastric and gastroesophageal junction cancer based on genetic information., Methods: This study recruited 154 patients who underwent curative gastrectomy for pathological stage II or III primary gastric and gastroesophageal junction adenocarcinoma. Genes associated with hepatic recurrence were comprehensively analyzed using whole-exome sequencing and gene expression profiling (GEP), followed by immunohistochemistry analysis for MAGEA10. The cumulative incidences of hepatic recurrence, relapse-free survival, and overall survival were evaluated., Results: A total of 12 patients with early hepatic recurrences were found within 2 years of surgery. Although there were no distinct gene mutations in recurrent patients, upregulation of MAGEA10 was identified in patients with early hepatic recurrence using GEP analysis. Immunostaining for MAGEA10 stained the cell nuclei in 29 (18.8%) of 154 samples. Furthermore, protein expression of MAGEA10 on immunohistochemistry was significantly related to a high MAGEA10 mRNA expression, high cumulative incidences of hepatic recurrence, and poor relapse-free survival. Overall survival did not differ significantly between positive and negative immunohistochemical staining for MAGEA10. The sensitivity and specificity of MAGEA10 staining for early hepatic recurrence were 58.3% and 84.5%, respectively., Conclusions: MAGEA10 represents a promising predictive marker for early hepatic recurrence after curative gastrectomy for gastric and gastroesophageal junction cancer.

Purpose: Liver metastasis (LM) is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). Here, we investigated the prognostic utility of several serum factors in mCRC patients with or without LM who were treated with anti-angiogenic agents in first-line (FL) or salvage-line (SL) settings., Methods: A combined cohort of 125 patients was analyzed in this single institute pooled analysis: FL cohort receiving bevacizumab (n = 71) and SL cohort receiving regorafenib (n = 54). Blood samples were obtained at baseline (BL) and during treatment, and serum factors were measured by ELISA. Overall survival (OS) was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard regression methods., Results: In univariate analysis of the combined cohort, right-sided CRC, primary unresected tumor, wild-type KRAS, LM, ≥ 2 metastatic sites, and SL were associated with shorter OS; in multivariable analysis, LM and SL remained significant. Serum angiopoietin-2 (Ang-2) levels ≥ 2190.3 pg/ml and interleukin (IL)-8 levels ≥ 15.1 pg/ml at BL were significantly associated with LM. Using these cut-off values, patients with higher Ang-2 or IL-8 levels at BL had shorter OS than those with lower BL levels (Ang-2: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.47-4.51, P = 0.001; IL-8: HR 4.31, 95%CI 2.11-8.79, P < 0.001). High serum IL-8 level remained a significant predictor of shorter OS in multivariable analysis (HR 3.24, 95%CI 1.47-7.16, P = 0.004)., Conclusion: Circulating IL-8 and Ang-2 levels are associated with LM in mCRC patients. IL-8 may be a prognostic marker of response to anti-angiogenic therapy, regardless of the treatment timing.

Background/purpose: The purpose of the present study was to assess long-term outcomes following liver resection for colorectal liver metastases (CRLM) with concurrent extrahepatic disease and to identify the preoperative prognostic factors for selection of operative candidates., Methods: In this retrospective, multi-institutional study, 3820 patients diagnosed with CRLM during 2005-2007 were identified using nationwide survey data. Data of identified patients with concurrent extrahepatic lesions were analyzed to estimate the impact of liver resection on overall survival (OS) and to identify preoperative, prognostic indicators., Results: Three- and 5-year OS rates after liver resection in 251 CRLM patients with extrahepatic disease (lung, n = 116; lymph node, n = 51; peritoneal, n = 37; multiple sites, n = 23) were 50.2% and 32.0%, respectively. Multivariate analysis revealed that a primary tumor in the right colon, lymph node metastasis from the primary tumor, serum carbohydrate antigen (CA) 19-9 level >37 UI/mL, the site of extrahepatic disease, and residual liver tumor after hepatectomy were associated with higher mortality. We proposed a preoperative risk scoring system based on these factors that adequately discriminated 5-year OS after liver resection in training and validation datasets., Conclusions: Performing R0 liver resection for colorectal liver metastases with treatable extrahepatic disease may prolong survival. Our proposed scoring system may help select appropriate candidates for liver resection., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: To collect large-scale data for further research to improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese society of Hepato-Biliary-Pancreatic Surgery. The joint committee was initiated to collect data since 2014 and has already reported data including the prognostic data of 3820 patients newly diagnosed with CRLM between 2005 and 2007., Methods: The data of patients newly diagnosed with CRLM after 2013 are continuously being registered prospectively, and herein, we report the data of the patients newly diagnosed with CRLM in 2013 and 2014., Results: The data of 3839 patients newly diagnosed with CRLM in 2013 and 2014 were registered from 156 departments (75%) of 152 institutions among 209 departments (from 201 institutions) that agreed to participate in this database system at its initiation. Finally, 3525 patients were enrolled in this study after a quality management process conducted by the joint committee. We report the comprehensive data obtained from 3525 patients, including clinicopathological findings, treatment strategies, and implementation status of chemotherapy., Conclusion: The joint committee will provide these raw data while updating prognostic data to researchers who will conduct meaningful studies that meet the aim of the joint committee., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background & Aims: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD., Methods: We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy-proven NAFLD diagnosed during 2002-2019. During follow-up, 14 patients (4.8%) developed hepatocellular carcinoma., Results: Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P = .041), but not HSD17B13 AG/GG (P = .776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis., Conclusions: In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice., Methods: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0., Results: A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2-16.9), and the median OS was 24.2 months (13.6-NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required., Conclusions: PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m 2 ) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m 2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m 2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m 2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m 2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Background: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC)., Patients and Methods: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI)., Results: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%., Conclusion: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: There are no optimal indication criteria for neoadjuvant chemotherapy (NAC) in patients with resectable colorectal liver metastases (CLM). The aim of this study was to prospectively assess the survival benefit of selective NAC administration in this patient population based on tumor characteristics., Methods: Borderline resectable CLM (BR-CLM) were defined as four or more liver metastases, CLM larger than 5 cm, or CLM with concomitant resectable extrahepatic metastases. From 2010 to 2015, NAC was administered to BR-CLM patients. Upfront surgery without NAC was performed to patients having clearly resectable CLM (less than 3 lesions, smaller than 5 cm, and no extrahepatic metastases: CR-US group). Survival outcomes of the two groups were assessed., Results: The BR-NAC group comprised 73 patients and the CR-US group 172. All patients in the BR-NAC group underwent subsequent resection, as none showed disease progression or chemotherapy-associated liver damage. The 3- and 5-year overall survival rates of the CR-US group were 83.0% and 74.0%, while patients in the BR-NAC group had comparable 3-year and 5-year overall survivals (80.5% and 66.6%, P = 0.397)., Conclusion: Defining BR-CLM based on tumor characteristics optimizes patient selection for NAC. Favorable overall survival can be achieved by upfront surgery in patients with clearly resectable CLM and by NAC in patients with BR-CLM.

Background: Panitumumab is the first human combinatorial antibody for the treatment of metastatic colorectal carcinoma. Dermatologic toxicity of all grades occurs in more than 90% of patients. However, there are few reports of purpura induced by anti-epidermal growth factor receptor antibody. Renal failure is also uncommon as an adverse event of anti-epidermal growth factor receptor antibody., Case Presentation: A 67-year-old Japanese man with advanced colon cancer received monotherapy with panitumumab. General malaise, bilateral edema of his legs, and bilateral purpura of his forearms developed 2 days after the second cycle of panitumumab. A skin biopsy was performed to evaluate the purpuric lesions on his left leg and leukocytoclastic vasculitis was diagnosed. Blood tests showed grade III acute renal failure with a blood urea nitrogen level of 33.8 mg/dL and a creatinine level of 3.10 mg/dL., Conclusions: This is the first reported case of leukocytoclastic vasculitis followed by purpura and acute renal failure associated with panitumumab.

A 70-year-old man with lower right quadrant abdominal discomfort was admitted to our hospital. Colonoscopy identified a villous tumor protruding into the cecal lumen from the appendiceal orifice. Abdominal computed tomography(CT)revealed a cecal tumor with a swollen appendix. An appendiceal cecal tumor with obliterative appendicitis was diagnosed, and we performed an appendicectomy with removal of part of the cecum. On pathological examination, well to moderately differentiated adenocarcinoma with infiltration of the proper muscular layer was diagnosed. No additional treatment was given as the patient refused further surgery and chemotherapy. However, a metastatic tumor in S4/8 of the liver was seen on CT 5 months after the initial surgery. A resection of liver metastasis was performed after chemotherapy. We report herein a rare case of primary appendiceal adenocarcinoma reoccurring shortly after surgery.

Background: High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer., Patients and Methods: Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate., Results: This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P = .018). The low-expression (cutoff < 15%) TK1 group experienced a smaller OS benefit (9.3 vs. 7.4 months; hazard ratio = 0.88; 95% confidence interval, 0.63-1.23; P = .45). For patients who received placebo, the high-expression TK1 group had a slightly worse prognosis than the low-expression TK1 group. The tendency of FTD/TPI efficacy concerning progression-free survival and disease control rate was not similar to that concerning OS between groups., Conclusion: Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Repeat hepatectomy is often required for hepatocellular carcinoma and metastatic tumors. However, this procedure is technically challenging, so laparoscopic repeat hepatectomy (LRH) has not been widely adopted. The aim of this study was to evaluate the feasibility and efficacy of LRH compared with open repeat hepatectomy (ORH) and laparoscopic primary hepatectomy (LPH)., Methods: We introduced laparoscopic hepatectomy at our institution in April 2014. We performed 127 LPH (LPH group) and 33 LRH procedures (LRH group) from April 2014 to April 2017; 37 patients underwent ORH from January 2010 to April 2017 (ORH group). This study retrospectively compared the patient characteristics and short-term outcomes of the LRH and ORH groups as well as the LRH and LPH groups., Results: There were no conversions to open surgery in the LRH group. In comparing the LRH and ORH groups, there were no significant differences in patient characteristics except for the type of approach to the previous hepatectomy (p = 0.004) and indocyanine green retention rate at 15 min (median 12.5 vs. 8.75%, p = 0.026). The LRH group had less blood loss (median 30 mL vs. 652 mL; p < 0.001), less intraoperative transfusion (6.1 vs. 32.4%; p = 0.006), and shorter postoperative hospital stays (median 6.5 days vs. 9.0 days; p < 0.001). There were no differences with regard to operation time, severe postoperative complications, and mortality. In comparing the LRH and LPH groups, there was a significant difference only in past history of abdominal surgery (100 vs. 61.4%; p < 0.001). In the short-term outcomes, the postoperative hospital stay was significantly shorter in the LRH group (median 6.5 days vs. 7 days; p = 0.033), and the other results were comparable between the two groups., Conclusions: LRH is feasible and useful for repeat hepatectomy, achieving good short-term outcomes.

The aberrant expression or alteration of microRNAs (miRNAs/miRs) contributes to the development and progression of cancer. In the present study, the functions of miR-96-5p in hepatocellular carcinoma (HCC) were investigated. It was identified that miR-96-5p expression was significantly upregulated in primary HCC tumors compared with their non-tumorous counterparts. A copy number gain was frequently observed at chromosomal region 7q32.2 in which the MIR96 locus is located, suggesting that gene amplification may be one of the mechanisms by which miR-96-5p expression is increased in HCC. Transfection of miR-96-5p mimic into HCC cells decreased the expression of CASP9, which encodes caspase-9, the essential initiator caspase in the mitochondrial apoptotic pathway, at the mRNA and protein levels. A putative binding site for miR-96-5p was identified in the CASP9 3'-untranslated region, and the results of a luciferase assay indicated that CASP9 is a potential direct target of miR-96-5p. The miR-96-5p mimic increased resistance to doxorubicin- and ultraviolet-induced apoptosis through the decrease in caspase-9 expression in HCC cells. Transfection of miR-96-5p inhibitor enhanced the cytotoxic effect of doxorubicin by increasing caspase-9 expression in the HCC cells, suggesting a synergistic effect between the miR-96-5p inhibitor and doxorubicin. In conclusion, the results of the present study suggest that miR-96-5p, which is frequently upregulated in HCC, inhibits apoptosis by targeting CASP9. Therefore, miR-96-5p may be a potential therapeutic target for HCC.

Objective: To evaluate prospectively the efficacy and safety of sorafenib, which has been the first-line treatment for advanced hepatocellular carcinoma (HCC), in Japanese HCC patients (pts) with not only Child-Pugh (C-P) A class but also C-P B class., Methods: Sorafenib was administered orally at the dose of 400 mg twice daily for pts with HCC and liver function of C-P score of 5-8. Administration was continued until the detection of disease progression or appearance of unacceptable toxicity. The primary endpoint was time to progression (TTP), and toxicity and the secondary endpoints included objective response, overall survival (OS)., Results: Forty C-P A pts and 12 C-P B pts were enrolled. The median TTP in the C-P A pts and C-P B pts was 3.3 months and 3.2 months, respectively. Among the pts with C-P A, complete response, partial response, and stable disease were achieved for 2.5%, 7.5% and 47.5%. Among the pts with C-P B, there were no treatment responses, 66.7% of pts had stable disease. The median OS in the C-P A pts and C-P B pts was 13.4 months and 7.4 months, respectively. With regard to toxicities, fewer C-P A pts experienced Grade 3/4 toxicities than C-P B pts (77.5% vs. 91.6%). There were no treatment-related deaths in either group of patients., Conclusions: This study shows sorafenib has similar effectiveness in the recent post-approval studies and is well-tolerated in Japanese pts with HCC and Child Pugh A class. Sorafenib should be used with great care for Child Pugh class B pts.

A 48-year-old woman with severe interstitial pneumonitis was diagnosed with right breast cancer(invasive ductal carcinoma, T1aN1M0, ER+, PgR-, HER2 3+)and underwent modified radical mastectomy.The patient was administered tamoxifen as adjuvant therapy.However, 1 year after the mastectomy, multiple liver metastases were found and the patient received 2 anti-HER2 agents, trastuzumab and pertuzumab.A complete response(CR)was observed with the disappearance of the liver metastases in 7 months.CR was maintained for 2 years after the initiation of treatment, and then, we started trastuzumab monotherapy, which has resulted in long-term disease control.

Background and Aim: The recommendedind ication of transcatheter arterial chemoembolization(TACE)for hepatocellular carcinoma(HCC)is Barcelona Clinic Liver Cancer(BCLC)stage B HCC. But there are some cases in which we do not perform TACE because of liver damage with malnutrition in stage B. So we examined whether branched-chain amino acid (BCAA)improve nutritional status and perform TACE to contribute the prolongation of HCC survival., Methods: This study included8 8 patients treatedfor liver cirrhosis with HCC. All patients initially receivedBCAA granules. In patients with unchangedor decreasedAlb levels, BCAA granules were discontinuedandBCAA enrichednutrient was started. TACE for HCC were performedin those with an improvedChild -Pugh score., Results: TACE were performedfollowing the aggressive intervention with BCAA nutritional education in 66 of 88(75%)patients. Finally, overall survival time was significantly extended in TACE group(p<0.0001)., Conclusion: Timely aggressive nutritional intervention in BCLC stage B HCC, early partial replacement with BCAA enrichednutrient before TACE may consequently contribute to improvement of the treatment outcome of HCC.

An 80-year-old man had a medical history of chronic hepatitis C and pancreatoduodenectomy. We detected recurrence of hepatocellular carcinoma, and performed transcatheter arterial chemoembolization, instead of radiofrequency ablation or surgery, because of the patient's medical history of bile duct reconstruction and liver dysfunction. On the second day, he was diagnosed with a gas-forming liver abscess and underwent liver abscess drainage. Clostridium perfringens and sordellii were detected by aspiration and the blood culture. Meropenem and Clindamycin were administered intravenously. He was treated shortly after the occurrence before the involvement of severe hemolysis and recovered from the acute phase.

Aim: In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after ≥2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of > 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness., Methods: Patients who underwent TACE for hepatocellular carcinomas > 3 cm in size or with > 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the "either" group, evaluated as either "ineffective" or "progressive," and the "both" group, that is, both "ineffective" and "progressive.", Results: The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (n = 23) and both (n = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (p = 0.0295)., Conclusions: Patients with both "ineffective" and "progressive" lesions are extremely likely to be TACE -refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered., (© 2018 S. Karger AG, Basel.)

We report a rare case of hepatic cholangiolocellular carcinoma (CoCC) with long-term observation. A 73-year-old woman was found to have a solitary hepatic tumor with a diameter of 10mm on dynamic computed tomography (CT), which showed peripheral enhancement in the arterial phase and enhancement retention in the delayed phase. Although it was initially diagnosed as hepatic hemangioma, the follow up examination conducted 16 months later revealed that the tumor had grown to 18mm. Doubling time of the tumor was calculated to be 177 days. Because magnetic resonance imaging results were not typical for hepatic hemangioma, hepatocellular carcinoma was suspected and partial hepatectomy was performed. Histologically, the tumor was comprised dense proliferation of small irregular tubules with fibrous stroma. Immunohistochemistry revealed that the carcinoma cells were positive for cytokeratin (CK) 7, CK19, and neurnal cell adhesion molecule. Cells were negative for hepatocyte paraffin 1. Periodic acid-Schiff and Alcian blue staining showed an absence of mucin in the tumor cells, and epithelial membrane antigen was strongly positive on the luminal surface of tubules. These findings were typical of CoCC;therefore, CoCC should be ruled out when dynamic CT images suggest hepatic hemangioma.

Background/aim: Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent operation at our Institution. The aim of this study was to identify novel genes displaying altered gene expression related to the survival and early recurrence after hepatectomy for hepatocellular carcinoma (HCC) using the results of integrated GEP analysis., Materials and Methods: The present study included 92 patients. Genes with aberrant expression were selected by the difference of expression levels with ≥10-fold change between tumor and non-tumor tissues., Results: GEP analysis showed that down-regulation was frequently observed in the PRSS8 (64%), CYP3A4 (61%) and EPCAM (57%) genes. Multivariate analysis revealed tumor stage ≥II (p=0.008) and down-regulation of the CYP3A4 gene (p=0.036) as independent predictor for overall survival. Furthermore, multivariate analysis identified maximum tumor diameter ≥74mm (p=0.008), presence of intrahepatic-metastasis (p=0.020), and down-regulation of CYP3A4 gene (p=0.019) as independent predictors for early recurrence., Conclusion: CYP3A4 was identified as a novel tumor suppressor gene related to a poor prognosis in HCC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer., Methods: Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status., Results: The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab., Conclusions: Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.

Aim: In general, transcatheter arterial chemoembolization(TACE)can obtain a high therapeutic effect on hypervascular tumors, but the definition of"hypervascular"is unclear. In this study, stainedtumor images on enhancedcomputedtomography( CT)were assessedaccord ing to CT-attenuation value. We investigatedwhether it is possible to estimate the treatment effect(TE)of TACE for hepatocellular carcinomas(HCCs)., Study Population and Methods: We studied 50 patients with unresectable HCCs who underwent TACE. A total of 141 tumors were diagnosed as HCC on enhanced CT. We measured andcalculatedthe ratios of CT-attenuation values of HCCs in the arterial phase to normal enhancedliver parenchyma in the portal phase(CT value ratio). We then evaluatedTE on each target nodule by enhancedCT, to examine the correlation between TE andthe CT value ratio., Results: The CT-attenuation values were 119(range 61-180)hounsfieldunits(HU)for HCC and8 3(49-141)HU for liver parenchyma, andthe CT value ratio was 1.47(0.7-2.6). TE was positively correlatedwith the CT value ratio(p=0.0005). The cut-off value that suggestedfavorable results for TACE was 1.7 by receiver operating characteristic(ROC)analysis., Conclusion: The CT value ratio is useful for recognition of hypervascular tumors. We obtained favorable results in cases with a CT value ratio of 1.7 or more.

A 78-year-old man visited our hospital with a prolapsed hemorrhoid. He was referred to the dermatology unit due to the thickness and redness of the perianal skin. He was diagnosed as having extra mammary Paget's disease by skin biopsy. After a biopsy of the anal polyp was performed to investigate the primary site, he was diagnosed with early anal canal cancer with Pagetoid spread and underwent a radical operation. Abdominoperineal resection with skin(D2 prx D3 lymphadenectomy) was performed with perineal reconstruction using a gracilis muscle graft. Postoperative surveillance without adjuvant therapy was performed because the pathological stage was stage I. Two years and 2 months after surgery, multiple liver metastases were found, and the patient was diagnosed with multiple liver, bone, and lymph node metastases(K-ras and UGT1A1 wild type)on PET. XELOX plus bevacizumab was used as first-line treatment and the liver metastases showed remarkable shrinkage; however, disease progression occurred in the bone. IRIS plus bevacizumab was started as second-line therapy but grade 3 hematotoxicity was observed during the first course. After 4 courses, it was difficult to maintain the therapy due to toxicity and cancer-related pain. The liver metastases had almost disappeared but the patient died 11 months after the initiation of chemotherapy.

Background: Human epidermal growth factor (HER) 2 positivity and its association with clinicopathological factors remain unclear in Japanese gastric cancer (GC) patients. We performed a prospective, multicenter, observational cohort study to evaluate HER2 protein expression and gene amplification in Japanese metastatic and recurrent GC patients, and explored its correlations with clinicopathological features., Methods: HER2 protein expression and gene amplification were centrally assessed in formalin-fixed, paraffin-embedded GC tissue by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Patient information was collected, and associations between clinicopathological factors and HER2 positivity (IHC score 3+ and/or FISH positive) and low HER2 expression (IHC score 0/FISH positive or IHC score 1+/FISH positive) were examined., Results: From September 2011 to June 2012, 1461 patients were registered across 157 sites, and the HER2 status of 1427 patients was evaluated. The rate of HER2 positivity was 21.2 %, whereas the rate of high HER2 expression (IHC score 2+/FISH positive or IHC score 3+) was 15.6 % and that of low HER2 expression was 7.0 %. Multiple logistic regression analysis identified intestinal type, absence of peritoneal metastasis, and hepatic metastasis as significant independent factors related to HER2 positivity. The intestinal type was confirmed to be the GC subtype predominantly associated with lower HER2 expression. Sampling conditions including number of biopsy samples, formalin concentration, and formalin-fixation time did not significantly affect HER2 positivity., Conclusions: HER2 expression in Japanese patients was comparable to that in other populations examined. Intestinal type was an independent factor related to HER2 positivity and low HER2 expression.

Background: A randomized phase III study of Japanese patients with advanced gastric cancer, the G-SOX trial, revealed that S-1 and oxaliplatin (SOX) combination therapy was noninferior to S-1 and cisplatin (CS) combination therapy. However, it is unclear whether the efficacy and safety in elderly patients were different between the two regimens., Methods: A total of 685 patients registered in the G-SOX trial were classified as elderly (70 years or older) or not elderly (younger than 70 years), and 663 patients (SOX therapy, elderly 113 of 333 patients, 34 %; CS therapy, elderly 99 of 330 patients, 30 %) and 673 patients (SOX therapy, elderly 114 of 338 patients, 34 %; CS therapy, elderly 101 of 335 patients, 30 %) were analyzed for efficacy and safety, respectively. Treatment delivery of SOX was also compared between elderly and nonelderly groups., Results: No differences in efficacy were identified between the elderly and nonelderly groups for either regimen. In the elderly groups, SOX therapy showed better trends in progression-free survival (hazard ratio 0.805, 95 % confidence interval 0.588-1.102) and overall survival (hazard ratio 0.857, 95 % confidence interval 0.629-1.167) compared with CS therapy, although there were no significant differences. Grade 3 or worse adverse events were less frequent in the elderly group receiving SOX than in the elderly group receiving CS except for the low incidence of sensory neuropathy (5.3 % vs 0 %), neutropenia (25.4 % vs 42.6 %), anemia (21.1 % vs 42.6 %), febrile neutropenia (1.8 % vs 10.9 %), increased creatinine level (0.9 % vs 3.0 %), and hyponatremia (7.9 % vs 18.8 %)., Conclusions: SOX is an effective and feasible therapy in both nonelderly and elderly patients with advanced gastric cancer. In elderly patients, SOX demonstrated favorable efficacy and safety compared with CS.

p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis and its incidence is increasing worldwide. Recently, several types of cells have been considered as the origin of ICC, namely cholangiocytes, liver progenitor cells, and hepatocytes. Here, we have established a novel mouse model of ICC by liver-specific Kras activation and Pten deletion. An activating mutation of Kras in combination with deletion of Pten was introduced in embryonic hepatic bipotential progenitor cells (so-called hepatoblasts) and mature hepatocytes using the Cre-loxP system. As a result, liver-specific Kras activation and homozygous Pten deletion cooperated to induce ICCs exclusively. In contrast, Kras activation in combination with heterozygous Pten deletion induced both ICCs and HCCs, whereas Kras activation alone resulted in HCCs but not ICCs. Furthermore, a cell-lineage visualization system using tamoxifen-inducible Cre-loxP demonstrated that the ICCs did not originate from hepatocytes but from cholangiocytes. Our data suggest that mice carrying liver-specific Kras activation in combination with homozygous Pten deletion should be useful for the investigation of therapeutic strategies for human ICC.

Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC.

Background: In decompensated liver cirrhosis, hypoalbuminemia still persists even after they have been treated with branched-chain amino acid (BCAA) granules. We prospectively evaluated whether BCAA enriched nutrient switched from BCAA granules would increase the serum albumin level, and consequently extend the survival time after hepatocellular carcinoma (HCC) treatment., Methods: This study included 77 patients treated for liver cirrhosis with HCC. After the nutritional assessment, all patients initially received BCAA granules. In patients with unchanged or decreased serum albumin levels, BCAA granules were discontinued and BCAA enriched nutrient was started. Transcatheter arterial chemembolization (TACE) for HCC were performed in those with an improved Child-Pugh score., Results: TACE were performed following the aggressive intervention with BCAA nutritional education in 54 of 77 (70.1%) patients. Finally, survival time was significantly extended in the TACE group (P<0.0001)., Conclusion: Timely aggressive nutritional intervention in Barcelona Clinic Liver Cancer stage B HCC, namely, early partial replacement with BCAA enriched nutrient may consequently improve the treatment outcome of HCC.

A 46-year-old man presented with hematochezia in October 2012. A circumferential type 2 rectal cancer was detected with colonoscopy. Contrast-enhanced CT showed multiple liver and lung metastases. Chemotherapy was administered after the diagnosis of cStage Ⅳ rectal cancer. After 1 course of XELOX plus Bmab, the treatment was changed to XELOX plus Cmab for 21 courses. An infusion reaction occurred during the 21st course. Because a complete response of the liver metastases and a reduction in size of the primary tumor had been achieved, we performed a low anterior resection in April 2014. The final pathological diagnosis was type 2, 10×25 mm, tub1, pMP, int, INF b, pN1 (251). There was no evidence of disease (NED) after the surgery. We are closely following up this patient with no postoperative chemotherapy, and as of July 2015, there is no sign of recurrence. We describe a case of a Stage Ⅳ rectal cancer that was resected with radical surgery after neoadjuvant chemotherapy. We also include a brief review of the literature.