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Cholangiolocarcinoma (CLC) is a primary liver carcinoma that resembles the canals of Hering and that has been reported to be associated with stem cell features. Due to its rarity, the nature of CLC remains unclear, and its pathological classification remains controversial. To clarify the positioning of CLC in primary liver cancers and identify characteristics that could distinguish CLC from other liver cancers, we performed integrated analyses using whole-exome sequencing (WES), immunohistochemistry, and a retrospective review of clinical information on eight CLC cases and two cases of recurrent CLC. WES demonstrated that CLC includes IDH1 and BAP1 mutations, which are characteristic of intrahepatic cholangiocarcinoma (iCCA). A mutational signature analysis showed a pattern similar to that of iCCA, which was different from that of hepatocellular carcinoma (HCC). CLC cells, including CK7, CK19, and EpCAM, were positive for cholangiocytic differentiation markers. However, the hepatocytic differentiation marker AFP and stem cell marker SALL4 were completely negative. The immunostaining patterns of CLC with CD56 and epithelial membrane antigen were similar to those of the noncancerous bile ductules. In contrast, mutational signature cluster analyses revealed that CLC formed a cluster associated with mismatch-repair deficiency (dMMR), which was separate from iCCA. Therefore, to evaluate MMR status, we performed immunostaining of four MMR proteins (PMS2, MSH6, MLH1, and MSH2) and detected dMMR in almost all CLCs. In conclusion, CLC had highly similar characteristics to iCCA but not to HCC. CLC can be categorized as a subtype of iCCA. In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA. © 2024 The Pathological Society of Great Britain and Ireland., (© 2024 The Pathological Society of Great Britain and Ireland.)

Purpose: In this research, we analyzed the expression of serpinB9 in hepatoblastoma and investigated the factors which enhance its expression., Method: SerpinB9 expression in hepatoblastoma cell lines and macrophages co-cultured with each other or stimulated by anticancer agents was examined using RT-qPCR and western blotting. Immunohistochemistry for SerpinB9 in hepatoblastoma specimens was performed. Single-cell RNA-sequence data for hepatoblastoma from an online database were analyzed to investigate which types of cells express SerpinB9., Result: HepG2, a hepatoblastoma cell line, exhibited increased expression of SerpinB9 when indirectly co-cultured with macrophages. Immunohistochemistry for the specimens demonstrated that serpinB9 is positive not in hepatoblastoma cells but in macrophages. Single-cell RNA sequence analysis in tissues from hepatoblastoma patients showed that macrophages expressed SerpinB9 more than tumor cells did. Co-culture of macrophages with hepatoblastoma cell lines led to the enhanced expression of SerpinB9 in both macrophages and cell lines. Anticancer agents induced an elevation of SerpinB9 in hepatoblastomas cell lines., Conclusion: In hepatoblastoma, SerpinB9 is thought to be more highly expressed in macrophages and enhanced by interaction with hepatoblastoma cell., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

An 82-year-old, male. He visited his local doctor with a chief complaint of dyspnea on exertion. Anemia was noted, and upper gastrointestinal endoscopy was performed, which revealed an ulcerative lesion in the gastric antrum. A biopsy revealed Group 5, tub2, and HER2 negative, with PD-L1≥5%. cT3N1H1(M1 HEP), cStage ⅣB was diagnosed based on CT scan showing enlarged #8 lymph node and a single liver metastasis in the 2 cm range in S6 of the liver. The patient was deemed unresectable and was started on SOX plus nivolumab therapy. On day 11 after initiation, the patient had Grade 3 diarrhea by CTCAE v5.0, and S-1 was withdrawn for 3 days, but was administered for 2 courses. CT and MRI after chemotherapy showed shrinkage of both the primary tumor and liver metastases; R0 resection was deemed possible, and pyloric gastrectomy, D2 lymph node dissection, and partial hepatic S6 resection were performed. The histological evaluation of response to treatment was Grade 1b, and the patient was in ypStage ⅠA. The patient has been alive without recurrence for 6 months postoperatively while receiving S-1 monotherapy on an outpatient basis.

Purpose: This study investigated the expression of interleukin 32 (IL-32) in hepatoblastoma, the most common primary pediatric liver tumor, and its possible roles in tumorigenesis., Methods: IL-32 expression was investigated in two hepatoblastoma cell lines (Hep G2 and HuH 6) in the steady state and after co-culture with macrophages by RNA-seq analysis and RT-qPCR, and after stimulation with chemotherapy. Cultured macrophages were stimulated by IL-32 isoforms followed by RT-qPCR and western blot analysis. IL-32 immunohistochemical staining (IHC) was performed using specimens from 21 hepatoblastoma patients. Clustering analysis was also performed using scRNA-seq data downloaded from Gene Expression Omnibus., Results: The IL-32 gene is expressed by hepatoblastoma cell lines; expression is upregulated by paracrine cell-cell communication with macrophages, also by carboplatin and etoposide. IL-32 causes protumor activation of macrophages with upregulation of PD-L1, IDO-1, IL-6, and IL-10. In the patient pool, IHC was positive only in 48% of cases. However, in the downloaded dataset, IL-32 gene expression was negative., Conclusion: IL-32 was detected in hepatoblastoma cell lines, but not in all hepatoblastoma patients. We hypothesized that stimulation such as chemotherapy might induce expression of IL-32, which might be a critical mediator of chemoresistance in hepatoblastoma through inducing protumor activation in macrophages., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The liver T 1 reduction rate can be used to assess liver function. However, higher doses of gadoxetic acid may shorten the liver T 1 value in the hepatobiliary phase and increase the T 1 reduction rate in patients with severe liver dysfunction, potentially overestimating liver function., Purpose: To verify the relationship between the gadoxetic acid dose and the liver T 1 reduction rate and ΔR 1 of the liver and spleen, and to clarify whether the ΔR 1 of hepatocytes, corrected for the effect of gadoxetic acid dose, could be used as an index of functional liver reserve., Material and Methods: We enrolled 13 patients with normal liver function (NLF); and 18, 8, and 3 patients with Child-Pugh classes A (CPA), B (CPB), and C (CPC) who underwent gadoxetic acid-enhanced magnetic resonance imaging. Phase-sensitive inversion recovery sequence was performed before and at 15 min after injection and T 1 maps were calculated. Liver and spleen ΔR 1 , liver T 1 reduction rate, and the liver-to-spleen ΔR 1 ratio were calculated., Results: Only the liver-to-spleen ΔR 1 ratio showed no correlation with gadoxetic acid dose in any group. The T 1 reduction rate was not significantly different between the CPA and CPB + CPC groups. The liver-to-spleen ΔR 1 ratio significantly differed between all groups., Conclusion: The liver and spleen ΔR 1 was dependent on the dose of gadoxetic acid in severe liver dysfunction. The liver-to-spleen ΔR 1 ratio improves the delineation of the CPA and CPB + CPC groups.

A 68-year-old man with dysphagia had advanced esophageal cancer with single liver metastasis(cT4bN2M1, cStage Ⅳb). After induction chemoradiotherapy, consisting of 2 courses of FP therapy and 40 Gy radiotherapy, thoracoscopic radical esophagectomy and laparoscopic partial resection of liver metastatic lesion were performed because the primary lesion was significantly reduced. Histopathological findings showed that the therapeutic effect of the primary lesion was Grade 3, and lymph node metastasis and liver metastasis disappeared, resulting in pathological CR. Postoperative chemotherapy was not performed. Esophageal cancer did not recur during 3 and a half years after the operation.

Background/aim: Biliary fistulas (BFs) following hepatic resection are a complication of concern, and methods to completely prevent BFs after hepatic resection have yet to be developed. Our aim was to study the use of systemically administered indocyanine green (ICG) for preventing bile leakage (BL) from the cut surface of the liver., Patients and Methods: The study sample comprised 26 patients who underwent hepatectomy without ICG (conventional observation group; CO-G) and 23 hepatectomy patients who underwent intraoperative detection of BL using systemically administered ICG (ICG observation group; IO-G). We compared the bilirubin levels in drainage effluent between patients in whom BL from the resected liver was observed using conventional assessment with the naked eye and those in whom ICG leakage was used as an indicator of BL. In the IO-G, we also compared the number of BL spots on the resected plane visible to the naked eye with the number of visible spots on an ICG camera., Results: Three days after surgery, the bilirubin levels in the drainage fluid of the IO-G were significantly lower than those in the CO-G (1.3 vs. 1.9 mg/dl, p=0.019). Two cases (7.7%) of International Study Group of Liver Surgery (ISGLS) grade B biliary fistula occurred in the CO-G, but none in the IO-G. In the IO-G, the number of BL spots detected just after hepatectomy was significantly higher using ICG camera observation than the naked eye observation (0.22 vs. 0.91 spots, p<0.001)., Conclusion: Observation with systemically administered ICG can detect BLs with more sensitivity than conventional observation with the naked eye. This enables rapid repair and may prevent biliary fistula., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tumor-associated macrophages (TAMs) have protumor functions in various cancers. However, their significance in hepatoblastoma, the most common liver tumor in children, remains unclear. The aim of this study was to explore the potential roles of TAMs in hepatoblastoma. Immunohistochemical analysis revealed that the density of CD204-positive TAMs was significantly higher in the embryonal component than in other histological subtypes of hepatoblastoma. An in vitro co-culture study with Huh6 cells and human monocyte-derived macrophages (HMDMs) showed that macrophage-colony-stimulating factor receptor (M-CSFR) was strongly up-regulated in the Huh6 cells that were directly co-cultured with HMDMs. The expressions of M-CSFR ligands (interleukin-34 and M-CSF) were also increased by co-culture with HMDMs. The proliferation of HepG2 cells (another hepatoblastoma cell line expressing M-CSFR) was inhibited by an M-CSFR inhibitor. M-CSFR was found to be highly expressed in the embryonal component and in recurrent lesions. The number of CD204-positive macrophages was also higher in the M-CSFR-positive areas than in the M-CSFR-negative areas. Thus, M-CSFR expression appeared to be induced by cell-cell contact with macrophages in hepatoblastoma cells, and M-CSFR inhibitor is potentially effective against M-CSFR-positive hepatoblastoma, especially recurrent cases., (© 2022. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background/aim: This study investigated the influence of surgery for metasynchronous liver metastasis in gastric cancer on prognosis., Patients and Methods: A retrospective study was conducted involving 21 consecutive patients with gastric cancer with metasynchronous distant metastasis only in the liver after curative gastrectomy. The patients were divided into two groups: those who underwent hepatic resection and those who did not. The clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analysed., Results: Among 981 gastrectomies performed in Tottori University Hospital between 2005 and 2019, 930 were curative. Among 153 cases of recurrence during the follow-up, 21 consecutive cases involving the liver only and metasynchronous recurrent metastasis on imaging were included in this study. The study included 16 males and five females with a median age of 70 years. No statistical difference in RFS (237 vs. 201 days; p=0.788) was observed between the hepatectomy and non-hepatectomy groups; however, OS (1,564 vs. 608 days, p=0.008) and DSS (1,597 vs. 608 days, p=0.006) were significantly prolonged in the hepatectomy group. Univariate and multivariate analyses revealed that hepatectomy was the only independent prognostic factor (hazard ratio=0.33; p=0.042)., Conclusion: Hepatic resection of heterogeneous liver metastases in gastric cancer seems to be a useful option that can be expected to cure the disease, which cannot be achieved by chemotherapy alone., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Gastric cancer (GC) is one of the most common malignancies, and the liver is the most common site of hematogenous metastasis of GC. AMIGO2 is a type I transmembrane protein that has been implicated in tumour cell adhesion in adenocarcinomas; however, its importance in GC remains undetermined., Methods: We analyzed AMIGO2 expression by immunohistochemistry using the specific monoclonal antibody for human AMIGO2 in 128 patients who underwent GC surgery to evaluate its relationship between various metastatic and clinical outcomes in GC., Results: Immunohistochemistry revealed that AMIGO2 expression was an independent prognostic factor for overall survival, disease-specific survival, and liver metastasis in GC patients., Conclusions: This study showed that AMIGO2 is induced in GC tissues and can mediate hepatic metastasis. Determining AMIGO2 expression in GC will help predict patient prognosis and the incidence of liver metastasis., (© 2022. The Author(s).)

Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed. Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Instruction: The human amphoterin-induced gene and open reading frame (AMIGO) was identified as a novel cell adhesion molecule of type I transmembrane protein. AMIGO2 is one of three members of the AMIGO family (AMIGO1, 2, and 3), and the similarity between them is approximately 40% at the amino acid level. We have previously shown that AMIGO2 functions as a driver of liver metastasis. Immunohistochemical analysis of AMIGO2 expression in colorectal cancer (CRC) using a commercially available anti-AMIGO2 mouse monoclonal antibody clone sc-373699 (sc mAb) correlated with liver metastasis and poor prognosis. However, the sc mAb was found to be cross-reactive with all three molecules in the AMIGO family., Methods: We generated a rat monoclonal antibody clone rTNK1A0012 (rTNK mAb) for human AMIGO2. The rTNK mAb was used to re-evaluate the association between AMIGO2 expression and liver metastases/clinical outcomes using the same CRC tissue samples previously reported with sc mAb., Results: Western blot analysis revealed that a rTNK mAb was identified as being specific for AMIGO2 protein and did not cross-react with AMIGO1 and AMIGO3. The rTNK mAb and sc mAb showed higher AMIGO2 expression, which correlates with a high frequency of liver metastases (65.3% and 47.5%, respectively), while multivariate analysis showed that AMIGO2 expression was an independent prognostic factor for liver metastases (p = 7.930E-10 and p = 1.707E-5). The Kaplan-Meier analyses showed that the rTNK mAb (p = 0.004), but not sc mAb (p = 0.107), predicted worse overall survival in patients with high AMIGO2 expression. The relationship between AMIGO2 expression and poor disease-specific survival showed a higher level of significance for rTNK mAb (p = 0.00004) compared to sc mAb (p = 0.001)., Conclusions: These results indicate that the developed rTNK1A0012 mAb is an antibody that specifically recognizes AMIGO2 by immunohistochemistry and can be a more reliable and applicable method for the diagnostic detection of liver metastases and worse prognosis in patients with high AMIGO2-expressing CRC., (© 2022. The Author(s).)

Background: The superiority of outcomes associated with anatomical resection (AR) versus those associated with non-anatomical resection (NAR) remains controversial in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance of AR on therapeutic outcomes of patients with small HCCs (≤ 5 cm), using propensity score-matched (PSM) analysis., Methods: A total of 195 patients who had undergone elective hepatic resection for small HCCs (≤ 5 cm) were included in this study. We conducted PSM analysis for baseline characteristics (age, sex, hepatitis virus status, retention rate of indocyanine green at 15 min, and Child-Pugh grade), preoperative serum α-fetoprotein, and tumor characteristics (tumor size, tumor number, portal vein invasion, and surgical margin status) to eliminate potential selection bias. The prognostic significance of AR on the disease-free and overall survival was analyzed in patients selected by PSM analysis., Results: Applying PSM analysis, the patients were divided into PSM-AR (N = 66) and PSM-NAR (N = 66) groups. Disease-free survival was significantly better in the PSM-AR group than that of the PSM-NAR group (P = 0.018), while there was no significant difference in the overall survival between the PSM-AR and PSM-NAR groups (P = 0.292). The univariate HRs of the PSM-AR group were 0.55 (95% CI, 0.33-0.90) for disease-free survival and 0.61 (95% CI, 0.24-1.53) for overall survival, respectively. Remnant liver recurrence was significantly lower in the AR group (P = 0.014)., Conclusions: AR may improve the disease-free survival in HCC patients with tumors of ≤5 cm diameter., (© 2021. The Society for Surgery of the Alimentary Tract.)

A 61‒year‒old woman observed that she had a lower limb edema approximately 1 month ago and began to feel a general malaise. The symptom was caused by multiple liver metastases, and the primary lesion was suspected to be an ovarian cancer. Peritoneal disseminations throughout the abdominal cavity were found in the exploratory laparotomy. No obvious primary lesion could be found in the searchable gastrointestinal tract. The patient was diagnosed with a gastrointestinal stromal tumor(GIST)based on the biopsy results of the peritoneal dissemination. Treatment with imatinib mesylate(imatinib) was initiated 13 days after surgery. The severe lower extremity edema disappeared within 2 months. Computed tomography (CT)scan showed a reduction of the multiple liver metastases and peritoneal dissemination, and the appearance and increase of calcifications in the tumor and cystic degeneration inside the liver metastasis. The abnormal accumulation observed by bone scintigraphy also disappeared. Imatinib has a long‒term effect on GIST of unknown primary origin with multiple liver metastases, peritoneal dissemination, and bone metastasis. Five years after the initiation of the treatment, the patient is still alive, and new lesions have not developed.

An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.

Background: The preoperative systemic inflammation has been reported to predict tumor recurrence and survival in various cancers, including colorectal liver metastases (CRLM). However, more sensitive biomarker is required to improve perioperative management of CRLM. Therefore, we developed a novel indicator; C-reactive protein-to-lymphocyte ratio (CLR). The aim of this study is to evaluate the prognostic significance of CLR in patients with CRLM after hepatic resection., Materials and Methods: The study comprised 197 patients who had undergone hepatic resection for CRLM between January 2000 and December 2018. We retrospectively investigated the relation between CLR and disease-free survival and overall survival after hepatic resection and compared their prognostic significance with that of the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio., Results: Optimal cutoff level of the CLR by receiver operating characteristics analysis was 62.8 × 10 -6 . By multivariate analysis, CLR was an independent predictor of disease-free survival [hazard ratio (HR): 1.463, 95% confidence interval (CI): 1.003-2.135, P = 0.048), whereas lymph node metastases>4 (HR: 1.804, 95% CI: 1.100-2.958, P = 0.019) and CLR (HR: 1.656, 95% CI: 1.007-2.724, P = 0.047) were independent predictors of overall survival, while the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio were not., Conclusions: CLR may be an independent and significant indicator of poor long-term outcomes in patients with CRLM after hepatic resection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The controlling nutritional status (CONUT) score has been reported to predict outcomes in patients with hepatocellular carcinoma (HCC). However, the prognostic significance of the CONUT score in patients with non-B non-C (NBNC) HCC remains to be established., Methods: The study comprised 246 patients who had undergone elective hepatic resection for HCC between April 2003 and October 2017. We retrospectively investigated the relation between preoperative CONUT score as well as clinicopathological characteristics and disease-free survival (DFS) as well as overall survival (OS)., Results: In univariate analyses, CONUT score was associated with DFS and OS in patients with NBNC-HCC (p ≤ 0.01), while there was no significant association of CONUT score with DFS and OS in patients with HBV- and HCV-related HCC (p ≥ 0.1). Of the 111 patients with NBNC-HCC, 97 (87.4%) had CONUT score ≤ 3 (low CONUT score) and the other 14 (12.6%) had CONUT score ≥ 4 (high CONUT score). In the patients with NBNC-HCC, multivariate analysis identified age ≥ 65 years (p = 0.03), multiple tumors (p < 0.01), and high CONUT score (p = 0.03) as the independent and significant predictors of DFS, while multiple tumors (p = 0.01), microvascular invasion (p < 0.01), and high CONUT score (p = 0.01) were the independent and significant predictors of OS., Conclusions: The CONUT score seems to be a reliable and independent predictor of both DFS and OS after hepatic resection for NBNC-HCC.

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development ( P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

Lessons Learned: Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types., Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor-β (TGF-β) RII receptor (a TGF-β "trap") fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death-ligand 1 (PD-L1). Bintrafusp alfa is designed to neutralize TGF-β signaling by "trapping" and sequestering all TGF-β isoforms, and this trap function is physically linked to PD-L1 blockade in the tumor microenvironment., Methods: NCT02699515 was a phase I, open-label, dose-escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety-assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response., Results: As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment-related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment-related deaths occurred. In the dose-escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose-proportional pharmacokinetics profile was observed at doses of >3 mg/kg., Conclusion: Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner.

Objective: To identify specific ultrasonographic features that differentiate hepatic angiomyolipoma (HAML) from hepatocellular carcinoma (HCC)., Methods: Twelve patients with HAML and 73 patients with HCC, whose diagnosis were pathologically confirmed at a single center in Japan between 2006 and 2016, were included in this study. The HAML and HCC cases were histologically evaluated and their histological growth patterns were compared. Using ultrasonographic data, we evaluated the imaging features representing the distinct histological differences. Ultrasonographic findings, reviewed by two examiners, were compared via interobserver variability analysis. This retrospective study was approved by the institutional ethics committee at our institute (No. 2017-1004)., Results: The enrolled patients were carefully divided into two case sets: discovery case set (6 HAML patients and 37 HCC patients) and validation case set (6 HAML patients and 36 HCC patients). In the discovery case set, half of the HAML cases had intratumoral regions showing a reticular growth pattern. None of the HCC cases appeared as a region with the reticular growth pattern. The regions with the reticular growth pattern present as an intratumoral hyper echoic foci on ultrasound images. The presence of the intratumoral hyper echoic foci was significantly associated with HAML (P < .01). In the validation case set, the intratumoral hyper echoic foci predicted HAML at a specificity of 100% and a sensitivity of 50%., Conclusions: Intratumoral hyper echoic foci, representing reticular growth pattern, can be a promising ultrasonographic finding to help differentiate HAML from HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively., Competing Interests: We declare the following conflict of interest: GS has more than 5% of the total shares of KanonCure Inc. The other authors have no conflict of interest.

Background/aim: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older., Patients and Methods: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16)., Results: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence., Conclusion: Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recent studies have investigated a novel inflammation-based prognostic system using the combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR). As platelet count decreases with liver damage, we hypothesized that COP-NLR could indicate both inflammation and hepatic reserve in patients with hepatocellular carcinoma (HCC). This study was conducted to clarify the prognostic significance of preoperative COP-NLR in patients with HCC., Patients and Methods: We enrolled 176 patients with histologically-proven HCC who underwent initial curative hepatectomy. Patients were assigned one point each for low platelet count (<15×10 4 /μl) or for high NLR (≥2.0), for hepatic-COP-NLR scores (h-COP-NLR) of 0, 1 or 2., Results: Five-year overall survival (OS) and recurrence-free survival (RFS) rates were 74.5±9%, and 62.2%±9.3% for score 0, 63.6±5.4% and 50.3%±5.6% for score 1, and 45.2±8.8% and 40.6±8.7% for score 2, respectively, and significantly differed (OS: p=0.01; RFS: p=0.03). In multivariate analysis, h-COP-NLR was an independent risk factor for tumor recurrence (HR=1.39, p=0.03) and death (HR=1.71, p=0.02)., Conclusion: h-COP-NLR was an independent predictor for prognosis of HCC patients after hepatic resection., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To evaluate the impact of DEPDC1 expression on patient prognosis after hepatic resection for hepatocellular carcinoma (HCC)., Patients and Methods: We reviewed data from 75 patients who underwent hepatic resection for HCC between 2004 and 2013. Recurrence at 2 years following resection, which mainly included metastatic recurrence, was defined as late recurrence., Results: DEPDC1 was up-regulated in HCC tissue and in non-tumor tissue of patients with HCC compared to normal liver (p<0.01 and p<0.01, respectively). High expression of DEPDC1 was associated with poor overall, disease-specific, and disease-free survival (p=0.02, p<0.01, and p<0.01, respectively). High DEPDC1 expression was an independent predictor of death and recurrence (p=0.03 and p<0.01, respectively). High expression of DEPDC1 in non-tumor liver was an independent risk factor for late recurrence (p=0.04)., Conclusion: High expression of DEPDC1 in tumor tissue appears to be associated with tumor progression and poor prognosis., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: We conducted this study to evaluate the impact of the postoperative mean arterial pressure (MAP) on surgical complications after hepatic resection., Methods: The subjects of this study were 199 patients who underwent hepatic resection for primary liver malignancy between 2004 and 2013. A clinically relevant postoperative complication was defined as a Clavien-Dindo grade ≥ III complication., Results: Based on an MAP cut-off value of 81.1 mmHg, the patients were grouped as follows: low MAP on both postoperative days (PODs) 1 and 2 (continuously low MAP), normal MAP on both PODs 1 and 2 (normal MAP), and others (transiently low MAP). The continuously low MAP group had the highest incidence of complications and the normal MAP group had the lowest incidence of complications compared with the expected incidence for this cohort (p < 0.01 and p = 0.01, respectively). Multivariate analysis revealed that both a continuously and transiently low MAP were independent predictors of postoperative complications (p = 0.03 and p < 0.01, respectively). Among the subtypes of complications, a low MAP had a significant relationship with ascites/pleural effusion and respiratory complications (p < 0.01 and p = 0.03, respectively)., Conclusions: A low MAP on POD 1 and/or 2 is an independent predictor of postoperative complications.

Background: Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma (HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve (TIC) of arterial phase on contrast-enhanced ultrasound (CEUS) as early imaging biomarkers of lenvatinib efficacy., Aim: To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC., Methods: We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). CEUS was performed at baseline before treatment (Day 0) and on day 7 (Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in (Slope), time to peak (TTP) intensity, and the total area under the curve (AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on mRECIST., Results: The rate of change for all TIC parameters showed significant differences between the responders ( n = 9) and non-responders ( n = 11) (Slope, P = 0.025; TTP, P = 0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and 0.939, respectively., Conclusion: CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC., Competing Interests: Conflict-of-interest statement: The authors of this manuscript having no conflicts of interest to disclose.

Background: Although non-small cell lung cancers (NSCLCs) harboring EGFR mutations initially respond well to EGFR-tyrosine kinase inhibitors (TKIs), they typically progress after approximately one year. The EGFR T790M mutation is the most common resistance mechanism. NSCLCs with T790M respond well to osimertinib; however, the heterogeneity of NSCLCs may limit the efficacy. Some patients exhibit a mixed response (MR), in which some lesions shrink and others progress, but little is known of the incidence and characteristics of such a response. We sought to determine the frequency and clinical course in MR patients., Methods: We retrospectively reviewed the records of patients who had received osimertinib for NSCLC with EGFR T790M., Results: Between April and December 2016, 48 patients were administered osimertinib. Seven patients (15%) exhibited one of two MR types: (i) progressive lesions that did not include the re-biopsy site (5 patients), and (ii) progressive lesions that included the re-biopsy site (2 patients). The most frequent progressive sites were liver and lung metastases (4 patients). Three patients continued osimertinib following an MR, one of whom had received local therapy for liver metastasis and achieved disease control on osimertinib for an additional four months., Conclusion: An MR was detected in 15% of NSCLC patients with T790M. This finding suggests that several different resistance mechanisms are active within a single patient who develops resistance to EGFR-TKIs. Osimertinib is basically effective for tumors that acquire resistance to EGFR-TKIs as a result of T790M mutation. Therefore, additional local therapy may be beneficial for patients who develop an MR to osimertinib., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

An 82-year-old man presented with hepatocellular carcinomas (HCCs) 24 years after achieving a sustained virological response (SVR) to an interferon for hepatitis C. His hepatic fibrosis stage was F1 when he was treated at 58 years. He was followed-up by annual blood tests and abdominal ultrasonography or computed tomography. After the IFN treatment, he had drunk approximately 100 g of ethanol. Serum aspartate aminotransferase and gamma-glutamyl transpeptidase levels had been elevated since 2012. To investigate the possible factors that affect hepatocarcinogenesis over 10 years after achieving an SVR, we reviewed the literature. Of 39 reported patients, 26, as well as ours, had one or more lifestyle-related factors, including body mass index ≥ 25 kg/m 2 , diabetes mellitus, impaired glucose tolerance, hepatosteatosis, or alcohol consumption. In our patient, aging and daily alcohol consumption might have triggered the development of HCCs.

Background: Malignant peritoneal mesothelioma is a rare aggressive tumor of the peritoneum. We report a rare case of resection of multiple localized malignant peritoneal mesotheliomas., Case Presentation: A 55-year-old Japanese woman was admitted to our hospital because liver tumors were detected by abdominal ultrasonography during a screening examination. Blood examination findings, including tumor makers, were within normal ranges. She had no evidence of exposure to asbestos. Computed tomography showed four hypervascular, round liver tumors, one in the lateral liver segment adjacent to the hepatic hilus, and the other three on the liver surface. Computed tomography angiography revealed that the tumor in the lateral segment had strong enhancement and was fed from the left gastric artery. In contrast, the other tumors showed no enhancement, and were fed from the right inferior phrenic artery. Abnormal accumulation was identified in the four tumors only with 18 F-fluorodeoxyglucose positron emission tomography. It was very difficult to obtain a definitive preoperative diagnosis, but surgical resection was performed because we considered potential malignancy. Laparotomy revealed the principal site of the tumor in the lateral segment was on the hepatoduodenal ligament, and all other tumors were on the diaphragm. A left lobectomy and partial diaphragmatic resection were performed. The final pathological diagnosis was multiple malignant epithelioid mesotheliomas. Our patient has had no recurrence for 20 months postoperatively., Conclusions: In general, malignant peritoneal mesotheliomas are classified as diffuse tumors, which are often unresectable and have a poor prognosis. However, early diagnosis and treatment, particularly with the localized type, as in our patient, could lead to long-term survival of the patient. We recommend that multiple malignant epithelioid mesotheliomas be included in the differential diagnosis for patients with subcapsular hepatic tumors.

Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome-wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55- and C7orf43-responsive sites exist between base pairs -58 and +36 and -169 and -59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes-associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non-tumor tissues, compared to normal liver tissues from non-HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Although Child-Pugh grade A patients with hepatocellular carcinoma (HCC) are candidates for curative resection, some may have a poor prognosis. The albumin-bilirubin (ALBI) grade, a measure of liver function based on albumin and bilirubin, has the potential to detect Child-Pugh grade A HCC patients with poor prognosis. Because components of the ALBI grade can be measured easily even after surgery, we explored the predictive values of ALBI in patient prognosis after HCC resection., Methods: In this retrospective case-control study, we included 136 HCC patients who underwent curative resection between January 2004 and December 2013 at our hospital. ALBI grade was calculated from laboratory data recorded the day before surgery and at post-operative day 5., Results: Pre- and post-operative ALBI grade predicted patients' long-term outcomes (P = 0.020 and P < 0.001, respectively, for overall survival, and P = 0.012 and P = 0.015, respectively, for recurrence-free survival). Post-operative ALBI grade was associated with patients' surgical factors of repeated hepatic resection (P = 0.012), intra-operative bleeding (P = 0.006), and surgery duration (P = 0.033). Furthermore, post-operative ALBI grade, rather than pre-operative ALBI grade, was an independent predictive factor of long-term outcome of Child-Pugh grade A patients with HCC., Conclusions: Post-operative ALBI grade is useful to predict the prognosis in patients after HCC resection., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Transcatheter arterial chemoembolization (TACE) is the standard therapy for patients with intermediate-stage hepatocellular carcinoma (HCC). This study aimed to determine whether combination therapy with radiofrequency ablation (RFA) and TACE was superior to TACE monotherapy for intermediate-stage HCC and identify cases in which this technique was the most effective., Materials and Methods: We selected patients with intermediate HCC who met the following eligibility criteria: (1) ≥ 20 years of age, (2) receiving initial therapy, (3) ≤7 tumors, and (4) maximum tumor diameter <5 cm. We performed propensity score matching (PSM) using potential confounding factors. We retrospectively compared the cumulative overall survival rate and recurrence-free survival rate between the TACE + RFA and TACE groups. Additionally, a sub-group analysis was performed for preoperative factors., Results: Among the 103 patients, 92 were selected using PSM. The cumulative overall survival rates at 1, 3, and 5 years for the TACE + RFA group were 97.4%, 70.4%, and 60.4%, respectively, which were significantly higher than those for the TACE group (92.7%, 55.7%, and 22.8%, respectively, p = .045). The recurrence-free survival rates at 0.5, 1, and 2 years for the TACE + RFA group were 80.0%, 58.6%, and 33.3%, respectively, which were significantly higher than those for the TACE group (34.5%, 8.8%, and 2.9%, respectively, p < .01). For the sub-group with α-fetoprotein (AFP) <100 ng/mL, the TACE + RFA group demonstrated a significantly improved prognosis than the TACE group (p = .036)., Conclusions: The addition of RFA to TACE improved cumulative overall and recurrence-free survival in patients with intermediate-stage HCC, especially in patients with AFP <100.

Background: Liver function in patients with hepatocellular carcinoma is generally graded according to the Child-Pugh system; however, some variables in the Child-Pugh grade are subjective. We developed a novel, objective score called the prothrombin time-international normalized ratio to albumin ratio. The aim of this study was to evaluate the prognostic value of this new score in patients with hepatocellular carcinoma after hepatic resection., Methods: The study comprised 199 patients who underwent elective hepatic resection for hepatocellular carcinoma between January 2003 and December 2014. We investigated retrospectively the relation between prothrombin time-international normalized ratio to albumin ratio, disease-free survival, and overall survival and compared the value of liver functional reserve between prothrombin time-international normalized ratio to albumin ratio and Child-Pugh grade., Results: The optimal cut-off level of the prothrombin time-international normalized ratio to albumin ratio was 0.288. In multivariate analysis, the independent and significant predictors of cancer recurrence consisted of hepatitis C virus infection (P = .043), preoperative retention rate of indocyanine green at 15 minutes ≥15% (P = .039), the presence of multiple tumors (P = .001) or microvascular invasion (P < .001), and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .022). The independent predictors of poor overall survival were microvascular invasion (P = .001) and prothrombin time-international normalized ratio to albumin ratio ≥0.288 (P = .001). In patients with a high prothrombin time-international normalized ratio to albumin ratio, pathologic liver cirrhosis (P < .001), postoperative ascites (P = .039), and postoperative liver failure (P = .040) were greater than for their counterparts., Conclusion: The prothrombin time-international normalized ratio to albumin ratio may reflect liver function and may be a novel indicator of poor long-term outcome in patients with hepatocellular carcinoma after hepatic resection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Postoperative complications may adversely affect oncological outcomes. The aim of this study was to evaluate the impact of postoperative complications on early-phase recurrence after curative resection for hepatocellular carcinoma (HCC)., Methods: We included 145 HCC patients who underwent initial and curative resection between January 2004 and December 2013. Postoperative complications of grade III or higher based on Clavien-Dindo classification were defined as clinically relevant postoperative complications. Recurrence within two years after hepatectomy was defined as early-phase recurrence., Results: Thirty-eight patients (26%) developed postoperative complications. The only predictive factor for postoperative complication was longer operative duration (P = 0.037). The disease-specific survival rate of patients with complication was lower than that of patients without complications (P = 0.015). Early-phase recurrence was observed in 20/38 (53%) patients who suffered postoperative complications and 36/107 (34%) patients with no complications, which was statistically significant (P = 0.039). Multivariate analysis identified four factors contributing to early-phase recurrence: high serum AFP level (P = 0.042), multiple tumors (P < 0.001), poor differentiation (P = 0.036) and presence of postoperative complication (P = 0.039)., Conclusions: Postoperative complication is an independent prognostic factor for early-phase recurrence after curative resection of HCC. Close observation of patients with postoperative complications may be a necessary treatment strategy for HCC., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background/aim: Probe-based confocal laser endomicroscopy (pCLE) is a novel diagnostic technique that can provide real-time imaging of tissues at the cellular level. In this study, pCLE was applied to liver tumors and its diagnostic value was evaluated., Patients and Methods: Ten patients who underwent hepatectomy for liver tumors were evaluated with pCLE from February to May 2017. Immediately after liver resection, pCLE evaluation was performed in the operating room as an ex vivo study. The newly-adopted "fluorescein-dripping method" was used for the observation., Results: First, the optimal fluorescein exposure time for the surface of liver was defined in the fluorescein-dripping method. Next, the distinctive findings in the cancerous region were investigated. The characteristic appearance of irregular arrangements of concentrated cells under fluorescein dripping was observed in six of seven hepatocellular carcinoma (HCC) tumors., Conclusion: In all HCC specimens, discrimination of the cancerous region from normal liver was possible with pCLE., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials. However, as patients receiving eribulin in daily practice do not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited., Methods: We identified patients with locally advanced or metastatic breast cancer, treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital, Tokyo, Japan. Patients who would have met the following eligibility criteria from the EMBRACE trial were included in the eligible group, and the rest were included in the ineligible group: 1) Eastern Cooperative Oncology Group Performance status 0-2; 2) adequate function of principal organs; and 3) absence of active infection. We compared the relative dose intensity (RDI), tumor response, progression-free survival (PFS), overall survival (OS), and adverse events between the groups. Nominal and continuous values were compared using the Fisher's exact test and Mann-Whitney U test, respectively. Survival outcomes were determined using Kaplan-Meier estimation, and between-group differences were assessed using the log-rank test., Results: Of the 203 patients included, 34 were classified into the ineligible group and 169 into the eligible group. Initial dose reduction and treatment discontinuation due to adverse events (AEs) were more common in the ineligible group (initial dose reduction: 23.5% in the ineligible group vs. 7.7% in the eligible group, p = 0.011; treatment discontinuation due to AEs: 11.8% vs. 3.0%, p = 0.045). However, RDI (66% vs. 71%, p = 0.130), response rate (15.6% vs. 18.1%, p = 1.000), PFS (3.7 months vs. 4.0 months, p = 0.913), OS (11.5 months vs. 16.1 months, p = 0.743), AEs requiring hospitalization (5.9% vs. 6.5%, p = 1.000), and grade 3/4 AEs were similar in both groups. PFS, OS, AEs requiring hospitalization, and discontinuation due to AEs in the eligible group were comparable to those found in previous phase III trials., Conclusion: The safety and efficacy of eribulin monotherapy was demonstrated in a broader patient population than that eligible for clinical trials. Eribulin may be a treatment option in these patients with locally advanced or metastatic breast cancer, considering dose reduction and pre-existing dysfunctions.

Background: The aim of this study is to investigate the association C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation based prognostic score, and long-term outcomes among patients with colorectal liver metastases (CRLM) after hepatic resection., Methods: We retrospectively investigated 106 patients who underwent hepatic resection for CRLM and explored the relationship between CRP/Alb ratio and long-term outcomes., Results: In multivariate analysis, more than 4 lymph node metastases (p = 0.003), presence of neo-adjuvant chemotherapy (p = 0.008) and CRP/Alb ratio ≥ 0.04 (p = 0.021) were independent and significant predictors of cancer recurrence, while more than 4 lymph node metastases (p = 0.001), presence of neo-adjuvant chemotherapy (p < 0.001), and CRP/Alb ratio ≥ 0.04 (p = 0.002) were independent and significant predictors of poor overall survival., Conclusions: The CRP/Alb ratio seems to be a predictor of poor long-term outcomes in patients with CRLM after hepatic resection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The Barcelona Clinic Liver Cancer (BCLC) classification is the most widely used staging system for hepatocellular carcinoma (HCC), but its prognostic ability in patients after resection has not been yet validated. The aim of this study was to evaluate the BCLC classification among patients after resection., Methods: The subjects were 196 patients who underwent hepatic resection for HCC between April 2003 and December 2014 at Jikei University Hospital. All patients were classified into a tumor stage according to the BCLC classification. Overall survival rate was calculated according to stages defined by the BCLC classification., Results: Overall survival rates at 1, 3 and 5-year were 100%, 95.2% and 95.2% in BCLC 0, 96.7%, 90.0% and 78.4% in BCLC A solitary, 86.2%, 86.2% and 86.2% in BCLC A multiple, 100.0%, 78.8% and 78.8% in BCLC B and 86.5%, 63.3% and 57.6% in BCLC C, respectively. Postoperative complications and mortality rates in relation to BCLC stage were comparable., Conclusion: The BCLC treatment algorithm should consider the role of resection also for multiple early, intermediate and advanced stages., (© 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Case 1: A 57-year-old woman with chronic hepatitis related to the hepatitis B virus was found to have a liver tumor on ultrasonography(US). Computed tomography(CT), magnetic resonance imaging(MRI), and angiography revealed 2 tumors in the liver. The patient underwent right anterior sectorectomy, and histopathologic analysis revealed mucosa-associated lymphoid tissue(MALT)lymphoma. Thirty months later, recurrence was confirmed using liver biopsy. CR was confirmed after radiation and chemotherapy, and the patient has survived. Case 2: A 71-year-old woman came to our hospital for rheumatism treatment. US, CT, and MRI revealed a tumor in the left lateral segment of the liver. The patient underwent laparoscopic partial liver resection and histopathologic analysis revealed MALT lymphoma. The patient has survived.

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

Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells.

Background: Recurrence patterns after hepatic resection has been poorly understood in view of tumor blood flow drainage (TBFD) area. Our goal was to clarify the recurrence patterns after anatomical versus nonanatomical hepatic resection for hepatocellular carcinoma (HCC)., Methods: A total of 424 consecutive patients with HCC, who were treated by curative resection (R0) at our hospital from 2001 to 2012, were evaluated. Among these, we compared the outcomes of the anatomical resection group (AR group, n = 243) and the nonanatomical resection group (NR group, n = 181). We performed an analysis of the recurrence patterns of HCC based on the preoperative CT during hepatic arteriography in these 424 patients., Results: Preoperative liver function was better in the AR group than the NR group (P < 0.001), and tumor size was larger in the AR group than the NR group (P < 0.001). HCC recurrence was recorded in 145 patients (59.7 %) of the AR group and 102 patients (56.4 %) of the NR group with no significant differences between the two groups (P = 0.590). The incidences of extrahepatic and intrahepatic recurrence (solitary/multiple) were similar between the two groups. In addition, the rate of recurrences by local dissemination, either recurrences in the same subsegment in the NR group or recurrences in the TBFD area in the AR group, was sufficiently low (1.4 %) as to be considered negligible., Conclusions: The incidence and patterns of HCC recurrence were similar between the anatomical and nonanatomical resection. Recurrence by local dissemination may be considered to be negligible in both surgical methods.

A 73-year-old woman underwent a craniotomy for an atypical meningioma in 1993, and underwent re-excision for local recurrence 4 years later. In 2008, a chest X-ray film revealed 2 nodules in the right lung. A wedge resection of S2 and a middle lobectomy of the right lung were performed. Pathological findings indicated that the 2 tumors originated from the intracranial meningioma resected in 1993. In 2013, a computed tomography (CT) scan demonstrated hypervascular masses in the liver (S4), pancreatic body, and lower portion of the right kidney. She underwent partial hepatectomy, distal pancreatectomy, and partial nephrectomy, and the final diagnosis was hepatic, pancreatic, and renal metastases from meningioma. After 10 months, a transcatheter arterial embolization (TAE) was performed for hepatic recurrence (S5). She is presently doing well, 5 months after TAE, without any signs of recurrence.

A 70s man with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) (Vp-HCC) in the main trunk (Vp4) was referred to our hospital. He was negative for hepatitis C virus (HCV) and hepatitis B virus (HBV), and his liver function was well preserved. The main tumor was in the right lobe and exceeded 10 cm in diameter. There were no intrahepatic metastases to the left lobe. The patient underwent stereotactic body radiation therapy (SBRT) (48 Gy/4 fractions) to the area of the PVTT. Six days after SBRT, the patient underwent right lobectomy for removal of PVTT. The postoperative course was uneventful, and low-dose 5-fluorouracil and cisplatin(FP)intra-arterial chemotherapy was administered for 3 months. Histopathological findings for the tumor indicated a poorly differentiated HCC, vp4, with moderate to severe tumor necrosis or degeneration in the area that received SBRT. Tumor markers (alpha-fetoprotein [AFP], proteins induced by vitamin K absence [PIVKA-II]) decreased within the normal range, and there was no apparent HCC recurrence 6 months after the hepatectomy. Multidisciplinary treatment combined with preoperative SBRT and radical resection for Vp-HCC was feasible and effective in this case.

Central bisegmentectomy (CBS) of the liver is an en bloc hepatic resection of Couiaud segments 4, 5, and 8. The indications for CBS include benign and malignant tumors occupying both the left medial and right anterior segments. However, CBS has rarely been reported. Here, we investigate CBS in patients with suboptimal liver function for whom an extended lobectomy is not an optimal solution. Each case was 1 of 8 patients who underwent CBS for hepatocellular carcinoma (HCC) or colorectal cancer liver metastasis (CRLM) at the Department of Surgery, Jikei University Hospital. Indications for CBS consisted of CRLM in 3 patients and HCC in 5 patients. The median duration of operation was 552 minutes, and median blood loss was 2263 g. No postoperative nor in-hospital mortalities occurred. In this study, 1-, 2-, and 3-year disease-free survival rates were 62.5%, 12.5%, and 12.5%, respectively, and 1-, 2-, and 3-year overall survival rates were 100%, 100%, and 85.7%, respectively. CBS is advocated for central liver tumors in patients with suboptimal liver function for whom extended lobectomy could result in less than optimal remnant liver volume and function.

Background: We examined the course of a primary hepatic neuroendocrine carcinoma (PHNEC) patient and analyzed the postoperative outcome of all reported PHNEC cases., Methods: A literature search for PHNEC cases was performed using PubMed. All reported cases and our present patient were analyzed in this study. Survival analysis was performed using the Kaplan-Meier method. Risk factors for the recurrence of PHNEC following hepatic resection were investigated., Results: A total of 43 patients were analyzed in this study. The 3-, 5-, and 7-year overall survival rates were 55%, 48%, and 48%, respectively. The 3-, 5-, and 7-year overall survival rates in surgery patients were 78% each, and 25%, 17%, and 17%, respectively in nonsurgery patients. Lymph node metastasis posed a significant risk factor for postoperative recurrence., Conclusions: Hepatic surgery is an appropriate therapeutic treatment for PHNEC without distant metastasis nor lymph node metastasis. Adjuvant chemotherapy might be necessary for PHNEC patients with lymph node metastases.

We report 2 cases of recurrent intrahepatic cholangiocarcinoma (ICC) with intrahepatic metastasis in the remnant liver in patients who underwent repeated hepatectomy and are currently alive and free of the disease. Case 1 involves a 53-year- old woman who underwent extended right hepatectomy for mass-forming type ICC (7-cm in diameter) in the right lobe. After 7 months, she experienced tumor recurrence, and exhibited a 3.8-cm solitary intrahepatic metastasis in the remnant left lateral segment. The patient underwent partial resection of the lateral segment and is currently disease-free at 2 years and 9 months after the recurrence. Case 2 involves a 59-year-old woman who underwent extended left hepatectomy for combined mass-forming and periductal-infiltrating-type ICC( 5-cm in diameter) in the left lobe. After 2 years and 3 months, she experienced tumor recurrence, and exhibited a 3-cm solitary intrahepatic metastasis in the remnant right anterior segment 8. She underwent partial resection of segment 8 and is currently disease-free at 2 years and 11 months after the recurrence. Most of the recurrences of ICC in the remnant liver exhibit multiple lesions or concomitant extrahepatic metastases; therefore, the indication of repeated hepatectomy for intrahepatic recurrence in the remnant liver is restrictive. However, most of the reported cases on repeated hepatectomy for intrahepatic recurrence involved a solitary metastasis in the remnant liver, and revealed a relatively favorable prognosis. Thus, we believe that a solitary recurrence of ICC in the remnant liver could be an indication for repeated hepatectomy.

Background/aims: Recent reports have demonstrated that patients with limited extrahepatic disease and bilobar disease can benefit from aggressive surgical resection in combination with chemotherapy. Therefore, we extended indication of hepatic resection for colorectal liver metastasis (CRLM) since 2004. In this report, we retrospectively assessed changes in our therapeutic strategy for CRLM., Methodology: The subjects were 67 patients who underwent hepatic resection for CRLM between January 2000 and December 2008. Patients were classified into two groups; early period (2000-2003) and late period(2004-2008). We assessed prognostic factors and change in our hepatic resection policy on operative indication for CRLM in relation to therapeutic outcome., Results: In multivariate analysis, more than 4 lymph node metastases (p=0.0277) and bilobar disease (p=0.0142) were significant predictors of disease- free survival, while significant predictor of overall survival were more than four lymph node metastases (p=0.0014) and bilobar disease (p=0.0392). Bilobar disease and presence of extrahepatic disease were significantly greater in late period. However, incidence of postoperative complications, disease-free and overall survivals in both periods were comparable., Conclusions: Practice to extend indication of hepatic resection for patients with advanced CRLM seems to increase the respectability rate without increasing morbidity and mortality, whenever a macroscopically curative resection with acceptable operative risk was thought possible.

Background/aims: Type B and C hepatic cirrhosis are main causes of hepatocellular carcinoma (HCC). In resected cases of HCC, residual liver function of type B cirrhotic patients tend to be better compared to type C cirrhotic patients. We compared clinical data of patients with type B hepatic cirrhosis with type C hepatic cirrhosis who underwent hepatic resection for HCC., Methodology: Subjects were 16 patients with type B hepatic cirrhosis and 20 patients with type C hepatic cirrhosis who underwent hepatic resection for HCC at Jikei University Hospital. Perioperative findings including age, gender, preoperative laboratory data including ICGR15, Child's classification, model for end-stage liver disease (MELD) score, tumor factor, type of resection, duration of operation, blood loss and incidence of post-operative complications, as well as disease-free and overall survival were analyzed., Results: In type B cirrhotic patients, the age was younger (p<0.001), pre-operative ICGR15 (p=0.004), hemoglobin (p=0.032), albumin (p=0.006), Child's classification (p=0.008), and MELD score (p=0.011) were better, and incidence of postoperative pulmonary complications were fewer (p=0.039) than type C cirrhotic patients. Preoperative ICG, in 11 of 16 type B cirrhotic patients were normal (<10%)., Conclusions: Residual liver function of type B cirrhotic patients were better than type C cirrhotic patients.