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Introduction: Because surgical resection with simultaneous hepatic artery (HA) resection and reconstruction for perihilar cholangiocarcinoma (PHC) is technically demanding, the surgical indication for this challenging procedure is controversial. Thus, this study aimed to evaluate the efficacy of simultaneous HA resection and reconstruction for PHC. Methods: Between January 2002 and January 2018, 13 patients with PHC underwent surgical intervention with simultaneous resection and reconstruction of the HA at Yamaguchi University Hospital (Ube, Japan) and Osaka University Hospital (Suita, Japan). Results: There were 2 cases (15.4%) of 90-day postoperative mortality. Nine patients (69.2%) developed major postoperative complications (Clavien-Dindo classification ≥IIIa). Curative resections (R0) were achieved in 8 cases (61.5%). The median survival time (MST) and 1- and 3-year survival rates after resection (including in-hospital deaths) were 20.9 months and 61.5 and 10.3%, respectively. The MST and 1- and 2-year survival rates of 8 patients who underwent R0 resection were significantly better than those of the other 5 patients (24.2 vs. 10.2 months, 75.0 vs. 40.0%, and 50.0 vs. 0.0%, respectively, p = 0.0228). Conclusions: Simultaneous HA resection and reconstruction is technically possible and may provide long-term survival in selected patients with locally advanced PHC.

Aim The impact of sustained virologic response (SVR) on surgical outcomes for patients with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the influence of SVR on long‐term surgical outcomes after hepatectomy. Methods This multicenter study included 504 patients who underwent curative resection for HCV‐related HCC. Patients with a history of HCC treatment, HBV infection, poor liver function, and tumor with major vascular invasion were excluded. Long‐term surgical outcomes (overall survival [OS] and recurrence‐free survival [RFS]) among patients who achieved SVR before hepatectomy (Pre‐SVR group: 58 patients), after hepatectomy (Post‐SVR group: 54 patients), and without SVR (Non‐SVR group: 186 patients) were compared after adjusting for 13 confounding factors. Using the surgically resected specimens, comparison of the pathological changes in liver fibrosis between the first and second hepatectomy were analyzed. Results Patients with SVR were younger, had better liver function, and less liver fibrosis compared to patients without SVR. Propensity score‐matched OS and RFS were significantly better in Pre‐SVR group than Non‐SVR group (P = .029 and P = .009, respectively). Inverse probability‐weighted OS and RFS were also significantly better in the Post‐SVR group (P = .001 and P = .021, respectively) than in the Non‐SVR group. Histopathological evaluation revealed that only the patients with SVR had regression of liver fibrosis (P, Although the achievement of sustained virologic response (SVR) is essential for improving survival in patients with hepatitis C virus (HCV) infection, its importance on surgical outcomes for HCV‐related hepatocellular carcinoma (HCC) is still controversial. In this multicenter study, we demonstrated the importance of achieving SVR before or after hepatectomy for improving long‐term surgical outcomes. These results can encourage patients with HCV‐related HCC to undergo antiviral therapy regardless of the timing.

A proteomic analysis of hepatocellular carcinoma (HCC) has revealed that Heat Shock Protein 70 (HSP70) is among the cancer antigen proteins of HCC. Moreover, we confirmed that HSP70 was highly expressed in HCC by immunohistochemical staining. Based on these results, we developed an HSP70 mRNA-transfected dendritic cell (DC) therapy for treating unresectable or recurrent HCC, and the phase I trial was completed successfully. Thus, we aimed to investigate the safety and efficacy of this therapy as a postoperative adjuvant treatment after curative resection for HCC to prevent recurrence by conducting a phase I/II randomized controlled clinical trial. Patients (n = 45) with resectable HCC of stages II–IVa were registered and randomly assigned into two groups (DC group: 31 patients, control group: 14 patients) before surgery. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were safety and overall survival. The DC therapy was initially administered at approximately 1 week after surgery, and twice every 3–4 weeks thereafter. No adverse events specific to the immunotherapy were observed in the DC group. There was no difference in DFS between the DC and control groups (p = 0.666). However, in the subgroup with HSP70-expressing HCC, DFS of the DC group tended to be better (p = 0.090) and OS of the DC group was significantly longer (p = 0.003) than those of the control group. The HSP70 mRNA-transfected DC therapy was performed safely as an adjuvant therapy. The prognosis of HSP70-expressing HCC cases could be expected to improve with this therapy.

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

Background This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. Methods HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients’ cohort; in total, 11 patients were enrolled for the recommended dose. Results Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. Conclusions This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

BACKGROUND/AIM There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. PATIENTS AND METHODS This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. RESULTS Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. CONCLUSION Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.

Background Only few studies in literature have analyzed the clinical effects of peritoneal lavage status in biliary tract cancers. Aim We aimed to assess the effect of cytology-positive peritoneal lavage on survival for patients with biliary tract cancer who underwent curative resection. Methods The KHBO1701 study was a multi-institutional retrospective study that assessed the clinical effects of peritoneal lavage cytology in biliary tract cancers. Using clinicopathological data from 11 Japanese institutions, we compared long-term outcomes between patients with cytology-positive and cytology-negative peritoneal lavage. Results Of 169 patients who underwent curative resection, 164 were cytology-negative, and five were cytology-positive. The incidence of portal invasion and preoperative carbohydrate antigen 19-9 levels were higher in the cytology-positive group than in the cytology-negative group. The incidence of peritoneal metastatic recurrence was also higher, and overall survival tended to be worse in the cytology-positive group. In contrast, recurrence-free survival was similar between the cytology-negative and cytology-positive groups. Conclusions The positive status of peritoneal lavage cytology could moderately affect the survival of patients with biliary tract cancers. Given that surgical resection is the only curative treatment option, it may be acceptable to resect biliary tract cancers without other non-curative factors, regardless of peritoneal lavage cytology status.

Surgical resection is the only curative treatment for pancreatic cancer. Arterial resection and reconstruction during pancreaticoduodenectomy for advanced pancreatic cancer remain controversial due to a high rate of complications. We report two cases of pancreatic cancer with hepatic artery resection and reconstruction using the right gastroepiploic artery during pancreaticoduodenectomy after neoadjuvant therapy. The patients underwent pancreaticoduodenectomy with resection of the right hepatic and common hepatic arteries. Achieving direct anastomosis was difficult; therefore, we planned hepatic artery reconstruction using the right gastroepiploic artery. We performed the reconstruction using an interrupted suture with end-to-end anastomosis. The first patient developed a postoperative pancreatic fistula, while the postoperative course of the second patient was uneventful. However, there were no adverse events related to the arterial reconstruction. R0 resection was achieved, and postoperative computed tomography revealed good patency of the reconstructed artery. Hepatic artery reconstruction using the right gastroepiploic artery in pancreatic cancer might be technically safe and might become one of the alternative options.

Laparoscopic liver resection is beneficial compared to open liver resection. This study aimed to evaluate whether laparoscopic liver resection could reduce postoperative infections. This study included 125 and 115 patients with liver tumors who underwent open and pure laparoscopic partial resections or left lateral sectionectomies, respectively. Propensity score matching and stabilized inverse probability of treatment weighting were carried out to compare the postoperative infectious complication rates between the two groups. Patients with tumors located in Couinaud segment 1, 7, or 8; with tumors adjacent to major vessels; or who underwent repeated resections were more likely to receive open resection. After propensity score matching, the superficial incisional surgical site infection rate tended to be lower in the laparoscopic liver resection group than in the open liver resection group. Moreover, overall infectious complication rate and superficial incisional surgical site infection rate were lower in the laparoscopic group (the cohort formed by the stabilized inverse probability of treatment weighting). Using the laparoscopic approach for partial resections and left lateral sectionectomies for liver tumors, the superficial incisional surgical site infection rate could be reduced.

Background and aims Imaging diagnosis of gallbladder cancer remains difficult to achieve preoperatively. We developed a novel approach based on laparoscopic whole‐layer cholecystectomy (LWLC) and laparoscopic gallbladder bed dissection (LGBD) for total biopsy, for ultimately determining the optimal treatment strategy for suspected gallbladder cancer detected on preoperative imaging. Here, we describe a case series of patients who underwent this procedure at our institution. Methods We retrospectively examined clinicopathological data of consecutive patients with suspected gallbladder carcinoma at Yamaguchi University Graduate School of Medicine from September 2016 to July 2018 on which a laparoscopic approach was used. Preoperative imaging findings suggestive of gallbladder cancer were defined as follows: elevated lesion >10 mm in diameter, increasing tumor size over time compared with the previous imaging, sessile lesion, irregular wall thickness lesion mimicking cancer, elevated lesion with dense enhancement, or positive results on fluorodeoxyglucose positron emission tomography. LWLC was performed for early‐stage or suspected malignant lesions without liver invasion, and LGBD was performed for lesions with an unclear border between the gallbladder and the liver. When postoperative pathological examination revealed the presence of gallbladder cancer invading into the subserosal layer, additional gallbladder bed resection and regional lymphadenectomy were considered. Patient characteristics, perioperative findings, pathological findings, and postoperative outcomes of patients who underwent LWLC or LGBD were reviewed retrospectively, and the short‐term outcomes of the laparoscopic approach were analyzed. Results Fifteen consecutive patients were included in the study. The median age of the patients was 63 years (IQR 42‐76 years); 7 patients were males. We performed LWLC in 12 cases and LBGD in 3 cases. Median (IQR) operation time was 159 (140‐193) min and median blood loss was 10 (5–30) mL. No bile leakage caused by intraoperative perforation of the gallbladder was seen. Median hospital stay was 7 (5–9) days. Only one patient developed postoperative complications (abdominal abscess). Histologically, gallbladder cancer was diagnosed in five cases (pT1a, n = 2; pT2, n = 3), and two of the pT2 patients underwent additional open surgery. Conclusions Our laparoscopic‐based approach for suspected gallbladder cancer might represent a safe strategy and could play an important role in defining the optimal treatment strategy.

Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC.

Background Colorectal cancer is the third most common cancer worldwide. If biomarkers can be identified in liquid biopsy, diagnosis and treatment can be optimized even when cancerous tissues are not available. The purpose of this study was to identify proteins from liquid biopsy that would be useful as markers of poor prognosis. Methods First, we comprehensively analyzed serum proteins to identify potential biomarkers and focused on serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). The relationship between LOX-1 and the prognosis of patients with colorectal cancer has not been reported. Next, we validated this marker using serum samples from 238 patients with colorectal cancer by ELISA and 100 tissue samples by immunohistochemical staining. Results The optimal cut-off value of serum LOX-1 was 538.7 pg/mL according to time-dependent receiver operating characteristics curve analysis. The overall survival of patients with high levels of serum LOX-1 was significantly poorer than that of individuals with low levels of LOX-1 in the training and test datasets. In multivariate analysis for overall survival, serum LOX-1 was an independent prognostic factor identified in liquid biopsy (hazard ratio = 1.729, p = 0.027). The prognosis of patients with high LOX-1 expression in tumor tissues was significantly poorer than that of individuals with low expression (p =0.047 ). Additionally, inflammatory factors such as white blood cell count, C-reactive protein level, neutrophil/lymphocyte ratio, and monocyte/lymphocyte ratio were significantly higher in the group with high serum LOX-1 levels. Conclusions Serum LOX-1 might be a useful biomarker of poor prognosis in colorectal cancer.

Objectives We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer. Methods A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21). Results In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133). Conclusions The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.

Background Cancer stem cells are thought to play important roles in carcinogenesis, recurrence, metastasis, and therapy-resistance. We have successfully induced cancer stem-like sphere cells (CSLCs) from hepatoma cell lines using a unique medium. Methods The human hepatoma cell line SK-HEP-1 was used as parental cells for CSLC induction. To assess the chemoresistance and liver metastasis, MTS assay and splenic injection were performed, respectively. RNA-seq analysis followed by gene set enrichment analysis (GSEA) was performed with cell line derivatives and clinical specimens of hepatoma. Protein expressions were conducted by western blotting, flow-cytometry, or ELISA. Knock-out experiments was accomplished by CRISPR-Cas9 genome-editing. Following rescue experiments were performed with an expression vector. Results The obtained CSLCs showed increased metastatic potentials and resistance to anti-cancer drugs including molecularly targeted drugs for liver cancer. Regarding immune resistance, CSLCs showed increased proportion of positive cells for PD-L1 and PD-L2. In contrast to decreased membrane-bound MICA/MICB, increased soluble MICA in the medium were observed in CSLCs compared to those from the parental cells. As a result of integrated analysis with RNA-seq, a RAB3B was identified as an up-regulated gene in both CSLCs and poor prognostic liver cancers. Mono-allelic RAB3B knock-out cells showed altered sphere formation, significantly lower chemoresistance, and metastatic potential than that of parental cells, and those were rescued by the complementation of RAB3B. The knock-out cells also showed decreased PD-L1 and PD-L2 expressions in sphere induction medium than those in cells cultured with normal medium. GSEA following RNA-seq with the derivative cells revealed that negative enrichment of G2M checkpoint and positive enrichment of interferon response in CSLCs. Conclusions Our induced CSLCs showed characteristic phenotypes such as metastatic ability, chemo- and immune-resistances. The up-regulation of RAB3B may plays important roles in CSLCs. Legal entity responsible for the study Ryouichi TSUNEDOMI. Funding Japan Society for the Promotion of Science. Disclosure All authors have declared no conflicts of interest.

Our previous study reported the effectiveness of the product of tumor number and size (NxS factor) as a predictor of the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy. The aim of the present study was to validate the prognostic value of scoring systems based on the NxS factor for HCC. The records of 940 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine and Osaka International Cancer Institute were analyzed. The discriminatory abilities of the mathematical integrated model for tumor staging (MITS) score, which combines the NxS factor with liver function, and known prognostic systems, including the Japan Integrated Staging system, the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program and the Tokyo system, were compared. Firstly, the present study demonstrated that a higher NxS factor was associated with decreased disease-free survival (DFS) and overall survival (OS) in patients with HCC (P

The optimal treatment for hepatocellular carcinoma (HCC) should be selected based on tumor conditions, liver functional reserve, and performance status. Surgical treatment, such as liver resection and liver transplantation, is the most favorable treatment method; however, its indication criteria differ according to each country’s guidelines. In Western countries, liver resection is indicated only for early-stage HCC patients with Barcelona-Clinic Liver Cancer staging classification (BCLC) 0/A. While in Asian countries, liver resection is one of the treatment options for advanced HCC, such as BCLC B/C. Recently, the treatment of HCC is about to enter a drastic transitional period. It started with the widespread use of minimally invasive surgery for HCC, followed by a high rate of hepatitis C virus eradication with the advent of direct acting antivirals and developing a multidisciplinary treatment for highly advanced HCC. As a result, the importance of liver resection for HCC is increasing, and it is time to reconsider the criteria for selecting treatment methods for HCC patients. This article outlines current topics in the surgical treatment of HCC.

Cancer stem-like cells (CSLCs) in solid tumors are resistant to conventional chemotherapy and molecularly targeted therapy, which is thought to contribute to cancer recurrence and metastasis. The present study aimed to identify biomarkers for pancreatic CSLCs (P-CSLCs). Using our previously reported methods, P-CSLC-enriched populations were generated from pancreatic cancer cell lines. The protein expression profiles of these populations were compared with those of parental cells using two-dimensional electrophoresis, tandem mass spectrometry, flow cytometry and immunohistochemistry. Protein expression in surgical specimens was also evaluated for relationships with clinical outcomes. A lysosomal cysteine protease, cathepsin B (CTSB), was significantly upregulated in P-CSLCs compared with that in the parental cells, as shown using western blotting. Flow cytometry analysis also confirmed that CTSB was more highly expressed on the surface of P-CSLCs compared with that on parental cells. Moreover, PCLCs had elevated cellular secretions of CTSB compared with the parental cells. Finally, CTSB expression was evaluated in 69 resected tumor specimens, and high expression was associated with the patients' clinicopathological features and surgical outcomes. The present results suggested that CTSB is a biomarker for poor survival in patients with pancreatic cancer, which is possibly associated with P-CSLCs. This novel biomarker may also have potential as a therapeutic target.

Background: Even with curative resection, the recurrence rate of HCC remains high, and effective adjuvant therapies are not currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated safety, antigen-specific CTL induction in PBMC, and a sign of efficacy (ASCO 2017 Abstract # 3086). We thus started a Phase I study of the same vaccination therapy as a perioperative immunotherapy setting in patients with resectable HCC (jRCTs061180058). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06-restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T-cell exhaustion, T-cell activation, and effector Treg induction. Tumor specimens were also subjected to HE staining and immunohistochemical staining for CD3, CD8, PD1, HSP70, and GPC3. Results: Nine patients were treated with preoperative vaccination, and resected surgical specimens and PBMC were examined. Pathohistological analysis revealed three response types: “hot cellular immunity”, “intermediate fumoral immunity”, and “cold response”. In three patients, massive infiltration of CD8+ and PD1+ T cells accompanied necrotic and fibrous regions, in which the targeted tumor antigens HSP70 and GPC3 were highly expressed, representing “hot cellular immunity”. Regarding “intermediate”, three patients showed necrotic regions with infiltrating macrophages. HSP70 and/or GPC3 were also highly expressed, but little infiltration of lymphocytes was evident. In the remaining three patients, “cold response” manifested as tumor comprising a pseudo-glandular pattern with no infiltration of T cells or macrophages. Two of these three patients showed no expression of targeted tumor antigens. CyTOF analysis of the tumors also revealed the percentages of CD3+ cells among live cells and of PD1+ cells among CD8+ cells were extremely low in cold response. However, this trend was not observed in PBMCs, suggesting the critical importance of TIL analysis. Conclusions: This novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially in those presenting target tumor-associated antigens with a non-pseudo-glandular type. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Combining this novel strategy with PD (L) 1 antibody may be warranted. Citation Format: Masao Nakajima, Shoichi Hazama, Koji Tamada, Keiko Udaka, Shun Doi, Michiie Sakamoto, Akira Saito, Shiro Akinaga, Hiroto Matsui, Yoshitaro Shindo, Satoshi Matsukuma, Yukio Tokumitsu, Shinobu Tomochika, Michihisa Iida, Shin Yoshida, Ryouichi Tsunedomi, Yuki Nakagami, Nobuaki Suzuki, Shigeru Takeda, Hiroaki Nagano. Immunological and histopathological tumor responses to a novel neoadjuvant peptide vaccine targeting HSP70 and GPC3 antigens in patients with resectable HCC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT251.

Management of multinodular hepatocellular carcinoma (HCC) in the intermediate Barcelona Clinic Liver Cancer (BCLC)-B stage is controversial. The aim of the present study as to identify the subgroup of patients with BCLC-B HCC who could benefit from liver resection. The present study retrospectively analyzed the outcomes of 65 patients (training cohort) who underwent liver resection for multinodular BCLC-B HCC. Cox's regression analysis was conducted to identify the independent prognostic factors for overall survival and to develop the prognostic score. As some authors have reported that maximum tumor size (cm) plus tumor number (N+S) is a prognostic factor in patients with BCLC-B HCC who undergo chemoembolization, the usefulness of this factor in patients who underwent liver resection was also evaluated. Subsequently, the validity of the prognostic score was assessed in an independent validation cohort (n=132). Multivariate analysis revealed that positivity for hepatitis C virus antibody (HCV-ab), platelet count ≤1010/l, N+S >8, and des-γ-carboxy prothrombin (DCP) >400 mAU/ml were independent prognostic factors for overall survival. The prognostic score differentiated two groups (≤2, ≥3) with distinct outcomes (median survival time 68.3 months vs. 29.1 months; P

We previously reported the effectiveness of the product of tumor number and size (NxS factor) for the prognosis of hepatocellular carcinoma (HCC) in patients following hepatectomy. The present study aimed to propose a new score based on the NxS factor to predict HCC recurrence following hepatectomy. A total of 406 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine were retrospectively analyzed to develop the new score. Among clinicopathological factors, including the NxS factor, the marker subset that achieved the best performance for prediction of early recurrence was assessed, and a prognostic model for HCC recurrence after curative hepatectomy (REACH) was developed. As the validation set, 425 patients who underwent hepatectomy for HCC at Yamaguchi University Graduate School of Medicine and Shimonoseki Medical Center were analyzed, and the prognostic ability of the REACH score was compared with that of well-known staging systems. Following analysis, the REACH score was constructed using six covariates (NxS factor, microscopic hepatic vein invasion, differentiation, serum albumin, platelet count and indocyanine green retention rate at 15 min). In the validation set, the REACH score predicted early recurrence in 73 of 81 samples, with a sensitivity of 89% and a specificity of 58%. The area under the curve (AUC) of the receiver operating characteristic curve of the REACH score was 0.78 and 0.74, respectively, for 1- and 2-year recurrence after hepatectomy; each AUC was higher than that of any of the other staging systems. Survival analysis indicated the REACH score had the best predictive value in disease-free and overall survival. The present findings demonstrated that the REACH score may be used to classify patients with HCC into high- and low-risk of recurrence, and to predict subsequent survival following hepatic resection.

The aim of this study was to develop an accurate predictive system for prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. We pooled data of clinicopathological features of 234 HCC patients who underwent curative hepatectomy. On the basis of the pooled data, we established a simple predictive staging system (PS score) scored by the mathematical product of tumor number and size, and degree of liver function. We compared the prognostic abilities of the PS score (score 0–3) with those of six well-known clinical staging systems. Then, we found that there were significant differences (P

CT enteroclysis（CTE）とは，水や等張性緩下剤等（Niflec®，Elental®等）の陰性造影剤を小腸チューブから注入し，全小腸を十分に拡張させた後Dynamic CTを撮影して小腸病変の診断を行う検査法である．海外ではクローン病に対する報告が多数なされており，腸管の炎症，狭窄や瘻孔に対して高い確率での検出が可能とされている．症例は30歳代男性．2006年に小腸大腸型クローン病と診断され，5－アミノサリチルサン（5-ASA）製剤内服と成分栄養剤で加療されていた．2008年，臀部痛が出現し，近医の造影CTで仙骨前面に膿瘍を認めたが保存的加療にて症状は軽快し，以後の受診歴はない．2009年4月，鮮血便を頻回に認め，上部・下部消化管内視鏡検査では出血源が同定されなかったことから小腸出血が疑われた．出血は絶食のみで自然止血したが，出血源の同定目的で当院へ転院となった．陰性造影剤としてNiflec®を用いてCTEを施行したところ，回腸の壁肥厚，狭窄および直腸との内瘻の形成が疑われ手術適応と判断し，当院外科で手術が行われた．術中所見でCTEにて検出された回腸直腸瘻が実際に確認された．従来クローン病における内瘻の診断には小腸X線造影検査が用いられてきたが，瘻孔を明確に描出するのは難しく，術中所見ではじめて瘻孔形成部位が確定することも少なくなかった．本症例では内瘻の存在および局在の同定にCTEが安全に実施でき，手術適応を判断する上で有用であったことから，文献的考察を加えて報告する．

症例は60歳代男性．2003年３月右肺大細胞癌に対し，右中下葉切除術が施行された．当院内科で経過観察中の2006年１月，嘔吐が出現し近医受診．腹部造影CTで小腸腫瘤を先進部とする腸重積および腸間膜，肝十二指腸靭帯，大動脈周囲のリンパ節腫大を認め，当科紹介入院となった．イレウス解除と診断目的に手術を施行した．小腸腫瘍による腸重積とリンパ節による十二指腸から空腸起始部にかけての腸管狭窄を認めたため，小腸腫瘍切除，胃空腸バイパス術を施行した．病理組織検査では肺大細胞癌小腸転移の診断であった．その後，内科にてゲムシタビン（GEM）/シスプラチン（CDDP）併用療法を施行されたが効果を認めなかった．本人の希望もあり，新たな化学療法は施行しない方針とした．

Background Direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) has been widely used for patients with septic shock around the world, but the prognostic factors have not been fully understood. We conducted a retrospective analysis to determine the prognostic factors in patients with septic shock who underwent PMX-DHP. Methods Twenty-nine patients with septic shock who underwent PMX-DHP were included in the study. The patients were divided into groups based on survival (n = 23) and non-survival (n = 6) 28 days after PMX-DHP, and the clinical data for the two groups before and after PMX-DHP were compared. Results In non-survivors, the vasopressor dependency index before PMX-DHP was significantly higher (p = 0.046), and the leukocyte count before PMX-DHP was significantly lower (p = 0.024) than in survivors. Furthermore, base excess after PMX-DHP was significantly lower in non-survivors (p = 0.007) than in survivors. The optimal cutoff points of the vasopressor dependency index, leukocyte count, and base excess identified by receiver operating characteristic curves were 0.499/mmHg, 1360/μL, and −6.4 mmol/L, respectively. And the score using these three cutoffs, termed the prognostic score, was related to the prognosis of septic shock patients who underwent PMX-DHP (area under the curve = 0.946). Conclusions The prognostic score, using three parameters which are immediately and readily available in early phase after starting PMX-DHP, might be useful to predict the prognosis of these patients.

Objective Enteral administration of synbiotics has been reported to be beneficial during various types of surgery, but its clinical value in elderly surgical patients remains unclear. The aim of this study was to quantitatively evaluate the changes in gut microbiota and environment induced by perioperative synbiotic therapy, and to investigate whether it is possible to reduce infectious complications in elderly patients undergoing gastroenterological surgery. Methods Forty-eight patients over the age of 70 y were randomized into a group receiving 7 d of preoperative and 10 d of postoperative synbiotic therapy (S group) and a control group without synbiotic therapy (C group). A fecal sample collected before and after surgery in each group was used for a quantitative evaluation of the microbiota. Results Forty-eight patients completed the trial (25 in the S group and 23 in the C group). Synbiotic therapy significantly maintained the status of Bifidobacterium and Lactobacillus , whereas the number of Enterobacteriaceae , Staphylococcus, and Pseudomonas was significantly decreased. The total organic acid and short-chain fatty acid concentrations were increased, and the pH was markedly decreased, in the S group compared with the C group. The incidence of postoperative infectious complications was 12% in the S group and 36% in the C group, however, the difference did not reach statistical significance ( P = 0.06). A multivariate analysis revealed that only the use of perioperative blood transfusion was an independent risk factor for infectious complications. Conclusions Synbiotic therapy improved the intestinal microbial environment, and might decrease the incidence of infectious complications in elderly surgical patients.

Background The purpose of this study was to retrospectively evaluate microbial examination of sputum on postoperative day one (POD1) and to determine risk factors for postoperative pneumonia (POP) after hepatectomy. Methods Two hundred ninety-four patients who expectorated sputum on POD1 after hepatectomy between 2003 and 2014 were investigated. Sputum samples were submitted for microbial examination. Risk factors for POP were identified using multivariable analysis. Results One hundred fifty-eight (53.7 %) of 294 patients had bacteria in their sputum on POD1. POP was observed in 24 (8.2 %) patients, with increased mortality in the patients with POP (0.74 vs 12.5 %, p 400 and bacteria in sputum on POD1 were independent risk factors for POP. Bacterial homology in sputum obtained on POD1 and onset day of POP was found in 13 of the 24 (54.2 %) patients with POP. In particular, in 13 patients with POP caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa, homology was confirmed in 9 patients (69.2 %). Conclusion A Brinkman index ≥400 and bacteria in sputum on POD1 increased the risk of POP. Presence of bacteria in sputum on POD1 may be useful in determining early treatment against POP after hepatectomy.