Shigenori Homma

Co-expression of mesothelin and CA125 correlates with unfavorable patient outcome in pancreatic ductal adenocarcinoma.

Objectives: Recent studies have shown that the high affinity of mesothelin-CA125 interaction might cause intracavitary tumor metastasis. We examined the clinicopathologic significance and prognostic implication of mesothelin and CA125 expression in pancreatic ductal adenocarcinoma. Methods: Tissue samples from 66 pancreatic ductal adenocarcinomas were immunohistochemically examined. Proportion and intensity of constituent tumor cells with mesothelin and CA125 expression were analyzed and classified as high-level expression, defined as expression by more than 50% of tumor cells and/or moderate to strong staining, or low-level expression otherwise. Results: A high level of mesothelin was correlated with a higher histological grade (P = 0.049) and the level of blood vessel permeation (P = 0.0006), whereas a high level of CA125 expression was correlated with a higher recurrence rate (P = 0.015). The expression of mesothelin was strongly correlated with that of CA125 (P = 0.0041). Co-expression of mesothelin and CA125 were associated with an unfavorable patient outcome (P = 0.0062). Conclusions: This is the first report showing that co-expression of mesothelin and CA125 were in pancreatic ductal adenocarcinoma, and such co-expression is associated with a poor prognosis. Our finding suggests that co-expression of these two factors plays a significant role in the acquisition of aggressive clinical behavior.

Comparison of Invasiveness Between Laparoscopy-Assisted Total Gastrectomy and Open Total Gastrectomy

BackgroundBecause only a few studies have been performed to date on the invasiveness of laparoscopy-assisted total gastrectomy (LATG) compared with open total gastrectomy (OTG), the minimal invasiveness of LATG has been unclear.MethodsThe OTG cohort contained 35 cases, which were performed from April 2003 to October 2005. The LATG cohort contained 46 cases, which were performed from November 2005 to November 2008. Postoperative changes over time in various parameters relating to minimal invasiveness were evaluated. We used the Wong-Baker FACES Pain Rating Scale to evaluate pain. Vital signs and a face scale were analyzed using daily maximum values on postoperative days (POD) 1–7. A hematological examination was performed on the preoperative day and POD 1, 4, 7, and 10. The number of days until oxygen saturation level (SaO2) was 95% or more in room air was used to evaluate respiratory function.ResultsSignificantly lower pain scores were obtained in the LATG group on POD 1, 4, 5, and 7. There was a significantly lower body temperature in the LATG group on POD 7. A significantly lower white blood cell count was revealed for LATG patients on POD 10, and for C-reactive protein on POD 1. Significantly higher serum total protein values were observed in the LATG group on POD 1, 4, and 7. Significantly lower blood sugar level was found in the LATG group on POD 4 and 7. The number of days until SaO2 was 95% or more in room air was significantly fewer in the LATG group.ConclusionsLATG seems to be a less invasive procedure than OTG.

First clinical trial of cancer vaccine therapy with artificially synthesized helper/ killer-hybrid epitope long peptide of MAGE-A4 cancer antigen

A patient with pulmonary metastasis of colon cancer was treated with artificially synthesized helper/killer‐hybrid epitope long peptide (H/K‐HELP) of MAGE‐A4 cancer antigen. The patient was vaccinated with MAGE‐A4‐H/K‐HELP combined with OK432 and Montanide ISA‐51. There were no severe side‐effects except for a skin reaction at the injection site. MAGE‐A4‐H/K‐HELP induced MAGE‐A4‐specific Th1 and Tc1 immune responses and the production of MAGE‐A4‐specific complement‐fixing IgG antibodies. Tumor growth and carcinoembryonic antigen tumor marker were significantly decreased in the final diagnosis. This is the first report that artificially synthesized MAGE‐A4‐H/K‐HELP induces Th1‐dependent cellular and humoral immune responses in a human cancer patient. (Cancer Sci 2012; 103: 150–153)

Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients

The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5‐fluorouracil derivative (TS‐1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS‐1‐based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide‐specific cytotoxic T lymphocyte (CTL) precursors in peripheral blood mononuclear cells and peptide‐specific IgG in the plasma of cancer patients. Patients were vaccinated with peptides (a maximum of four) biweekly in combination with or without three different doses of TS‐1 (20, 40 and 80 mg/m2/day). Although grade 3 toxicity, including anemia (one patient) and neutropenia (one patient) were observed, the combination therapy was generally well tolerated. An increase in peptide‐specific IgG after the sixth vaccination was observed in the vast majority of patients irrespective of the dose of TS‐1 used. In contrast, an increase in peptide‐specific interferon‐γ production by CTL was most evident in patients who were administered the highest dose of TS‐1. Furthermore, in the patients who received 80 mg/m2/day TS‐1, CTL‐mediated cytotoxicity against cancer cells was maintained at the prevaccination level. These results indicate that administration of the standard dose (80 mg/m2/day) of TS‐1 in combination with a personalized peptide vaccination does not necessarily impede immunological responses in cancer patients, and could actually maintain or augment them. (Cancer Sci 2007; 98: 1113–1119)

Luminal membrane expression of mesothelin is a prominent poor prognostic factor for gastric cancer

Background:Mesothelin is expressed in various types of malignant tumour, and we recently reported that expression of mesothelin was related to an unfavourable patient outcome in pancreatic ductal adenocarcinoma. In this study, we examined the clinicopathological significance of the mesothelin expression in gastric cancer, especially in terms of its association with the staining pattern.Methods:Tissue specimens from 110 gastric cancer patients were immunohistochemically examined. The staining proportion and intensity of mesothelin expression in tumour cells were analysed, and the localisation of mesothelin was classified into luminal membrane and/or cytoplasmic expression.Results:Mesothelin was positive in 49 cases, and the incidence of mesothelin expression was correlated with lymph-node metastasis. Furthermore, luminal membrane staining of mesothelin was identified in 16 cases, and the incidence of luminal membrane expression was also correlated with pT factor, pStage, lymphatic permeation, blood vessel permeation, recurrence, and poor patient outcome. Multivariate analysis showed that luminal membrane expression of mesothelin was an independent predictor of overall patient survival.Conclusion:We described that the luminal membrane expression of mesothelin was a reliable prognostic factor in gastric cancer, suggesting the functional significance of membrane-localised mesothelin in the aggressive behaviour of gastric cancer cells.

IL-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.

Percutaneous transhepatic gallbladder drainage followed by elective laparoscopic cholecystectomy in patients with moderate acute cholecystitis under antithrombotic therapy.

Standard treatment for acute cholecystitis (AC) in patients receiving antithrombotic drugs has not been established. We evaluated the safety of percutaneous transhepatic gallbladder drainage (PTGBD) followed by elective laparoscopic cholecystectomy (LC) in patients with moderate AC who were receiving antithrombotics.

Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies.

Does reduced-port laparoscopic surgery for medically uncontrolled ulcerative colitis do more harm than good?

Reduced‐port laparoscopic surgery is a novel minimally invasive surgery. However, reduced‐port surgery for ulcerative colitis (UC) remains controversial. Here, we describe the clinical outcomes of single‐incision plus one port laparoscopic surgery (SILS + 1) for medically uncontrolled UC.