Masahiro Katsuda

Reconstruction after proximal gastrectomy for early gastric cancer in the upper third of the stomach: An analysis of our 13-year experience

BACKGROUND Fundoplication during esophagogastrostomy (EG) after proximal gastrectomy (PG) is a useful procedure to prevent reflux esophagitis, but it is unclear how much of the remnant stomach should be wrapped around the esophagus. METHODS We analyzed data from 101 patients who underwent PG for upper third early gastric cancer between 1999 and 2011. In all, 64 patients underwent EG, 25 underwent jejunal interposition (JI), and 12 underwent jejunal pouch interposition (JPI). We compared intraoperative details and postoperative outcomes, and investigated the relationships between the degree of the fundoplication during EG and endoscopic findings. RESULTS The length of the operation was significantly shorter in the EG group than in the other 2 groups (P < .05), and the intraoperative blood loss was significantly less in the EG group (P < .05). The JI and the JPI groups had significantly greater rates of early complications than did the EG group (P = .01). Reflux esophagitis was present in 22% of patients in the EG group, 8% in the JPI group, and none in the JI group. In the EG group, reflux esophagitis was significantly less common in patients with a >180° wrap of the remnant stomach around the esophagus than in patients with a smaller wrap (P = .0008). The rate of body weight loss was significantly less in the EG group compared with the other 2 groups (P < .05). CONCLUSION Considering the low invasiveness of the procedure and postoperative outcomes, we consider that EG with a >180° wrap as the optimal reconstructive procedure.

Inhibition of IL-17A in Tumor Microenvironment Augments Cytotoxicity of Tumor-Infiltrating Lymphocytes in Tumor-Bearing Mice

It remains controversial whether IL-17A promotes or inhibits cancer progression. We hypothesized that IL-17A that is locally produced in the tumor microenvironment has an important role in angiogenesis and tumor immunity. We investigated the effect of inhibiting IL-17A at tumor sites on tumor growth and on local and systemic anti-tumor immunity. MC38 or B16 cells were inoculated subcutaneously into mice, and intratumoral injection of an adenovirus vector expressing siRNA against the mouse IL-17A gene (Ad-si-IL-17) significantly inhibited tumor growth in both tumor models compared with control mice. Inhibition of IL-17A at tumor sites significantly suppressed CD31, MMP9, and VEGF expression in tumor tissue. The cytotoxic activity of CD8+ T cells from tumor-infiltrating lymphocytes in mice treated with Ad-si-IL-17 was significantly higher than in control mice; however, CD8+ T cells from splenocytes had similar activity levels. Suppression of IL-17A at tumor sites led to a Th1-dominant environment, and moreover, eliminated myeloid-derived suppressor cells and regulatory T cells at tumor sites but not in splenocytes. In conclusion, blockade of IL-17A at tumor sites helped suppress tumor growth by inhibiting angiogenesis as well as cytotoxic T lymphocytes activation at tumor sites.

Complications of endoscopic submucosal dissection for gastric noninvasive neoplasia: an analysis of 647 lesions.

Purpose: This study aimed to determine risk factors for postoperative complications of gastric endoscopic submucosal dissection (ESD). Methods: This retrospective study included 647 lesions in 580 consecutive patients who underwent ESD for gastric noninvasive neoplasia from January 1, 2002 through December 31, 2011. Results: The overall perforation rate was 5.1%. Multivariate logistic regression analysis indicated that perforation was significantly associated with tumors in the greater curvature of the stomach (P<0.0001), scars in tumor lesions (P=0.002), long operative time (P=0.007), and tumors in the remnant stomach (P=0.036). The bleeding rate after gastric ESD was 3.9%. Multivariate logistic regression analysis indicated a statistically significant association between postoperative bleeding and oral anticoagulant or antiplatelet drugs (P<0.0001), dialysis (P=0.009), and use of antihypertensive drugs (P=0.015). Conclusion: It is important to perform gastric ESD with particular care in patients with risk factors.

Prognostic significance of IL-17 mRNA expression in peritoneal lavage in gastric cancer patients who underwent curative resection

Peritoneal dissemination is frequently detected in patients with advanced gastric cancer. The peritoneal cavity is a compartment in which an immunologic host-tumor interaction can occur. There are no reports on the relationship between IL-17 expression in peritoneal lavage and prognosis in gastric cancer patients. Therefore, we investigated the expression of IL-17 mRNA in peritoneal lavage from gastric cancer patients and assessed the association of its expression with clinicopathological parameters and prognosis. Peritoneal lavage was obtained from 114 patients with gastric cancer at initial surgery. Seventy-nine patients underwent curative resection. Among these 79 patients, IL-17 mRNA expression was associated with the depth of tumor invasion (p<0.05). Twelve of the 79 patients who underwent curative resection died, and 9 of those 12 developed peritoneal metastasis. Notably, among the 79 patients who underwent curative resection, those with high expression of IL-17 mRNA in peritoneal lavage had significantly prolonged survival when compared to these patients with low expression of IL-17 mRNA in peritoneal lavage (p<0.05) as evidence by the survival curves. In a multivariate analysis, low expression of IL-17 mRNA in peritoneal lavage and tumor size were found to be independent significant predictive factors for prognosis (HR, 7.91; 95% CI, 1.65-38.03) in the patients who underwent curative resection. IL-17 mRNA expression in peritoneal lavage is a reliable prognostic factor for patients undergoing curative resection for gastric cancer. Low IL-17 expression in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer.

An armed oncolytic herpes simplex virus expressing thrombospondin‐1 has an enhanced in vivo antitumor effect against human gastric cancer

Advanced gastric cancer is a common disease, but the conventional treatments are unsatisfactory because of the high recurrence rate. One of the promising new therapies is oncolytic virotherapy, using oncolytic herpes simplex viruses (HSVs). Thrombospondin‐1 (TSP‐1) suppresses tumor progression via multiple mechanisms including antiangiogenesis. Our approach to enhance the effects of oncolytic HSVs is to generate an armed oncolytic HSV that combines the direct viral oncolysis with TSP‐1‐mediated function for gastric cancer treatment. Using the bacterial artificial chromosome (BAC) system, a 3rd generation oncolytic HSV (T‐TSP‐1) expressing human TSP‐1 was constructed for human gastric cancer treatment. The enhanced efficacy of T‐TSP‐1 was determined in both human gastric cancer cell lines in vitro and subcutaneous tumor xenografts of human gastric cancer cells in vivo. In addition, we examined the apoptotic effect of T‐TSP‐1 in vitro, and the antiangiogenic effect of T‐TSP‐1 in vivo compared with a non‐armed 3rd generation oncolytic HSV, T‐01. No apparent apoptotic induction by T‐TSP‐1 was observed for human gastric cancer cell lines TMK‐1 cells but for MKN1 cells in vitro. Arming the viruses with TSP‐1 slightly inhibited their replication in some gastric cancer cell lines, but the viral cytotoxicity was not attenuated. In addition, T‐TSP‐1 exhibited enhanced therapeutic efficacy and inhibition of angiogenesis compared with T‐01 in vivo. In this study, we established a novel armed oncolytic HSV, T‐TSP‐1, which enhanced the antitumor efficacy by providing a combination of direct viral oncolysis with antiangiogenesis. Arming oncolytic HSVs may be a useful therapeutic strategy for gastric cancer therapy.

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

We investigated peptide cocktail vaccine OCV‐C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single‐arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28‐day treatment cycle, patients received weekly subcutaneous injection of OCV‐C01 for 48 weeks and gemcitabine was administered intravenously at 1,000 mg/m2 on days 1, 8 and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease‐free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide‐specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months [95% confidence interval (CI), 11.1–20.6] and the DFS rate at 18 months was 34.6% (95% CI, 18.3–51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8–82.5). The administration of OCV‐C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A‐specific CTL responses and without (p = 0.027), and between patients with KIF20A expression and without (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A‐specific CTL responses. OCV‐C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer.

Antitumor immune response of dendritic cells (DCs) expressing tumor‐associated antigens derived from induced pluripotent stem cells: In comparison to bone marrow‐derived DCs

It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC‐based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell‐derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow‐derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (+) cytotoxic T lymphocytes (CTLs) was assayed using a 51Cr‐release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100‐specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor‐associated antigen‐specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine.

Endoscopic submucosal dissection for gastric tumors in various types of remnant stomach.

BACKGROUND AND STUDY AIMS The aim of this study was to examine the clinical outcomes of endoscopic submucosal dissection (ESD) for gastric tumors in various types of remnant stomach. PATIENTS AND METHODS Between January 2002 and March 2013, ESD was performed for 750 gastric tumors. Of these lesions, 49 were in a remnant stomach, and were included in the study. RESULTS The en bloc resection rate was 100 %. The curative resection rate was 82 %. The rate of perforation was high in patients with gastric conduits (28.6 %). Perforation was significantly more common in patients with lesions located on the suture line (4.9 % vs. 50.0 %; P = 0.0043). CONCLUSION ESD for gastric tumors in the remnant stomach can be considered feasible and safe in clinical practice. However, the procedure is technically more difficult in patients with a gastric conduit, due to the increased risk of perforation at the suture line.

Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA

Recently, dendritic cells (DC) transfected with tumor RNA have been used as a cancer vaccine. The efficacy of a cancer vaccine using DC transfected tumor RNA was examined. Of particular interest was whether a vaccine using DC transfected with recrudescent tumor RNA is effective for the treatment of a regrowing tumor after prior immunotherapy. In addition, the usefulness of co‐transfection of granulocyte macrophage colony‐stimulating factor (GM‐CSF) mRNA to augment the DC vaccine was examined. CT26 tumor‐bearing mice were immunized by s.c. injection with DC transfected with CT26 mRNA (DC‐CT26). The cytotoxic activity against CT26 in mice immunized with DC‐CT26 was significantly higher than that in the control group (P < 0.001) and was augmented by GM‐CSF mRNA co‐transfection (P < 0.05), resulting in remarkable therapeutic efficacy in CT26 s.c. tumor models. Cytotoxic T lymphocytes induced by the vaccination using DC transfected with mRNA from the recrudescent tumor showed a potent cytotoxicity against the recrudescent CT26 tumor cells, which was significantly higher than the cytotoxicity induced by the vaccination using DC‐CT26 (P < 0.05). In addition, in a recrudescent tumor model, this vaccination suppressed the regrowing s.c. tumors, and was augmented by GM‐CSF mRNA co‐transfection (P < 0.05). These results suggested that vaccination therapy using DC simultaneously transfected with whole tumor RNA and GM‐CSF mRNA could generate therapeutic immune responses even against recrudescent tumor after prior vaccination. (Cancer Sci 2008; 99: 407–413)

Randomized clinical trial of landiolol hydrochloride for the prevention of atrial fibrillation and postoperative complications after oesophagectomy for cancer

Atrial fibrillation is common after oesophageal surgery. The aim of this study was to evaluate whether landiolol hydrochloride was effective and safe in the prevention of atrial fibrillation after oesophagectomy, and to see whether a reduction in incidence of atrial fibrillation would reduce other postoperative complications.