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Yuka Ohe, Sachio Fushida, Takahisa Yamaguchi, Jun Kinoshita, Hiroto Saito, Koichi Okamoto, Keishi Nakamura, Hidehiro Tajima, Itasu Ninomiya, Tetsuo Ohta Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, JapanCorrespondence: Sachio FushidaDepartment of Gastroenterological Surgery, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa 920-8641, JapanTel +8176-265-2362Email fushida@staff.kanazawa-u.ac.jpIntroduction: Platelets are one factor promoting tumor development. Conversely, lymphocytes are one factor for immune protection. The peripheral blood platelets–lymphocyte ratio (PLR) is useful as an inflammation/immune indicator to predict postoperative recurrence and prognosis of a variety of malignancies. The peripheral blood neutrophil–lymphocyte ratio (NLR) has also been reported as a useful inflammation/immune indicator. However, there are few studies evaluating the relationship between these peripheral blood indicators and the effectiveness of chemotherapy. Thus, we examined these relationships in gastric cancer patients.Patients and Methods: Between 2005 and 2018, 41 gastric cancer patients treated with preoperative DCS therapy (docetaxel, cisplatin, and S-1) therapy followed by gastrectomy were evaluated. Data for peripheral blood tests prior to the initiation of chemotherapy were used. The effectiveness of chemotherapy was determined using Response Evaluation Criteria in Solid Tumors (RECIST) and the pathological response of primary lesions (Ef grade). The relationship between the blood test results and the effectiveness of chemotherapy was evaluated.Results: Each optimal cut-off value of peripheral inflammation/immune indicators was calculated through ROC curves. Although the pathological responder (Ef grade 2 or 3) revealed significantly better prognosis than the non-responder (Ef grade 0-1b), no relationship was found between responder according to RECIST and prognosis (P=0.014, P=0.992). In univariate analysis, a low PLR (< 180, P=0.005), low NLR (< 2.6, P=0.019), high lymphocyte (≥ 1.43, P=0.019) and high PNI (≥ 40, P=0.032) were identified as prognostic markers, whereas PLR was the only marker correlated with pathological response (P=0.031).Conclusion: PLR obtained prior to chemotherapy might be a useful indicator for predicting chemosensitivity owing to the simplicity of its procedure.Keywords: gastric cancer, preoperative chemotherapy, chemosensitivity, platelet-lymphocyte ratio

Sachio Fushida,1 Jun Kinoshita,1 Katsunobu Oyama,1 Takashi Fujimura,2 Tomoya Tsukada,3 Takahisa Yamaguchi,1 Itasu Ninomiya,1 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan; 2Department of Surgery, Toyama City Hospital, Toyama, Japan; 3Department of Surgery, Toyama Prefectural Central Hospital, Toyama, Japan Background: Scirrhous gastric cancer (SGC) is highly invasive and metastatic because of its interactions with stromal cells, such as fibroblasts and macrophages, and extracellular matrix, leading to a higher incidence of peritoneal metastasis (PM) than other gastric cancers (GCs). Taxane-based intraperitoneal chemotherapy (IPC) is a promising therapy for PM. We retrospectively analyzed outcomes of multidisciplinary therapies that included IPC for SGC. Patients and therapy: Of 1,679 GC patients treated between 1990 and 2012, we analyzed 119 patients who underwent multidisciplinary therapy for SGC. Patients without PM received gastrectomy with lymphadenectomy and resection of involved adjacent organs followed by intraoperative IPC using cisplatin. Patients with PM received chemotherapy using fluorouracil, with or without methotrexate plus IPC using cisplatin before 2000, and S-1 plus IPC using paclitaxel or docetaxel since 2000. Results: Of the 119 patients, 73 (61%) had PM and 63 (53%) had positive peritoneal lavage cytology. Of the 89 gastrectomy patients, 30 (34%) had macroscopic residual tumors (R2). Of the patients treated since 2000, 66 (100%) received S-1 plus taxanes and 44 patients (67%) received taxane-based IPC. Median survival time was significantly longer in the post-2000 group (22.8 months) than in the pre-2000 group (9.5 months). In univariate analysis, lavage cytology, PM, taxane-based IPC, gastrectomy, and R2 resection were significant prognostic factors. However, only R2 resection was an independent prognostic factor in multivariate analysis (hazard ratio: 5.53, 95% CI: 2.05–14.93). Conclusion: As use of taxane-based IPC is not an independent prognostic factor, new multidisciplinary therapies are necessary to avoid R2 resections. Keywords: peritoneal metastasis, intraperitoneal chemotherapy, taxanes

Toru Kurata, Sachio Fushida, Jun Kinoshita, Katsunobu Oyama, Takahisa Yamaguchi, Mitsuyoshi Okazaki, Tomoharu Miyashita, Hidehiro Tajima, Itasu Ninomiya, Tetsuo Ohta Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan Background: Characterized by aggressive proliferation, extensive stromal fibrosis, and resulting drug resistance, peritoneal dissemination in gastric cancer remains associated with poor prognosis. Interaction between cancer and stromal cells accelerates tumor progression via epithelial–mesenchymal transition (EMT), which is one of the major causes of tissue fibrosis, and human peritoneal mesothelial cells (HPMCs) play important roles as cancer stroma in peritoneal dissemination. Transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT, and Smad proteins play an important role in the TGF-β signaling pathway. Eribulin mesylate (eribulin), a nontaxane microtubule dynamics inhibitor used for the treatment of advanced breast cancer, inhibits EMT changes in triple-negative breast cancer cells. We examined its ability to inhibit tumor progression and EMT changes resulting from the interaction between gastric cancer cells and HPMCs and to act synergistically with 5-fluorouracil (5-FU), a key drug for gastric cancer. Materials and methods: Proliferation of gastric cancer cells and HPMCs isolated from healthy omentum was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Following gastric cancer cell/HPMC coculture, EMT markers were detected by immunofluorescence, immunohistochemistry, and Western blotting; invasion assays were performed; and TGF-β and Smad phosphorylation were assessed by Western blotting and enzyme-linked immunosorbent assay. A mouse fibrotic tumor xenograft model was established using gastric cancer cell/HPMC cocultures. The effect of eribulin and/or 5-FU was tested in each case. Results: Eribulin significantly suppressed gastric cancer cell proliferation and EMT changes in MKN-45 gastric cancer cells and HPMCs induced by their interaction in vitro. Eribulin inhibited EMT at much lower concentrations (≥0.5 nM for MKN-45 and ≥0.1 nM for HPMCs) than its half maximal inhibitory concentrations (2.2 nM for MKN-45 and 8.1 nM for HPMCs), and this resulted, at least partly, from the downregulation of TGF-β/Smad signaling. Eribulin administration of ≥0.1 mg/kg suppressed tumor progression (0.1 mg/kg, p=0.02), and fibrosis was inhibited by lower dose (0.05 mg/kg, p=0.008) in the xenograft model. Furthermore, 0.05 mg/kg administration with 5-FU brought about synergistic antitumor effects (p=0.006). Conclusion: Low-dose eribulin combined with 5-FU might be a promising therapy for peritoneal dissemination in gastric cancer. Keywords: peritoneal dissemination, cancer–stromal interaction, human peritoneal mesothelial cell, TGF-β, Smad, synergism

Mitsuyoshi Okazaki,1 Sachio Fushida,1 Tomoya Tsukada,1 Jun Kinoshita,1 Katsunobu Oyama,1 Tomoharu Miyashita,1 Itasu Ninomiya,1 Shinichi Harada,2 Tetsuo Ohta1 1Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan; 2Center for Biomedical Research and Education, School of Medicine, Kanazawa University, Ishikawa, Japan Background: In patients with gastric cancer, one of the greatest obstacles to effective chemotherapy is the development of chemoresistance. It has been previously reported that hypoxia-inducible factor-1 alpha (HIF-1α) is associated with acquisition of chemoresistance, and more recent studies have also noted an association of pyruvate kinase muscle 1 (PKM1) and chemoresistance. The purpose of this study was to identify the effect of HIF-1α and PKM1 expression on the development of acquired chemoresistance using a paclitaxel (PTX)-resistant gastric cancer cell line.Materials and methods: A cancer cell line resistant to PTX was established from MKN45 cells by stepwise exposure to drug (rMKN45-PTX). The expressions of HIF-1α, apoptosis, vascular endothelial growth factor (VEGF), multidrug transporters and glycolytic enzyme were examined by Western blotting, enzyme-linked immunosorbent assay and immunohistochemistry. We also assessed the tumor proliferation by subcutaneous tumor and peritoneal dissemination of mouse xenograft model.Results: The resistance index was 6.1 by determining as the ratio of the 50% growth inhibition (IC50) of rMKN45-PTX/IC50 of MKN45. Expression of nuclear factor kappa B and HIF-1α was increased in rMKN45-PTX cells compared with the parent cells. Expression of Bax and caspase-3 was significantly downregulated, whereas expression of Bcl-xL, P-glycoprotein, multidrug resistance-associated protein and VEGF was increased in rMKN45-PTX. The expression level of PKM1 was upregulated in rMKN45-PTX, leading to an increase in the PKM1/PKM2 ratio. Using xenograft models, we demonstrated that mouse subcutaneous tumors derived from rMKN45-PTX were significantly larger than those derived from MKN45 cells.Conclusion: Under the stress of chemotherapeutic agent exposure, high expression of HIF-1α affects various downstream genes. Although the underlying mechanism is unknown, our data suggest that PKM1 is also a molecular target for gastric cancer treatment. Keywords: HIF-1α, PKM1, chemoresistance, gastric cancer

Sachio Fushida,1 Jun Kinoshita,1 Masahide Kaji,2 Katsunobu Oyama,1 Yasuo Hirono,3 Tomoya Tsukada,2 Takashi Fujimura,4 Tetsuo Ohta1 On behalf of the Digestive Disease Support Organization Study Group 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, 2Department of Surgery, Toyama Prefectural Central Hospital, Toyama, 3First Department of Surgery, Fukui University Hospital, Fukui, 4Department of Surgery, Toyama City Hospital, Toyama, Japan Background: Weekly paclitaxel (wPTX) is the preferred second-line chemotherapy for gastric cancer in Japan. Histone deacetylase inhibitors have been shown to decrease proliferation through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One histone deacetylase inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel (PTX), shown in a murine gastric cancer model. This Phase II trial was designed to evaluate the benefits of adding VPA to wPTX in patients with gastric cancer refractory to first-line treatment with fluoropyrimidine.Patients and methods: The patients were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m2 intravenously on days 1, 8, and 15, every 4 weeks, or a dose of PTX plus VPA taken everyday at 7.5 mg/kg twice daily. Random assignment was carried out at the data center with a minimization method adjusted by the Eastern Cooperative Oncology Group performance status (0–1 vs 2), prior chemotherapy (first-line vs second-line), and measurable lesions (presence vs absence). The primary end point was the overall survival (OS) rate, and the secondary end points were the progression-free survival rate and safety analysis.Results: Sixty-six patients were randomly assigned to receive wPTX (n=33) or wPTX plus VPA (n=33). The median OS was 9.8 months in the wPTX group and 8.7 months in the wPTX plus VPA group (hazard ratio 1.19; 95% CI 0.702–2.026; P=0.51). The median progression-free survival was 4.5 months in the wPTX group and 3.0 months in the wPTX plus VPA group (hazard ratio 1.29; 95% CI 0.753–2.211; P=0.35). Grade 3–4 adverse events were neutropenia (3.1%), pneumonia (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%).Conclusion: No statistically significant difference was observed between wPTX and wPTX plus VPA for OS. Keywords: valproic acid, paclitaxel, second- or third-line therapy, advanced gastric cancer

Sachio Fushida,1,2 Katsunobu Oyama,1,2 Masahide Kaji,2 Yasuo Hirono,2 Jun Kinoshita,1,2 Tomoya Tsukada,1,2 Hideaki Nezuka,2 Tatsuo Nakano,2 Masahiro Noto,2 Koji Nishijima,2 Takashi Fujimura,2 Tetsuo Ohta1,2 1Department of Gastroenterological Surgery, Kanazawa University Hospital, 2Digestive Disease Support Organization (DDSO), Kanazawa, Japan Background: Tiotropium, a long-acting inhaled anticholinergic drug, has been widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the issue of whether perioperative tiotropium improves postoperative outcomes for gastric cancer patients with COPD remains unclear. Thus, the aim of this study was to determine the efficacy of perioperative tiotropium intervention for gastric cancer patients with COPD.Patients and methods: Eighty-four gastric cancer patients with mild-to-moderate COPD were randomly assigned to receive perioperative pulmonary rehabilitation alone (control group) or pulmonary rehabilitation with 18 µg of tiotropium once daily (tiotropium group). The patients in the tiotropium group received tiotropium for more than 1 week before surgery and for 2 weeks after surgery. Spirometry was performed prior to group assignment and at 2 weeks after surgery. Postoperative complications, forced expiratory volume in 1 second, forced vital capacity, and the ratio of forced expiratory volume in second to forced vital capacity (%) were compared between the two groups.Results: There were no significant differences between the two groups in terms of age, body mass index, smoking, gastrectomy incision, operation time, and bleeding volume (all P>0.05). Postoperative complications and pulmonary functions did not differ significantly between the control and tiotropium groups. A subgroup analysis of gastric cancer patients with moderate COPD showed that perioperative tiotropium intervention significantly decreased the rate of postoperative complications compared with the control group (P=0.046). However, even after gastrectomy, many patients with mild COPD in both the control and tiotropium groups showed improved pulmonary function.Conclusion: Although perioperative tiotropium intervention had no significant effects in gastric cancer patients with mild COPD, it may be beneficial in those with moderate COPD. Therefore, the next prospective study should further evaluate perioperative tiotropium intervention for gastric cancer patients with moderate-to-severe COPD. Keywords: gastric cancer, COPD, tiotropium