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Although miR-29b levels in peritoneal exosomes was markedly reduced in patients with peritoneal metastases(PM), their role has not been fully clarified. Bone marrow derived mesenchymal stem cells(BMSC)were transfected with miR-29b- integrating lentivirus and exosomes isolated from culture supernatants using ultracentrifugation. The effects of the exosomes on human peritoneal mesothelial cells(HPMC)were examined in vitro. The in vivo effect of murine BMSC-derived exosomes was examined with a syngeneic PM model. Culture of HPMC with TGF-β1 decreased expression of E-cadherin and calretinin with increased expression of vimentin, totally restored by adding miR-29b-rich exosomes. The exosomes inhibited proliferation and migration of HPMC, and inhibited adhesion of gastric cancer cells to HPMC. Intraperitoneal(IP)transfer of miR- 29b-rich exosomes every 3 days markedly reduced the number of PM of a murine gastric cancer cell, YTN16P, on the mesentery of C57/BL6 mice. IP administration of miR-29b-containing exosome suppresses the development of PM of gastric cancer.

Small extracellular vesicles (sEV) contain various microRNAs (miRNAs) and play crucial roles in the tumor metastatic process. Although miR-29b levels in peritoneal exosomes were markedly reduced in patients with peritoneal metastases (PM), their role has not been fully clarified. In this study, we asked whether the replacement of miR-29b can affect the development of PM in a murine model. UE6E7T-12, human bone marrow-derived mesenchymal stem cells (BMSCs), were transfected with miR-29b-integrating recombinant lentiviral vector and sEV were isolated from culture supernatants using ultracentrifugation. The sEV contained markedly increased amounts of miR-29b compared with negative controls. Treatment with transforming growth factor-β1 decreased the expression of E-cadherin and calretinin with increased expression of vimentin and fibronectin on human omental tissue-derived mesothelial cells (HPMCs). However, the effects were totally abrogated by adding miR-29b-rich sEV. The sEV inhibited proliferation and migration of HPMCs by 15% (p < 0.005, n = 6) and 70% (p < 0.005, n = 6), respectively, and inhibited adhesion of NUGC-4 and MKN45 to HPMCs by 90% (p < 0.0001, n = 5) and 77% (p < 0.0001, n = 5), respectively. MicroRNA-29b-rich murine sEV were similarly obtained using mouse BMSCs and examined for in vivo effects with a syngeneic murine model using YTN16P, a highly metastatic clone of gastric cancer cell. Intraperitoneal (IP) transfer of the sEV every 3 days markedly reduced the number of PM from YTN16P in the mesentery (p < 0.05, n = 6) and the omentum (p < 0.05, n = 6). Bone marrow mesenchymal stem cell-derived sEV are a useful carrier for IP administration of miR-29b, which can suppress the development of PM of gastric cancer., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The peritoneal cavity contains many site-specific immune cells which constitute a unique immune microenvironment. However, it is unclear how the local immune signature is altered in patients with peritoneal metastases (PM)., Methods: Peritoneal lavage fluid or ascites were obtained from 122 patients with various stages of gastric cancer (GC). Cells recovered from peritoneal fluids were immunostained with mAbs for lymphocyte-, macrophage- and tumor cell-specific antigens and the frequencies of leukocyte subsets and antigen expression levels were evaluated with multi-color flowcytometry., Results: The proportions of CD8(+) T cells, CD3(+)CD56(+) NKT-like cells, and CD3(-)CD56(+) NK cells to CD45(+) leukocytes were significantly reduced in patients with PM compared to those without PM. In patients with PM, the rates of CD8 (+) T cells and NKT-like cells correlated inversely with the tumor leukocyte ratio (TLR), the relative frequency of CD326(+) tumor cells to CD45(+) leukocytes. In contrast, the proportion of CD19(+) B cells was significantly increased in patients with PM, and their proportion correlated positively with the TLR and peritoneal carcinomatosis index (PCI) score. In patients with PM, CD14(+) macrophages tended to be increased with enhanced expression of CD14, CD16 and a M2-macrophage marker, CD163. In particular, macrophages in patients with high TLR contained many granules with high side scatter and CD14 expression in their flow profile compared to those without PM., Conclusion: PM are accompanied by a drastic change in phenotypes of lymphocyte and macrophage in the peritoneal cavity, which might be involved in the development and progression of intraperitoneal tumor growth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takahashi, Kurashina, Yamaguchi, Kanamaru, Ohzawa, Miyato, Saito, Hosoya, Lefor, Sata and Kitayama.)

Background/aim: Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) blockade therapy is widely used for the treatment of patients with metastatic gastric cancer (GC). However, it is unclear how PD-1 antibodies affect the local immunity related to the growth of peritoneal metastases (PM). The clinical efficacy of PD-1/PD-L1 inhibitors against PM from GC has not been clearly determined., Materials and Methods: We established a highly metastatic subclone of murine GC cells to the peritoneum, YTN16P, by in vivo selection and evaluated the effects of intravenous (IV) or intraperitoneal (IP) administration of anti-PD-1 antibody on PM in immunocompetent mice model. Phenotypes of immune cells in the spleen and peritoneal metastatic lesions were determined with flow cytometry and immunohistochemistry., Results: IP inoculation of YTN16P (1×10 6 ) resulted in multiple mesenteric metastases after 3 weeks. IV and IP administration of anti-PD-1mAb reduced the number of metastases to the mesentery by 30~40% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, whereas those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb., Conclusion: PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors, which can partially suppress the PM from GC regardless of the route of administration. Adding anti-PD-1 antibody to chemotherapeutic regimens may enhance their anti-tumor effects against PM, which can lead to the prolongation of survival of patients with GC with peritoneal involvement., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions., Methods: A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6-diamidino-2-phenylindole (DAPI) and FVS780. Using FCM, tumor-leukocyte ratio (TLR) were calculated from CD45(-)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(-) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel., Results: TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = -0.490) and CD8(+) T cells (r = -0.648). In PM (-) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (

Background: Intraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC)., Patients and Methods: Patients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m 2 on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m 2 on day 1, and S-1 was administered at 80 mg/m 2 /day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored., Results: Forty-four patients received SOX + IP-PTX with a median (range) of 16 (1-48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4-88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5-100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths., Conclusions: Combination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.

Gastrointestinal stromal tumors (GIST) in patients under 18 years of age are classified as pediatric GIST. Pediatric GIST are extremely rare, and there are no reports of laparoscopic-endoscopic cooperative surgery for these lesions. We report the use of non-exposed endoscopic wall-inversion surgery as a laparoscopic-endoscopic cooperative surgery-related procedure for the treatment of a pediatric GIST. The case involved a 17-year-old male patient who presented with anemia and was found to have a bleeding gastric tumor. The tumor was resected transorally using the non-exposed endoscopic wall-inversion surgery technique. No gene mutation of c-Kit or Platelet-Derived Growth Factor Receptor α (PDGFRα) was found, and the final pathological diagnosis was epithelial-type GIST due to a succinate dehydrogenase abnormality. Follow-up included a CT scan every 4 months. No recurrence has occurred to date., (© 2018 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Many types of immune cells appear in peritoneal cavity after abdominal surgery. In patients who underwent laparotomy due to gastric cancer, peritoneal lavages were obtained before and after surgical procedure. Cells were recovered from intermediate layer after Ficoll-Hypaque centrifugation and analyzed for phenotypes and functions, especially focused on low density neutrophils (LDN). The number of CD66b (+) LDN with mature phenotype was markedly elevated in postoperative as compared with preoperative lavages. Short term culture of the purified LDN produced many threadlike structures positive for SYTOX, nucleic acid staining, as well as histone and myeloperoxidase, suggesting the NETs formation. Human gastric cancer cells, MKN45, OCUM-1 and NUGC-4, were selectively attached on the NETs, which was totally abolished by the pretreatment of DNAse I. Intraperitoneal (IP) co-transfer of the LDN with MKN45 in nude mice strongly augments the metastasis formation on peritoneum, which was strongly suppressed by the following IP administration of DNAse I. Many NETs-like structures were detected on the surface of human omental tissue resected by gastrectomy. NETs on peritoneal surface can assist the clustering and growth of free tumor cells disseminated in abdomen. Disruption of the NETs by DNAse might be useful to prevent the peritoneal recurrence after abdominal surgery.

Objective: Adenosquamous carcinoma originating in the stomach is an unusual neoplasm with few existing histological studies. This study was aimed to gain insight into the histogenetic and clinicopathological characteristics of gastric cancer with squamous cell carcinoma (SCC) components., Methods: From January 2001 to June 2010 a total of 1735 patients underwent a resection of gastric cancer. Histopathologically, eight patients had adenocarcinoma containing SCC components, in which the proportion of SCC components was above 25% of the total tumor mass in four patients. The immunohistochemical and clinicopathological characteristics of these eight patients were analyzed., Results: The median survival duration was 22 months. Adenocarcinoma was present at the superficial layer of all tumors and SCC was primarily present at sites with deep invasion. Immunohistochemically, adenocarcinoma components were positive for cytokeratin (CK) 8/18/19 and CK7 in all cases. SCC components were positive for carcinoembryonic antigen and CK7 in more than 60% of patients. Expression patterns of p53 product were identical in both components. SCC components were positive for 34βE12 and adenocarcinoma components were negative for 34βE12 in all patients., Conclusions: SCC components are derived from squamous metaplasia in a pre-existing adenocarcinoma. A gastric adenocarcinoma with SCC components is associated with various patterns of metastasis and both SCC and adenocarcinoma components have the potential for metastasis. Gastric cancer with SCC components is a clinically aggressive tumor., (© 2012 The Authors. Journal of Digestive Diseases © 2012 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

Background: To decrease the incidence of internal hernia after laparoscopic gastric bypass, current recommendations include closure of mesenteric defects. Laparoscopic gastric resection is used increasingly for the treatment of gastric cancer, but the incidence of internal hernia in the treated patients has not been studied., Methods: This study retrospectively reviewed 173 patients who underwent laparoscopic resection for gastric cancer at one institution, including distal and total gastric resections with antecolic Roux-en-Y reconstruction., Results: An internal hernia occurred in 4 (7%) of 58 patients whose jejunojejunal mesenteric defect was not closed a mean of 326 days after surgery. All the patients underwent reoperation with reduction and repair of the hernia. In 115 subsequent cases, with closure of the mesenteric defect, internal hernias did not occur (0/115 cases; p < 0.05)., Conclusion: Based on the current recommendations for patients undergoing bariatric surgery, closure of this potential hernia defect is mandatory after laparoscopic gastrectomy with a Roux-en-Y reconstruction for gastric cancer.

Background: In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear., Methods: We retrospectively studied patients with gastric cancer who received S-1 on alternate days., Results: A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events., Conclusion: Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.

Background: The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required., Methods: We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments., Results: In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment., Conclusion: Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.

Purpose: Our purpose was to study the characteristics of colorectal neoplasms in patients with gastric cancer (GC)., Methods: The study group comprised GC patients who underwent colonoscopy before resection of their GC. We examined the prevalence, site, and histology of colorectal neoplasms, as well as the clinicopathological features and treatment of the patients who had synchronous colorectal cancers (CRC). The logistic regression model was applied to investigate the features of the GC patients with concurrent CRC., Results: We studied 466 GC patients (mean age 64.5 years; 147 women, 319 men), 143 (31%) of whom had a family history of gastrointestinal cancer. Synchronous colorectal adenoma and cancer were detected in 182 (39%) and 18 (4%) patients, respectively. Among the 18 synchronous CRCs, 11 were in the early stages and 10 of these were resected endoscopically. The other eight required simultaneous open radical surgery. All the GC patients with synchronous CRC were older than 50 years. Statistical analysis did not show a significant difference between the features of the patients with and those without concurrent CRC., Conclusions: The possibility of synchronous colorectal neoplasms in GC patients cannot be disregarded in clinical practice; however, screening of the large bowel may not be necessary in GC patients younger than 50 years.

Background: Many patients with gastric cancer respond to TS-1, but some fail to respond or have recurrence. Second-line therapy is needed., Methods: We performed a pilot study in patients with advanced gastric cancer who did not respond to TS-1 or who had disease recurrence. The patients received oral doxifluridine (600 mg/day) on days 1 to 21 and an intravenous infusion of paclitaxel (70 mg/m(2)) on days 7, 14, and 21 of a 28-day cycle. The treatment was repeated until disease progression or prohibitive toxicity. Response rate, duration of response, median survival time (MST), effects on pleural effusion, ascites, and other signs, and toxicity were evaluated., Results: The study group comprised 52 patients. The response rate was 28%. The duration of response was 103 days. The MST after the start of second-line treatment was 175 days (95% confidence interval, 135 to 224 days). Pleural effusion or ascites resolved or decreased in 73% of the patients. Hair loss occurred in 32 patients (62%), and leukopenia developed in 28 (54%, grade 3 in 1 patient and grade 2 or lower in the others). The MST after the start of treatment with TS-1 was about 16 months., Conclusion: A combination of doxifluridine and weekly paclitaxel is expected to be an effective second-line treatment for gastric cancer not responding to TS-1, especially in patients with malignant ascites or pleural effusion. However, it remains unclear whether paclitaxel plus doxifluridine results in a better response and survival benefit than paclitaxel alone in this subgroup of patients. Further studies are therefore necessary.

We report a patient with unresectable advanced gastric cancer who has been being treated by TS-1 administration on alternate days for 2 years. The patient was a 50-year-old female with type 4 gastric cancer accompanied by Schnitzler metastasis and pleural effusion. TS-1 administration was initiated at a daily dose of 100 mg with a schedule of 4-week administration and 2-week suspension. However, grade 2 hepatic dysfunction and leukocytopenia developed. When the daily TS-1 administration was changed to alternate-day administration at the same dose, no side effects were observed, allowing the continuation of treatment. She has maintained a minor response (MR)-no change (NC) for 1 year and 5 months, and is still symptom-free and being treated on an outpatient basis at present, 2 years after treatment. TS-1 is an anti-cancer drug that plays a central role in chemotherapy for gastric cancer. However, in some patients, side effects sometimes develop using the routine administration method, making continuation of administration difficult. Alternate-day TS-1 administration has great potential as a protocol that produces long-term anti-tumor effects while reducing side effects.

We report 3 cases in which palliation was achieved with every-other-day administration of TS-1 for recurrent or non-curative advanced gastric carcinoma that had resulted in obstructive jaundice. Two patients had received MTX-5-FU chemotherapy as first-line therapy and showed progressive disease, presenting with obstructive jaundice 6-24 months later. One of them experienced obstructive jaundice 2 months after surgery. After lowering serum bilirubin via per-cutaneous transhepatic biliary drainage (PTBD), TS-1 was given not in full dose but every other day based upon Shirasaka's theory, as well as for fear of further liver damage. Palliation in terms of long NC and/or decreased serum CEA level persisted for 4-14 months without severe liver dysfunction. Other side effects of the drug were negligible. Shirasaka's theory stresses the difference in proliferation cycles between cancer cells and normal tissue cells (GI tract, bone marrow, etc.); therefore, with every-other-day administration of chemotherapeutic agents, the cytotoxic effects against tumors would be augmented while the adverse reactions in normal cells could be reduced. The present experience seems to support the theoretical and clinical feasibility of every-other-day TS-1 administration for unresectable gastric cancer.