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Background: Data on the long-term oncological outcomes of patients who undergo conversion surgery (CS) in gastric cancer (GC) patients with peritoneal metastasis (PM) are limited. Methods: GC patients with PM who received intraperitoneal (ip) and systemic chemotherapy between April 2015 and January 2021 were enrolled. Multivariate analysis was performed to identify risk factors associated with survival. Clinicopathological and survival outcomes were compared between those with CS and those without CS (NCS). The paclitaxel (PTX) plus tegafur–gimeracil–oteracil potassium capsules (S-1) (PS) + ip PTX and oxaliplatin plus S-1 (SOX) + ip PTX groups were matched in a 1:1 ratio using propensity score matching. Oncological and survival data were collected and analyzed. Results: A total of 540 patients who received ip chemotherapy via subcutaneous port and systemic chemotherapy were analyzed and 268 patients were enrolled, including 113 who underwent CS and 155 who did not. Overall survival (OS) were 27.0 months and 11.8 months in the CS and NCS groups (P < 0.0001), respectively. R0 resection was an independent prognostic factor for patients who underwent CS. The OS of patients with or without ovariectomy was 21.3 or 12.0 months (P < 0.0001). No difference of clinicopathological and survival outcomes was found between the PS + ip PTX and SOX + ip PTX groups. Conclusion: Conversion therapy is safe and adverse events were manageable. CS improves the survival of GC patients with PM after ip and systemic chemotherapy. R0 is an important prognostic factor. Furthermore, outcomes are comparable between the PS + ip PTX and SOX + ip PTX groups. [ABSTRACT FROM AUTHOR]

Background: The prognosis of advanced gastric cancer (GC) invading the gastric serosa remains poor, mainly owing to high incidence of peritoneal recurrence. Patients with peritoneal metastases are often treated with neoadjuvant intraperitoneal and systemic chemotherapies (NIPS). Good responders to NIPS often undergo conversion gastrectomy. This study aims to explore biomarkers predicting the occurrence of peritoneal metastasis (PM) and evaluating the efficacy of NIPS in GC patients. Methods: We collected six peritoneal lavage (PL) samples from two patients with PM, two without PM, and two with diminished PM after NIPS via intraperitoneal access ports. We equally isolated microRNAs from exosomes derived from PL samples for deep sequencing. Two microRNAs (hsa-let-7g-3p and hsa-miR-10395-3p) were identified, and their expression levels were examined in PL samples of 99 GC patients using qRT-PCR. Moreover, we performed in vivo and in vitro functional assays to investigate effects of these microRNAs on metastasis and chemoresistance of GC cells. Results: Exosomal microRNA expression profiling of six PL samples indicated that the microRNA signature in exosomes of PLs from patients with diminished PM was similar to that from patients without PM. Expression levels of hsa-let-7g-3p and hsa-miR-10395-3p were associated with PM. In vivo and in vitro functional assays confirmed that hsa-let-7g-3p and hsa-miR-10395-3p are involved in GC metastasis and chemoresistance. Conclusion: PL-derived exosomes in GC contain large amounts of microRNAs related to PM. Moreover, hsa-let-7g-3p and hsa-miR-10395-3p could be used as biomarkers predicting PM and NIPS efficacy and are involved in GC metastasis and chemoresistance. [ABSTRACT FROM AUTHOR]

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of modified FLOT regimen (fluorouracil plus leucovorin, oxaliplatin and docetaxel) for treating Chinese patients with metastatic adenocarcinoma of stomach.Methods: Chinese patients with untreated advanced or metastatic stomach adenocarcinoma were enrolled. Docetaxel (D), oxaliplatin (O) and leucovorin were administrated intravenously on day 1. Fluorouracil (F) was administrated continuous intravenously on day 1 for 48 h. The treatment was repeated every 2 weeks. The start doses of docetaxel and oxaliplatin were 40 mg/m2 and 65 mg/m2, respectively. Dose escalation followed a 3 + 3 design. Total 6 dose levels were set to determine the MTD and RD. Fluorouracil and leucovorin were given as fix doses at 2200 mg/m2 and 200 mg/m2, respectively. Adverse events that occurred in the first 2 cycles were recorded to determine dose-limiting toxicity (DLT). The primary endpoints were MTD and RD determination.Results: A total of 18 patients were treated in 5 dose levels. DTL occurred in one patient of level 4 (grade 3 hypophosphatemia). Other 3 patients were enrolled in level 4 and no DLTs were observed. In level 5, 2 patients suffered grade 4 neutropenia after first cycle of treatment and were defined as DLTs. Therefore, level 5 (D/O/F: 50/75/2200 mg/m2) was defined as MTD and level 4 (D/O/F: 45/75/2200 mg/m2) was defined as RD. Common adverse events in first two cycles were nausea, anorexia, leukopenia, neutropenia and anemia. For 16 patients assessable for tumor response, 7 patients had partial response (43.7%) and 5 experienced stable disease. Disease control rate were 75% (12/16). Two patients underwent conversion operation after 6 cycles of treatment. One pathological complete response (case in level 3) and one pathological partial response (case in level 2) were observed. Median progression-free survival was 4.4 months (95% CI 2.9-5.9 months) in 14 patients.Conclusions: The RD of modified FLOT regimen in Chinese patients with advanced gastric cancer was docetaxel 45 mg/m2, oxaliplatin 75 mg/m2, leucovorin 200 mg/m2 and fluorouracil 2200 mg/m2 on day 1 of every 14-day cycle. Its efficacy will be assessed by further phase II study. [ABSTRACT FROM AUTHOR]

Background/aim: Epithelial-mesenchymal transition (EMT) plays a role in cancer progression. Previous studies have suggested that discoidin domain receptor 2 (DDR2) is related to tumor progression and EMT. However, the role of DDR2 in regulating gastric cancer (GC) metastasis and in EMT has not been elucidated. In this study, we aimed to determine DDR2 expression and its clinical relation in GC and to investigate the effects of DDR2 on EMT and its underlying mechanisms.Methods: DDR2 expression and the relation to patients' clinicopathological features were assayed by Western blot or immunohistochemical staining. The effects of DDR2 overexpression were investigated using in vivo tumorigenicity and xenograft models. The effects of DDR2 on EMT marker expression were assayed by Western blot and immunofluorescence. The possible role of the mTORC pathway in these processes was explored.Results: DDR2 showed high expression in GC tissues and cells. DDR2 expression was negatively correlated with E-cadherin expression and positively correlated with N-cadherin and vimentin expression. High DDR2 expression is correlated with unfavorable pathoclinical features such as multiple tumor locations and intestinal-type GC. In xenograft models, DDR2 overexpression promoted tumor formation. Furthermore, DDR2 expression impacted on the invasion and motility of GC cells, accompanied by changes in EMT marker expression. Finally, our results revealed that DDR2 facilitates GC cell invasion and EMT through mTORC2 activation and AKT phosphorylation.Conclusion: DDR2 is upregulated and correlated with unfavorable clinical features of GC patients. DDR2 promotes tumor formation and invasion through facilitating EMT process via mTORC2 activation and AKT phosphorylation. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer. Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial. [ABSTRACT FROM AUTHOR]