Background: The prognostic superiority of preoperative chemoradiotherapy (pre-CRT) over preoperative chemotherapy (pre-CT) in patients with locally advanced gastric cancer remains controversial. Herein, we evaluated the efficacy and safety of pre-CRT relative to those of pre-CT in this cohort. Methods: This open-label, phase III, randomized controlled trial was conducted at 4 medical centers in China. Eligible patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma were randomly assigned (1:1) to receive either 3 cycles of oxaliplatin and S-1 (SOX), followed by surgery and 3 postoperative cycles of SOX (pre-CT), or 1 cycle of SOX, followed by concurrent chemoradiotherapy, a second cycle of SOX, surgery, and 3 postoperative cycles of SOX (pre-CRT). The primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included 3-year overall survival (OS), R0 resection rate, pathological complete response (pCR) rate, treatment-related toxicity, and postoperative complications. Results: Due to premature trial termination, only 204 patients were enrolled, and an efficacy analysis was conducted on 194 eligible patients. The baseline characteristics were well balanced between the 2 groups. The DFS and OS were indistinguishable between the 2 groups. The 3-year DFS rates were 53.6% in the pre-CRT group and 53.9% in the pre-CT group [hazard ratio (HR), 1.02; 95% confidence interval (CI), 0.70 to 1.50; log-rank P = 0.913]. The 3-year OS rates were 62.8% in the pre-CRT group and 60.5% in the pre-CT group (HR, 0.97; 95% CI, 0.63 to 1.47; log-rank P = 0.874). The R0 resection rates were 81.0% and 74.5% in the pre-CRT and pre-CT groups, respectively. Additionally, the pCR rate was higher in the pre-CRT group (12.0%) than in the pre-CT group (2.1%). Treatment-related toxic effects were comparable between the 2 groups. Conclusion: This trial did not demonstrate a survival advantage for pre-CRT over pre-CT in patients with locally advanced gastric or gastroesophageal adenocarcinoma.

Fibroblast activation protein (FAP) is a promising theranostic target in stroma-rich malignancies. However, conventional FAP inhibitors exhibit rapid tumor washout, limiting their application in targeted radionuclide therapy. To address this limitation, we rationally designed two novel FAP-targeted radioligands, FAPI-RuiJ01 and FAPI-RuiJ02, by integrating glutathione or cysteine as hydrophilic linkers, respectively. In preclinical evaluations, FAPI-RuiJ01 showed sub-nanomolar FAP binding affinity (IC50 = 0.55 nM), enhanced hydrophilicity, prolonged tumor retention, low hepatosplenic uptake, and favorable tumor-to-background contrast. FAPI-RuiJ02 also exhibited FAP-specific uptake and improved hydrophilicity, however, its tumor uptake, retention and dosimetric profile were not consistently superior to those of FAPI-04 and were less favorable than those of FAPI-RuiJ01. In a preliminary first-in-human positron emission tomography/computed tomography (PET/CT) study of patients with gastric cancer (n = 5 per group), 68Ga-FAPI-RuiJ01 and 68Ga-FAPI-RuiJ02 showed higher uptake than 68Ga-FAPI-04 in metastatic lesions (P < 0.05), whereas in primary lesions, higher numerical values were observed without reaching statistical significance. For therapeutic evaluation, the tracers were labeled with Terbium-161 (161Tb), a radionuclide that emits both β- particles and Auger electrons. 161Tb-FAPI-RuiJ02 did not significantly inhibit tumor growth and showed therapeutic efficacy comparable to that of 161Tb-FAPI-04. 161Tb-FAPI-RuiJ01 suppressed primary tumor growth and reduced the lung metastatic burden in an orthotopic 4T1 breast cancer model. Mechanistically, 161Tb-FAPI-RuiJ01 induced substantial DNA double-strand breaks in vitro, and in vivo it promoted tumor cell death while suppressing proliferation. Transcriptomic and flow cytometric profiling further revealed that this treatment was associated with the enrichment of interferon-related signaling, along with remodeling of the immune microenvironment. Collectively, these findings support FAPI-RuiJ01 as a promising FAP-targeted theranostic radioligand that warrants further evaluation in metastatic malignancies.

Aim: Patients with KRAS-mutated colorectal cancer (CRC) frequently exhibit resistance to conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted therapies. This study investigates the role of the transcription factor KLF5 in mediating proliferation and chemoresistance in KRAS-mutated CRC, aiming to identify novel therapeutic strategies to improve treatment outcomes. Methods: We analyzed the association between KLF5 expression, KRAS mutation status, and patient prognosis using CRC tissue microarrays and public datasets. Proliferative capacity and oxaliplatin sensitivity were compared between KRAS-mutated and wild-type patient-derived organoids. RNA sequencing and CUT&Tag sequencing were employed to assess KLF5-mediated chromatin accessibility and downstream transcriptional regulation in KRAS-mutated CRC cells. In vitro and in vivo functional studies were conducted using three pairs of KRAS-mutated CRC cell lines (with KLF5 knockdown or overexpression) to evaluate KLF5's impact on proliferation, cell cycle progression, stemness, and oxaliplatin response. Results: KRAS-mutated CRC demonstrated enhanced proliferative capacity and oxaliplatin resistance, accompanied by KLF5 upregulation. In KRAS-mutated CRC cells, KLF5 promoted chromatin accessibility to initiate downstream transcription programs regulating cell cycle progression, platinum drug resistance, and apoptosis. Mechanistically, KLF5 drives oxaliplatin resistance by promoting proliferation through upregulation of the CDK4/6-Cyclin D1 axis, enhancing stemness via LGR5 and Nanog, and activating the XIAP/Bcl-2-dependent anti-apoptotic signaling pathway. In vivo experiments further confirmed that KLF5-overexpressing KRAS-mutated CRC tumors exhibited accelerated growth and reduced oxaliplatin sensitivity. Conclusion: This study reveals that aberrantly elevated KLF5 promotes proliferation and chemoresistance in KRAS-mutated CRC. Targeting KLF5 represents a promising strategy to enhance chemotherapeutic response in this aggressive CRC subtype, offering a rationale for clinical translation.

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events.Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

This prospective study investigated whether PET parameters from F-18-FDG and Ga-68-fibroblast activation protein inhibitor (FAPI)-04 PET/CT can predict a pathologic response to neoadjuvant chemotherapy (NAC) early in patients with locally advanced gastric cancer (LAGC). Methods: The study included 28 patients with LAGC who underwent F-18-FDG PET/CT and Ga-68-FAPI-04 PET/CT at baseline and after 1 cycle of NAC. PET parameters including SUV and tumor-to-background ratio (TBR), as well as the change rate of SUV and TBR, were recorded. Patients were classified as major or minor pathologic responders according to postoperative pathology findings. We compared the PET parameters between the 2 pathologic response groups and different treatment regimens and analyzed their predictive performance for tumor pathologic response. Results: Major pathologic responders had significantly lower Ga-68-FAPI change rates (percentage SUVmax [%SUVmax], percentage SUVpeak [%SUVpeak], and percentage TBR [%TBR]) than minor pathologic responders. Among the PET parameters, Ga-68-FAPI %SUVmax (area under the curve, 0.856; P = 0.009), %SUVpeak (area under the curve, 0.811; P = 0.022), and %TBR (area under the curve, 0.864; P = 0.007) were significant parameters for early prediction of pathologic response to NAC in LAGC; they had the same predictive accuracy of 89.29%, with the thresholds of decrease to at least 52.43%, 60.46%, and 52.96%, respectively. In addition, Ga-68-FAPI %SUVmax and %TBR showed significant differences between the different treatment regimens. Conclusion: In this preliminary study, Ga-68-FAPI-04 PET change rate parameters were preferable to F-18-FDG in predicting pathologic response to NAC at an early stage in LAGC. Ga-68-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens. These findings may help optimize the treatment for patients with LAGC

Intraperitoneal chemotherapy combined with systemic chemotherapy is one of the therapeutic modalities currently used for the treatment of gastric cancer patients with peritoneal metastasis. This study was designed to evaluate the efficacy and safety of sintilimab plus S-1 combined intraperitoneal and intravenous paclitaxel. This is an open-label, single-center, phase II study including 36 gastric adenocarcinoma patients with peritoneal metastases diagnosed by laparoscopy. All enrolled patients received sintilimab, intraperitoneal and intravenous paclitaxel plus oral S-1 every three weeks. Conversion operation should be considered when a patient responds to the regimen and the peritoneal metastasis disappears. After gastrectomy, the protocol treatment is repeated until disease progression, unacceptable toxicity, investigator decision or patient withdrawal. The primary end point is the one-year survival rate.

Although recent advances in systemic chemotherapy have improved the clinical outcomes of gastric cancer patients with peritoneal metastasis, the peritoneum still represents a common site of treatment failure and disease recurrence. Neoadjuvant intraperitoneal-systemic chemotherapy has been acknowledged as a more aggressive treatment for gastric cancer patients with peritoneal metastasis. In this multicenter phase III randomized controlled trial, 238 patients will be randomly separated into two groups in a 2:1 ratio after laparoscopic exploration. The experimental arm will receive the proposed neoadjuvant intraperitoneal-systemic chemotherapy regimen, whereas the control group will receive a Paclitaxel + S-1 (PS) chemotherapy regimen. The endpoints for the study are overall survival, response rate, gastrectomy radicality rate, progression-free survival and adverse events.

Although gastric cancer with para-aortic lymph node (PAN) metastasis is commonly regarded as unresectable, surgeons have explored the optimal treatment for patients with PAN metastases limited to No.16a2/b1 in the past few decades. Preoperative systemic therapy combined with D2 gastrectomy plus PAN dissection may improve the prognosis of these patients. In this multicenter phase II trial, 29 gastric cancer patients with PAN metastasis limited to No.16a2/b1 will receive preoperative treatment with nab-paclitaxel, oxaliplatin, S-1 (nab-POS: nab-paclitaxel, oxaliplatin, S-1) and sintilimab followed by D2 gastrectomy plus PAN dissection; and postoperative treatment with oral S-1, intravenous sintilimab and intraperitoneal paclitaxel. The end points for the study are 3-year overall survival, 3-year disease-free survival, pathological response rate, incidence of postoperative complications and adverse events.

ObjectiveThe extent of regional lymphadenectomy for proximal gastric cancer (PGC) has remained a controversy and a matter of considerable debate for a long time. We retrospectively analyzed the clinicopathological features to investigate the predictive factors for No. 5 and/or No. 6 lymph node metastases (LNMs) and evaluate the feasibility of performing proximal gastrectomy (PG) with preservation of No. 5 and/or No. 6 lymph nodes for these patients.MethodPatients who had undergone total gastrectomy plus D2 lymphadenectomy in the Department of Gastrointestinal Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, from January 2008 to December 2017 were retrospectively collected and analyzed.ResultsAmong the 395 eligible patients in our study, 34 patients (8.61%) had No. 5 and No. 6 LNM. The degree of differentiation, Borrmann classification, vascular or perineural invasion, tumor diameter, depth of invasion, and other perigastric LNM were associated with No. 5 and/or No. 6 LNM. Multivariate analyses showed that tumor diameter ≥4 cm, No. 4 LNM positive, and No. 7, No. 8, No. 9 LNM positive were independent risk factors of No. 5 and/or No. 6 LNM. No. 5 and/or No. 6 LNM was not observed in the 105 patients who were staged from T1 to T3 and were found to be without independent risk factors.ConclusionThe metastatic rate of No. 5 and/or No. 6 lymph node of the proximal gastric adenocarcinoma was closely associated with the diameter of the tumor and other perigastric LNMs. It is feasible to preserve No. 5 and No. 6 lymph nodes with PG for the T1–T3 patients with lower risk of No. 5 and/or No. 6 LNM.

OBJECTIVES:We aimed to investigate the role of [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT for the initial assessment of gastric cancer and to explore the factors associated with their uptake. METHODS:This study enrolled 62 patients with histopathologically confirmed gastric cancer. We compared the diagnostic performance of [68Ga]FAPI-04, [18F]FDG, and combined dual-tracer PET/CT. The standardized uptake value (SUV) and tumor-to-background ratio (TBR) were also measured, and the factors that influence tracer uptake were analyzed. RESULTS:[68Ga]FAPI-04 PET/CT detected more primary lesions (90.3% vs 77.4%, p = 0.008) and peritoneal metastases (91.7% vs 41.7%, p = 0.031) and demonstrated higher SUVmax and TBR values (p < 0.001) of primary lesions compared to [18F]FDG PET/CT. Dual-tracer PET/CT significantly improved the diagnostic sensitivity for the detection of distant metastases, compared with stand-alone [18F]FDG (97.1% vs 73.5%, p = 0.008) or [68Ga]FAPI-04 (97.1% vs 76.5%, p = 0.016) PET/CT. Subsequently, treatment strategies were changed in nine patients following [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT. Nevertheless, [68Ga]FAPI-04 uptake was primarily influenced by the size and invasion depth of the tumor. Both [68Ga]FAPI-04 and [18F]FDG PET/CT showed limited sensitivity for detecting early gastric cancer (EGC) (37.5% vs 25.0%, p > 0.05). CONCLUSIONS:In this initial study, [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT were complementary and improved sensitivity for the detection of distant metastases pre-treatment in gastric cancer and could improve treatment stratification in the future. [68Ga]FAPI-04 had limited efficacy in detecting EGC. KEY POINTS:• [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT are complementary to each other for improving diagnostic sensitivity in the initial evaluation of distant metastases from gastric cancer. • [68Ga]FAPI-04 PET/CT showed limited sensitivity in detecting EGC. • Need for further validation in a larger multi-centre prospective study.

Background: Neoadjuvant chemotherapy (NAC) plays an important role in the therapeutic strategy of locally advanced gastric cancer (LAGC). However, the response of LAGC after NAC varies among different patients. The objective response after NAC has proven to be an excellent indicator for benefiting from NAC, yet effective predictors of objective response are still lacking. The present study aimed to identify potential predictors of objective response in LAGC patients treated with NAC. Methods: Clinicopathological data from 267 patients with LAGC who received NAC and met the inclusion criteria between July 2009 and December 2018 were retrospectively reviewed. Patients were randomly divided into the training and test sets at a 2:1 ratio. Univariate analysis was used to investigate whether any factors were correlated with objective response in the training set. Multivariate logistic regression analysis was applied to find independent predictors. A risk score model was then constructed based on the independent predictors, and its performance in predicting objective response was validated in the test set. Results: Univariate analysis found that gender, age, short axis diameter of the largest regional lymph node (LNmax), serum total protein content, CEA detection value, tumor location, tumor differentiation, signet ring cell carcinoma component and Borrmann type were potential predictors for objective response. In multivariate logistic regression analysis, gender, LNmax and signet ring cell carcinoma component were independent predictors for objective response. Based on independent predictors, we developed a prediction model for objective response. Conclusions: We found gender, LNmax and signet ring cell carcinoma component were independent predictors for objective response. The prediction model is a good tool to predict the objective response for LAGC patients treated with NAC, which can be applied to guide clinical practice.

Background Preoperative chemotherapy (PCT) has been considered an important treatment for advanced gastric cancer (AGC). The tumor regression grade (TRG) system is an effective tool for the assessment of patient responses to PCT. Pathological complete response (TRG = 0) of the primary tumor is an excellent predictor of better prognosis. However, which patients could achieve pathological complete response (TRG = 0) after chemotherapy is still unknown. The study aimed to find predictors of TRG = 0 in AGC. Methods A total of 304 patients with advanced gastric cancer from July 2009 to November 2018 were enrolled retrospectively. All patients were randomly assigned (2:1) to training and internal validation groups. In addition, 124 AGC patients receiving PCT from December 2018 to June 2020 were included prospectively in the external validation cohort. A prediction model for TRG = 0 was established based on four predictors in the training group and was validated in the internal and external validation groups. Results Through univariate and multivariate analyses, we found that CA199, CA724, tumor differentiation and short axis of the largest regional lymph node (LNmax) were independent predictors of TRG = 0. Based on the four predictors, we established a prediction model for TRG = 0. The AUC values of the prediction model in the training, internal and external validation groups were 0.84, 0.73 and 0.82, respectively. Conclusions We found that CA199, CA724, tumor differentiation and LNmax were associated with pathological response in advanced gastric cancer. The prediction model could provide guidance for clinical work.

Abstract Background In this study, we tried to access the efficacy and safety of oxaliplatin plus S-1 with intraperitoneal paclitaxel (PTX) for the treatment of Chinese advanced gastric cancer with peritoneal metastases. Patients and methods Thirty patients diagnosed with advanced gastric cancer underwent laparoscopic exploration and were enrolled when macroscopic disseminated metastases (P1) were confirmed. PTX was diluted in 1 l of normal saline and IP administered through peritoneal port at an initial dose of 40 mg/m2 over 1 h on day1,8, respectively. Oxaliplatin was administered intravenously at an initial dose of 100 mg/m2 on day1, and S-1 was administered orally at an initial dose of 80 mg/m2 for 14 days followed by 7 days rest, repeated by every 3 weeks. Results Of all these 30 patients, the median number of cycles was 6 (range 2–16) due to the limitation of hematotoxicity and peripheral neuropathy by oxaliplatin. There were 11 (36.7%) patients received conversion surgery. The median progression free survival (PFS) was 6.6 months (95% CI = 4.7–8.5 months) and the median overall survival (OS) was 15.1 months (95% CI = 12.4–17.8 months). The grade 3–4 hematological toxicities were leucopenia (23.3%), neutropenia (23.3%), anemia (16.7%), and thrombocytopenia (20%), respectively. The grade 3–4 non-hematological toxicities were tolerated, most of which were peripheral sensory neuropathy (40%) due to oxaliplatin, diarrhea (20%), nausea and vomiting (26.7%). Conclusions SOX+ip PTX regimen was effective in advanced gastric cancer with peritoneal metastasis. Survival time was significantly prolonged by conversion surgery. Grade 3–4 toxicities were uncommon. Large scale clinical trial is necessary to get more evidence to identify its efficacy. Trail registration ChiCTR, ChiCTR-IIR-16009802. Registered 9 November 2016,

Background For gastric cancer (GC) with extensive lymph node metastasis (bulky N2 and/or para-aortic lymph node metastases), there is no standard therapy worldwide. In Japan, preoperative chemotherapy (PCT) followed by D2 gastrectomy plus para-aortic lymph node dissection (PAND) is considered the standard treatment for these patients. However, in China, the standard operation for GC patients with only bulky N2 metastases was D2 gastrectomy. Besides, after PCT, whether doing PAND improves survival or not is debatable for GC patients with para-aortic lymph node (PAN) metastases. Therefore, we conducted this study to investigate whether D2 lymphadenectomy alone is suitable for these patients after PCT. Methods We retrospectively collected data on patients from our electronic medical record system. GC patients with bulky N2 and/or PAN metastases who underwent D2 lymphadenectomy alone after PCT were enrolled. The survival outcomes and chemotherapy responses were analyzed and compared with the results of the JCOG0405 study. Results From May 2009 to December 2017, a total of 83 patients met all eligibility criteria and were enrolled. The median survival duration for all patients was 40.0 months. The 3-year and 5-year OS rates for all patients were 50.3% and 45.6%, respectively. For patients with only bulky N2 metastasis, the 3-year and 5-year OS rates were 77.1% and 71.6%, respectively, which were similar to the results of the JCOG0405 study (82.7% and 73.4%). For patients with only PAN metastases, the 3-year and 5-year OS rates were 50.0% and 50.0%, respectively, which seemed to be lower than those of the JCOG0405 study (64.3% and 57.1%). For patients with bulky N2 and PAN metastases, the 3-year and 5-year OS rates were 7.4% and 0.0%, respectively, which were lower than those of the JCOG0405 study (20.0% and 20.0%). Conclusion The results of our study suggest that D2 lymphadenectomy alone is suitable for GC patients with only bulky N2 metastasis after PCT. However, D2 lymphadenectomy alone perhaps is not suitable for patients with bulky N2 and PAN metastases after PCT.

Background For locally advanced gastric cancer (LAGC) with serosal invasion (cT4NxM0), adjuvant chemotherapy (AC) after D2 gastrectomy is the standard therapy in Asia. However, perioperative chemotherapy (PCT) combined with D2 gastrectomy is mostly suggested in Europe and America. As a part of PCT, the value of neoadjuvant chemotherapy (NAC) is unclear. We investigated whether NAC could further improve survival and other outcomes for these patients. Methods Patients with cT4NxM0 gastric cancer who underwent D2 gastrectomy were analyzed. The patients were divided into two groups based on whether they received NAC: the neoadjuvant chemotherapy (NAC) and direct surgery (S) groups. After propensity score matching (1:1 ratio), survival and perioperative outcomes were analyzed between the two groups. Results A total of 902 patients met all the eligibility criteria and were enrolled. After propensity score matching, 221 matched pairs of patients were identified. The median overall survival (OS) and disease-free survival (DFS) of all patients were 75.10 and 43.67 months, respectively. The median OS of patients in the NAC and S groups were undefined and 29.80 months, respectively (P<0.0001). The median DFS of patients in the NAC and S groups were undefined and 22.60 months (P<0.0001). There were no significant differences in the radical degrees of operation between the two groups (P=0.07). However, there were significant differences in postoperative hospital stay (P<0.001) and complications (P=0.037) between the two groups. Conclusion This study suggested NAC can further improve prognosis and prevent recurrence in LAGC (cT4NxM0) patients. NAC is feasible and safe for LAGC (cT4NxM0) patients, and does not increase the risk of perioperative surgery.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1-T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1-T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1-T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov).

Background: The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma. Methods: Treatment-naive patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/m(2) on day 1) and two cycles of apatinib (500 mg/day for 21 days) at 3-week intervals, followed by surgery. The primary end-point was pathologic response rate (pRR). This trial is registered at ChiCTR.gov.cn: ChiCTR-OPC-16010061. Results: Of 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P < 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3% -92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2% -26.3%). Downstaging of overall TNM stage was observed in 16(55.2%) patients. During neoadjuvant therapy, 10 ( 34.5%) patients had grade >= III adverse events. No treatment- related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients. Conclusion: SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (Clinical-Trials.gov:NCT04208347). (C) 2020 The Authors. Published by Elsevier Ltd. This is an open access

Background Even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) have individually have improved overall survival (OS) and progression-free survival (PFS) rates in advanced Gastric Cancer (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been acknowledged as prophylaxis for peritoneal carcinomatosis (PC) in AGC patients and in this study, we aim at investigating the safety and efficacy of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intraoperative HIPEC followed by adjuvant chemotherapy (AC). Methods In this multicenter Phase III randomized controlled trial, 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration. The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen. The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60mins at 43 ± 0.5 °C with 80 mg/m 2 of Paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intraoperative HIPEC followed by 5 cycles of SOX regimen chemotherapy. The end-points for the study are 5 year PFS, 5 year OS, peritoneal metastasis rate (PMR) and morbidity rate. Discussion This study is one of the first to combine NLHIPEC with NAC in the preoperative phase which is speculated to provide local management of occult peritoneal carcinomatosis or peritoneal free cancer cells while NAC will promote tumor downsizing and down-staging. The addition of the intraoperative HIPEC is speculated to manage dissemination due to surgical trauma. Where the roles of intraoperative HIPEC and NAC have individually been investigated, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence. It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15% and decrease PMR after gastrectomy of curative intent. Trial registration World Health Organization Clinical Trials - International Registry Platform (WHO-ICTRP) with Registration ID ChiCTR1900024552 , Registered Prospectively on the 16th July, 2019.

Objective To investigate the clinical efficacy of esophagogastrostomy using seromuscular double-flap technique following laparoscopy-assisted proximal gastrectomy. Methods The clinical data of one patient with gastrointestinal stromal tumor at the gastric cardia who underwent laparoscopy-assisted proximal gastrectomy in September 2019 was retrospectively analyzed. We reviewed the literature about esophagogastrostomy using seromuscular double-flap technique following proximal gastrectomy and summarized the clinical data. Results This case was a 67-year-old male patient. The patient was diagnosed as gastrointestinal stromal tumor at the gastric cardia by both preoperative imaging and postoperative pathologic examination. Laparoscopy-assisted proximal gastrectomy and esophagogastrostomy using seromuscular double-flap technique was performed. The total operative time and anastomosis time were 280 min and 100 min, respectively. The intraoperative blood loss was 40 mL. The time to the first postoperative flatus was 3 d. The time to the liquid diet was 4 d. The duration of postoperative hospital stay was 8 d. No postoperative short-term complication was found. No reflux esophagitis was shown two months postoperatively with endoscopy. The literature review showed that the occurrence of anastomotic leakage, anastomotic bleeding, anastomotic stenosis, and reflux esophagitis of esophagogastrostomy using seromuscular double-flap technique were 0-4.2%, 0-0.7%, 4.0%-29.1%, and 0-8.3%, respectively. Conclusions Esophagogastrostomy using seromuscular double-flap technique following laparoscopy-assisted proximal gastrectomy was safe and effective in terms of preventing gastroesophageal reflux. It can be applied in highly selected patient with upper-third gastric tumor. High attention is still required to prevent and treat the postoperative anastomotic stenosis.

BACKGROUND: The signaling adapter protein CrkL plays vital roles in multiple cancers. However, the expression pattern of CrkL protein and its clinical significance have not been well characterized in human gastric cancer (GC) so far. OBJECTIVE: To investigate the association of tissue-based CrkL protein expression level with the clinicopathological characteristics and prognosis of GC patients. METHODS: The expression level of CrkL protein in 380 GC patients was analyzed by immunohistochemistry. The associations of CrkL protein expression level with clinicopathologicalal characteristics and clinical outcome were evaluated. RESULTS: Compared with the matched adjacent non-tumor tissues, CrkL protein expression level was significantly up-regulated in tumor tissues. In addition, there was a positive correlation between CrkL and Ki67 expression levels in GC patients. An elevated CrkL level statistically correlated with aggressive clinicopathologicalal characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified tissue-based CrkL level as an independent predictor for the unfavorable prognosis of GC. CONCLUSIONS: These results indicate that CrkL protein may serve as a novel prognostic biomarker in GC.