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Purpose The application of laparoscopic-assisted total gastrectomy (LATG) for resectable gastric cancer (GC) remains controversial compared with open total gastrectomy (OTG), especially for advanced gastric cancer (AGC) patients according to the inconsistent results demonstrated in the previous studies. The aim of this study was to evaluate the short-term and long-term outcomes between LATG and OTG in a population with more than 80% AGC patients by applying propensity score matching (PSM) method. Methods The data of 365 clinical stage I–III GC cases who underwent total gastrectomy with D2 lymphadenectomy were retrospectively collected from January 2011 to April 2018 in the Department of Gastrointestinal Surgery IV of Peking University Cancer Hospital. Propensity scores were generated through taking all covariates into consideration and 131 pairs of patients receiving either LATG or OTG were matched. Intraoperative, postoperative, and survival parameters were compared in the matched groups accordingly. Risk factors for postoperative complications and overall survival were further analyzed. Results Patient characteristics in the LATG and OTG groups were well balanced after PSM. LATG showed advantages with respect to shorter time to ambulation, first flatus, and first whole liquid diet intake. No significant differences were found between the two groups with regard to postoperative complications as well as overall survival in terms of different pathological stage. Older age was found as an independent risk factor for postoperative complications, and pathological stage for overall survival as well. Conclusion LATG appears to have comparable surgical and oncological safety with OTG by experienced surgeons.

BackgroundSome high-quality clinical trials have proven the efficacy and safety of perioperative and postoperative S-1 with oxaliplatin (peri-SOX and post-SOX) for patients with locally advanced gastric cancer (LAGC) undergoing D2 gastrectomy. However, little is known about how health-related quality of life (HRQOL) changes over time in patients receiving peri-SOX or post-SOX chemotherapy.MethodsA prospective observational cohort (NCT04408859) identified 151 eligible patients with LAGC who underwent D2 gastrectomy with at least six cycles of peri-SOX or post-SOX chemotherapy from 2018 to 2020. HRQOL was assessed using the EROTC QLQ-C30 and its gastric module, QLQ-STO22, at indicated measurements, including the baseline, 1st, 3rd, 6th and 12th month after initiation of therapy. Baseline characteristics, therapeutic effects, and longitudinal HRQOL were compared between the peri-SOX and post-SOX groups after propensity score matching. HRQOL changes over time and the risk factors for scales with severe deterioration were further analyzed.ResultsNo statistically significant differences in longitudinal HRQOL were observed between patients in the peri-SOX and post-SOX groups, with comparable surgical outcomes and adverse chemotherapy events. Scales of social functioning, abnormal taste, and anxiety improved earlier in the peri-SOX group than in the post-SOX group. Score changes in both groups indicated that general deterioration and slower recovery usually occurred in the scales of physical, social, and role functioning, as well as symptoms of fatigue, reflux, diarrhea, and anxiety.ConclusionPeri-SOX showed a longitudinal HRQOL comparable to post-SOX in patients with LAGC who underwent D2 gastrectomy. The peri-SOX group had better performance in social functioning, abnormal taste, and anxiety at some measurements.

Mutated KRAS promotes the activation of the MAPK pathway and the progression of colorectal cancer (CRC) cells. Aberrant activation of the PI3K pathway strongly attenuates the efficacy of MAPK suppression in KRAS‐mutated CRC. The development of a novel strategy targeting a dual pathway is therefore highly essential for the therapy of KRAS‐mutated CRC. In this study, a quadruple‐depleting system for the KRAS, MEK1, PIK3CA, and MTOR genes based on CRISPR/SaCas9 was developed. Adenovirus serotype 5 (ADV5) was integrated with two engineered proteins, an adaptor and a protector, to form ADV‐protein complex (APC) for systemic delivery of the CRISPR system. Quadruple‐editing could significantly inhibit the MAPK and PI3K pathways in CRC cells with oncogenic mutations of KRAS and PIK3CA or with KRAS mutation and compensated PI3K activation. Compared with MEK and PI3K/MTOR inhibitors, quadruple‐editing induced more significant survival inhibition on primary CRC cells with oncogenic mutations of KRAS and PIK3CA. The adaptor specifically targeting EpCAM and the hexon‐shielding protector could dramatically enhance ADV5 infection efficiency to CRC cells and significantly reduce off‐targeting tropisms to many organs except the colon. Moreover, quadruple‐editing intravenously delivered by APC significantly blocked the dual pathway and tumor growth of KRAS‐mutated CRC cells, without influencing normal tissues in cell‐ and patient‐derived xenograft models. Therefore, APC‐delivered quadruple‐editing of the MAPK and PI3K pathways shows a promising therapeutic potential for KRAS‐mutated CRC., Aberrant activation of the PI3K pathway interferes with the therapeutic efficacies of MAPK signaling inhibitors in KRAS‐mutated colorectal cancer (CRC). However, overlapping toxicities of small molecule inhibitors limit the treatment effects of combined therapy targeting the MAPK and PI3K pathways. Multiplex genome editing may provide a novel dual‐inhibition strategy for KRAS‐mutated CRC. A quadruple‐depleting system of KRAS, MEK1, PIK3CA, and MTOR based on CRISPR/SaCas9, which were packaged by ADV5 and integrated with two engineered proteins, an adaptor and a protector, to enhance infection efficiency and specificity to CRC cells, could effectively and specifically block tumor progression of KRAS‐mutated CRC models through systemic delivery without vital organ injury, providing a potential option for CRC therapy.

The majority of patients with microsatellite stable (MSS) colorectal cancer (CRC) do not benefit from the immunotherapies directed at rescuing T-cell functions. Therefore, complete understanding of T-cell phenotypes and functional status in the CRC microenvironment is desirable. Here, we applied single-cell mass cytometry to mold the T-cell phenotype in 18 patients with MSS CRC for better understanding of CRC as a systemic disease and to search for tumor-driven T-cell profile changes. We show interpatient and intrapatient phenotypic diversity of T-cell subsets. We revealed increased immunosuppressive/exhausted T-cell phenotypes at tumor lesions. CD8+ CD28- immunosenescent T cells with impaired proliferation capacity dominate the T-cell compartment. As per the transcriptome and quantitative real time-PCR analysis, the accumulation of immunosuppressive cells is driven by the tumor microenvironment. T-cell profiles are similar between patients at early and late stages, indicating that the immunosuppressive microenvironment is formulated early during CRC development. Mapping of T-cell infiltration and understanding of the mechanisms underlying their regulation may provide valuable information to boost the immune response in patients with MSS CRC.