[Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy].

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.

MiR-181a mediates Ang II-induced myocardial hypertrophy by mediating autophagy.

OBJECTIVE: To investigate the relationship between miR-181a and cardiac hypertrophy and autophagy in rats with myocardial hypertrophy, and whether miR-181a regulates the autophagy through ATG5, thereby participating in the occurrence and development of myocardial hypertrophy. MATERIALS AND METHODS: The rat model of myocardial hypertrophy was established via the abdominal aortic coarctation. The expression of miR-181a in cardiac tissues was detected via reverse transcription-polymerase chain reaction (RT-PCR). The expressions of autophagy-related proteins, ATG5 and LC3II/LC3I, in cardiac tissues, were detected via Western blotting (WB). After the primary culture of myocardial cells in rats, they were stimulated via Angiotensin II (Ang II) to observe the effects of autophagy inhibitor 3-methyladenine (3-MA) and overexpression of ATG5 on the expression of hypertrophic genes in myocardial cells, respectively. The expressions of autophagy-related proteins ATG5 and LC3II/LC3I were detected via WB, the autophagic rate was observed via flow cytometry and the changes in autophagic vacuoles of myocardial cells were observed using the transmission electron microscope. The changes in mRNA and protein expressions of ATG in myocardial cells were observed after the overexpression of miR-181a or the inhibition of miR-181a activity. The changes in miR-181a and the expression of hypertrophic genes in myocardial cells after Ang II stimulation were observed via RT-PCR. RESULTS: In rats with myocardial hypertrophy, the cardiac autophagy was increased and the expression of miR-181a in hypertrophic myocardium was downregulated. 3-MA inhibited the ATG5-induced autophagy and improved the Ang II-induced myocardial hypertrophy, while the overexpression of ATG5 enhanced the myocardial autophagy and the expression of hypertrophic genes. MiR-181a regulated the ATG5-induced myocardial autophagy, and its downregulation mediated the Ang II-induced myocardial hypertrophy. CONCLUSIONS: The enhancement of ATG5-induced myocardial autophagy mediates the Ang II-induced myocardial hypertrophy. ATG5 is the target gene of miR-181a, it can regulate the myocardial autophagy via ATG5, thus mediating the Ang II-induced myocardial hypertrophy.