[Postoperative complications and their influence on the prognosis factors in gastric cancer patients receiving neoadjuvant treatment].

Objective: To investigate postoperative complications of patients undergoing neoadjuvant therapy followed by radical gastrectomy, and to analyze their influence on the prognosis. Methods: A retrospective case-control study was used. Case inclusion criteria: (1) gastric adenocarcinoma confirmed by histopathology; (2) preoperative imaging examination showed no distant metastasis or peritoneal dissemination; (3) undergoing radical gastrectomy and D2 lymph node dissection after neoadjuvant therapy; (4) complete clinicopathological and follow-up data. According to the above criteria, clinical data of 490 gastric cancer patients who underwent radical gastrectomy in the Cancer Hospital of Chinese Academy of Medical Sciences, Peking Union Medical College from January 2008 to December 2018 were retrospectively collected, including 358 males and 132 females with mean age of (55.0±10.6) years. Neoadjuvant chemotherapy regimens included SOX (S-1+ oxaliplatin, n=151), XELOX (capecitabine+oxaliplatin, n=155), FLOT (docetaxel+oxaliplatin+fluorouracil, n=66), and DOS (docetaxel+ oxaliplatin+S-1, n=68). Preoperative concurrent chemoradiotherapy was performed in 100 patients. SOX regimen was used for 2-4 cycles as induction chemotherapy plus concurrent chemoradiotherapy (3D IMRT+S-1). Postoperative complications were defined as surgery-related complications, mainly including hemorrhage, anastomotic leakage, obstruction, anastomotic stenosis, pulmonary infection, abdominal infection, etc. Postoperative complications were graded according to Clavien-Dindo classification. Log-rank test and Cox regression model were used for univanriate multivariate prognostic analysis, respectively. Results: A total of 101 complications ocaured after operation in 87 (17.8%) patients, including 29 cases of major complications (Clavien-Dindo III to V), and 58 cases of minor complications (Clavien-Dindo I to II). Multivariate analysis showed that age > 65 years (HR=3.077, 95% CI: 1.827-5.184, P<0.001) and total gastrectomy (HR=1.735, 95% CI: 1.069-2.814, P=0.026) were independent risk factors for postoperative complications in patients with gastric cancer undergoing neoadjuvant therapy and radical gastrectomy (both P<0.05). The follow-up period was 0.7 to 131.8 months (median 21.5 months), and the 5-year overall survival rate was 47.4%. The 5-year overall survival rates of the complication group (87 cases) and the non-complication group (403 cases) were 33.2% and 50.9%, respectively (P=0.001). Multivariate analysis showed that age (HR=1.906, 95% CI: 1.248-2.913, P=0.003), ypTNM II to III stage (II stage: HR=5.853, 95% CI: 1.778-19.260, P=0.004; III stage: HR=10.800, 95% CI: 3.411-34.189, P<0.001), surgery time>3.5 h (HR=1.492, 95% CI: 1.095-2.033, P=0.011), total gastrectomy (HR=1.657, 95% CI: 1.216-2.257, P=0.001) and postoperative complications (HR=1.614, 95% CI: 1.125-2.315, P=0.009) were independent risk factors for prognosis, and postoperative adjuvant therapy (HR=0.578, 95% CI: 0.421-0.794, P=0.001) was an independent protective factor for prognosis. Conclusions: The occurrence of postoperative complications in gastric cancer patients undergoing neoadjuvant therapy is closely related to the age of the patients and the range of surgical resection. It is beneficial to improve the prognosis for these patients by paying more attention to the prevention of postoperative complications and the reinforcement of postoperative adjuvant therapy.

Mechanistic studies on the base-catalyzed transformation of neocarzinostatin chromophore: roles of bulged DNA.

Nucleic acid bulges have been implicated in a number of biological processes and are specific cleavage targets for the enediyne antitumor antibiotic neocarzinostatin chromophore (NCS-chrom) in a base-catalyzed, radical-mediated reaction. Studies designed to elucidate the detailed mechanism of the base-catalyzed activation of NCS-chrom and to evaluate the roles of bulged DNA in its activation are described. They show that nucleobases in the DNA bulge are not required to form an effective bulge pocket but enhance the binding of the wedge-shaped activated drug molecule. Analysis of solvent deuterium isotope effects on NCS-chrom degradation and DNA cleavage efficiency experiments suggests that the spirolactone biradical 6 is a relatively stable species and that intramolecular quenching of the C2 radical of 6 to form the biologically active cyclospirolactone radical 7a occurs first (pathway a in Scheme 2), leaving the C6 radical to abstract the hydrogen atom from the DNA deoxyribose and to form the cyclospirolactone 8. Binding of the activated drug at the bulge site is required, but not sufficient, for efficient 8 formation, whereas cleavage of bulged DNA is not essential. Efficient generation of 8, but inefficient DNA damage generation, comes mainly from the likely high off-rate of 7a binding. The finding that thymidine 5'-carboxylic acid-ended oligonucleotide fragment can be formed in the reaction suggests that the process of DNA cleavage is rather slow and that sequential oxidations of the target 5'-carbon are possible. Study of the effect of solvent (methanol) concentration on NCS-chrom degradation indicates that bulged DNA acts to assist the intramolecular quenching of the radical at C2 by C8' ' of the naphthoate moiety by excluding solvent from the binding pocket, thus preventing the formation of spirolactones 9, and by blocking radical polymerization. Because in the absence or near absence of solvent methanol 8 formation does not reach even 10% that formed in the presence of bulged DNA, it is possible that the DNA bulge also induces a conformational change in the drug to promote the intramolecular reaction.