Fei Shan

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg⁻¹ every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6–62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79–19.12), 8.18 months (95% CI = 6.67–10.48) and 17.48 months (95% CI = 12.35–26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67–not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63–31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027

Background: Laparoscopic gastrectomy (LG) for gastric cancer has rapidly developed and become more popular in recent decades. Additional high-quality randomized controlled trial (RCT) studies comparing LG versus open gastrectomy (OG) for gastric cancer (GC) have been published in recent years. An updated systematic review is warranted. The aim of our meta-analysis was to comprehensively evaluate the short- and long-term outcomes of LG versus OG for GC. Materials and methods: The PubMed, Embase, Web of Science, and Cochrane Center Register of Controlled Trials databases were comprehensively searched to identify RCTs comparing LG versus OG for GC published between January 1994 and December 7, 2021. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines. All RCTs comparing the short- and long-term outcomes of LG with those of OG were included. A random effects model was adopted with significant heterogeneity (I² > 50%), while a fixed effects model was employed in all other cases (I² ≤ 50%). Results: A total of 26 RCTs with 8301 patients were included in this meta-analysis. The results indicated that the intraoperative complication rate was comparable between the LG group and the OG group (OR=1.14, 95% CI [0.76, 1.70], I²=0%, p=0.53). The LG group had fewer postoperative complications than the OG group (OR=0.65, 95% CI [0.57, 0.74], I²=26%, pI²=10%, p=0.10; OR=1.11, 95% CI [0.59, 2.09], I²=0%, p=0.74, respectively). The number of lymph nodes retrieved by the LG group was less than that of the OG group (MD=−1.51, 95% CI [−2.29, −0.74], I²=0%, pI²=23%, p=0.003), but the distal resection margin distance in the two groups was comparable (MD=−0.21, 95% CI [−0.47, 0.04], I²=0%, p=0.10). The time to first ambulation was shorter in the LG group than in the OG group (MD=−0.14, 95% CI [−.26, −0.01], I²=40%, p=0.03). The time to first flatus was also shorter in the LG group than in the OG group (MD=−0.15, 95% CI [−0.23, −0.07], I²=4%, p=0.0001). However, the first time on a liquid diet was comparable between the two groups (MD=−0.30, 95% CI [−0.64, 0.04], I²=88%, p=0.09). Furthermore, the postoperative length of stay was shorter in the LG group than in the OG group (MD=−1.26, 95% CI [−1.99, −0.53], I²=90%, p=0.0007). The 5-year overall survival (OS) was comparable between the two groups (HR=0.97, 95% CI [0.80, 1.17], I²=0%, p=0.73), and the 5-year disease-free survival (DFS) was also similar between the LG group and OG group (HR=1.08, 95% CI [0.77, 1.52], I²=0%, p=0.64). Conclusion: LG is a technically safe and feasible alternative to OG with the advantages of a fewer postoperative complication rate, faster recovery of gastrointestinal function, and greater cosmetic benefit for patients with GC. Meanwhile, LG has comparable long-term outcomes to OG for GC.

When the fuzzy factors is in the sample or noise around the classification surface which is the decisive factor for the summary of support vector machines (SVM), the operation results of SVM will be greatly affected. In this case, the noise must be effectively removed to minimize the impact on the sample. Here, the method of “one class to the rest class” is used to establish fault classifier, and a decision algorithm combining binary tree with fuzzy support vector machine is proposed. In this algorithm, the noise points near the classification surface in the samples are removed by SDWFCM (Spacial distance weighted fuzzy C-Means) method firstly. Then, based on the fuzzy feature representation method, the fuzzy support vector machine is improved by combining the fuzzy membership degree determination method and the basis of the threshold determination after fuzzy programming. The support vector machine can effectively process the composite samples of mixed fuzzy samples, in order to accomplish the fault diagnosis of a certain type of equipment.

Background: Mutations in genes encoding DNA polymerase epsilon (POLE) and delta 1 (POLD1) can lead to defects in the DNA replication, resulting in a hypermutated tumor phenotype, which might help identify potential responders to immunotherapy. This study aims to comprehensively investigate the different variants of POLE/POLD1 mutants and how it related to MSI/MMR status and TMB levels within a large Chinese population. Methods:Among 15640 Chinese patients who underwent NGS testing, the prevalence of POLE/POLD1 mutants was analyzed and the high frequencies of POLE/POLD1 variants as well as their relations with MMR/MSI and TMB were explored. Results: POLE and POLD1 mutations were highly distributed in endometrial cancer (11.1% and 9.3%), colorectal cancer (5.9% and 4.5%), and gastric cancer (4.6% and 3.3%). In our study, the mutation frequency of POLE was 3.4%, including p.Ala252Val (9.2%), p.Pro286Arg (2.7%), p.Val411Leu (1.3%), p.Asp601Glu (6.0%), p.Lys425Gln (2.9%) and p.Phe1849Val (1.8%). Variants of p.Ala252Val, p.Pro286Arg and p.Val411Leu displayed high TMB levels (median 71.4 muts/Mb, 236.7 muts/Mb and 220 muts/Mb, respectively) while variants of p.Asp601Glu, p.Lys425Gln, p.Phe1849Val and p.Asn2098His had a rather low TMB, ranging from 5.2-8.1 muts/Mb. It is worth mentioning that 37.5% of p. Pro286Arg and 87.5% of Val411Leu variants had concurrent loss-of-function mutations of MMR (MMR^LOF), while MMR^LOF rarely occurred in the other variants.For POLD1, the mutation frequency in Chinese patients was 2.8%, including p.Arg119His (18.8%), p.Glu57del (16.5%) and p.Asp987Thrfs (3.3%). p.Arg119His variants showed a high TMB level of 65.6 muts/Mb and most occurred in lung cancer. Variants of p.Asp987Thrfs, p.Pro116Hisfs and p.Arg19His had similar TMB levels (p>0.05), while much lower TMB levels was found in p.Glu57del (3.3 muts/Mb, pLOF mutations while it was barely observed in POLE/POLD1-WT (0.5%). The TMB levels of POLE/POLD1 mutations were significantly higher than that of the POLE/POLD1-WT (17.7 vs 2.9 muts/Mb, p10 muts/Mb, 22.6% of them were POLE/POLD1 mutations. And in samples with TMB >100 muts/Mb, as high as 82% of samples were found carrying POLE/POLD1 mutations. Conclusion: POLE/POLD1 mutations were found in Chinese patients in multiple tumors. Different POLE/POLD1 variants were associated with different MMR status and TMB levels. In addition to MMR, POLE/POLD1 mutations might be another distinct means of inducing high TMB. Citation Format: Yongning Jia, Yaqun Xin, Hongling Yuan, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Comprehensive analysis of POLE/POLD1 variants, MMR deficient/MSI, and tumor mutational burden in Chinese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5751.

Background: The activin type II receptor (ACVR2), which is a member of the transforming growth factor beta (TGF-β) receptor family, is frequently mutated in colorectal cancer (CRC) and gastric cancer (GC). However, the incidence of ACVR2 mutations in MSI-H patients remains unclear. The aim of this study is to evaluate ACVR2A mutation characteristics and to examine its associations between the high microsatellite instability (MSI-H) and ACVR2A mutations in CRC and GC. Materials and Methods: We analyzed data from two cohorts: a Chinese cohort and the TCGA cohort. The Chinese cohort consisted of 1960 patients with CRC and GC, including 140 MSI-H samples and 1820 MSS samples. MSI status of these patients was derived from tumor-normal paired sequence data by targeted next generation sequencing (NGS). The TCGA cohort consists of 570 patients whose MSI status was determined. NGS data and clinical information were downloaded from the cBioPortal database (https://www.cbioportal.org). The abundance of tumor immune infiltrates was estimated by the Tumor Immune Estimation Resource (TIMER) 2.0 algorithm using gene expression data. Results: In the Chinese cohort, ACVR2A mutations were identified in 204 (18.6%) of 1960 patients, including 125 (61%) MSI-H patients and 79 (39%) MSS patients. Meanwhile, in all 140 MSI-H samples, 125 (90%) samples harbored AVCR2A mutation. The main variant of ACVR2A is loss of function mutation (ACVR2A^LOF), including p.K437del(65%, 132/204), p.D96del(5%, 11/204), p.Asp96ins(4%, 9/204), and etc. ACVR2A^LOF were detected in 161 patients (78.9%, 161/204), of which 125 (77%) were MSI-H and 36 (22%) were MSS. In the TCGA cohort, there were 102 (102/570) MSI-H samples, and 43% (44/102) of MSI-H samples carried ACVR2A mutation. Compared to the Chinese cohort, the ACVR2A mutation frequency in MSI-H samples was significantly lower in the TCGA cohort (43% vs 90%, pLOF mutations were observed in 30 MSI-H samples and 6 MSS samples. In both cohorts, patients with ACVR2A^LOF mutations exhibited higher TMB (pLOF mutations. Furthermore, in the TCGA cohort, we found that the Tumor Infiltrating Lymphocytes (TILs) of CD4+ T cells and macrophage cells were significantly lower in ACVR2A^LOF samples than those without ACVR2A^LOF mutations (pLOF was strongly correlated with MSI-H in patients of CRC and GC in both cohorts, especially in the Chinese population. Patients with ACVR2A^LOF mutations have similar genomic characteristics to MSI-H, with high TMB, high PD-L1 expression, and therefore can serve as a potential biomarker for selecting candidates for immunotherapy. Citation Format: Yongning Jia, Hongling Yuan, Yaqun Xin, Fei Pang, Fei Shan, Shuangxi Li, Honglin Zhu, Ziyu Li. Loss-of-function mutations in ACVR2A are correlated with microsatellite instability in gastric and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5752.

Background: In patients undergoing surgical resection for gastric cancer, postoperative complications—in particular, postoperative infections—remain an important problem and can result in delayed recovery and increased postoperative mortality. Objective: To investigate the association between perioperative anesthesia management and postoperative infectious complications in patients undergoing resection for gastric cancer. Design: Retrospective cohort study. Setting: A single-center study performed from April 1, 2015, to June 30, 2018, at Peking University Cancer Hospital. Patients: Patients who underwent resection for gastric cancer. Main Outcome Measures: Demographic information, perioperative data (including anesthesia-related data, surgery-related data, and cancer diagnosis), and information on postoperative recovery were recorded. The primary outcome was incidence of postoperative infection; the secondary outcome was length of hospital stay. The associations between perioperative factors and postoperative infectious complications were analyzed using multivariable logistic regression models and the classification tree method. Results: A total of 880 patients were included in the study; of these, 111 (12.6%) had postoperative infectious complications during hospitalization, including 78 surgical site infections and 62 remote infections. After correction for confounding factors on logistic multivariable analysis, perioperative use of glucocorticoids was associated with a lower incidence of postoperative infection (hazard ratio 0.968, 95% confidence interval 0.939 to 0.997, P=0.029), and intraoperative systolic blood pressure < 90 mmHg for > 10 min was associated with a higher incidence of postoperative infection (hazard ratio 2.112, 95% confidence interval 1.174 to 3.801, P=0.013). In addition, older age, preoperative hypoproteinemia, and total gastrectomy were identified as independent predictors of postoperative infection. Conclusion: For patients with gastric cancer, perioperative use of glucocorticoids and avoiding intraoperative hypotension may decrease the incidence of postoperative infectious complications.

Purpose To compare the short-term surgical outcomes of laparoscopic and open total/proximal gastrectomy using transorally inserted anvil (OrVil^TM). Method Patients diagnosed with gastric cancer and underwent total or proximal gastrectomy using OrVil^TM for reconstruction were included. Clinical and pathological characteristics, as well as postoperative outcomes, were analyzed. Propensity score matching was used to balance baseline factors. Results From April 2012 to April 2020, 199 patients at our center were included. A total of 166 underwent open total or proximal gastrectomy (OTG/OPG), and 33 underwent laparoscopic total or proximal gastrectomy (LTG/LPG). Twenty-seven patients from each group were paired with propensity score matching. The operation time was significantly shorter in the OTG/OPG group after matching. The overall complication rate and the incidence of each complication did not show significant differences between the two groups before and after matching. Conclusion LTG/LPG and OTG/OPG using OrVil^TM for the alimentary tract reconstruction are both feasible and can achieve similar short-term outcomes.