Importance Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy.Objective To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100).Design, Setting, and Participants Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021.Interventions Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years.Main Outcomes and Measures The primary end point was overall survival time from randomization.Results Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%).Conclusions and Relevance Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo.

Supplementary Table S4. Proteins identified by mass spectrometry from the TMEFF2 co-immunoprecipitate sample.

Supplementary Table S5. Mutation summary in patients.

Supplementary Table S1. The extent of inflammation in pre-cancerous lesions of Renji dataset.

Supplementary Table S2. Sequence of primers for real-time PCR.

Background: The phase III ORIENT-16 trial evaluated sin (a PD-1 inhibitor) versus placebo plus chemo as first-line (1L) treatment in pts with advanced G/GEJ adenocarcinoma. Sin+chemo previously showed a significant improvement in OS vs chemo in pts with PD-L1 combined positive score (CPS) ≥5 (HR 0.660; 95% CI 0.505-0.864; P=0.0023) and in all pts (HR 0.766; 95% CI 0.626-0.936; P=0.0090), with a median follow-up of 18.8 months (m) at interim analysis (Xu, et al. Ann Oncol 2021). Here we report the results from the final analysis (NCT03745170). Methods: This double-blind, phase III trial enrolled 650 pts ≥18 years of age with untreated, unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma, regardless of PD-L1 expression. Pts were randomized 1:1 to receive sin (3 mg/kg in pts weighing <60 kg or 200 mg in pts weighing ≥60 kg, IV Q3W) or placebo plus chemo (oxaliplatin 130 mg/m2 IV Q3W for up to 6 cycles, capecitabine 1000 mg/m2 PO Bid d1-14 Q3W) for 24 months. The primary endpoints were OS in pts with CPS ≥5 and all randomized pts. The data cutoff date for the final analysis was Sep 2, 2022. Results: With a median follow-up of 33.9 m, sin+chemo continued to show OS benefit over chemo in all pts (15.2 vs 12.3 m; HR 0.681 [95% CI: 0.571, 0.812]; P<0.0001); estimated OS rates at 24 and 36 m for sin+chemo vs chemo were 37.6% vs 20.6% and 26.0% vs 10.7%, respectively. OS benefits with sin+chemo vs chemo across subgroups were generally consistent with the previous report. The updated PFS was superior with sin+chemo vs chemo (HR 0.638, 95% CI 0.530-0.768; P<0.0001). The updated confirmed ORR per RECIST v1.1 was 58.2% vs 48.8% in all pts with measurable disease at baseline, with a median DoR of 9.9 vs 7.0 m, respectively; 47.8% of responders in sin+chemo group and 25.9% of responders in chemo group had DoR ≥12 m. In pts with CPS ≥5, significant OS benefit (median OS 19.2 vs 12.9 m; HR 0.587 [95% CI: 0.467, 0.738]; P<0.0001) and superior PFS (HR 0.621, 95% CI 0.490-0.787; P<0.0001) with sin+chemo over chemo remained. A delayed numerical OS improvement was observed for subgroup pts with CPS <5. No new or unexpected safety signals were identified. Conclusion: The previously reported significant OS benefit with sin+chemo vs chemo was more evident in CPS ≥5 pts and in all pts with 15 m of additional follow-up, further confirming sin+chemo as a standard of care for 1L treatment of G/GEJ adenocarcinoma. Citation Format: Jianming Xu, Haiping Jiang, Yueyin Pan, Kangsheng Gu, Shundong Cang, Lei Han, Yongqian Shu, Jiayi Li, Junhui Zhao, Hongming Pan, Suxia Luo, Yanru Qin, Qunyi Guo, Yuxian Bai, Yang Ling, Yingmei Guo, Yuling Chen, Yan Wang, Hui Zhou. First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT078.

Supplementary Table S3. Clinicopathologic features of patients with gastric cancer according to the expression status of TMEFF2.

在全球范围内,非小细胞肺癌是一种发病率和死亡率均较高的常见恶性肿瘤.随着诊疗水平的不断进步,其死亡率虽有所下降,但预后仍较差.因此,积极探寻可靠的预后指标尤为重要.既往研究表明,肿瘤的发生发展与炎症相关.本研究通过对常见的炎性指标对非小细胞肺癌预后的影响进行综述,旨在为临床诊治提供依据.

肺癌是全球常见的致死率最高的恶性肿瘤.越来越多的研究表明,对于晚期非小细胞肺癌一线治疗后没有进展的患者,维持治疗使患者无进展生存期和总生存期明显获益.传统上对于没有检测到驱动基因的非小细胞肺癌患者,仅能接受化疗,其有效性低,且副作用大,寻找更加有效的治疗方案迫在眉睫.随着新药的层出不穷,本文对如何优化驱动基因阴性的晚期非小细胞肺癌患者的维持治疗,从而提高患者生存期作一综述.

Background Apatinib improves progression-free survival and overall survival with an acceptable safety profile in Chinese patients with chemotherapy-refractory advanced or metastatic gastric cancer. However, the efficacy and safety of apatinib are unclear for elderly patients. This study was undertaken to prospectively investigate the efficacy and safety of apatinib for elderly patients with unresectable advanced or metastatic gastric cancer, who experienced progression to at least one lines of chemotherapy. Methods This open-label, single-arm, phase II study enrolled patients aged ≥60 years with advanced gastric cancer, who experienced progression to one or more lines of chemotherapy at five centers in China. Patients received apatinib in an oral dose of 500mg or 250mg daily according to the research physicians’ decision. The primary end point was progression-free survival, and the secondary end points were objective response rate, disease control rate, overall survival, and safety. Results Forty-eight patients were enrolled between June 2017 and September 2019. The median age was 65.5 years (range 60–80 years). Twenty-seven patients (56.3%) started treatment with an initial dose of 500 mg and 21 patients (43.7%) with 250 mg. The median progression-free survival and overall survival were 3.00 months (95% confidence interval, 2.17–3.84) and 8.10 months (95% confidence interval, 4.35–11.85), respectively. The objective response rate and disease control rate assessed by the investigators were 16.7% and 72.9%, respectively. The common side effects were fatigue (58.3%), hypertension (47.9%), abdominal pain (33.3%), proteinuria (29.2%), leukopenia (22.9%), and neutropenia (20.8%). Hypertension (22.9%) was the major grade 3/4 toxicity. Conclusion These data suggest that apatinib is effective and relatively tolerable for elderly patients with unresectable advanced or metastatic gastric cancer who have received at least first-line chemotherapy.

OBJECTIVE:The incidence of gastric cancer is declining in parts of Asia including China. This study was designed to investigate the incidence and mortality trend of gastric cancer in different regions and ethnic groups in Xining of Qinghai-Tibet Plateau.METHODS:Data of gastric cancer from January 2009 to December 2016 were collected from Disease Control Center in Xining for repeated cross-sectional study.PRIMARY OUTCOME MEASURES:Gastric cancer.PARTICIPANTS:Xining resident population with pathological diagnosis of gastric cancer.MAIN OUTCOME MEASURE:Age, gender composition ratio, morbidity, mortality and trends.RESULTS:There were 4822 new cases of gastric cancer from 2009 to 2016, including 3583 males and 1239 females; 2290 cases were in villages and 2532 in towns. Male incidence rate (38.37/100,000) was higher than female (13.35/100,000). The incidence in rural areas (39.29/100,000) was higher than in urban areas (20.59/100,000). During 2009-2016, there were 2109 gastric cancer deaths in Xining, 1543 in males and 566 in females. There were 1185 cases in villages and 924 in cities. Male mortality (16.64/100,000) was higher than female (6.42/100,000). The mortality rate in rural areas (20.40/100,000) was higher than in urban areas (7.62/100,000).CONCLUSION:Overall morbidity and mortality rates of gastric cancer are on the rise in Xining. Male morbidity and mortality rates are higher than female ones, and rural areas are higher than urban areas.

BACKGROUND:Gastric cancer (GC) is one of the most common malignant tumors and the second most frequent cause of cancer death worldwide. Crocin is a kind of bioactive constituent found in the stigmas of saffron, which has shown various pharmacological activities.METHODS:In this study, we investigated the inhibitory effect of crocin on gastric cancer AGS cells proliferation and explored the underlying mechanism. A series of methods were used including cell counting kit assay, gene microarray analysis, qRT-PCR, Celigo image cytometry, cell clone formation assay, Western blot, and cell xenograft growth in vivo.RESULTS:The results indicated that crocin inhibited AGS cells proliferation and promoted cell apoptosis. Further studies suggested that crocin decreased a series of genes expression, among which TPM4 gene downregulation inhibited the tumor cells proliferation and tumor growth in mice, and overexpression of TPM4 gene abolishes the inhibitory effect of crocin. Further study using microarray analysis suggested that knocking down of TPM4 altered genes related to the proliferation and apoptosis of cells.DISCUSSION:Crocin could inhibit the gastric cancer cells AGS cells proliferation by regulating TPM4 gene expression, and TPM4 may be a promising therapeutic target for GC treatment.

随着分子生物学技术的日益发展,基于基因检测指导下的精准医疗已成为非鳞非小细胞肺癌的主要诊治模式.目前临床应用较广的基因检测技术大致分为:基因芯片(gene chip)技术、二代测序技术(next generation sequencing technologies,NGS)、扩增阻滞突变系统(amplification refractory mutation system,ARMS)、Cobas、数字聚合酶链反应(digital polymerase chain reaction,dPCR)和荧光原位杂交技术(fluorescence in situ hybridization,FISH)等,这些技术各有独特的优势与不足,本文综述不同基因检测技术在非鳞非小细胞肺癌临床应用中的研究进展.

INTRODUCTION:The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. METHODS:ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. RESULTS:Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment. CONCLUSIONS:The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

Gastric cancer is the fourth most common cause of cancer death globally and the second most common in Asia. Many studies suggest that Crocin has the potential for gastric cancer antineoplastic combined chemotherapy protocols. Here we investigated genomic changes related to the inhibitory effect of Crocin, and elucidated the molecular mechanism of this inhibition in gastric carcinoma cells. We found that, compared with the control group, 216 significantly upregulated and 301 significantly downregulated genes were identified in Crocin-treated AGS cells. Many of these differentially expressed genes in AGS cells are involved in Nrf2-mediated oxidative stress response, p53 signaling, and integrin signaling, which suggested the mechanism of Crocin functions in therapy of gastric cancer. In summary, our study indicates that Crocin has the potential for gastric cancer adjuvant treatment through reducing cell oxidative stress levels.

Importance:Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non-small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established. Objectives:To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay. Design, Setting, and Participants:This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019. Exposure:Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously. Main Outcomes and Measures:Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test. Results:A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × μg/mL; for 500-L group: 12 331.42 [2472.58] hour × μg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti-PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively. Conclusions and Relevance:In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.

肺癌是全球恶性肿瘤死亡的首要原因,在我国,肺癌是男性和女性癌症死亡的第一原因.肺癌的发生是一个复杂的过程,涉及遗传、环境等多种因素,约90％的肺癌可能由吸烟引起.由于女性肺癌有其独特的分子表达谱、组织病理学及激素代谢特征,因此被认为是独立于男性肺癌的疾病.本文综述了女性肺癌的主要发病危险因素、临床特点及治疗策略.

免疫是保证人体健康的一种生理功能.目前,人类对其认识和发展共经历了4个阶段(经验免疫学、科学免疫学、现代免疫学、应用免疫学).其中,在应用免疫学阶段中,衍生出很多分支,例如:免疫治疗、免疫预防及免疫营养等.随着免疫治疗在恶性肿瘤中的崭露头角,不仅证明了其在恶性肿瘤治疗中的可行性和重要性,而且使得人们将该思路拓展到解决肿瘤患者营养不良的问题上.这种通过调节免疫治疗营养不良的方法被称为"免疫营养治疗",并在近几年临床实践中有了较快速的发展.其中,胃癌作为营养不良发生率最高的癌种,免疫营养治疗在胃癌中的发展备受关注.人们希望通过这种治疗方式降低围术期的不良临床结局、延长患者的总生存时间,此外还迫切希望其可改善患者的生活质量.本文对胃癌患者易发生营养不良的机制、免疫营养维持肠道屏障的作用、常见的免疫营养素在胃癌围术期患者的应用、机制、疗效等进行综述,为胃癌患者围术期的免疫营养治疗提供临床参考.

In recent years, with the continuous development of driving gene rare mutations of advanced non-small cell lung cancer (NSCLC) patients and molecular biology technology, molecular detection and individualized therapy have become standard diagnosis and treatment strategies for patients with advanced NSCLC. The driving gene of NSCLC has become a research focus. The development of molecular detection technology, the discovery of new driving gene and the continuous emergence of new drugs have made the treatment of rare target mutations in NSCLC increasingly precise. This article retrieves and screens out the documents published in recent years which are related to driving gene rare mutations in patients with advanced NSCLC, and analyzes the relevant research progress. It is hoped that more reasonable and accurate treatment plans can be formulated for NSCLC patients to guide the clinical research of NSCLC treatment.