The RESOLVE study demonstrated a disease-free survival (DFS) benefit from perioperative SOX compared to adjuvant CapOx in patients with gastric or gastro-oesophageal junction (G/GOJ) adenocarcinoma who underwent D2 gastrectomy. Here, we aim to update on the 5-year overall survival (5yOS%) results. The phase III, open-label, randomized controlled RESOLVE study (NCT01534546) enrolled patients with stage cT4aN+M0 or cT4bNanyM0 G/GOJ adenocarcinoma. Patients were 1:1:1 randomly assigned to adjuvant CapOx, adjuvant SOX, or perioperative SOX and underwent standard gastrectomy with D2 lymphadenectomy. The adjuvant CapOx group received 8 cycles of oxaliplatin (130 mg/m2, d1) with capecitabine (1000 mg/m2, bid, d1-14). The adjuvant SOX group received oxaliplatin and oral S-1 at a dose depending on body surface area (40-60 mg bid, d1-14). The perioperative SOX group received 3 cycles of preoperative SOX plus 5 cycles of postoperative SOX followed by 3 cycles of S-1 monotherapy. The primary endpoint was 3-year DFS, and second endpoints included 5yOS% and safety. Between 08/2012 and 02/2017, 1022 patients were included in mITT population and analyzed. With a median follow up time of 62.8 months, 495 recurrences and 416 deaths were observed by 07/04/2022. Perioperative SOX improved 5yOS% compared with adjuvant CapOx (60.0% vs. 52.1%; HR 0.79, 95%CI [0.62-1.00]; p=0.049). Adjuvant SOX was not inferior to postoperative CapOx (61.0% vs. 52.1%; HR 0.77, 95%CI [0.61-0.98]; p=0.033). Perioperative SOX improved 5yDFS% compared with adjuvant CapOx (53.2% vs. 45.8%; HR 0.79, 95%CI [0.63-0.98]; p=0.034). Adjuvant SOX was not inferior to adjuvant CapOx (50.8% vs. 45.8%; HR 0.86, 95%CI [0.69-1.06]; p=0.164). No additional adverse events were observed. The update on the RESOLVE survival analysis revealed improved survival in patients with G/GOJ adenocarcinoma undergoing D2 gastrectomy with perioperative SOX therapy compared to adjuvant CapOx, and adjuvant SOX was not inferior to adjuvant CapOx.

Lung large-cell neuroendocrine carcinoma (LCNEC) was once a subtype of lung large-cell carcinoma (LCLC), and it was later classified as a high-grade neuroendocrine carcinoma alongside small-cell lung cancer (SCLC). Because of the low incidence and extremely difficult diagnosis of LCNEC and LCLC, clinicians are apt to confuse these two diseases, making it meaningful to compare the differences in clinicopathological features and postoperative prognosis between the two kinds of cancer patients through real-world data.

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.

ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i.

e21521 Background: ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i. Methods: We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18. Results: We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). T P53 was the most frequently co-mutated gene (n = 4) followed by HER2 (n = 2), NSD1 (n = 2) and RARA (n = 2). Treatment history of 9 advanced LADC patients were collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p < 0.001). Conclusions: To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.

Background Surgery alone is not sufficient to achieve satisfactory prognosis for locally advanced gastric cancer (LAGC), and perioperative therapies have been proposed to improve survival outcome. However, the optimal modality and regimen of perioperative chemotherapy are yet to be identified. This study compared the efficacy and safety of SOX as perioperative chemotherapy versus SOX or XELOX as postoperative chemotherapy after D2 gastrectomy in patients with LAGC. Methods The RESOLVE Trial is a three-arm, randomized, multicenter, open-label phase III trial. Patients with stage cT4a/N+M0 or cT4bNxM0 gastric or gastro-esophageal junction adenocarcinoma were enrolled. All patients received standard gastrectomy with D2 lymphadenectomy. Arms A and B respectively received 8 cycles of adjuvant XELOX (capecitabine 1000 mg/m2, bid, d1-14, oxaliplatin 130 mg/m2, d1, q3W) or SOX (TS-1: 40-60 mg bid, d1-14, oxaliplatin: 130 mg/m2 d1, q3W). Arm C received 3 cycles of neoadjuvant SOX and 5 cycles of adjuvant SOX followed by 3 cycles of TS-1. The primary endpoint was 3-year disease-free survival rate (3yDFS%) in the mITT population. Results A total of 1094 patients were randomized between 08/2012 and 02/2017, 364/365/365 in arm A/B/C, and 454 recurrences/deaths were observed by 07/2019. Baseline characteristics were similar between arms (overall, male 75.2%; median age 60.0 years; GEJ 36.5%). Peri-operative SOX improved 3yDFS% compared with post-operative XELOX (3yDFS%, 62.0% in Arm C, 54.8% in Arm A; HR 0.79, 95%CI [0.62-0.99]; p = 0.045). Post-operative SOX was non-inferior to post-operative XELOX (3yDFS%, 60.3% in Arm B, 54.8% in Arm A; HR 0.85, 95%CI [0.67-1.07]; p = 0.162). Resection rate was 90.4% in Arm A, 92.7% in Arm B, and 85.5% in Arm C, respectively. Thirty-day mortality rate was all 0.9% for Arms A, B and C. Conclusions Perioperative SOX is superior to post-operative XELOX while post-operative SOX is non-inferior to post-operative XELOX for LAGC after D2 gastrectomy. It provides the evidence of perioperative SOX in LAGC. Clinical trial identification NCT01534546. Legal entity responsible for the study The authors. Funding Taiho Pharmaceutical Co., Ltd. Disclosure All authors have declared no conflicts of interest.

Increasing evidence suggests that intestinal microbiota dysbiosis and chronic inflammation contribute to colorectal cancer (CRC) development. γδ T cells represent a major innate immune cell population in the intestinal epithelium that is involved in the maintenance of gut homeostasis, inflammation regulation, and carcinogenesis. The important contributions of γδ T cells are (i) to perform a protective role in the context of barrier damage and pathogenic microorganism translocation; (ii) to exert either pro- or anti-inflammatory effects at different inflammatory stages; and (iii) to boost the crosstalk between immune cells and tumor microenvironment, inducing a cascade of suppressive immune responses. Understanding the crucial role of γδ T cells would enable us to manipulate these cells during the CRC sequence and improve the efficacy of tumor therapy.

Summary Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response, including over-activation of T and B cell development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A) is involved essentially in immune cell regulation and is also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE. Serum levels of Sema5A were tested by enzyme-linked immunosorbent assay (ELISA) in 152 SLE patients and 48 healthy controls. The message ribonucleic acid (mRNA) expression levels of Sema5A and ADAM metallopeptidase domain 17 (ADAM17) in the peripheral blood mononuclear cells (PBMC) from 43 patients with SLE and 19 healthy controls were detected by the real-time–quantitative polymerase chain reaction (qPCR). Serum Sema5A levels were increased significantly in SLE patients compared with healthy controls (P < 0·001). Elevated levels of Sema5A were correlated positively with 24-h proteinuria excretion (r = 0·558, P < 0·0001), SLE disease activity index (SLEDAI) (r = 0·278, P = 0·0006) and C-reactive protein (CRP) (r = 0·266, P = 0·002), but negatively with planet (PLT) (r = –0·294, P = 0·0003) and complement 3 (C3) (r = –0·287, P = 0·0004) in SLE patients. Patients with elevated Sema5A levels showed higher incidence of rash, serositis and nephritis (P < 0·05 or P < 0·001). Patients with decreased PLT, C3 or positive for proteinuria also showed elevated Sema5A (P < 0·001 or P < 0·05). The mRNA ADAM17 was increased in SLE patients and correlated positively with serum Sema5A levels. Our data demonstrated that elevated serum Sema5A in SLE patients correlated with disease activity and are involved in kidney and blood system damage; ADAM17 might be involved in the release of secreted Sema5A.