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Prospective evidence regarding the combination of programmed cell death (PD)−1 and angiogenesis inhibitors in treating locally advanced gastric cancer (LAGC) is limited. In this multicenter, randomized, phase 2 trial (NCT04195828), patients with gastric adenocarcinoma (clinical T2-4N + M0) were randomly assigned (1:1) to receive neoadjuvant camrelizumab and apatinib combined with nab-paclitaxel plus S-1 (CA-SAP) or chemotherapy SAP alone (SAP) for 3 cycles. The primary endpoint was the major pathological response (MPR), defined as <10% residual tumor cells in resection specimens. Secondary endpoints included R0 resection rate, radiologic response, safety, overall survival, and progression-free survival. The modified intention-to-treat population was analyzed (CA-SAP [ n  = 51] versus SAP [ n  = 53]). The trial has met pre-specified endpoints. CA-SAP was associated with a significantly higher MPR rate (33.3%) than SAP (17.0%, P  = 0.044). The CA-SAP group had a significantly higher objective response rate (66.0% versus 43.4%, P  = 0.017) and R0 resection rate (94.1% versus 81.1%, P  = 0.042) than the SAP group. Nonsurgical grade 3-4 adverse events were observed in 17 patients (33.3%) in the CA-SAP group and 14 (26.4%) in the SAP group. Survival results were not reported due to immature data. Camrelizumab and apatinib combined with chemotherapy as a neoadjuvant regimen was tolerable and associated with favorable responses for LAGC. Neoadjuvant treatment represents a therapeutic option for locally advanced gastric cancer (LAGC). Here the authors report the results of a randomized phase 2 trial of camrelizumab (anti-PD1) and apatinib (anti-VEGFR2) combined with nab-paclitaxel plus S-1 versus chemotherapy alone as neoadjuvant treatment for LAGC.

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time‐dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow‐up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages, which may affect the design of future clinical trials. Patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages.

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.

Background Clinical T4 (cT4) stage gastric cancer presents with frequent postoperative recurrence and poor prognosis. This study is to evaluate the oncological efficacy of laparoscopic radical total gastrectomy combined with postoperative prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with cT4N + M0 gastric cancer who received neoadjuvant chemotherapy. Methods We reviewed the clinicopathological data of 174 patients with clinical T4 gastric cancer who underwent neoadjuvant chemotherapy followed by laparoscopic radical total gastrectomy between June 2017 and December 2021. Among them, 142 were included in the non-HIPEC group, and 32 in the HIPEC group. Patients in both groups were paired based on propensity score in a 2:1 ratio to assess disparities in tumor recurrence and long-term survival. Results After matching, there were no significant differences in the clinicopathological data between the two groups. The peritoneum (16.1%) and distant organs (10.9%) were the most frequent locations for recurrence. Prior to matching, the recurrence rates were similar at all sites for both groups. Compared with those in the non-HIPEC cohort, the recurrence rates at all sites, the lung, and the peritoneum were notably lower in the HIPEC cohort. Prior to matching, the 3-year overall survival and disease-free survival rates were similar between the two groups; following matching, the HIPEC group exhibited notably greater survival rates than did the non-HIPEC group. The disparities in survival rates between the groups became even more pronounced after conducting a stratified analysis among patients with stage III disease. Conclusions Neoadjuvant chemotherapy combined with prophylactic HIPEC after laparoscopic radical gastrectomy can effectively reduce the rate of peritoneal metastasis in patients with cT4N + M0 advanced gastric cancer and significantly improve the prognosis of such patients, which is of great clinical value.

Purpose Open-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors. Methods Patients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy. Results Between November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients ( n  = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients ( n  = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression. Conclusion LBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.

Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC. To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC. This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020. Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle. The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome. A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed. This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings. ClinicalTrials.gov Identifier: NCT03192735.

Purpose The purpose of this paper is to study the seismic performance of the energy-saving block and invisible multi-ribbed frame composite walls (EBIMFCW), changing the shear-span ratio as the test parameter, the low-cycle reciprocating loading tests of six 1/2 scale wall models were carried out. Design/methodology/approach The test design method and analysis are used for the seismic performance of the EBIMFCW. Findings With the increase of shear-span ratio: the walls tend to occur bending failure even more, the initial stiffness of the wall decreases, the overall ductility of the wall is improved and the walls tend to occur bending failure. Originality/value The previous studies do not involve the seismic performance of EBIMFCW under different shear-span ratios. Therefore, the paper studies the hysteresis behavior, ductility, stiffness degradation and energy dissipation performance of EBIMFCW under different shear-span ratios.

Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.

Background. Remnant gastric cancer (RGC) is a rare malignant tumor with poor prognosis. There is no universally accepted prognostic model for RGC. Methods. We analyzed data for 253 RGC patients who underwent radical gastrectomy from 6 centers. The prognosis prediction performances of the AJCC7th and AJCC8th TNM staging systems and the TRM staging system for RGC patients were evaluated. Web-based prediction models based on independent prognostic factors were developed to predict the survival of the RGC patients. External validation was performed using a cohort of 49 Chinese patients. Results. The predictive abilities of the AJCC8th and TRM staging systems were no better than those of the AJCC7th staging system (c-index: AJCC7th vs. AJCC8th vs. TRM, 0.743 vs. 0.732 vs. 0.744; P>0.05). Within each staging system, the survival of the two adjacent stages was not well discriminated (P>0.05). Multivariate analysis showed that age, tumor size, T stage, and N stage were independent prognostic factors. Based on the above variables, we developed 3 web-based prediction models, which were superior to the AJCC7th staging system in their discriminatory ability (c-index), predictive homogeneity (likelihood ratio chi-square), predictive accuracy (AIC, BIC), and model stability (time-dependent ROC curves). External validation showed predictable accuracies of 0.780, 0.822, and 0.700, respectively, in predicting overall survival, disease-specific survival, and disease-free survival. Conclusions. The AJCC TNM staging system and the TRM staging system did not enable good distinction among the RGC patients. We have developed and validated visual web-based prediction models that are superior to these staging systems.

BackgroundPrevious retrospective studies have shown that laparoscopic spleen-preserving D2 total gastrectomy (LSTG) for advanced upper third gastric cancer (AUTGC) is safe. However, all previous studies were underpowered. We therefore conducted a prospective, multicenter study to evaluate the technical safety and feasibility of LSTG for patients with AUTGC.MethodsPatients diagnosed with AUTGC (cT2-4a, N−/+, M0) underwent LSTG at 19 institutions between September 2016 and October 2017 were included. The number of No. 10 lymph node (LN) dissections, metastasis rates, intraoperative and postoperative complications were investigated.ResultsA total of 251 patients were enrolled in the study, and 242 patients were eligible for the per protocol analysis. The average numbers of No. 10 LN dissections and metastases were 2.4 and 0.1, respectively. Eighteen patients (7.4%) had No. 10 LN metastases, and among patients with advanced gastric cancer, the rate of No. 10 LN metastasis was 8.1% (18/223). pN3 status was an independent risk factor for No. 10 LN metastasis. Intraoperative complications occurred in 7 patients, but no patients required conversion to open surgery or splenectomy. The overall postoperative complication rate was 13.6% (33/242). The major complication and mortality rates were 3.3% (8/242) and 0.4% (1/242), respectively. The number of retrieved No. 10 LNs, No. 10 LN metastasis and TNM stage had no significant influence on postoperative complication rates.ConclusionLSTG for AUTGC was safe and effective when performed by very experienced surgeons, this technique could be used in patients who needed splenic hilar lymph node dissection.