Background Early and accurate assessment of treatment response is crucial for determining therapeutic strategy in patients with locally advanced rectal cancer (LARC), particularly in those desiring organ preservation. By visualizing tumor glycolysis and granzyme B release from cytotoxic immune cells, respectively, [18F]FDG and [68Ga]Ga-GZP PET imaging may provide a promising strategy for precise response evaluation during neoadjuvant immunochemoradiotherapy. Methods This prospective, single-center study enrolled high-risk LARC patients undergoing neoadjuvant short-course radiotherapy (SCRT) and six-cycle immunochemotherapy. Paired imaging with [18F]FDG PET/CT and [68Ga]Ga-GZP PET/MR was performed at baseline and after two treatment cycles. The status of clinical complete response (cCR) or pathological complete response (pCR) after therapy was determined by the combination of digital rectal examination, endoscopic ultrasound, enhanced MRI, or surgery. Changes in PET parameters were analyzed for associations with pCR and cCR. Receiver operating characteristic (ROC) curves were used to assess predictive performance. Results A total of 20 eligible patients (8 men, 12 women; mean age, 53.10 years) were enrolled and completed the entire trial, and all patients had microsatellite instability-high/deficient mismatch repair LARC. [18F]FDG PET parameters significantly decreased post two-cycle treatment, while [68Ga]Ga-GZP SUVmax increased (P < 0.001). After treatment, pCR and cCR rates were 53.85% (7/13) and 70.0% (14/20), respectively. Patients with pCR/cCR exhibited greater reductions in FDG-MTV than those with non-pCR/cCR (P < 0.05), whereas GZP-SUVmax-2 was significantly higher in the cCR patients (P < 0.05). The accuracies of ΔFDG-MTV% (cutoff = 73.19%) for predicting pCR (P = 0.039) and cCR (P = 0.032) were 84.62% and 80.0%, respectively. GZP-SUVmax-2 (cutoff = 2.85) held the accuracies of 76.92% and 80.0% for pCR (P = 0.116) and cCR (P = 0.058), respectively. Conclusions [18F]FDG PET/CT is a valuable tool for early prediction of treatment response in LARC, with ΔFDG-MTV% significantly associated with pCR and cCR. Though post-treatment GZP-SUVmax reflects interpatient differences in immune response, [68Ga]Ga-GZP PET fails to predict pCR and cCR. These findings support ΔFDG-MTV% as a reliable early imaging biomarker for identifying candidates who are likely to benefit from organ-preserving management.

The optimal follow-up strategy for patients with locally advanced gastric cancer (LAGC) receiving neoadjuvant therapy (NAT) remains unknown. Traditional follow-up strategies based on relatively fixed intervals fail to fully account for dynamic changes in recurrence risk. This study aimed to develop a personalized postoperative follow-up strategy using dynamic programming (DP) to optimize follow-up arrangements based on individual patient characteristics and dynamic recurrence risks. This study included 3397 patients with LAGC who underwent surgery after NAT at 21 medical centers between 2018 and 2023. By integrating multiple prognostic indicators using a random survival forest model, we estimated individual time-adjusted cumulative hazards. A conditional inference tree was then used to stratify patients into low-, medium-, and high-risk groups. The DP algorithm was employed to determine the optimal follow-up arrangements for recurrence detection. A Markov decision-analytic model was used to identify the most cost-effective follow-up strategy. Compared with the guideline strategies, the DP-based strategy significantly reduced the average delayed detection time, particularly in the high-risk group. Furthermore, the cost-effectiveness analysis showed that the DP-based strategy achieved the best incremental cost-effectiveness ratio. Finally, we determined that the optimal numbers of follow-ups for the low-, medium-, and high-risk groups were 9, 10, and 13, respectively. The study demonstrates that the DP-based personalized follow-up strategy significantly improved the efficiency of recurrence detection and resource utilization in LAGC. These findings highlight the potential of DP algorithms in clinical decision-making and provide a foundation for future personalized follow-up studies.

Hypofractionated radiotherapy (HFRT) has emerged as a potent orchestrator of the tumor immune microenvironment (TIME). However, the key metabolic trajectories and intercellular metabolic communication triggered by HFRT that dictate immune outcomes in microsatellite stable (MSS) colorectal cancer (CRC) remain unclear. Here, we demonstrate that HFRT‑exposed CRC cells upregulate the ketogenic enzyme HMGCS2, leading to accumulation of β‑HB in the TIME. This tumor‑derived β‑HB predominantly acts on mono-macrophages, and this metabolic interaction plays a dominant role in HFRT‑induced antitumor immunity. Mechanistically, β‑HB induces an immunostimulatory M1-like polarization of monocyte-derived macrophages (MDMs) via lysine β‑hydroxybutyrylation (Kbhb) at histone H3 lysine 27 (H3K27bhb), which epigenetically activates AP-1-mediated pro-inflammatory programs to prime CD8+ T cells. Clinically, post-HFRT serum β‑HB could represent a specific predictive biomarker for pathological complete response. Furthermore, early results from an ongoing phase II study indicate that combining HFRT with exogenous β‑HB supplementation and immunochemotherapy supports the translational potential of this therapeutic strategy.

Abnormal lactate metabolism and lysine lactylation (Kla) have emerged as critical factors driving tumor immune evasion through dual mechanisms of tumor metabolic reprogramming and epigenetic regulation. Tumor cells produce lactate through multiple metabolic pathways, which is then exported via monocarboxylate transporters to accumulate in the tumor microenvironment (TME). Within the TME, lactate acts as a key substrate driving the Kla of both histone and non-histone proteins. Lactate and Kla synergistically drive tumor immune evasion by acting on both tumor cells and immune cells, ultimately driving tumor initiation, proliferation, metastasis, and therapeutic resistance. Currently, therapeutic strategies targeting lactate metabolism have emerged as a research hotspot for breaking tumor immune evasion, which encompass three directions: inhibiting lactate production, blocking lactate transport, and reversing abnormal Kla. Some candidate drugs have entered clinical trials and demonstrated preliminary efficacy, yet challenges remain, including insufficient specificity, off-target toxicity, and resistance mediated by tumor metabolic plasticity. Therefore, this review systematically summarizes the mechanisms of lactate production and transport within the TME, the regulation of Kla, and their role in mediating tumor immune evasion. Anti-tumor therapeutic strategies and recent research advances targeting lactate metabolism are also clarified, which provide a theoretical basis for elucidating the metabolic mechanisms of tumor immune evasion and developing novel metabolic-immune combination therapies.

11539 Background: SDH deficiency causes succinate accumulation and metabolic defects in gastrointestinal stromal tumor (GIST) and paraganglioma. Olverembatinib downregulates lipid uptake protein CD36, restricting fatty acid supply required for SDH-deficient GIST cell growth. We report updated clinical and translational results from study HQP1351SJ0003 (NCT03594422) of olverembatinib in SDH-deficient GIST and paraganglioma. Methods: Patients (pts) (≥ 12 years) with GIST and other solid tumors received olverembatinib 30 to 50 mg PO QOD. Primary cells from tumor tissues of 9 pts with SDH-deficient GISTs were used for ex vivo analyses. All samples were collected at Sun Yat-sen University Cancer Center, with informed consent from pts. Cell migration/invasion was evaluated by wound healing, Transwell migration, and Matrigel invasion assays. Lipid levels were quantitated by LC-MS. Knockdown of CD36 and p38 was done by siRNA. Protein levels were assessed by western blot. Results: As of November 13, 2025, a total of 32 pts, including 26 pts with IHC-confirmed SDH-deficient GIST, had received olverembatinib. The median age of pts with SDH-deficient GIST was 30 (range 13-56) years; 19 (73.1%) were female. Twenty-five pts (96.2%) had received ≥ 1 TKI and 13 (50.0%) ≥ 3. Six (23.1%) pts experienced PR as best response, and the median PFS was 25.7 (range 12.9-NR) months. An additional six pts with paraganglioma had received olverembatinib (all were SDH-deficient as determined by either negative SDHB IHC or SDHB gene mutation). The median age was 47.5 (range 31-61) years; all were male. Best responses were observed in four pts, with SD lasting ≥ 4 cycles (CBR, 66.7%); SD represents meaningful clinical benefit in this slow-growing tumor type. The median PFS was 8.25 (range 1.87-NR) months. SDH-deficiency was associated with a higher risk of tumor metastasis. In SDH-deficient (vs. SDH-competent) GIST cells, significantly higher linoleic acid levels were observed. Supplementation of free fatty acids promoted SDH-deficient cell migration, which could be inhibited by olverembatinib at 30 nM. In addition, siRNA knockdown of p38, a kinase target of olverembatinib, and treatment with two p38 inhibitors significantly downregulated CD36 protein levels, suggesting that p38 regulates cellular CD36. Further, western blot analysis showed that olverembatinib dose-dependently inhibited CD36 protein and phosphorylated p38 protein levels in primary cells from SDH-deficient pts. These findings suggest olverembatinib suppresses fatty acid-promoted migration via the p38-CD36 pathway. Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST and paraganglioma. Mechanistically, olverembatinib inhibits fatty acid–promoted invasion and migration of SDH-deficient GIST by targeting the p38-CD36 signaling pathway. Clinical trial information: NCT03594422 .

BACKGROUND:Follicular thyroid carcinoma (FTC) is the second most common subtype of thyroid malignancy, with distant metastases most often to the bones, lungs, brain, and liver, and only rarely to other sites. Rectal follicular thyroid-like carcinoma is a rare condition characterized by infiltration of FTC within the rectal wall. There are almost no literature reports. CASE SUMMARY:We report a case of rectal thyroid-like follicular carcinoma in a 61-year-old woman. The patient presented with intermittent rectal bleeding, and a colonoscopy revealed a mass in the mid-rectum. She underwent laparoscopic resection of the lesion, and was diagnosed with rectal thyroid-like follicular carcinoma by postoperative pathology. After a laparoscopic partial rectal resection, she was discharged on postoperative day 7. At 6 months postoperatively, the patient was still alive. CONCLUSION:Rectal follicular thyroid-like carcinoma may arise from malignant struma ovarii, highlighting the need to consider ovarian origins in atypical metastases of FTC.

ABSTRACT Our previous clinical trials had demonstrated that neoadjuvant hypofractionated radiotherapy (HFRT) combined with immunotherapy yields promising clinical outcomes in locally advanced rectal cancer (LARC). However, this combined modality benefits only a subset of patients, highlighting the need to uncover the mechanisms underlying how successful immunotherapy changes the tumor microenvironment to favor tumor control. Here, we showed that HFRT increases ISG15+MHC‐I+ neutrophil infiltration, which exhibits antigen‐presenting capabilities and is crucial for successful neoadjuvant therapy in rectal cancer. Mechanistically, HFRT promotes IFN‐α release, which activates the NOD1/NF‐κB pathway to drive MHC‐I expression in neutrophils. Adoptive transfer of ex vivo‐generated ISG15+MHC‐I+ neutrophils in mouse models enhanced intratumoral CD8+ T cell infiltration, synergizing with anti‐PD‐1 therapy to suppress tumor growth. This study uncovers an HFRT‐induced neutrophil subset that bridges local radiation with systemic immunity, providing a potential strategy to convert “cold” tumors to “hot” phenotypes for enhanced immunotherapy efficacy in microsatellite stability LARC.

e15652 Background: Short-course radiotherapy (SCRT) combined with chemotherapy as neoadjuvant therapy has been proven to increase the pathological complete response (pCR) rate for locally advanced rectal cancer (LARC). Radiotherapy and immunotherapy exhibit a synergistic effect. Ivonescimab, a tetrameric bispecific antibody targeting PD-1 and VEGF, has the potential to produce synergistic anti-tumor effects. This study aimed to evaluate the efficacy and safety of SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients. Methods: In this single-arm, single-center, phase II trial, LARC patients who met at least one of the following high-risk criteria—cT4, cN2, EMVI (+), MRF (+) or lateral lymph node (+) —were enrolled. All patients should have a tumor inferior margin ≤10 cm above the anal verge, and received SCRT followed by 6 cycles of Ivonescimab (20mg/kg or 10mg/kg, Q3W) and CAPOX (capecitabine: 1000mg/m2, bid, po, d1-14; oxaliplatin: 130mg/m2, ivgtt, d1; Q3W). Surgery was performed 1 week after the completion of neoadjuvant therapy. The primary endpoint was the pCR rate, while the secondary endpoints include 3-years Event-Free Survival rate, R0 resection rate, quality of life, overall survival and safety. Results: As of December 25, 2025, a total of 49 patients were enrolled. Among these patients, 33(67.3%) were male, with a mean age of 59 years (range, 37-73). 25(51.0%) patients had cT4 disease, and 22(44.9%) had cN2. The rates of CRM (+), MRF (+) and EMVI (+) were 67.3%, 63.3% and 67.3%, respectively. Tumor response was evaluable in 42 patients, among whom 39 underwent surgical resection. The pCR rates were 48.7% (19/39), while the complete response rates (pCR + cCR) were 47.6% (20/42). All surgical procedures achieved R0 resection. During the neoadjuvant treatment period, treatment-related adverse events (TRAEs) of any grade occurred in all patients (100%). The most common TRAEs were lymphocyte count decreased (100%), anemia (93.9%), weight loss (73.5%), and anorexia (73.5%). Grade ≥3 TRAEs were observed in 67.3% of patients, with the most common being lymphocyte count decreased (46.9%), anemia (22.4%), and weight loss (16.3%). Conclusions: SCRT followed by Ivonescimab and CAPOX as neoadjuvant therapy in LARC patients seems to demonstrate safety and promising efficacy. Clinical trial information: NCT06802666 . Surgical and post-operative pathological outcomes. Surgical population N=39 Pathological complete response (ypT0N0), n(%) 19(48.7) Tumor regression grading, n (%) 0 19(48.7) 1 12(30.8) 2 7(17.9) 3 1(2.6) Pathological tumor stage, n (%) ypT0 19(48.7) ypTis 1(2.6) ypT1 3(7.7) ypT2 5(12.8) ypT3 10(25.6) ypT4 1(2.6) Pathological node stage, n (%) ypN0 35(89.7) ypN1 3(7.7) ypN2 1(2.6) Surgical resection status, n (%) R0 39(100)

Background Metabolites sculpt the immunosuppressive tumor microenvironment (TME) that facilitates immune evasion. As a crucial signaling lysophospholipid, lysophosphatidylserine (LysoPS) correlates with advanced disease stages in multiple tumor types. However, the mechanisms by which LysoPS drives gastric cancer peritoneal metastasis remain undefined. Methods Single-cell transcriptomic profiling of primary tumors, normal peritoneum, and metastatic lesions delineated mechanisms underlying LysoPS-mediated tumor-associated macrophages (TAMs) reprogramming. Immunohistochemistry and multiplex immunofluorescence validated GPR34-high TAMs infiltration in peritoneal metastases. Functional validation was performed using molecular assays and in vivo models. Results LysoPS accumulated in ascites from patients with gastric cancer peritoneal metastasis, establishing an immunosuppressive TME that drove malignant progression. Using single-cell transcriptome sequencing, we identified a distinct subset of TAMs highly expressing GPR34 enriched in gastric cancer peritoneal metastases, which correlates with tumor progression and immune evasion. Mechanistically, LysoPS engagement of GPR34 activated ERK/c-Jun signaling, transcriptionally upregulating AXL and CD36 to enhance efferocytosis. This effect drove TAMs toward an immunosuppressive phenotype, characterized by enhanced interleukin-10 and transforming growth factor-β secretion. GPR34 inhibitor attenuated M2-like TAMs infiltration while bolstering cytotoxic T cells recruitment and curtailing programmed cell death protein 1 (PD-1)+T cells accumulation. Furthermore, combination with anti-PD-1 therapy synergistically suppressed tumor growth beyond monotherapy efficacy. Conclusions LysoPS-GPR34 axis synergized with efferocytosis to amplify TAMs immunosuppressive properties, fostering an immune-evasive microenvironment; GPR34 inhibitor thus represents a promising strategy to potentiate PD-1 blockade efficacy in gastric cancer peritoneal metastasis.

In the past 5 years, clinical trials on immune checkpoint inhibitors (ICIs) for the treatment of locally advanced rectal cancer (LARC) have flourished globally, and China has become one of the leading regions in this field. In response to the breakthrough progress and accumulation of evidence from key clinical trials, the Chinese Society of Colorectal Surgery has recognised the need for updated consensus guidance on the development of perioperative and organ-preserving treatment strategies for LARC. This expert consensus guidance provided unified standards for the indications, medication regimens, efficacy evaluations and follow-up of ICIs in this population, with a focus mainly on perioperative management and organ-sparing strategies. The diagnostic part of this consensus guidance is based on the internationally recognised definition of mismatch repair/microsatellite instability detection and emphasises the importance of multidisciplinary teams in treatment decision-making. In terms of treatment, based on the results of key trials that have changed clinical practice in the past 5 years, this expert consensus provides graded recommendations for the duration of preoperative immunotherapy and the necessity of postoperative adjuvant therapy, local resection and organ preservation strategies. Moreover, we refined the management process for the safety of perioperative immunotherapy. This document aims to provide a reference for surgeons; internal medicine, radiation therapy, pathology and imaging physicians; patients and nursing staff involved in the treatment of LARC, as well as health policy makers.

Peritoneal dissemination is a major cause of mortality in gastric cancer (GC), yet its molecular underpinnings remain incompletely defined. By integrating single-cell transcriptomic profiling of primary tumors and peritoneal lesions with functional and mechanistic studies, we identified a hypoxia-sensitive GC cell population that emerges during peritoneal metastasis and exhibits heightened autophagic activity and metastatic potential. Hypoxic stress robustly induced the deubiquitinase USP33 in GC cells, and high USP33 expression correlated with adverse clinical outcome. Gain- and loss-of-function assays demonstrated that USP33 enhances autophagy and promotes proliferation, invasion, and survival of GC cells. Proteomic and biochemical analyses revealed that USP33 directly interacts with the autophagy regulator ATG101 and stabilizes it by removing K48-linked polyubiquitin chains at lysine residues 106 and 191, thereby sustaining autophagic flux and facilitating peritoneal colonization. Upstream, hypoxia activated EPAS1/HIF2A, which bound to and transcriptionally upregulated USP33, establishing a hypoxia-responsive EPAS1-USP33-ATG101 axis. Disruption of this axis, either by USP33 silencing or pharmacological inhibition of EPAS1, suppressed autophagy-dependent peritoneal metastasis and prolonged survival in vivo. Collectively, our findings define a mechanistic link between hypoxia, oncogenic autophagy, and peritoneal dissemination in GC, and highlight the EPAS1-USP33-ATG101 axis as a promising therapeutic target in advanced disease.Abbreviations CQ: chloroquine; DEGs: differentially expressed genes; GC: gastric cancer; GCPM: gastric cancer peritoneal metastasis; HIFs: hypoxia-inducible factors; HREs: hypoxia-responsive elements; KEGG: Kyoto Encyclopedia of Genes and Genomes; PM: peritoneal metastasis; TME: tumor microenvironment; USPs: ubiquitin-specific peptidases; UMI: unique molecular identifier.

Background:Increasing evidence indicates that tumor cellular senescence can impair antitumor immunity and promote skin cutaneous melanoma (SKCM) progression. However, effective methods for assessing tumor cellular senescent status and tumor immune microenvironment (TIME) status remain lacking. This study intends to establish a novel Senescence-TIME Risk Score (STIRS) based on senescence and TIME related genes to predict prognosis and immunotherapy responsiveness in SKCM patients, thereby providing new strategies for current clinical personalized treatment. Methods:We identified distinct senescent microenvironment patterns using t-distributed stochastic neighbor embedding (t-SNE) based on a set of senescence marker genes and predicted the TIME in SKCM using the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm. Based on this, we divided the SKCM cohort into three groups: low-senescence & high-immunity, high-senescence & low-immunity, and mixed. We analyzed differentially expressed genes (DEGs) between the first two groups. Gene ontology (GO) enrichment analysis, kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, gene set enrichment analysis (GSEA), and the construction of protein-protein interaction (PPI) network were used to investigate the functional relevance of DEGs. We screened DEGs using least absolute shrinkage and selection operation (LASSO) regression and random forest (RF) algorithm to construct the STIRS. Patients were grouped by the median of STIRS, and differences in expression of immune cells and immune checkpoints between groups were examined. The predictive capability of STIRS for immunotherapy was validated. Finally, we knocked down the core risk gene in the B16 cell line to validate its function. Results:We identified 994 DEGs predominantly enriched in TIME- and senescence-related pathways. The constructed STIRS comprises six signature genes. Patients in the high-STIRS group exhibited significantly poorer survival than those in the low-STIRS group, and STIRS negatively correlated with immune response and immunotherapy responsiveness. A nomogram integrating STIRS and clinical indicators demonstrated satisfactory predictive performance for SKCM patient prognosis. These findings validate the STIRS model as a reliable independent prognostic indicator. Additionally, knockdown of the core risk gene keratin 17 (KRT17) inhibited the invasion and proliferation of B16 cells, demonstrating the role of KRT17 in the progression of SKCM. Conclusion:This study proposed a novel STIRS model and selected the core risk gene KRT17 for functional validation, which had potential as a prognostic tool and a guide for creating personalized therapies for SKCM patients.

361 Background: Neoadjuvant chemoimmunotherapy is revolutionizing the treatment landscape for solid tumors. However, a subset of patients exhibited limited therapeutic response. Metabolomic profiling of non-responding patients revealed aberrant polyol pathway activation, with sorbitol accumulation identified as a novel immune-modulatory mechanism. To address this challenge , we initiated a randomized controlled trial evaluating the safety and efficacy of chemoimmunotherapy combined with a sorbitol-restricted diet in locally advanced gastric cancer (LAGC) patients. Methods: Key inclusion criteria were: age ≥ 18 years; histologically confirmed gastric cancer with locally advanced disease as defined by the AJCC 8th Edition; and no prior systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either neoadjuvant chemoimmunotherapy (3-week cycles of SOX plus PD-1 antibody tislelizumab) combined with sorbitol-supplemented diet (2 g per dose, three times daily during treatment weeks； intervention group), or neoadjuvant chemoimmunotherapy (control group). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, disease control rate (DCR), and R0 resection rate. Exploratory endpoints included treatment-related adverse events (TRAEs), progression-free survival (PFS), and overall survival (OS). Clinical trial registration: NCT06826079. Results: This interim analysis included the first 26 patients (13 per arm) of a planned 86-patient cohort. Demographic characteristics were comparable between groups, with the investigational arm comprising 8 males and 5 females (mean age 59 years, range 45-72) and the control arm 9 males and 4 females (mean age 56 years, range 48-68). Gastric signet ring cell carcinoma (GSRCC), prevalence showed a numerical trend favoring the investigational arm (46.2% vs 30.8%, p=0.42). Both groups demonstrated identical pCR rates (23.1%, 3/13 per arm), but the investigational arm exhibited superior MPR rates (61.5% vs 38.5%, p=0.039) and significantly higher ypN0 status achievement (76.9% vs 38.5%, p=0.012), with the GSRCC subgroup showing similar trends (MPR: 50% vs 25%; ypN0: 67.7% vs 25%). Both groups maintained 100% R0 resection and DCR rate. Safety profiles were comparable, with any-grade TRAEs occurring in 53.8% (7/13) of the investigational arm and 46.2% (6/13) of controls, and grade ≥3 TRAEs in 15.4% (2/13) per arm. Diarrhea was predominant in the investigational group, while leukopenia was most frequent in controls. Conclusions: This interim analysis demonstrates that the addition of a sorbitol-supplemented diet to neoadjuvant chemoimmunotherapy significantly enhances therapeutic efficacy in LAGC patients while maintaining a comparable safety profile. Clinical trial information: NCT06826079 .

Local resection (LR) offers comparable prognosis to pancreaticoduodenectomy for benign and low-grade malignant duodenal tumors (DT). However, the LR rate remains low due to the difficulty in determining appropriate indications. This study aims to assess the impact of multidisciplinary team (MDT) on surgical procedure (SP) and complications in DT. Clinical data from Centers A and B between 2019 and 2023 were analyzed. Utilizing the unique setting of Center A which operated both MDT and single-discipline treatment (SDT) pathways in parallel, we compared three cohorts: A-MDT, A-SDT, and B-SDT (from Center B). Following this comparison, a multivariate logistic regression analysis was performed, collapsing the groups into MDT and SDT categories to isolate its effect on outcomes. A total of 66 patients were included in study, with 22 patients in each group. The proportion of patients undergoing LR was 91

Background Although some prospective clinical studies have shown comparable oncological outcomes between laparoscopic and open surgery for advanced gastric cancer, the 3-year recurrence-free survival rate of patients who undergo laparoscopic radical gastrectomy is lower than that of patients who undergo open radical gastrectomy. Animal experiments have also shown that laparoscopic surgery may increase the risk of peritoneal metastasis during carbon dioxide pneumoperitoneum. Previous single-centre clinical trials have confirmed that HIPEC can effectively eliminate free cancer cells, thereby improving the survival rate of patients with advanced gastric cancer. In this study, we aimed to investigate the safety and efficacy of the combination of laparoscopic gastrectomy with HIPEC in advanced gastric cancer to reduce the incidence of peritoneal metastasis. Methods A total of 616 patients will be randomly divided into 2 groups at a 1:1 ratio using central randomization after laparoscopic exploration in this prospective, randomized, controlled, open, multicentre clinical trial. The experimental arm will receive laparoscopic or robotic D2 surgery with 2 cycles of HIPEC treatment followed by 6–8 cycles of adjuvant chemotherapy, whereas the control group will undergo laparoscopic or robotic D2 surgery followed by 6–8 cycles of systemic chemotherapy. The primary endpoint for this study is 5-year recurrence-free survival. The secondary endpoints are the 5-year overall survival rate, peritoneal metastasis rate, peritoneal metastasis-free survival, regional recurrence rate, distant metastasis rate, toxicity and side effects of the treatment program. Discussion This is the first multicentre randomized controlled clinical study exploring whether HIPEC can prevent peritoneal metastasis after laparoscopic or robotic radical gastrectomy under carbon dioxide pneumoperitoneum for advanced gastric cancer. Minimally invasive surgery under carbon dioxide pneumoperitoneum can cause tremendous changes in the peritoneal microenvironment, increasing the risk of gastric cancer cell peritoneal dissemination and metastasis. In previous studies, the roles of HIPEC and laparoscopic gastrectomy for advanced gastric cancer have been confirmed. The innovation of this study lies in observing whether the combination of HIPEC can decrease the risk of peritoneal metastasis and recurrence in patients with advanced gastric cancer after laparoscopic or robotic gastrectomy under carbon dioxide pneumoperitoneum. Trial registration: The trial was registered on 14/05/2023 under clinicaltrials.gov (Identifier: NCT05871099).

Background Contemporary evidence highlights a paucity of systematic research addressing the prognostic implications of total targeted therapy duration in the neoadjuvant setting. Parallel to this, the optimal timeframe for preoperative therapy remains a subject of unresolved debate in clinical practice. In this study, we estimated the impact of total targeted therapy duration on prognosis in patients with gastrointestinal stromal tumors (GIST) undergoing neoadjuvant imatinib therapy. Methods In this nationwide study, we retrospectively analyzed the clinical data from 186 GIST patients receiving neoadjuvant imatinib therapy from January 2010 to December 2021. Clinical data including baseline characteristics, treatment pattern, treatment outcome, adverse events and survival status were collected. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and safety. Cox regression analysis was used to analyze the prognostic factors of PFS and OS. Results Among 186 patients, 149 (80.1%) were aged ≤65 years and 110 (59.1%) were male. Regarding neoadjuvant imatinib treatment duration, 59 patients (31.7%) had less than 6 months, 97 (52.2%) patients had 6 to 12 months, and 30 (16.1%) patients had more than 12 months. Multivariate Cox regression analysis indicated that residual mitotic index (>5/50 HPF: HR = 5.80, 95% CI: 2.56-13.15, P < 0.001), non-R0 resection (HR = 11.50, 95% CI: 4.71-28.08, P < 0.001), and adjuvant imatinib therapy (HR = 0.23, 95% CI: 0.07-0.74, P = 0.014) were independent prognostic factors for PFS, while residual mitotic index (>5/50 HPF: HR = 4.40, 95% CI: 1.29-15.06, P = 0.018), multivisceral resection (HR = 4.07, 95% CI: 1.09-15.19, P = 0.037), and adjuvant imatinib therapy (HR = 0.04, 95% CI: 0.01-0.17, P < 0.001) were independent prognostic factors for OS. Maximally selected log-rank analysis identified 35 months and 45 months as the optimal cut-offs for adjuvant and total targeted therapy durations, respectively. No significant difference was found in PFS and OS among patients with different neoadjuvant imatinib therapy durations (P = 0.233, P = 0.326). Conclusions Prolonged adjuvant and total targeted therapy durations correlate with improved survival in GIST patients receiving neoadjuvant imatinib, whereas neoadjuvant imatinib duration alone does not independently affect long-term outcomes. Additionally, a low residual mitotic index remains a robust histopathological predictor of favorable prognosis.

Neoadjuvant chemoimmunotherapy (NCIT) is an important treatment strategy for locally advanced gastric cancer (LAGC). Although proton pump inhibitors (PPIs) are frequently prescribed in oncology settings, their impact on the efficacy of perioperative immunotherapy remains unclear. This multicenter retrospective cohort study included 107 patients with LAGC who received NCIT followed by curative-intent gastrectomy (January 2020‒December 2023). Patients receiving potassium-competitive acid blockers were included in the PPI group. Clinicopathological characteristics, pathological response, disease-free survival (DFS), and overall survival (OS) were compared, and multivariable Cox regression models identified independent prognostic factors. The PPI group comprised 48 (44.9

Supplementary data tables, figures, and legends

Activated macrophages release macrophage extracellular traps (METs), which are a major cause of tissue damage in sepsis. However, the molecular mechanisms governing their production remain poorly characterized. In this study, we demonstrate that MET levels are markedly elevated in both the liver and circulation in a lipopolysaccharide (LPS)-induced sepsis model. The immunometabolite itaconate—a product of the enzyme aconitate decarboxylase 1 (Acod1)—emerged as a critical suppressor of this pathway. Genetic ablation of immune responsive gene 1 (Irg1) resulted in heightened MET release, exacerbated hepatic injury, and decreased survival in septic mice. In contrast, the itaconate derivative 4-octyl itaconate (4-OI) robustly suppressed MET formation and ameliorated liver damage. Mechanistically, 4-OI activated the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in scavenging of intracellular reactive oxygen species (ROS), which suppressed ROS-dependent activation of peptidylarginine deiminase 4 (PAD4), thereby inhibiting histone citrullination and subsequent MET release. The suppression of MET formation by 4-OI is mediated through an Nrf2-dependent mechanism, as its absence abolishes this suppression, revealing the Nrf2–ROS–PAD4 axis's key role. The findings reveal a new metabolic-immune pathway: itaconate reduces sepsis-linked liver injury by using Nrf2 to suppress METs, suggesting a novel clinical treatment approach.