Colorectal cancer (CRC) remains a major global health burden with limited therapeutic options. This study identifies phosphomannomutase 2 (PMM2) as a key oncogenic driver in CRC. PMM2 is significantly upregulated in CRC tissues and cell lines, correlating with advanced tumor stages, lymphatic metastasis, and poor patient survival. Functional assays reveal that PMM2 knockdown inhibits CRC cell proliferation, migration, invasion, and glycolytic activity (reducing glucose uptake, ATP/lactate production, and extracellular acidification rate). Mechanistically, PMM2 interacts with transcriptional regulator TRIM28, promoting TRIM28 nuclear translocation, recruiting transcription factor E2F4, and enhancing KIFC3 transcription by binding to its promoter. KIFC3 mediates PMM2-driven glycolysis, as KIFC3 knockdown partially reverses PMM2-induced metabolic reprogramming and tumor growth in xenograft models. Patient-derived organoid studies further confirm PMM2’s role in promoting CRC progression through the PMM2-KIFC3 axis. Collectively, these findings establish PMM2 as a prognostic biomarker and potential therapeutic target in CRC, highlighting its critical role in metabolic reprogramming and tumorigenesis.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, yet chemotherapy resistance, tumor recurrence, and systemic toxicity limit current therapies. Here, we developed a multimodal Cu2-xSe@ZIF-8-crizotinib (CSZC) nanoplatform that integrates chemosensitization, photodynamic therapy (PDT), and self-sustaining chemodynamic therapy (CDT). The core-shell structure, consisting of ultrafine Cu2-xSe nanocrystals confined within a ZIF-8 framework, enables efficient crizotinib loading through mesoporous confinement and it-it interactions. Under near-infrared (808 nm) irradiation, photocatalysis converts O2 into cytotoxic singlet oxygen (1O2), inducing mitochondrial dysfunction and DNA damage. Meanwhile, the acidic tumor microenvironment triggers ZIF-8 degradation, promoting Cu+/Cu2+-mediated Fenton-like conversion of H2O2 into hydroxyl radicals (& sdot;OH). Concurrently, released crizotinib inhibits ALK/ROS1 signaling and enhances ROS-induced endoplasmic reticulum stress, forming a drug-sensitization/ROS-amplification feedback loop. This PDT-CDT-chemotherapy synergistic strategy provides an effective approach to enhance chemosensitivity and antitumor efficacy in CRC.

Colorectal cancer (CRC), a common and lethal malignancy, has been a major global health challenge, as current clinical treatments are constrained by poor precision, severe side effects, and the complex tumor microenvironment. It is noteworthy that nanotechnology has brought about significant breakthroughs in traditional medicine, enabling the development of intelligent nanoscale systems tailored to specific requirements to overcome the drawbacks of clinical CRC treatments. Herein, a versatile nanotherapeutic agent is developed via integrating superparamagnetic iron oxide (SPIO) nanoparticles (NPs), carbon (C) intermediate layer, and outermost polydopamine (PDA) layer for CRC therapy. The as-designed SPIO@C@PDA NPs effectively serve as a photothermal therapy (PTT) agent for thermal ablation and a carrier for cisplatin delivery. The combination of PTT and chemotherapy holds promise in overcoming the limitations of monotherapy, which can avoid the administration of high-dose cisplatin, mitigate side effects, and achieve synergistic antitumor effectiveness. Hence, this innovative platform leverages the combination of functional materials to eradicate CRC and validate the feasibility of synergistic chemo-photothermal therapy.

The ketogenic diet (KD), an emerging nutritional intervention for cancer, reprograms cellular energy metabolism from glucose to ketone bodies, including acetoacetate (AcAc), acetone (Ac), and β-hydroxybutyrate (BHB). However, the mechanisms connecting ketone body signal sensing to tumor growth suppression remain elusive. Here, we show that RagC, a key component of mTORC1 pathway, senses BHB but not AcAc and Ac, to dictate tumor suppression. KD-derived BHB inhibits mTORC1 activity by promoting β-hydroxybutyrylation (Kbhb) of RagC at lysine 349 (K348 in mice). Mechanistically, RagC-K349bhb is dynamically catalyzed by p300 and erased by SIRT1, disrupting RagC interaction with Raptor/mTOR and blocking mTORC1 recruitment to lysosomes. Clinically, BHB-mediated RagC-K349bhb suppresses colorectal cancer (CRC) growth via mTORC1 inhibition in both RagC-K348R knockin mice and CRC patient-derived samples. Thus, we identify a BHB sensing mechanism by mTORC1 and highlight the potential role of RagC-K349bhb as a therapeutic target for BHB-based CRC treatment.

BACKGROUND:Three-dimensional (3D) self-assembly of organoids or tumoroids based on 3D rebuilding environment (3DRE) aims to preserve the biological characteristics of original tumors, but whether the self-assembly process is influenced by 3DREs remains unknown. We here compared the colorectal cancer (CRC) tumoroids cultured using different 3DREs, including dome culture (DG), ultra-low adherence culture without Matrigel(UA) or with Matrigel (UAG), and hanging-drop without Matrigel (HD) and with Matrigel (HDG). METHODS:CRC cells were cultured to form tumoroids using DG, UA, UAG, HD, and HDG, respectively. The differences between these tumoroids were examined using light observation, histological staining, RNA sequencing, and drug sensitivity testing. RESULTS:The CRC cells aggregated with each other and formed larger, converged tumoroids in the UA and the HD compared to the Matrigel. Histochemical examination revealed that the tumoroids maintained the CRC-specific characteristics of forming lumens and biomarkers, but the number of lumens decreased, and the cell arrangement was in disorder with increasing impetus of 3DREs that promote cell aggregation ranging from DM, UA to HD. RNA sequencing revealed that the tumoroids retained a similar gene expression pattern, but the oncogenes related to metastasis and poor prognosis were upregulated, and development and morphogenesis-related genes were downregulated when cultured in the UA and HD compared to the Matrigel. However, the drug sensitivity test showed that the tumoroids, regardless of the methods they were derived, maintained similar sensitivity to drugs. CONCLUSIONS:We demonstrated that CRC tumoroids developed towards disordered self-assembly in adaptation to the environment without a matrix, but this adaptation did not alter tumor-specific phenotypes and drug sensitivity.

Interleukin (IL)-15 is critical for intestinal homeostasis, but the precise origin and functions of IL-15 involved in inflamed mucosal healing are not fully understood. This study demonstrated that IL-15/IL-15Rα signaling was up-regulated during wound healing in 5-fluorouracil (5-FU)-induced intestinal mucositis. Moreover, a subset of podoplanin+ stromal cells located adjacent to crypts were the primary cellular source of IL-15 following gut damage. Stroma-specific IL-15 proved to be crucial for the regeneration of damaged intestine. The deletion of IL-15Rα in intestinal epithelial cells compromised the recovery from intestinal injury. Moreover, compared with IL-15, IL-15/IL-15Rα complex can more efficiently promote intestinal epithelial repair. When stimulating human-derived ileal organoids, IL-15/IL-15 complex induced epithelial proliferation through an STAT3-HIF-1α signaling axis and afforded protection against 5-FU-induced epithelial damage. These findings innovatively demonstrated that stroma-specific IL-15 coordinates epithelial IL-15Rα to accelerate wound healing in response to gut damage.

Combination regimens of immunotherapy and chemotherapy have become the standard treatment for HER2-negative advanced gastric cancer (AGC). Here, we evaluate the therapeutic efficacy of first-line treatment regimens across different PD-L1 expression, circulating tumor DNA (ctDNA) and T-cell receptor (TCR). This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression. In the CPS < 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (p = 0.04) and ORR (p = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50

e16082 Background: The relative high recurrence rate in locally advanced gastric or gastroesophageal junction (G/GEJ) cancer with Her2 overexpression after surgery, along with the absence of a standard neoadjuvant treatment protocol, necessitates exploration of novel approaches for this patient population. Methods: In this study, we conducted a retrospective analysis of clinical characteristics, postoperative pathological results, and survival data for patients who underwent neoadjuvant treatment and subsequent surgery at our center from September 2020 to December 31, 2022. The inclusion criteria were as follows: 1) pathologically confirmed adenocarcinoma of the G/GEJ; 2) diagnosed as cT3-4 or N+ by enhanced CT and endoscopic ultrasound; 3) Her2 immunohistochemistry 3+ or 2+ with Fish positive in biopsy specimens; 4) discussed in a multidisciplinary team for the need for neoadjuvant treatment; 5) received 2-4 cycles of neoadjuvant therapy; 6) underwent radical D2 surgery; 7) had complete follow-up data. Results: Seventy-three patients met the inclusion criteria, with 19 receiving chemotherapy + anti-PD-1, 10 receiving chemotherapy + anti-Her2, and 44 receiving chemotherapy alone. Their pCR rates were 31.6%, 10%, and 2.3%, respectively (P = 0.003); MPR rates were 42.1%, 30%, and 11.4% (P = 0.022). As of the last follow-up on December 31, 2023, the median DFS for the chemotherapy group was 18.1 months (95% confidence interval 14.9-21.3); median DFS for the other two groups had not been reached. DFS analysis revealed differences in median DFS among different neoadjuvant treatment regimens (P = 0.025); further pairwise comparisons indicated that this difference mainly stemmed from the chemotherapy + anti-Her2 group compared to the chemotherapy group. Conclusions: In locally advanced gastric and gastroesophageal junction cancer with Her2 overexpression, neoadjuvant chemotherapy combined with anti-Her2 treatment improves the pCR rate and prolongs DFS compared to neoadjuvant chemotherapy alone.

Background & aims: Malnutrition is prevalent among hospitalised patients, and increases the morbidity, mortality, and medical costs; yet nutritional assessments on admission are not routine. This study assessed the clinical and economic benefits of using an artificial intelligence (AI)-based rapid nutritional diagnostic system for routine nutritional screening of hospitalised patients. Methods: A nationwide multicentre randomised controlled trial was conducted at 11 centres in 10 provinces. Hospitalised patients were randomised to either receive an assessment using an AI-based rapid nutritional diagnostic system as part of routine care (experimental group), or not (control group). The overall medical resource costs were calculated for each participant and a decision-tree was generated based on an intention-to-treat analysis to analyse the cost-effectiveness of various treatment modalities. Subgroup analyses were performed according to clinical characteristics and a probabilistic sensitivity analysis was performed to evaluate the influence of parameter variations on the incremental cost-effectiveness ratio (ICER). Results: In total, 5763 patients participated in the study, 2830 in the experimental arm and 2933 in the control arm. The experimental arm had a significantly higher cure rate than the control arm (23.24% versus 20.18%; p 1/4 0.005). The experimental arm incurred an incremental cost of 276.52 CNY, leading to an additional 3.06 cures, yielding an ICER of 90.37 CNY. Sensitivity analysis revealed that the decisiontree model was relatively stable. Conclusion: The integration of the AI-based rapid nutritional diagnostic system into routine inpatient care substantially enhanced the cure rate among hospitalised patients and was cost-effective. Registration: NCT04776070 (https://clinicaltrials.gov/study/NCT04776070). (c) 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Adoptive cell therapy (ACT) has revolutionized the treatment of patients with cancer. The success of ACT depends largely on transferred T cell status, particularly their less-differentiated state with stem cell-like properties, which enhances ACT effectiveness. Stem cell-like memory T (TSCM) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. TSCM cells are promising candidates for cancer immunotherapies, whereas maintenance of a more stem-cell-like state before transfer is challenging. Here, we established a highly efficient protocol for generating CD8+ TSCM cells from peripheral blood mononuclear cells (PBMCs). The process involved activating PBMCs using anti-CD3 monoclonal antibody and RetroNectin, followed by a transient-resting culture period (24 h) and subsequent long-term expansion in vitro with interlukien-2. We report that this transient-resting culture after activation preserves CD8+ T cells in a stem memory phenotype (CD95+ CD45RA+ CCR7+) compared to the conventional culture method. Further, this approach reduces the expression of T cell immunoglobulin mucin-3, an exhaustion marker, and increases the expression of T cell factor-1, a master regulator of stemness even after long-term culture compared to the conventional culture method. In conclusion, our study presents a simplified and cost-effective method for generating and expanding CD8+ TSCM cells ex vivo. This approach streamlines the optimization of cancer immunotherapy using ACT.

BackgroundMetastatic gastric cancer (MGC) patients with progression on first-line treatment still have poor outcomes on chemotherapy. The KEYNOTE-061 study demonstrated that pembrolizumab, a PD-1inhibitor, was not better than paclitaxel as second-line therapy for MGC. Herein, we explored the efficacy and safety of PD-1inhibitor based treatment for MGC patients in the second line.MethodsIn this observational, retrospective study, we enrolled MGC patients treated with anti-PD-1 based therapy as second-line in our hospital. We primarily assessed the treatment’s efficacy and safety. We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses.ResultsWe enrolled 129 patients with an objective response rate (ORR) of 16.3% and a disease control rate (DCR) of 79.1%. Patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents had ORR of 19.6% and higher DCR of 94.1%. The median progression-free survival (PFS) was 4.10 months, and the median overall survival (OS) was 7.60 months. In univariate analysis, patients treated with PD-1inhibitor combined with chemotherapy and anti-angiogenic agents and with prior anti-PD-1 history were significantly associated with favorable PFS and OS. In the multivariate analysis, different combination therapy and prior anti-PD-1 history were independent prognosis biomarkers for PFS and OS. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 28 (21.7%) patients. Common adverse events (AEs) included fatigue, hyper/hypothyroidism, neutrophil decrease, anemia, skin reactions, proteinuria, and hypertension. We did not observe treatment-related deaths.ConclusionOur current results indicated that PD-1-inhibitor and chemo-anti-angiogenic agents combination therapy and prior PD-1 treatment history might improve clinical activity for GC immunotherapy as second-line treatment with acceptable safety profiles. Further studies are needed to verify those outcomes for MGC in other centers.

Abstract Background Previous investigations suggest that systemic inflammation markers are able to provide prognostic value in several cancers. This study seeks to characterize the ability of pretreatment platelet-to-lymphocyte ratio (PLR) to prognosticate advanced or metastatic gastric cancer patients (AGC or MGC, respectively) receiving immunotherapy. Methods AGC and MGC patients exposed to PD-1 inhibitors from January 2016–August 2021 in the Chinese PLA General Hospital were recruited. Correlations between PLR and overall survival (OS), progression-free survival (PFS), and immunotherapy-associated tumor response rates were determined. Results 237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42–0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43–0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05). Conclusions Pre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.

Background: Ovarian clear cell carcinoma (OCCC), which is resistant to traditional treatment, has a poor prognosis. Immune checkpoint inhibitors (ICIs) have been emerged in the past decade and are now widely used in clinics. However, OCCC reportedly responds poorly to ICIs, and ICI monotherapy is rarely used for patients with OCCC. Methodology & Results: We report the case of a patient with refractory OCCC who received an ICI (nivolumab) monotherapy treatment and achieved a complete response despite the occurrence of pseudoprogression. Nivolumab was discontinued after 2 years, and the patient remained in complete remission more than a year after treatment withdrawal. Conclusion: This is the first report of complete remission being achieved in a case of refractory OCCC after pseudoprogression during nivolumab monotherapy.

e16024 Background: Immune checkpoint inhibitors have been approved for first- or third-line treatment of metastatic gastric cancer. However, pembrolizumab alone did not improve overall survival compared to second-line chemotherapy in the KEYNOTE-061 study. We aimed to explore the safety and efficacy of a three-drug regimen by carrying out a clinical study of PD-1 inhibitor combined with albumin paclitaxel and apatinib (VEGFR inhibitor) in the second-line treatment for patients with metastatic gastric cancer(mGC). Methods: This study was a single-center, single-arm phase II clinical study. patients harboring microsatellite stable (MSS) who had previously failed in first-line treatment were enrolled. The enrolled patients were given PD-1 inhibitor (PD-1 inhibitor selected according to the patients’ requirements) in combination with albumin paclitaxel (125 mg/m2 IV, D1, 8 days or 250 mg/m2 IV, D1, 250 mg and apatinib 250 or 500 mg orally for D1-21 days, every 3 weeks as a cycle). The primary endpoints were progression-free survival (PFS) and objective response rate (ORR), while the secondary endpoints were overall survival (OS) and safety (AEs), disease control rate (DCR). Results: From July 11, 2019 to December 1, 2021, a total of 23 patients were enrolled, of whom 10 had negative PD-L1 expression, 1 had PD-L1 > 70% expression, and 4 had positive PD-L1 expression. Preliminary results showed 8 cases had partial response (PR), 10 cases had stable disease (SD), and 5 cases of progression disease (PD). ORR was 34.8% and DCR was 78.3%. The median PFS was 5.04 m, and the median OS was not reached. The main adverse reactions of grade 1 to 2 were bone marrow suppression (42.8%), hand-foot reaction (21.4%), hypertension (21.4%), gastrointestinal bleeding (13.0%), hypothyroidism (8.7%), and liver function damage (8.7%). No grade 3-4 adverse reactions were reported. Conclusions: PD-1 inhibitor combined with albumin paclitaxel and apatinib in the second-line treatment of metastatic gastric cancer showed certain efficacy and safety. At present, this study is ongoing to further confirm the anti-tumor effect and survival benefit of this regimen. Clinical trial information: NCT04182724.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-018-0783-3.

Background Fruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients. Methods A total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated. Results Among the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported. Conclusions Fruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.

BackgroundThere are limited treatment options for advanced biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer. We compared the efficacy and safety of PD-1 inhibitors plus chemotherapy and chemotherapy alone as first-line treatment in patients with advanced BTC.MethodsWe retrospectively reviewed patients with BTC treated at the oncology department of the Chinese PLA general hospital receiving PD-1 inhibitor with chemotherapy (anti-PD-1+C group) or chemotherapy alone (C group). Propensity Score Matching (PSM) (1:1) was performed to balance potential baseline confounding factors. Progression-free survival (PFS) was analyzed using Kaplan–Meier survival curves with log-rank tests. Objective response rate (ORR), disease control rate (DCR), and safety were also analyzed.ResultsThis study included 75 patients who received PD-1 inhibitors (including Pembrolizumab, Nivolumab, Sintilimab, Toripalimab) plus chemotherapy and 59 patients who received chemotherapy alone. After matching, there were no significant differences between the two groups for baseline characteristics. Within the matched cohort, the median PFS was 5.8m in the anti-PD-1+C group, which was significantly longer than the C group, at 3.2m (HR: 0.47, 95% CI 0.29 to 0.76, P = 0.004). The ORR was 21.7% and DCR was 80.4% in the anti-PD-1+C group, while the ORR was 15.2% and DCR was 69.6% in the C group. No significant differences were found in the ORR and DCR between the two groups (P=0.423, P=0.231). Grade 3 or 4 treatment was related to adverse events (AEs) that occurred in the anti-PD-1+C group, namely hypothyroidism (n=3, 6.5%), rash (n=2, 4.2%), and hepatitis (n=1, 2.2%). There was no AE-related death. The grade 3-4 leukopenia rate was similar in the two groups (4.3% vs. 6.5%).ConclusionsAnti-PD-1 therapy plus chemotherapy prolonged the PFS compared with chemotherapy alone in advanced BTC with controllable AEs. Further clinical trials are needed to confirm this result.

Background Biomarkers such as prevailing PD-L1 expression and TMB have been proposed as a way of predicting the outcome of immunotherapy in patients with advanced gastric cancer (AGC) and metastatic gastric cancer (MGC). Our study aims to investigate whether there is a link between pretreatment hemoglobin (Hb) levels and survival to immunotherapy in patients with AGC and MGC. Methods We retrospectively reviewed patients with AGC or MGC treated at the oncology department of the Chinese PLA general hospital receiving PD-1 inhibitor. The Propensity Score Matching (PSM) (1:1) was performed to balance potential baseline confounding factors. Progression-free survival (PFS) and overall survival (OS) was analyzed among different Hb level (normal Hb group and decreased Hb group). Objective response rate (ORR), disease control rate (DCR) were also analyzed. Univariate analysis and multivariate analysis were performed further to validate the prognostic value of Hb level. Results We included 137 patients with AGC and MGC who received PD-1 inhibitors (including Pembrolizumab, Nivolumab, Sintilimab, Toripalimab) in this study. After PSM matching, there were no significant differences between the two groups for baseline characteristics. Within the matched cohort, the median PFS was 7.8 months in the normal Hb level group and 4.3 months in the decreased Hb group (HR 95% CI 0.5(0.31, 0.81), P=0.004). The OS was 14.4 months with normal Hb level as compared with 8.2 months with decreased Hb level(HR 95% CI 0.59(0.37, 0.94), P=0.024). The ORR was 40.7% and DCR was 83.0% in the normal Hb group, while the ORR was 25.5% and DCR was 85.1% in the decreased Hb group. No significant differences were found in the ORR and DCR between the two groups (P=0.127, P=0.779). Univariate analysis and multivariate analysis showed that Hb level was only independent predictor for PFS and baseline Hb level was significant prognostic factor influencing the OS. Only when patients had normal Hb level, anti-pd-1 monotherapy or combined with chemotherapy was superior to anti-pd-1 plus anti-angiogenic therapy with respect to PFS (10.3 m vs 2.8 m, HR 95% CI 0.37(0.15, 0.95), P=0.031) and OS(15 m vs 5.7 m, HR 95% CI 0.21 (0.08, 0.58), P=0.001). Conclusions Our study have demonstrated that pretreatment Hb level was an independent prognostic biomarker in term of PFS and OS with immunotherapy for AGC and MGC patients. Correction of anemia for GC patients as immunotherapy would be a strategy to improve the survival. More data was warranted to further influence this finding.

Background PD-1/PD-L1 inhibitors have made remarkable achievements in the field of tumor treatment. However, most patients do not benefit from PD-1/PD-L1 inhibitor therapy, and some patients experience adverse reactions. Therefore, finding ideal prognostic indicators to predict the efficacy of PD-1/PD-L1 inhibitors and selecting populations that can potentially benefit clinically are crucial. The purpose of this retrospective analysis was to investigate the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients with advanced tumors using PD-1 inhibitors to identify patients who may have a better response to PD-1 inhibitors. Methods The clinical data of 121 patients with advanced cancer at the Affiliated Tumor Hospital of Zhengzhou University were retrospectively analyzed. The receiver operating characteristic (ROC) curve was used to determine the best cutoff value of the LMR, and subsequently, the patients were divided into high- and low-LMR groups. Kaplan-Meier and log-rank tests were used to draw survival curves. Univariate and multivariate analyses used Cox proportional hazard regression models to assess the association between the LMR and overall survival (OS) or progression-free survival (PFS). Results The ROC curve showed that the areas under the curve at baseline and 6 weeks after anti-PD-1 antibody treatment LMR (LMR-week 1 and LMR-week 6, respectively) were 0.593 (P=0.164) and 0.713 (P=0.002), respectively. The optimal cutoff value of LMR-week 6 was 4.15, and in a total of 121 patients, 66 and 55 presented with LMR-week 6 <4.15 and ≥4.15, respectively. A low LMR-week 6 was associated with poor OS and PFS (P<0.001). The multivariate analysis showed that the independent factors related to OS were Eastern Cooperative Oncology Group (ECOG) performance status and LMR-week 6, and the independent factors related to PFS were smoking history, ECOG performance status, and LMR-week 6. The objective response rates (ORR) in the high- and low-LMR-week 6 groups were 32.7% and 7.6%, respectively, and were associated with elevated LMR-week 6 (P<0.001). Conclusions LMR-week 6 is significantly related to the effect of anti-PD-1 antibody treatment; therefore, LMR-week 6 can be used as an early surrogate indicator for stratification in patients who respond better to anti-PD-1 drugs.

RNA结合模体蛋白(RBM)家族几乎在所有细胞中均有表达,而且在进化上高度保守.以前的研究表明,RBM5在膀胱尿路上皮癌(bladder urothelial carcinoma,BUC)组织中表达下调,由此引起的细胞凋亡减少,进而促进肿瘤的进展.然而,RBM5氨基酸序列与其同源的RBM6在膀胱尿路上皮癌中的作用及相关机制尚不清楚.本研究检测RBM6在膀胱尿路上皮癌中的表达,探索其在膀胱癌细胞系中过表达对细胞增殖和凋亡的影响.利用qRT-PCR和Western印迹等技术,研究发现,RBM6在人膀胱尿路上皮癌组织和所检测的2个膀胱癌细胞系中表达均显著下调,并且其下调程度与患者的预后不良呈正相关.MTS检测细胞增殖的结果显示,RBM6过表达导致细胞增殖活性下降.细胞克隆形成实验结果也表明,RBM6过表达抑制细胞克隆形成能力(P＜0.01).原位末端转移酶标记技术(terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay,TUNEL染色)检测细胞凋亡表明,在RBM6过表达的细胞中,TUNEL阳性细胞数由对照组的17.17±3.27增加到44.00±8.04(P＜0.05).RBM6抗增殖及促凋亡的作用机制研究发现,在T24细胞中过表达RBM6后,β-联蛋白(β-catenin)和G1/S-特异性细胞周期蛋白-D1(G1/S-specific cyclin-D1,cyclin D1) mRNA表达水平分别降低65％和79％,对应的蛋白质水平分别降低60％和73％;反之,细胞周期蛋白依赖性激酶抑制因子1A (cyclin dependent kinase inhibitor 1A,CDKN1A/p21) mRNA表达水平升高约1.9倍,对应蛋白质水平升高约1.8倍.重要的是,糖原合酶激酶3beta(glycogen synthase kinase-3 beta,GSK-3β)磷酸化水平升高约2.4倍.细胞过表达β-联蛋白促进细胞增殖(P＜0.05),而利用小分子化合物LY294002促进GSK-3β磷酸化后,抑制细胞增殖(P＜0.05).综上所述,RBM6通过GSK-3β/β-catenin调节途径对膀胱尿路上皮癌细胞发挥抗增殖和促进凋亡作用.干预该调节途径可能是治疗膀胱尿路上皮癌的潜在靶点.