Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune chec...Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.展开更多
Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell dea...Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.展开更多
Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and com...Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.展开更多
In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhanc...In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.展开更多
Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Method...Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.展开更多
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of h...BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-rel...BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.展开更多
BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concur...BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.展开更多
To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regu...To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.展开更多
BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascula...BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascular drugs used alone or in combination.The pathogenesis of AVB in this population may involve tumor-related factors,treatment-induced effects,or progression of underlying portal hypertension.Identifying high-risk factors for AVB is crucial for the management of this patient population.AIM To develop and validate a risk prediction model for AVB occurrence in cirrhotic HCC patients receiving ICI-based systemic therapy.METHODS This retrospective study analyzed 286 HCC patients(2021-2022)receiving ICIs(mono-/combination therapy),randomly split into training(n=184)and validation(n=102)cohorts.In the training cohort,bleeding vs nonbleeding groups were compared for general information,etiological data,laboratory indicators,tumor staging,systemic treatment drugs,variceal bleeding history,and endoscopic treatment history.Risk factors for AVB were identified and used to establish a logistic regression model for predicting bleeding,which was further validated in the validation cohort.RESULTS The bleeding group had significantly higher proportions of patients with platelet count≥100×10^(9)/L,alphafetoprotein≥400 ng/mL,tumor diameter≥5 cm,portal vein tumor thrombosis,ascites,bleeding history,prior endoscopic treatment,albumin-bilirubin grade level 2-3,fibrosis-4 index(FIB-4)≥4.57,and prognostic nutritional index<45 compared to the non-bleeding group.Multivariate analysis identified tumor diameter≥5 cm,portal vein thrombosis,bleeding history,and elevated FIB-4 as independent risk factors for bleeding(P<0.05).A predictive model based on these factors showed good discrimination,with area under the receiver operating characteristic curve values of 0.861(training)and 0.816(validation).CONCLUSION A history of pre-ICI bleeding significantly increases recurrent bleeding risk,necessitating close monitoring.The FIB-4 fibrosis model,combined with tumor features,can also serve as a predictive factor for bleeding.展开更多
BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as le...BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.展开更多
Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune ...Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.展开更多
Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs sele...Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.展开更多
BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of a...BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC,we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.AIM To evaluate the value of postoperative combined therapy(PCT)with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included.Recurrence-free survival(RFS)and overall survival were assessed using propensity score matching and inverse probability of treatment weighting.Cox regression analysis was used to identify factors affecting recurrence,and subgroup analysis was conducted to investigate the impact of medications on different populations.Treatment-related adverse events and liver function measurements were evaluated.RESULTS A total of 150 patients were recruited,of whom 30 underwent PCT and 120 did not.After adjusting for confounders,patients who underwent PCT had better RFS at 6 and 12 months than those who did not(P>0.05).Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting,although the difference was not statistically significant(P>0.05).A maximum diameter of>5 cm,vascular invasion,satellite nodules,and high gamma-glutamyl transferase levels were independent risk factors for recurrence(P<0.05).No significant interaction effects were observed in subgroup analyses.The most prevalent adverse event was hypertension(66.7%).PCT was associated with an increased risk of hepatic impairment which may predict RFS rates(P=0.041).CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT.Hepatic impairment during treatment may indicate recurrence,and close monitoring of liver function and HBV infection is recommended.展开更多
Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or e...Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or exacerbation after receiving immune checkpoint inhibitors(ICIs).A European multicenter study has reported a reactivation rate of 28.7%in this population3.ICIs also trigger de novo psoriatic lesions,which mirror conventional lesion subtypes(plaque,guttate,erythrodermic,or pustular).展开更多
BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings....BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings.The combination of targeted therapies with immune checkpoint inhibitors(ICIs)has shown potential in addressing the limitations of single-agent treatments.AIM To evaluate the efficacy and safety of targeted therapy(TT)alone and in combination with ICIs for metastatic CRC(mCRC).METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC.A total of 99 patients treated with regorafenib or fruquintinib,with or without ICIs,were enrolled.Propensity score matching(PSM)and inverse probability weighting(IPW)were employed to balance baseline characteristics.The primary endpoint was progression-free survival(PFS),while overall survival(OS)and safety were secondary.RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses(original:6.0 vs 3.4 months,P<0.01;PSM:6.15 vs 4.25 months,P<0.05;IPW:5.6 vs 3.3 months,P<0.01).Although the median OS showed a trend toward improvement in the combination group,the difference was insignificant.Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression(hazard ratio=0.38,P<0.001).Adverse events(AEs)were generally manageable with both regimens,while serious AEs(grade 3-4)were primarily hypertension,fatigue,and reduced platelet counts.All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug,and no treatment-related deaths were observed.CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC,accompanied by a favorable safety profile.These findings underscore the benefits of combination therapy in this setting,warranting further investigation in larger prospective clinical trials.展开更多
Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitor...Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.展开更多
Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited surviv...Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.展开更多
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金supported by the National Natural Science Foundation of China(Grant Nos.82203539 and 92259102)Provincial Cooperation Project of Science and Technology Department of Sichuan Province(Grant No.2023YFSY0043)the National Key Research and Development Program of China(Grant No.2023YFC3402100).
文摘Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Natural Science Foundation of China(Nos.81672791 and 81872300)+2 种基金the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute and Qilu Group.
文摘Immunological evasion is one of the defining characteristics of cancers,as the immune modification of an immune checkpoint(IC)confers immune evasion capabilities to tumor cells.Multiple ICs,such as programmed cell death protein-1(PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),can bind to their respective receptors and reduce tumor immunity in a variety of ways,including blocking immune cell activation signals.IC blockade(ICB)therapies targeting these checkpoint molecules have demonstrated significant clinical benefits.This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers.Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment.In this review,we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels,including epigenetic regulation,transcriptional regulation,and post-translational modifications.In addition,we provide a summary of the medications targeting various nodes in the regulatory pathway,and highlight the potential of newly identified IC molecules,focusing on their potential implications for cancer diagnostics and immunotherapy.
文摘Survival rates for metastatic lung cancer, including non-small cell lung cancer （NSCLC） and small cell lung cancer （SCLC）, are poor with S-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system-- with its capacity for memory, exquisite specificity and central and universal role in human biology--immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.
文摘In the interaction between a tumor and the immune system,immune checkpoints play an important role,and in tumor immune escape,co-inhibitory immune checkpoints are important.Immune checkpoint inhibitors(ICIs)can enhance the immune system's killing effect on tumors.To date,impressive progress has been made in a variety of tumor treatments;PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors.However,glioblastoma(GBM)still lacks an effective treatment.Recently,a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab.Therefore,the use of immune checkpoints in the treatment of GBM still faces many challenges.First,to clarify the mechanism of action,how different immune checkpoints play roles in tumor escape needs to be determined;which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined.Second,to optimize combination therapies,how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed.All of these concerns require extensive basic research and clinical trials.In this study,we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments,summarized the state of ICIs in preclinical studies and clinical trials involving GBM,and speculated on the therapeutic prospects of ICIs in the treatment of GBM.
基金supported by the National Natural Science Foundation of China(No.81602104).
文摘Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.
基金This study was approved by the ethics committee of the First People’s Hospital of Fuzhou City(No.FZ202103).
文摘BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
文摘BACKGROUND Esophageal cancer is a serious global health concern with poor prognosis in advanced stages.Immune checkpoint inhibitors(ICIs)have shown promise in enhancing survival,but they are associated with immune-related adverse events,including potentially life-threatening myocarditis.Moreover,ICI-induced myocarditis can be asymptomatic,necessitating early diagnosis.Specific risk factors and biomarkers for esophageal cancer remain poorly characterized.AIM To investigate the determinants of ICI-associated asymptomatic myocarditis in patients with esophageal cancer and explore potential early biomarkers.METHODS A retrospective analysis was conducted on 202 cancer patients who received treatment at Shanxi Province Cancer Hospital from July 2019 to July 2024.RESULTS Older age,male gender,and elevated creatine kinase isoenzymes(CK-MB)and CK levels were found to be significant risk factors for asymptomatic myocarditis.The myocarditis occurrence group had higher CK-MB(3.05 ng/mL vs 5.02 ng/mL;P<0.001)and CK levels(187.29 U/L vs 212.25 U/L;P=0.005),and the predictive value of age,gender,CK,and CK-MB was low[are under the receiver operating characteristic curve(AUC)=0.579-0.608].However,their combination in a predictive model showed improved diagnostic capability,with an AUC of 0.808.CONCLUSION Age,gender,and cardiac biomarker levels considerably contribute to the risk of ICI-related myocarditis in patients with esophageal cancer.The integration of these factors into a predictive model enhances early diagnosis,facilitating personalized risk management.
文摘BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.
基金supported by Jiangsu Commission of Health(No.x202308)The Suzhou Gusu Health Talents Scientific Research Project(No.GSWS2021052).
文摘To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.
基金Supported by Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-034AHebei Province 2025 Traditional Chinese Medicine Scientific Research Project Plan,No.T2025008.
文摘BACKGROUND Acute variceal bleeding(AVB)represents a life-threatening complication in hepatocellular carcinoma(HCC)patients undergoing systemic therapy,mainly including immune checkpoint inhibitors(ICIs)and antivascular drugs used alone or in combination.The pathogenesis of AVB in this population may involve tumor-related factors,treatment-induced effects,or progression of underlying portal hypertension.Identifying high-risk factors for AVB is crucial for the management of this patient population.AIM To develop and validate a risk prediction model for AVB occurrence in cirrhotic HCC patients receiving ICI-based systemic therapy.METHODS This retrospective study analyzed 286 HCC patients(2021-2022)receiving ICIs(mono-/combination therapy),randomly split into training(n=184)and validation(n=102)cohorts.In the training cohort,bleeding vs nonbleeding groups were compared for general information,etiological data,laboratory indicators,tumor staging,systemic treatment drugs,variceal bleeding history,and endoscopic treatment history.Risk factors for AVB were identified and used to establish a logistic regression model for predicting bleeding,which was further validated in the validation cohort.RESULTS The bleeding group had significantly higher proportions of patients with platelet count≥100×10^(9)/L,alphafetoprotein≥400 ng/mL,tumor diameter≥5 cm,portal vein tumor thrombosis,ascites,bleeding history,prior endoscopic treatment,albumin-bilirubin grade level 2-3,fibrosis-4 index(FIB-4)≥4.57,and prognostic nutritional index<45 compared to the non-bleeding group.Multivariate analysis identified tumor diameter≥5 cm,portal vein thrombosis,bleeding history,and elevated FIB-4 as independent risk factors for bleeding(P<0.05).A predictive model based on these factors showed good discrimination,with area under the receiver operating characteristic curve values of 0.861(training)and 0.816(validation).CONCLUSION A history of pre-ICI bleeding significantly increases recurrent bleeding risk,necessitating close monitoring.The FIB-4 fibrosis model,combined with tumor features,can also serve as a predictive factor for bleeding.
基金Supported by the Capital’s Funds for Health Improvement and Research,No.SF202222175.
文摘BACKGROUND The CRAFITY score is mainly utilized for hepatocellular carcinoma(HCC)patients receiving atezolizumab and bevacizumab,with little investigation in its predictive capacity for alternative regimens,such as lenvatinib and programmed cell death protein 1(PD-1)inhibitors,which are widely utilized in Chinese clinical practice.AIM To look at the predictive significance of the CRAFITY score in HCC patients taking lenvatinib and PD-1 inhibitors.METHODS The retrospective investigation consisted of 192 patients with incurable HCC who received lenvatinib and PD-1 inhibitors between January 2018 and January 2022.Patients were stratified according to CRAFITY score(based on baseline alphafetoprotein and C-reactive protein levels)into CRAFITY-low,CRAFITY-intermediate,and CRAFITY-high groups.Overall survival(OS)and progressionfree survival(PFS)were assessed using Kaplan-Meier analysis,and independent prognostic factors were identified through Cox regression analysis.Nomograms were created to forecast survival for a year.RESULTS The median PFS and OS were the longest for patients in the CRAFITY-low group,followed by those in the CRAFITY-intermediate and CRAFITY-high groups(median PFS:8.4 months,6.0 months,and 3.1 months,P<0.0001;median OS:33.4 months,19.2 months,and 6.6 months,P<0.0001).Both the objective response rate(5%,19.6%,and 22%,P=0.0669)and the disease control rate(50%,76.5%,and 80%,P=0.0023)were considerably lower in the CRAFITY-high group.The findings from the multivariate analysis showed that a nomogram which included the tumor number,prior transarterial chemoembolization history,and CRAFITY score predicted 12-month survival with an area under the curve of 0.788(95%confidence interval:0.718-0.859),which was in good agreement with actual data.CONCLUSION The CRAFITY score is a valuable predictor of survival and treatment outcomes in patients receiving lenvatinib and PD-1 inhibitors.
文摘Hepatocellular carcinoma(HCC),a primary malignancy of the liver and leading cause of cancer-related mortality worldwide,poses substantial therapeutic challenges,particularly in advanced and unresectable stages.Immune checkpoint inhibitors(ICIs)have emerged as critical therapeutic agents,targeting immune checkpoint pathways to restore antitumor immune responses.Combinations such as atezolizumab(anti-programmed cell death ligand 1 with bevacizumab antivascular endothelial growth factor),as well as antibodies directed against cytotoxic T-lymphocyte associated protein 4 and programmed cell death protein 1(e.g.,ipilimumab and nivolumab),have demonstrated improved clinical outcome in selected patients.However,the overall efficacy of ICIs remains hindered by variable response rate and primary or acquired resistance.Recent evidence suggests that the gut microbiome plays a pivotal role in modulating host immune responses and may significantly influence the therapeutic efficacy of ICIs.Dysbiosis within the gut-liver axis has been implicated not only in pathogenesis and progression of HCC but also diminishing immunotherapy effectiveness.Emerging studies highlight the potential of microbiome-targeted interventions including dietary modulation,prebiotics,probiotics,and fecal microbiota transplantation to enhance ICIs responsiveness.This review explores the evolving interplay between the gut microbiota and immunotherapy in HCC,with a focus on microbiome-based strategies aimed at optimizing clinical outcomes.
文摘Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.
基金Supported by the Key Research and Development Projects of Anhui Province,No.202104j07020048National Key Research and Development Program of China,No.2022YFA1304500.
文摘BACKGROUND Currently,there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma(HBV-HCC)after radical resection.Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC,we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.AIM To evaluate the value of postoperative combined therapy(PCT)with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included.Recurrence-free survival(RFS)and overall survival were assessed using propensity score matching and inverse probability of treatment weighting.Cox regression analysis was used to identify factors affecting recurrence,and subgroup analysis was conducted to investigate the impact of medications on different populations.Treatment-related adverse events and liver function measurements were evaluated.RESULTS A total of 150 patients were recruited,of whom 30 underwent PCT and 120 did not.After adjusting for confounders,patients who underwent PCT had better RFS at 6 and 12 months than those who did not(P>0.05).Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting,although the difference was not statistically significant(P>0.05).A maximum diameter of>5 cm,vascular invasion,satellite nodules,and high gamma-glutamyl transferase levels were independent risk factors for recurrence(P<0.05).No significant interaction effects were observed in subgroup analyses.The most prevalent adverse event was hypertension(66.7%).PCT was associated with an increased risk of hepatic impairment which may predict RFS rates(P=0.041).CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT.Hepatic impairment during treatment may indicate recurrence,and close monitoring of liver function and HBV infection is recommended.
基金supported by grants from the National Natural Science Foundation of China(Nos.82373372 and U22A20330)Key Project of Research and Development Plan in Heilongjiang Province(Nos.2022ZX06C01 and JD2023SJ40)+1 种基金National Cancer Center Climbing Fund(No.NCC201908A03)Beijing Xisike Clinical Oncology Research Foundation(No.Y-HR2020MS-0900).
文摘Psoriasiform rash is a notable immune-related cutaneous adverse event(ircAE)accounting for approximately 5%of all ircAEs1,2.Patients with cancer and pre-existing psoriasis face elevated risk of disease recurrence or exacerbation after receiving immune checkpoint inhibitors(ICIs).A European multicenter study has reported a reactivation rate of 28.7%in this population3.ICIs also trigger de novo psoriatic lesions,which mirror conventional lesion subtypes(plaque,guttate,erythrodermic,or pustular).
基金Supported by Hebei Provincial Medical Science Research Project Program,No.20240164.
文摘BACKGROUND Colorectal cancer(CRC)is among the most prevalent and deadly cancers globally,particularly in China.Treatment challenges remain in advanced and metastatic cases,especially in third-and fourth-line settings.The combination of targeted therapies with immune checkpoint inhibitors(ICIs)has shown potential in addressing the limitations of single-agent treatments.AIM To evaluate the efficacy and safety of targeted therapy(TT)alone and in combination with ICIs for metastatic CRC(mCRC).METHODS A multicenter retrospective observational study was conducted to evaluate the efficacy and safety of TT alone and in combination with ICIs for mCRC.A total of 99 patients treated with regorafenib or fruquintinib,with or without ICIs,were enrolled.Propensity score matching(PSM)and inverse probability weighting(IPW)were employed to balance baseline characteristics.The primary endpoint was progression-free survival(PFS),while overall survival(OS)and safety were secondary.RESULTS Patients who received combined therapy showed significantly longer median PFS rates compared to those who underwent TT in all analyses(original:6.0 vs 3.4 months,P<0.01;PSM:6.15 vs 4.25 months,P<0.05;IPW:5.6 vs 3.3 months,P<0.01).Although the median OS showed a trend toward improvement in the combination group,the difference was insignificant.Cox regression analysis revealed that combining TT with ICIs significantly reduced the risk of disease progression(hazard ratio=0.38,P<0.001).Adverse events(AEs)were generally manageable with both regimens,while serious AEs(grade 3-4)were primarily hypertension,fatigue,and reduced platelet counts.All AEs were controlled effectively by symptomatic treatment or discontinuation of the drug,and no treatment-related deaths were observed.CONCLUSION The combination of TT with ICIs offers a significant advantage in terms of PFS for patients with advanced mCRC,accompanied by a favorable safety profile.These findings underscore the benefits of combination therapy in this setting,warranting further investigation in larger prospective clinical trials.
基金Supported by the National Key Sci-Tech Special Project of China,No.2018ZX10302207the Beijing Natural Science Foundation,No.7222191+3 种基金the Beijing Natural Science Foundation,No.7244426the Fundamental Research Funds for the Central Universities,Peking University,No.PKU2024XGK005the Peking University Medicine Seed Fund for Interdisciplinary Research,No.BMU2021MX007 and No.BMU2022MX001Fundamental Research Funds for the Central Universities,Peking University People’s Hospital Scientific Research Development Funds,No.RDY2020-06 and No.RDJ2022-14.
文摘Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.
文摘Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.
