The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these app...Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these approaches have not yet transformed the treatment landscape for pancreatic cancer.The unique tumor microenvironment(TME)of pancreatic cancer,characterized by dense fibrotic stroma and immunosuppressive myeloid cells,poses significant barriers to effective immunotherapy.Current research highlights the need for an in-depth understanding of the TME and the development of strategies to overcome its immunosuppressive properties.Recent studies have explored various immunotherapeutic approaches,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell therapies,some of which have shown promising results in preclinical and early clinical trials.Furthermore,combining immunotherapy with traditional treatments,such as chemotherapy and radiotherapy,has shown potential for enhancing antitumor efficacy,although targeted therapies for pancreatic cancer are still in their early stages and are being investigated for their ability to disrupt specific molecular pathways involved in tumor growth and survival.This review provides a comprehensive overview of the advances in immunotherapy and targeted therapies for pancreatic cancer,discussing the current state of research,clinical outcomes,and future directions for improving patient prognosis.展开更多
Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the...Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.展开更多
Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,ta...Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.展开更多
Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms...Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms, requiring histopathology for diagnosis. Surgery remains the standard of care for localized disease, serving both diagnostic and therapeutic purposes, though adjuvant chemotherapy has shown limited efficacy. In metastatic CDC, the gemcitabine-cisplatin regimen is commonly used due to its resemblance to urothelial cancer and supportive data from prospective studies. Newer therapies offer promise in advanced cases. Immune checkpoint inhibitors, such as nivolumab alone or with ipilimumab, have shown benefits in patients with high PD-L1 expression. Targeted therapies like cabozantinib demonstrated efficacy and safety as first-line treatments in phase II trials, while sunitinib and sorafenib have shown responses in various case reports and cohorts. However, combining chemotherapy with bevacizumab did not improve outcomes in phase II trials. Despite therapeutic advances in urothelial cancers and clear cell renal tumors, the CDC entity remains a challenging malignancy, emphasizing the need for continued research to understand the true efficacy of treatment and to prolong survival in advanced disease.展开更多
Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the an...Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.展开更多
Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantati...Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantation are the gold standard for the radical treatment of HCC.However,due to the heterogeneity and high invasiveness of HCC,the rates of local and distant recurrence are extremely high,with over 70%of patients experiencing recurrence within 5 years after treatment,significantly impacting the long-term quality of life.Therefore,researchers are exploring other treatment methods to reduce tumor recurrence and improve patient survival.To date,extensive research has concentrated on new alternative therapies,including radiotherapy(e.g.,selective internal radiotherapy),targeted drug therapy(e.g.,sorafenib and lenvatinib),and immunotherapy(e.g.,immune checkpoint inhibitors),which have played an integral role in the comprehensive treatment of HCC.This review mainly focuses on the cutting-edge advancements in these treatment methods for HCC and their potential role in reducing HCC recurrence.展开更多
Immunotherapy has transformed cancer treatment,marked by the approval of numerous antibody-based drugs.However,the limitations of antibodies in pharmacokinetics including long half-lives,limited oral bioavailability a...Immunotherapy has transformed cancer treatment,marked by the approval of numerous antibody-based drugs.However,the limitations of antibodies in pharmacokinetics including long half-lives,limited oral bioavailability and immunogenicity,have prompted the pursuit of small molecule-based immunotherapy.Traditional drug discovery strategies,which focus on blocking protein activity through inhibitors,face persistent hurdles,such as reliance on accessible binding pockets,poor selectivity,and the emergence of drug resistance.Targeted protein degradation(TPD)technologies have emerged as powerful tools to address these limitations,offering significant therapeutic advantages over conventional inhibition strategies,particularly for historically "undruggable" targets.In recent years,small molecule-based protein degraders have rapidly advanced in cancer immunotherapy.In this review,we highlight recent progress in TPD-driven small-molecule drug discovery and summarize the application of these technologies in cancer immunotherapy,including degraders targeting PD-1/PD-L1,chemokine receptors,IDO1,AhR,and others.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a major global contributor to cancer-related mortality,with advanced stages presenting substantial therapeutic challenges.Although targeted immunotherapy shows potential,many...BACKGROUND Hepatocellular carcinoma(HCC)is a major global contributor to cancer-related mortality,with advanced stages presenting substantial therapeutic challenges.Although targeted immunotherapy shows potential,many patients exhibit poor responses,underscoring the need for predictive tools to optimize treatment strategies.Emerging data indicate that ultrasound features(e.g.,tumor stiffness)and serum biomarkers may serve as predictors of treatment outcomes.However,an integrated model for these predictors remains unavailable.This paper introduces a machine learning-based approach that combines ultrasound and serological data to forecast immunotherapy efficacy in patients with advanced HCC.AIM To develop a non-invasive predictive model for targeted immunotherapy in advanced HCC,incorporating both internal and external validation.METHODS Patients with advanced HCC who received targeted immunotherapy at two medical centers were enrolled and divided into internal training,internal validation,and external validation cohorts.Comprehensive clinical data were gathered.Initially,13 machine learning algorithms were tested using the internal training cohort.The algorithm yielding the highest area under the curve(AUC)in the internal validation cohort was selected to construct a predictive model,termed the Target Immunotherapy Predictive Model(TIPM).TIPM performance was then compared with that of traditional tumor staging systems(tumor-node-metastasis,Barcelona Clinic Liver Cancer,China Liver Cancer,Hong Kong Liver Cancer,and C-reactive protein and alpha-fetoprotein in immunotherapy).RESULTS A total of 306 patients participated in the study,with 143 in the internal training cohort,62 in the internal validation cohort,and 101 in the external validation cohort.In the internal validation cohort,the random forest model achieved the highest AUC(0.975,95%confidence interval:0.924-0.998).The key predictors for TIPM were tumor size,platelet count,tumor stiffness change,and white blood cell count.During external validation,TIPM outperformed conventional models,reaching an AUC of 0.899(95%confidence interval:0.840-0.957).Calibration curves demonstrated strong concordance with observed outcomes,while decision curve analysis confirmed TIPM’s enhanced clinical value.Additional metrics,such as the net reclassification index and integrated discrimination improvement,further supported TIPM’s superior predictive accuracy.CONCLUSION TIPM provides a robust tool for predicting targeted immunotherapy efficacy in advanced HCC,facilitating personalized treatment planning.展开更多
BACKGROUND Early symptoms of hepatocellular carcinoma(HCC)are not obvious,and more than 70%of which does not receive radical hepatectomy,when first diagnosed.In recent years,molecular-targeted drugs combined with immu...BACKGROUND Early symptoms of hepatocellular carcinoma(HCC)are not obvious,and more than 70%of which does not receive radical hepatectomy,when first diagnosed.In recent years,molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC(aHCC).Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.AIM To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.METHODS Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected.Signal intensity of intrahepatic nodules was measured,and the hepatobiliary relative enhancement ratio(RER)was calculated.Progression-free survival(PFS)of patients with high and low reinforcement of HCC nodules was compared.The model was validated using receiver operating characteristic curves.Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.RESULTS Univariate and multivariate analyses revealed that the RER,neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy(P<0.05).The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876(95%confidence interval:0.781-0.971,P<0.05),the optimal cutoff value was 0.904,diagnostic sensitivity was 87.5%,and specificity was 79.2%.Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio<5,plateletto-lymphocyte ratio<300,prognostic nutritional index<45,and RER<0.9 significantly improved PFS.CONCLUSION AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS.Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.展开更多
Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regul...Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha(SIRPα)on macrophages and dendritic cells(DCs).Although early enthusiasm drove broad clinical development,recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential.The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations.Clinical challenges,including anemia,thrombocytopenia,suboptimal pharmacokinetics,and limited single-agent efficacy,underscore the need to develop safer,more selective approaches.Emerging next-generation strategies,such as SIRPα-directed agents,bispecific antibodies,and conditionally active therapeutics,are designed to enhance safety and tumor selectivity and reduce systemic toxicity.In addition,spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations,including with“eat-me”signals(e.g.,calreticulin[CALR])orDNA damage response therapies(e.g.,poly(ADP-ribose)polymerase[PARP]inhibitors).Rather than signaling failure,these developments underscore the need for precision,context-specific applications,and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.展开更多
BACKGROUND Targeted therapy combined with anti-programmed cell death 1 immunotherapy(TP)and trifluridine/tipiracil(TAS-102)combined with bevacizumab(TB)are two common therapies for patients with late-line therapy in m...BACKGROUND Targeted therapy combined with anti-programmed cell death 1 immunotherapy(TP)and trifluridine/tipiracil(TAS-102)combined with bevacizumab(TB)are two common therapies for patients with late-line therapy in microsatellite stable(MSS)metastatic colorectal cancer(mCRC).However,it is still unclear which therapy can bring better prognosis.AIM To evaluate the effectiveness and safety of TP vs TB as the late-line regimen for MSS mCRC in the real world.METHODS This is a dual-center retrospective cohort study conducted in Peking University First Hospital and Jilin Cancer Hospital.Patients with MSS mCRC who had received at least the second line treatment were eligible.Propensity score(PS)would be calculated to balance the baseline characteristics of two cohorts.Progression-free survival(PFS)was set as the primary endpoint.The Kaplan-Meier method and Cox proportional hazard model were used to evaluate PFS and to estimate hazard ratios(HRs)and 95%confidence intervals(CIs).Landmark analysis was performed to create segmented survival curves,studying the impact of treatment regimen on prognosis during different follow-up periods.RESULTS Between July 2019 and March 2025(data cutoff),127 eligible patients were enrolled,with 88 and 39 patients assigned to the TP and TB cohorts,respectively,based on treatment allocation.At a global median follow-up of 9.73 months,the crude median PFS was 3.9 months(95%CI:3.03-5.53)in the TP cohort vs 4.17 months(95%CI:2.87-5.6)in the TB cohort,yielding a nonsignificant HR of 1.43(95%CI:0.94-2.18,P=0.092;TB as reference).Multivariate Cox regression analysis,adjusted for sex,age>60 years,Eastern Cooperative Oncology Group performance status,RAS mutation,primary tumor location(left vs right),number of metastatic organs(liver/lung),and treatment line(≥3rd line),demonstrated an adjusted HR of 1.23(95%CI:0.80-1.88,P=0.348).PS-based analyses using three methodologies:Inverse probability weighting,PS matching(post-matching n=55 vs 30),and PS-adjusted multivariate Cox regression.These analyses revealed consistent nonsignificant trends favoring TB,with HRs for TP of 1.26(95%CI:0.76-2.10,P=0.077),1.42(95%CI:0.87-2.34,P=0.164),and 1.26(95%CI:0.76-2.10,P=0.367),respectively.Notably,landmark PFS analyses at 90,120,and 150 days demonstrated a significantly higher proportion of TP patients maintaining disease control beyond these timepoints(P=0.048,0.031,and 0.035,respectively),suggesting sustained clinical benefits in TP responders.CONCLUSION TP and TB demonstrated similar PFS in both crude and PS-adjusted analyses.However,patients who derived benefits from TP therapy exceeding 90 days showed more sustained clinical advantages compared to TB.Our study suggests that for patients with MSS mCRC who respond to TP therapy in later-line treatments,this regimen could provide additional prolonged clinical benefits,which warrants further validation through large-scale cohort investigations.展开更多
Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb to...Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb toⅢb of HCC treatment.In recent years,immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research.At the same time,targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC,and their clinical application has been quite mature.HCC is the sixth most common malignant tumor in the world.When it comes to its treatment,different therapies have different indications,and their individual efficacies are not satisfactory,which makes the exploration of the use of combination therapy in HCC treatment become a new trend.In this paper,the status of the three therapies and the progress of their combined application are briefly reviewed.展开更多
Programmed cell death protein 1(PD-1)/programmed death ligand 1(PD-L1)is a significant immune checkpoint,and the dysfunction of this axis contributes to tumor metastasis and immune escape.PI3K/Akt/mTOR and MAPK signal...Programmed cell death protein 1(PD-1)/programmed death ligand 1(PD-L1)is a significant immune checkpoint,and the dysfunction of this axis contributes to tumor metastasis and immune escape.PI3K/Akt/mTOR and MAPK signal network induces PD-1/PD-L1 expression and facilitates tumor progression.Transcriptional factors such as hypoxia induced factors,PTEN,p53,CDK5,BRD4,STAT modulate PD-1/PDL1 expression.PD-1/PD-L1 level is also regulated via epigenetic and post-translational manner.The underlying mechanisms mentioned above may provide potential targets for tumor treatment.At present,the combination therapy of PD-1/PD-L1 monoclonal antibodies plus small molecular inhibitors has achieved good outcomes in tumor treatment.展开更多
Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,s...Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.展开更多
BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more effi...BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.展开更多
Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) app...Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.展开更多
BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and ...BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。展开更多
Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, ...Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.展开更多
Mechanical forces in the tumor microenvironment(TME)are associated with tumor growth,proliferation,and drug resistance.Strong mechanical forces in tumors alter the metabolism and behavior of cancer cells,thus promotin...Mechanical forces in the tumor microenvironment(TME)are associated with tumor growth,proliferation,and drug resistance.Strong mechanical forces in tumors alter the metabolism and behavior of cancer cells,thus promoting tumor progression and metastasis.Mechanical signals are transformed into biochemical signals,which activate tumorigenic signaling pathways through mechanical transduction.Cancer immunotherapy has recently made exciting progress,ushering in a new era of“chemo-free”treatments.However,immunotherapy has not achieved satisfactory results in a variety of tumors,because of the complex tumor microenvironment.Herein,we discuss the effects of mechanical forces on the tumor immune microenvironment and highlight emerging therapeutic strategies for targeting mechanical forces in immunotherapy.展开更多
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
文摘Pancreatic cancer remains one of the most challenging malignancies to treat,with a poor prognosis and limited therapeutic options.Despite the success of immunotherapy and targeted therapies for other cancers,these approaches have not yet transformed the treatment landscape for pancreatic cancer.The unique tumor microenvironment(TME)of pancreatic cancer,characterized by dense fibrotic stroma and immunosuppressive myeloid cells,poses significant barriers to effective immunotherapy.Current research highlights the need for an in-depth understanding of the TME and the development of strategies to overcome its immunosuppressive properties.Recent studies have explored various immunotherapeutic approaches,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell therapies,some of which have shown promising results in preclinical and early clinical trials.Furthermore,combining immunotherapy with traditional treatments,such as chemotherapy and radiotherapy,has shown potential for enhancing antitumor efficacy,although targeted therapies for pancreatic cancer are still in their early stages and are being investigated for their ability to disrupt specific molecular pathways involved in tumor growth and survival.This review provides a comprehensive overview of the advances in immunotherapy and targeted therapies for pancreatic cancer,discussing the current state of research,clinical outcomes,and future directions for improving patient prognosis.
基金supported by the Nature Science Foundation of Liaoning Province,Nos.2022-MS-211,2021-MS-064,and 2024-MS-048(all to YC).
文摘Alzheimer’s disease,a devastating neurodegenerative disorder,is characterized by progressive cognitive decline,primarily due to amyloid-beta protein deposition and tau protein phosphorylation.Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer’s disease.Conventional drugs,such as donepezil,can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline.Currently,active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer’s disease and other transgenic animal models,attracting considerable attention.However,the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab.This review first discusses the advancements in the pathogenesis of Alzheimer’s disease and active and passive immunotherapies targeting amyloid-beta and tau proteins.Furthermore,it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects.Although some antibodies have shown promise in patients with mild Alzheimer’s disease,substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer’s disease.
文摘Tau plays a crucial role in several neurodegenerative diseases,collectively referred to as tauopathies.Therefore,targeting potential pathological changes in tau could enable useful therapeutic interventions.However,tau is not an easy target because it dynamically interacts with microtubules and other cellular components,which presents a challenge for tau-targeted drugs.New cellular models could aid the development of mechanism-based tau-targeted therapies.
文摘Collecting duct carcinoma (CDC), or Bellini duct carcinoma, is a rare and aggressive subtype of renal cell carcinoma, accounting for 0.2% - 1% of cases. It often presents at an advanced stage with nonspecific symptoms, requiring histopathology for diagnosis. Surgery remains the standard of care for localized disease, serving both diagnostic and therapeutic purposes, though adjuvant chemotherapy has shown limited efficacy. In metastatic CDC, the gemcitabine-cisplatin regimen is commonly used due to its resemblance to urothelial cancer and supportive data from prospective studies. Newer therapies offer promise in advanced cases. Immune checkpoint inhibitors, such as nivolumab alone or with ipilimumab, have shown benefits in patients with high PD-L1 expression. Targeted therapies like cabozantinib demonstrated efficacy and safety as first-line treatments in phase II trials, while sunitinib and sorafenib have shown responses in various case reports and cohorts. However, combining chemotherapy with bevacizumab did not improve outcomes in phase II trials. Despite therapeutic advances in urothelial cancers and clear cell renal tumors, the CDC entity remains a challenging malignancy, emphasizing the need for continued research to understand the true efficacy of treatment and to prolong survival in advanced disease.
基金funded by the Major Research Plan of the National Natural Science Foundation of China(No.92159202)the National Key Research and Development Program of China(No.2021YFA1100500)+1 种基金the Leading Innovation Team Project of Hangzhou Medical College(No.CXLJ202401)the Key Research and Development Plan of Zhejiang Provincial Department of Science and Technology(No.2024C03051)。
文摘Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.
基金Supported by the National Natural Science Foundation of China,No.82270634Third Affiliated Hospital of Naval Medical University,No.tf2024yzyy01.
文摘Hepatocellular carcinoma(HCC)is one of the most common malignant tumors globally and is the most prevalent type of primary liver cancer,posing a heavy burden on global health.Surgical resection and liver transplantation are the gold standard for the radical treatment of HCC.However,due to the heterogeneity and high invasiveness of HCC,the rates of local and distant recurrence are extremely high,with over 70%of patients experiencing recurrence within 5 years after treatment,significantly impacting the long-term quality of life.Therefore,researchers are exploring other treatment methods to reduce tumor recurrence and improve patient survival.To date,extensive research has concentrated on new alternative therapies,including radiotherapy(e.g.,selective internal radiotherapy),targeted drug therapy(e.g.,sorafenib and lenvatinib),and immunotherapy(e.g.,immune checkpoint inhibitors),which have played an integral role in the comprehensive treatment of HCC.This review mainly focuses on the cutting-edge advancements in these treatment methods for HCC and their potential role in reducing HCC recurrence.
基金supported by the National Natural Science Foundation of China(No.82173668,82373706).
文摘Immunotherapy has transformed cancer treatment,marked by the approval of numerous antibody-based drugs.However,the limitations of antibodies in pharmacokinetics including long half-lives,limited oral bioavailability and immunogenicity,have prompted the pursuit of small molecule-based immunotherapy.Traditional drug discovery strategies,which focus on blocking protein activity through inhibitors,face persistent hurdles,such as reliance on accessible binding pockets,poor selectivity,and the emergence of drug resistance.Targeted protein degradation(TPD)technologies have emerged as powerful tools to address these limitations,offering significant therapeutic advantages over conventional inhibition strategies,particularly for historically "undruggable" targets.In recent years,small molecule-based protein degraders have rapidly advanced in cancer immunotherapy.In this review,we highlight recent progress in TPD-driven small-molecule drug discovery and summarize the application of these technologies in cancer immunotherapy,including degraders targeting PD-1/PD-L1,chemokine receptors,IDO1,AhR,and others.
基金Supported by Natural Science Foundation of Fujian Province,No.2022J011285 and No.2023J011480Fuzhou Municipal Bureau of Science and Technology Program Fund,No.2021-S-109+1 种基金Provincial Subsidy Fund for Health and Wellness from Fujian Provincial Department of Finance,No.BPB-2022YXJFujian Provincial Health Technology Project,No.2020GGB032。
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a major global contributor to cancer-related mortality,with advanced stages presenting substantial therapeutic challenges.Although targeted immunotherapy shows potential,many patients exhibit poor responses,underscoring the need for predictive tools to optimize treatment strategies.Emerging data indicate that ultrasound features(e.g.,tumor stiffness)and serum biomarkers may serve as predictors of treatment outcomes.However,an integrated model for these predictors remains unavailable.This paper introduces a machine learning-based approach that combines ultrasound and serological data to forecast immunotherapy efficacy in patients with advanced HCC.AIM To develop a non-invasive predictive model for targeted immunotherapy in advanced HCC,incorporating both internal and external validation.METHODS Patients with advanced HCC who received targeted immunotherapy at two medical centers were enrolled and divided into internal training,internal validation,and external validation cohorts.Comprehensive clinical data were gathered.Initially,13 machine learning algorithms were tested using the internal training cohort.The algorithm yielding the highest area under the curve(AUC)in the internal validation cohort was selected to construct a predictive model,termed the Target Immunotherapy Predictive Model(TIPM).TIPM performance was then compared with that of traditional tumor staging systems(tumor-node-metastasis,Barcelona Clinic Liver Cancer,China Liver Cancer,Hong Kong Liver Cancer,and C-reactive protein and alpha-fetoprotein in immunotherapy).RESULTS A total of 306 patients participated in the study,with 143 in the internal training cohort,62 in the internal validation cohort,and 101 in the external validation cohort.In the internal validation cohort,the random forest model achieved the highest AUC(0.975,95%confidence interval:0.924-0.998).The key predictors for TIPM were tumor size,platelet count,tumor stiffness change,and white blood cell count.During external validation,TIPM outperformed conventional models,reaching an AUC of 0.899(95%confidence interval:0.840-0.957).Calibration curves demonstrated strong concordance with observed outcomes,while decision curve analysis confirmed TIPM’s enhanced clinical value.Additional metrics,such as the net reclassification index and integrated discrimination improvement,further supported TIPM’s superior predictive accuracy.CONCLUSION TIPM provides a robust tool for predicting targeted immunotherapy efficacy in advanced HCC,facilitating personalized treatment planning.
基金Supported by Natural Science Foundation of Henan Province,No.242300421286the research and practice project of higher education reform in Henan Province,No.2023SJGLX124Ythe research and practice project of higher education reform of Zhengzhou University,No.2023ZZUJGXM114.
文摘BACKGROUND Early symptoms of hepatocellular carcinoma(HCC)are not obvious,and more than 70%of which does not receive radical hepatectomy,when first diagnosed.In recent years,molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC(aHCC).Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.AIM To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.METHODS Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected.Signal intensity of intrahepatic nodules was measured,and the hepatobiliary relative enhancement ratio(RER)was calculated.Progression-free survival(PFS)of patients with high and low reinforcement of HCC nodules was compared.The model was validated using receiver operating characteristic curves.Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.RESULTS Univariate and multivariate analyses revealed that the RER,neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy(P<0.05).The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876(95%confidence interval:0.781-0.971,P<0.05),the optimal cutoff value was 0.904,diagnostic sensitivity was 87.5%,and specificity was 79.2%.Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio<5,plateletto-lymphocyte ratio<300,prognostic nutritional index<45,and RER<0.9 significantly improved PFS.CONCLUSION AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS.Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.
文摘Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha(SIRPα)on macrophages and dendritic cells(DCs).Although early enthusiasm drove broad clinical development,recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential.The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations.Clinical challenges,including anemia,thrombocytopenia,suboptimal pharmacokinetics,and limited single-agent efficacy,underscore the need to develop safer,more selective approaches.Emerging next-generation strategies,such as SIRPα-directed agents,bispecific antibodies,and conditionally active therapeutics,are designed to enhance safety and tumor selectivity and reduce systemic toxicity.In addition,spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations,including with“eat-me”signals(e.g.,calreticulin[CALR])orDNA damage response therapies(e.g.,poly(ADP-ribose)polymerase[PARP]inhibitors).Rather than signaling failure,these developments underscore the need for precision,context-specific applications,and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.
基金Supported by the National High Level Hospital Clinical Research Funding(Multi-Center Clinical Research Project of Peking University First Hospital),No.2022CR65.
文摘BACKGROUND Targeted therapy combined with anti-programmed cell death 1 immunotherapy(TP)and trifluridine/tipiracil(TAS-102)combined with bevacizumab(TB)are two common therapies for patients with late-line therapy in microsatellite stable(MSS)metastatic colorectal cancer(mCRC).However,it is still unclear which therapy can bring better prognosis.AIM To evaluate the effectiveness and safety of TP vs TB as the late-line regimen for MSS mCRC in the real world.METHODS This is a dual-center retrospective cohort study conducted in Peking University First Hospital and Jilin Cancer Hospital.Patients with MSS mCRC who had received at least the second line treatment were eligible.Propensity score(PS)would be calculated to balance the baseline characteristics of two cohorts.Progression-free survival(PFS)was set as the primary endpoint.The Kaplan-Meier method and Cox proportional hazard model were used to evaluate PFS and to estimate hazard ratios(HRs)and 95%confidence intervals(CIs).Landmark analysis was performed to create segmented survival curves,studying the impact of treatment regimen on prognosis during different follow-up periods.RESULTS Between July 2019 and March 2025(data cutoff),127 eligible patients were enrolled,with 88 and 39 patients assigned to the TP and TB cohorts,respectively,based on treatment allocation.At a global median follow-up of 9.73 months,the crude median PFS was 3.9 months(95%CI:3.03-5.53)in the TP cohort vs 4.17 months(95%CI:2.87-5.6)in the TB cohort,yielding a nonsignificant HR of 1.43(95%CI:0.94-2.18,P=0.092;TB as reference).Multivariate Cox regression analysis,adjusted for sex,age>60 years,Eastern Cooperative Oncology Group performance status,RAS mutation,primary tumor location(left vs right),number of metastatic organs(liver/lung),and treatment line(≥3rd line),demonstrated an adjusted HR of 1.23(95%CI:0.80-1.88,P=0.348).PS-based analyses using three methodologies:Inverse probability weighting,PS matching(post-matching n=55 vs 30),and PS-adjusted multivariate Cox regression.These analyses revealed consistent nonsignificant trends favoring TB,with HRs for TP of 1.26(95%CI:0.76-2.10,P=0.077),1.42(95%CI:0.87-2.34,P=0.164),and 1.26(95%CI:0.76-2.10,P=0.367),respectively.Notably,landmark PFS analyses at 90,120,and 150 days demonstrated a significantly higher proportion of TP patients maintaining disease control beyond these timepoints(P=0.048,0.031,and 0.035,respectively),suggesting sustained clinical benefits in TP responders.CONCLUSION TP and TB demonstrated similar PFS in both crude and PS-adjusted analyses.However,patients who derived benefits from TP therapy exceeding 90 days showed more sustained clinical advantages compared to TB.Our study suggests that for patients with MSS mCRC who respond to TP therapy in later-line treatments,this regimen could provide additional prolonged clinical benefits,which warrants further validation through large-scale cohort investigations.
基金supported by National Key Research and Development Program of China Grant under No.2019YFC0118100。
文摘Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb toⅢb of HCC treatment.In recent years,immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research.At the same time,targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC,and their clinical application has been quite mature.HCC is the sixth most common malignant tumor in the world.When it comes to its treatment,different therapies have different indications,and their individual efficacies are not satisfactory,which makes the exploration of the use of combination therapy in HCC treatment become a new trend.In this paper,the status of the three therapies and the progress of their combined application are briefly reviewed.
文摘Programmed cell death protein 1(PD-1)/programmed death ligand 1(PD-L1)is a significant immune checkpoint,and the dysfunction of this axis contributes to tumor metastasis and immune escape.PI3K/Akt/mTOR and MAPK signal network induces PD-1/PD-L1 expression and facilitates tumor progression.Transcriptional factors such as hypoxia induced factors,PTEN,p53,CDK5,BRD4,STAT modulate PD-1/PDL1 expression.PD-1/PD-L1 level is also regulated via epigenetic and post-translational manner.The underlying mechanisms mentioned above may provide potential targets for tumor treatment.At present,the combination therapy of PD-1/PD-L1 monoclonal antibodies plus small molecular inhibitors has achieved good outcomes in tumor treatment.
基金Supported by National Natural Science Foundation of China,No.81970453,and No.82270634Shanghai Science and Technology Innovation Action Plan Project,No.20XD1405100.
文摘Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.
基金This study was reviewed and approved by the Ethics Committee of Zhongshan People’s Hospital(Approval No.2022-029).
文摘BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma(HCC),and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than mono-therapy.However,the mechanisms underlying this innovative treatment modality have not been elucidated.AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy(HAIC)of FOLFOX in patients with unresectable HCC.METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy,immunotherapy,and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.RESULTS The objective response rate was 60.4%(32/53),complete response was 24.5%(13/53),partial response was 35.9%(19/53),and stable disease was 39.6%(21/53).The median duration of response and median progression-free survival were 9.1 and 13.9 months,respectively.The surgical conversion rate was 34.0%(18/53),and 1-year overall survival was 83.0%without critical complicating diseases or adverse events(AEs).CONCLUSION The regimen of HAIC of FOLFOX,targeted therapy,and immunotherapy was curative for patients with unresectable HCC,with no serious AEs and a high rate of surgical conversion.
文摘Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.
文摘BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。
文摘Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81972455 and 81902358)。
文摘Mechanical forces in the tumor microenvironment(TME)are associated with tumor growth,proliferation,and drug resistance.Strong mechanical forces in tumors alter the metabolism and behavior of cancer cells,thus promoting tumor progression and metastasis.Mechanical signals are transformed into biochemical signals,which activate tumorigenic signaling pathways through mechanical transduction.Cancer immunotherapy has recently made exciting progress,ushering in a new era of“chemo-free”treatments.However,immunotherapy has not achieved satisfactory results in a variety of tumors,because of the complex tumor microenvironment.Herein,we discuss the effects of mechanical forces on the tumor immune microenvironment and highlight emerging therapeutic strategies for targeting mechanical forces in immunotherapy.
