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
In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is...In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.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
Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agen...Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agents and small-molecule agents has significantly advanced our ability to target the disease more effectively[2].In the current review,we summarize the outcomes of targeted therapies in rosacea,mainly focusing on interleukin(IL)-17 inhibitors and Janus kinase(JAK)inhibitors.展开更多
BACKGROUND Many studies have found that sarcopenia is related to the survival of patients with liver cancer,which may lead to worse prognosis.AIM To investigate the relationship between skeletal muscle mass and progno...BACKGROUND Many studies have found that sarcopenia is related to the survival of patients with liver cancer,which may lead to worse prognosis.AIM To investigate the relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy by meta-analysis.METHODS PubMed,Embase,Cochrane Library,and Web of Science were searched for clinical studies on the relationship between skeletal muscle index(SMI)and the prognosis of patients with liver cancer receiving targeted therapy from inception to March 1,2022.Meta-analysis and sensitivity analysis of the data were performed using Stata 16.0 software.RESULTS A total of 6877 studies were searched,and finally 12 articles with 1715 cases were included.Meta-analysis result of 8 articles showed that compared with non-low SMI group,the overall survival(OS)of patients with liver cancer in the low SMI group was significantly shorter(hazard ratio=1.60,95%confidence interval:1.44-1.77,P=0.000).Meta-analysis result of 4 articles showed that,compared with low SMI group,patients in the nonlow SMI group had longer OS(hazard ratio=0.59,95%confidence interval:0.38-0.91,P=0.018).CONCLUSION Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy.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
Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through ...Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.展开更多
Colorectal cancer(CRC)with liver metastasis remains a significant therapeutic challenge,particularly in cases of postoperative recurrence.While transarterial chemoembolization(TACE)and targeted therapies have shown pr...Colorectal cancer(CRC)with liver metastasis remains a significant therapeutic challenge,particularly in cases of postoperative recurrence.While transarterial chemoembolization(TACE)and targeted therapies have shown promise individually,the efficacy combining these for treating postoperative recurrent CRC with liver metastasis requires further investigation.AIM To evaluate the efficacy and safety of TACE combined with targeted therapies for postoperative recurrent CRC with liver metastasis.METHODS This observational study enrolled 75 patients with postoperative recurrent CRC accompanied by liver metastasis between January 2020 and December 2023.All patients received combined treatment with TACE and targeted therapy:Bevacizumab(40 patients,53.3%),cetuximab(25 patients,33.3%),or panitumumab(10 patients,13.3%).Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors 1.1 criteria,with overall survival(OS)and progression-free survival as the primary endpoints.Quality of life was assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire at baseline and after six months of treatment.RESULTS The median OS was 28 months(95%confidence interval:24-32 months),and the median progression-free survival was 12 months(95%confidence interval:10-14 months).Patients treated with bevacizumab showed significantly better survival outcomes than those treated with cetuximab/panitumumab(median OS,30 vs 24 months,P=0.015).The overall response rate was 58.7%,with a disease control rate of 86.7%.Quality of life scores improved significantly across all domains,with greater improvements observed in the bevacizumab group.Treatment-related adverse events were manageable,with grade 3-4 events occurring in 13.3%of the patients and no treatment-related mortality.CONCLUSION The combination of TACE with targeted therapy,particularly bevacizumab,has demonstrated promising efficacy and acceptable safety for the treatment of postoperative recurrent CRC with liver metastasis.This multimodal approach not only improved survival outcomes but also enhanced the patients’quality of life,suggesting its potential as a valuable treatment strategy for this challenging condition.展开更多
Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its ...Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.展开更多
Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune...Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.展开更多
Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly...Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly accepted that disruption of SS18-SSX function represents a therapeutic means of treating synovial sarcoma,but emerging evidence suggests that upon depletion of SS18-SSX,an anti-apoptotic signal surprisingly arises to protect synovial sarcoma cell survival.In this article,we discuss the controversial roles of SS18-SSX’s transcriptional activity in synovial sarcoma biology and outline a synergistic strategy for overcoming the resistance of synovial sarcoma cells to SS18-SSX targeted therapeutics.展开更多
BACKGROUND The incidence of colon cancer has been progressively increasing over time,whereas penile metastasis of colon cancer has remained exceedingly uncommon.Since the prognosis for colon cancer with BRAF_(V600E)mu...BACKGROUND The incidence of colon cancer has been progressively increasing over time,whereas penile metastasis of colon cancer has remained exceedingly uncommon.Since the prognosis for colon cancer with BRAF_(V600E)mutation is relatively unfavorable,further exploration and investigation are still required to develop treatment strategies for such rare cases.CASE SUMMARY About one year after surgery and chemotherapy,a 50-year-old patient with sigmoid colon cancer developed a mass at the base of the patient's penis,accompanied by severe tenderness and pain during urination.With disease progression,multiple metastatic nodules also emerged in other regions of the penis,including the coronal sulcus.The nodules located in the coronal sulcus were excised for histopathological examination.The histopathological findings revealed that the nodules were metastases originating from the sigmoid colon cancer,with a BRAF V600E mutation detected.This prompted a modification of the therapy regimen of cetuximab,dabrafenib and trametinib,which effectively held back the progression of penile metastasis in the patient.CONCLUSION Combining the BRAF/MEK-targeted therapy with cetuximab demonstrates a favorable therapeutic response in BRAF_(V600E)-mutated colon cancer with penile metastasis.展开更多
Hemoptysis is a severe complication of pulmonary hypertension (PH) with a low in- cidence of 6%-11%.^([1-4])Although occurring in all forms of PH,it is more commonly seen in pulmonary arterial hypertension (PAH),assoc...Hemoptysis is a severe complication of pulmonary hypertension (PH) with a low in- cidence of 6%-11%.^([1-4])Although occurring in all forms of PH,it is more commonly seen in pulmonary arterial hypertension (PAH),associated with congenital heart disease (PAH-CHD).^([5,6])Since enlarged bronchial arteries are a frequent source of pulmonary bleeding,the primary treatment focuses on bronchial artery embolization (BAE),especially for chronic thromboembolic pulmonary hypertension (CTEPH) patients^([7,8]).However,there is disagreement regarding medical therapy,which has received little attention in the recently published PH guidelines.^([5,6])展开更多
In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of...In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of targeted therapy. This article analyzes the latest research results at home and abroad. For patients with metastatic renal cell carcinoma, sunitinib and pizopanib are the first choice for targeted drugs. The drug dose starts from the standard dose, and the disease can be increased as appropriate when the disease progresses;When responding, it should be treated or reduced in time. When using an anti-VEGF inhibitor, the patient's blood pressure should be closely monitored. When the patient has high blood sugar or diabetes, anti-VEGF inhibitors should be preferred.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
The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more ...The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more options in targeted strategy were offered and can therefore be tailored in different clinical settings for individual patient.Targeting of the abnormal angiogenesis process is the first significant clinical breakthrough which revolutionized the treatment of advanced ovarian cancer,followed by the advent of poly-(ADP)-ribose polymerase(PARP)inhibitors.These two strategies represented by bevacizumab and olaparib respectively underwent tests of numerous clinical trials.In recent years,immune checkpoint inhibitors(ICIs)have been incorporated into the blueprint of ovarian cancer treatment though the effectiveness still left much to be desired.Herein,we systematically outlined recent advances in targeted therapy for ovarian cancer and summarized the landmark clinical trials for each targeted therapy including angiogenesis inhibitors,PARP inhibitors and ICIs.展开更多
AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the im...AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model. METHODS:rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines.To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin,Western blotting and ELISA were performed.The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor,etoposide,were evaluated in a mouse liver tumor model. RESULTS:Topoisomerase inhibitors,including camptothecin and etoposide,were found to increase the endostatin exPression level in vitro.The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active.In animal experiments,the combined therapy of topoisomerase inhibitor,etoposide with the rAAV-endostatin vector had the best tumor- suppressive effect and tumor foci were barely observed in livers of the treated mice.Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice.Finally,the mice treated With rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models. CONCLUSION:rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.展开更多
Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic ...Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.展开更多
Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte a...Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.展开更多
Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AM...Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AML diagnosis was dependent on morphology,aided initially only by cytochemistry.Unlike acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and 1980s.The advent of reliable cytogenetics changed the entire prognostic outlook of AML.With karyotypic analysis,different groups of AML could be classified and stratified for various therapies.Unique mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the cells.All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML patients.The efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes.Responses can be predicted and measured accurately.Such targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing toxicity.The focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of AML.This review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as those that are currently in development.展开更多
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 CAMS Innovation Fund for Medical Science(CIFMS),No.CAMS-2016-I2M-3-025Beijing Hope Run Special Fund of Cancer Foundation of China,No.LC2020L05.
文摘In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.
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.
文摘Dear Editor,Rosacea is characterized by persistent or transient erythema,papules,pustules,telangiectasia,and/or phymatous lesions[1].Although multiple treatments are available for rosacea,the advent of biological agents and small-molecule agents has significantly advanced our ability to target the disease more effectively[2].In the current review,we summarize the outcomes of targeted therapies in rosacea,mainly focusing on interleukin(IL)-17 inhibitors and Janus kinase(JAK)inhibitors.
基金Supported by Chongqing Young and Middle-aged Medical High-end Talents,No.YXGD202405Chongqing District and County Head Goose Talents,Chongqing Science and Technology and Health Joint Scientific Research Project on Traditional Chinese Medicine,No.2024ZYYB036Chongqing Banan District Science and Technology and Health Joint Scientific Research Project on Traditional Chinese Medicine,No.BNWJ202300112.
文摘BACKGROUND Many studies have found that sarcopenia is related to the survival of patients with liver cancer,which may lead to worse prognosis.AIM To investigate the relationship between skeletal muscle mass and prognosis in patients with liver cancer receiving targeted therapy by meta-analysis.METHODS PubMed,Embase,Cochrane Library,and Web of Science were searched for clinical studies on the relationship between skeletal muscle index(SMI)and the prognosis of patients with liver cancer receiving targeted therapy from inception to March 1,2022.Meta-analysis and sensitivity analysis of the data were performed using Stata 16.0 software.RESULTS A total of 6877 studies were searched,and finally 12 articles with 1715 cases were included.Meta-analysis result of 8 articles showed that compared with non-low SMI group,the overall survival(OS)of patients with liver cancer in the low SMI group was significantly shorter(hazard ratio=1.60,95%confidence interval:1.44-1.77,P=0.000).Meta-analysis result of 4 articles showed that,compared with low SMI group,patients in the nonlow SMI group had longer OS(hazard ratio=0.59,95%confidence interval:0.38-0.91,P=0.018).CONCLUSION Skeletal muscle mass is positively correlated with OS in patients with liver cancer receiving targeted therapy.
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(Nos.82272847,82304417,82303529,82171333)China Postdoctoral Science Foundation(Nos.2023TQ0307,2023M743231,2023M730971)+2 种基金Science and Technology Project of Henan Province(No.242102311204)Postdoctoral Fellowship Program of CPSF(No.GZB20230675)Modern Analysis and Computer Center of Zhengzhou University.
文摘Colon-targeted oral drug delivery systems are one of the most promising therapeutic strategies for alleviating and curing inflammatory bowel disease(IBD),but they still face challenges in successfully passing through the harsh gastrointestinal environment and intestinal mucus barrier.To overcome the gastrointestinal barriers for oral drug delivery mentioned above,a“spore-like”oral nanodrug delivery platform(Cur/COS/SC NPs)has been developed.Firstly,chitooligosaccharides(COS)are encapsulated on the surface of Curcumin nanoparticles(Cur NPs)to form carrier-free nanoparticles(Cur/COS NPs).Subsequently,inspired by the natural high resistance of spore coat(SC),SC is chosen as the“protective umbrella”to encapsulate Cur/COS NPs for precision targeted therapy of IBD.After oral administration,SC can effectively protect NPs through the rugged gastrointestinal environment and exhibit excellent intestinal mucus penetration characteristics.Moreover,the negatively-charged Cur/COS/SC NPs specifically target positivelycharged inflamed colon via electrostatic interactions.It is demonstrated that Cur/COS/SC NPs can promote the expression of tight junction proteins,inhibit aberrant activation of the Toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB(TLR4/MyD88/NF-κB)signaling pathway,and downregulate the levels of pro-inflammatory factors,exhibiting excellent anti-inflammatory effects.Notably,it is found that Cur/COS/SC NPs can significantly increase the richness and diversity of gut microbiota,and restore the homeostasis of gut microbiota by inhibiting pathogenic bacteria and promoting probiotics.Hence,Cur/COS/SC NPs provide a safe,efficient,and feasible new strategy for IBD treatment.
基金Supported by 2023 Hebei Provincial Medical Scientific Research Project Plan,No.20231304.
文摘Colorectal cancer(CRC)with liver metastasis remains a significant therapeutic challenge,particularly in cases of postoperative recurrence.While transarterial chemoembolization(TACE)and targeted therapies have shown promise individually,the efficacy combining these for treating postoperative recurrent CRC with liver metastasis requires further investigation.AIM To evaluate the efficacy and safety of TACE combined with targeted therapies for postoperative recurrent CRC with liver metastasis.METHODS This observational study enrolled 75 patients with postoperative recurrent CRC accompanied by liver metastasis between January 2020 and December 2023.All patients received combined treatment with TACE and targeted therapy:Bevacizumab(40 patients,53.3%),cetuximab(25 patients,33.3%),or panitumumab(10 patients,13.3%).Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors 1.1 criteria,with overall survival(OS)and progression-free survival as the primary endpoints.Quality of life was assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire at baseline and after six months of treatment.RESULTS The median OS was 28 months(95%confidence interval:24-32 months),and the median progression-free survival was 12 months(95%confidence interval:10-14 months).Patients treated with bevacizumab showed significantly better survival outcomes than those treated with cetuximab/panitumumab(median OS,30 vs 24 months,P=0.015).The overall response rate was 58.7%,with a disease control rate of 86.7%.Quality of life scores improved significantly across all domains,with greater improvements observed in the bevacizumab group.Treatment-related adverse events were manageable,with grade 3-4 events occurring in 13.3%of the patients and no treatment-related mortality.CONCLUSION The combination of TACE with targeted therapy,particularly bevacizumab,has demonstrated promising efficacy and acceptable safety for the treatment of postoperative recurrent CRC with liver metastasis.This multimodal approach not only improved survival outcomes but also enhanced the patients’quality of life,suggesting its potential as a valuable treatment strategy for this challenging condition.
基金Supported by the Science and Engineering Research Board,No.PDF/2016/002730.
文摘Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy,radiotherapy and immunotherapy,which greatly impacts its lethality.The hedgehog(HH)signaling cascade,originally known for its roles in embryonic development,regulates growth,proliferation and cancer stem cell(CSC)self-renewal.The glioma-associated oncogene homolog(GLI)transcription factors play crucial roles in melanoma.However,oncogenic B-Raf proto-oncogene,serine/threonine kinase(BRAF)steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling.Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal.Interestingly,the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation,a process that is counteracted by the deacetylating actions of histone deacetylase(HDAC)1/2.Therefore,inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form,thus representing an attractive druggable target.Notably,both HDAC1 and HDAC2 are induced by HH signaling,creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2.Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma.However,the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation.In this article,we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling,and the pivotal role this interaction plays in the self-renewal of melanoma stem cells.A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.
基金supported by grants from the National Key Research and Development Program of China(No.2023YFA1800403)The Science and Technology Commission of Shanghai Municipality(No.21S11907800)Key Research and Development Program of Ningxia(No.2023BEG02010).
文摘Signal transducer and activator of transcription 3(STAT3)is a member of the transcription factors involved in regulating many physiological and pathological processes,such as cell proliferation,angiogenesis and immune escape.STAT3 has been identified as a potential therapeutic target for various cancers.Although numerous STAT3 inhibitors have been discovered and optimized to directly inhibit STAT3 activity,they are not yet authorized for clinical use and only a few have entered clinical trials.Furthermore,several proteolysis-targeting chimera(PROTAC)molecules with STAT3 degrading effects have been developed.The event-driven action of PROTAC overcome the drawbacks of STAT3,a traditional undruggable target,and addressed possible resistance to small-molecule inhibitors by degrading the entire STAT3 protein.In this review,we presented a brief introduction to STAT3 and its functions in various cancers,and systematically overviewed the pharmacological effects of inhibitors targeting different domains of STAT3 in the last three years,the structural characterization of the main scaffold,the design strategies,and the pharmacological activities of the substituents.Also,the binding patterns and interactions of some inhibitors with STAT3 were analyzed in detail and the recent advances in STAT3 degraders are also summarized.We anticipate that this perspective will contribute to the design and optimize more novel effective and specific STAT3 inhibitors or degraders for carcinoma treatment.
文摘Synovial sarcoma is a high-grade soft tissue malignancy characterized by a unique fusion gene known as SS18-SSX.The SS18-SSX fusion protein acts as an oncogenic driver of synovial sarcoma,and it has thus been commonly accepted that disruption of SS18-SSX function represents a therapeutic means of treating synovial sarcoma,but emerging evidence suggests that upon depletion of SS18-SSX,an anti-apoptotic signal surprisingly arises to protect synovial sarcoma cell survival.In this article,we discuss the controversial roles of SS18-SSX’s transcriptional activity in synovial sarcoma biology and outline a synergistic strategy for overcoming the resistance of synovial sarcoma cells to SS18-SSX targeted therapeutics.
基金National Natural Science Foundation of China,No.81871981Natural Science Foundation of Guangdong Province,No.2022A1515012348 and No.2023A1515010457.
文摘BACKGROUND The incidence of colon cancer has been progressively increasing over time,whereas penile metastasis of colon cancer has remained exceedingly uncommon.Since the prognosis for colon cancer with BRAF_(V600E)mutation is relatively unfavorable,further exploration and investigation are still required to develop treatment strategies for such rare cases.CASE SUMMARY About one year after surgery and chemotherapy,a 50-year-old patient with sigmoid colon cancer developed a mass at the base of the patient's penis,accompanied by severe tenderness and pain during urination.With disease progression,multiple metastatic nodules also emerged in other regions of the penis,including the coronal sulcus.The nodules located in the coronal sulcus were excised for histopathological examination.The histopathological findings revealed that the nodules were metastases originating from the sigmoid colon cancer,with a BRAF V600E mutation detected.This prompted a modification of the therapy regimen of cetuximab,dabrafenib and trametinib,which effectively held back the progression of penile metastasis in the patient.CONCLUSION Combining the BRAF/MEK-targeted therapy with cetuximab demonstrates a favorable therapeutic response in BRAF_(V600E)-mutated colon cancer with penile metastasis.
基金supported by Liaoning Xingliao Talent Project (Grant No. XLYC2007020)。
文摘Hemoptysis is a severe complication of pulmonary hypertension (PH) with a low in- cidence of 6%-11%.^([1-4])Although occurring in all forms of PH,it is more commonly seen in pulmonary arterial hypertension (PAH),associated with congenital heart disease (PAH-CHD).^([5,6])Since enlarged bronchial arteries are a frequent source of pulmonary bleeding,the primary treatment focuses on bronchial artery embolization (BAE),especially for chronic thromboembolic pulmonary hypertension (CTEPH) patients^([7,8]).However,there is disagreement regarding medical therapy,which has received little attention in the recently published PH guidelines.^([5,6])
基金This study was supported by National Natural Science Foundation of China (81572207)
文摘In recent years, with the deepening of research on the pathogenesis of renal cell carcinoma, anti-VEGF receptor inhibitors and mTOR inhibitors have been produced, making metastatic renal cell carcinoma into the era of targeted therapy. This article analyzes the latest research results at home and abroad. For patients with metastatic renal cell carcinoma, sunitinib and pizopanib are the first choice for targeted drugs. The drug dose starts from the standard dose, and the disease can be increased as appropriate when the disease progresses;When responding, it should be treated or reduced in time. When using an anti-VEGF inhibitor, the patient's blood pressure should be closely monitored. When the patient has high blood sugar or diabetes, anti-VEGF inhibitors should be preferred.
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.
文摘The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more options in targeted strategy were offered and can therefore be tailored in different clinical settings for individual patient.Targeting of the abnormal angiogenesis process is the first significant clinical breakthrough which revolutionized the treatment of advanced ovarian cancer,followed by the advent of poly-(ADP)-ribose polymerase(PARP)inhibitors.These two strategies represented by bevacizumab and olaparib respectively underwent tests of numerous clinical trials.In recent years,immune checkpoint inhibitors(ICIs)have been incorporated into the blueprint of ovarian cancer treatment though the effectiveness still left much to be desired.Herein,we systematically outlined recent advances in targeted therapy for ovarian cancer and summarized the landmark clinical trials for each targeted therapy including angiogenesis inhibitors,PARP inhibitors and ICIs.
基金Supported by a faculty research grant of Yonsei University College of Medicine for 2002,No.2002-06
文摘AIM:rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer.However, a sustained and high protein delivery is required to achieve the desired therapeutic effects.We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model. METHODS:rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines.To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin,Western blotting and ELISA were performed.The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor,etoposide,were evaluated in a mouse liver tumor model. RESULTS:Topoisomerase inhibitors,including camptothecin and etoposide,were found to increase the endostatin exPression level in vitro.The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active.In animal experiments,the combined therapy of topoisomerase inhibitor,etoposide with the rAAV-endostatin vector had the best tumor- suppressive effect and tumor foci were barely observed in livers of the treated mice.Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice.Finally,the mice treated With rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models. CONCLUSION:rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences[CIFMS](Grant Nos.2021-I2M-1-014 and 2022-I2M-2-002).
文摘Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.
文摘Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of patients.Accurate AML diagnosis was dependent on morphology,aided initially only by cytochemistry.Unlike acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and 1980s.The advent of reliable cytogenetics changed the entire prognostic outlook of AML.With karyotypic analysis,different groups of AML could be classified and stratified for various therapies.Unique mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the cells.All these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML patients.The efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic subtypes.Responses can be predicted and measured accurately.Such targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing toxicity.The focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of AML.This review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as those that are currently in development.
