Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess sign...Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess significant immunomodulatory properties in addition to their established direct tumoricidal effects.Emerging immunotherapies have revolutionized the clinical management of various cancer types.Conventional therapy and immunotherapy have demonstrated remarkable clinical efficacy,leading to numerous ongoing clinical investiga-tions exploring their potential synergistic effects.However,trials investigating the combination of conventional therapy and immunotherapy have shown limited synergistic therapeutic efficacy.This unsatisfactory clinical outcome may be attributed to the suboptimal design of the combination approach and the inadequate understanding of the mechanisms and impacts of radiotherapy,chemotherapy,targeted ther-apy regimens(including dosing,timing,and administration route),and surgery on both cancer cells and the host immune system.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of conventional therapy alone or in combination with immunotherapy.We proposed that optimizing the dosing,timing,and route of administration of conventional therapies can enhance the synergistic efficacy of combination therapies,thus offering significant clinical advantages.展开更多
Neuroendocrine neoplasms(NENs)are relatively rare tumors that arise from peptidergic neurons and neuroendocrine cells.NENs are highly heterogeneous and can occur in any part of the body,with a particular prevalence in...Neuroendocrine neoplasms(NENs)are relatively rare tumors that arise from peptidergic neurons and neuroendocrine cells.NENs are highly heterogeneous and can occur in any part of the body,with a particular prevalence in the digestive system.NENs consist of a range of tumor types and the biological behaviors exhibit significant differences.NENs are classified into well-differentiated neuroendocrine tumors(NETs)and poorly differentiated neuroendocrine carcinomas(NECs).NETs can be further classified and graded into the following three categories:low-grade NETs,grade 1(NET G1);intermediate-grade NET G2;and high-grade NET G3.NECs include large cell-type NEC(LCNEC)and small cell-type NEC(SCNEC),both of which are considered high grade.Currently,the main treatments for advanced NENs are biological treatments,targeted therapy,chemotherapy,and newer treatments that are still under development,such as immunotherapy and peptide receptor radionuclide therapy(PRRT).However,owing to the rarity of NENs,pharmaceutical company investment is limited and few phase Ⅲ studies have targeted advanced NENs.Most current research consists of investigator-initiated phase Ⅰ and Ⅱ clinical trials or largescale retrospective studies.NEN treatment should be chosen carefully because it is cumbersome and complicated,as indicated above.Herein,we comprehensively summarize the clinical application status and research progress for advanced NEN treatment regimens,especially for advanced NETs,which may help to create awareness on NENs among medical professionals across specialties.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
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
BACKGROUND Recently,several endoscopic techniques have been used to improve the R0 resection rate of rectal neuroendocrine neoplasms(R-NENs).However,none of these methods can achieve 100%complete resection(CR),particu...BACKGROUND Recently,several endoscopic techniques have been used to improve the R0 resection rate of rectal neuroendocrine neoplasms(R-NENs).However,none of these methods can achieve 100%complete resection(CR),particularly in the vertical direction.Endoscopic full-thickness resection(EFTR)has proven to be an effective method for the treatment of submucosal tumors but is seldom utilized in the eradication of R-NENs.AIM To review cases of R-NENs removed using EFTR and to evaluate the safety and efficacy of this technique.METHODS This retrospective cohort study enrolled 160 patients with pathologically confirmed R-NENs,including 132 who underwent endoscopic submucosal dissection(ESD)and 28 who underwent EFTR.Lesions were categorized as<1 cm,1-2 cm,and>2 cm in size.CR rate,en bloc resection rate,operation time,and complications were evaluated.Subgroup analyses and follow-up were also performed.RESULTS EFTR achieved 100%CR rates for lesions<1 cm and 1-2 cm,compared with 67.0%and 50.0%,respectively,in the ESD group.En bloc resection and successful removal of the R-NENs were achieved in all patients.Meanwhile,EFTR showed performance comparable to ESD in terms of operation time,hospitalization cost,and postoperative adverse events,except for a one-day longer hospital stay.We also analyzed the invasion depth of R-NENs based on full-thickness specimens.The data showed that 80%of lesions(<1 cm)and 85.7%of lesions(1-2 cm)had invaded the SM3 level or deeper at the time of resection.For ESD specimens,46.6%(<1 cm)and 89.3%(1-2 cm)of lesions had infiltrated more than 2000μm beneath the muscularis mucosae.CONCLUSION EFTR has shown superior performance in the resection of small R-NENs compared with that of ESD.展开更多
BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnose...BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.展开更多
Neuroendocrine neoplasms(NENs)are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system.Gastroenteropancreatic NENs(GEP-NENs)are the most common subtype of NEN...Neuroendocrine neoplasms(NENs)are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system.Gastroenteropancreatic NENs(GEP-NENs)are the most common subtype of NENs.Historically,GEP-NENs have been regarded as infrequent and slow-growing malignancies;however,recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades.In addition,an increasing number of studies have proven that GEP-NENs result in a limited life expectancy.These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed.Therefore,there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs.In this review,we have summarized the limitations and recent advancements in our comprehension of the epidemiology,clinical presentations,pathology,molecular biology,diagnosis,and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.展开更多
Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC case...Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.展开更多
BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain lim...BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.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
The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagn...The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagnostic techniques,such as sentinel lymph node biopsy(SLNB),has markedly diminished the extent of surgery required for regional lymph nodes.展开更多
Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular v...Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular vesicles central to intercellular communication,have emerged as innovative tools in cancer diagnostics,prognosis,and therapy.Their role in modulating the immune response and the tumor microenvironment makes them particularly attractive for cancer immunotherapy.This review provides a comprehensive overview of exosome biology,with a focus on their role in immune modulation and potential therapeutic applications.We explore the progress and challenges of exosome-based immunotherapy in cancer,followed by a discussion on the current state of bladder cancer immunotherapy.Additionally,we highlight the roles of exosomes in bladder cancer,emphasizing their diagnostic and prognostic applications.Despite promising preclinical studies and a growing number of clinical trials in other cancers,exosome-based therapies remain underexplored in bladder cancer.We discuss the current clinical trials related to exosomes in bladder cancer and propose their potential future role in immunotherapy.Finally,we address the challenges and opportunities in translating exosome-based therapies from bench to bedside,emphasizing the need for further preclinical and clinical investigations.This review emphasized the potential of exosome-based immunotherapy as a transformative approach for bladder cancer diagnosis and treatment.展开更多
Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited re...Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.展开更多
Perivascular epithelioid cell tumors(PEComas)are a diverse group of mesenchymal neoplasms.While they have been described throughout the genitourinary system,PEComas are quite rare within the bladder.We present the cas...Perivascular epithelioid cell tumors(PEComas)are a diverse group of mesenchymal neoplasms.While they have been described throughout the genitourinary system,PEComas are quite rare within the bladder.We present the case of a 37-year-old male who presented in clot retention and was found to have a bladder PEComa.Staging images seemingly demonstrated solid tumor confinement to the bladder and pelvis.Intraoperative pathology revealed peritoneal metastasis.The patient underwent a pelvic mass excision and partial cystectomy.The patient had plans for adjuvant chemotherapy,but later returned to the hospital and passed away from acute hypoxic respiratory failure.展开更多
To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cr...To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cross-sectional pilot study provides valuable insights into the clinicopathological features and treatment outcomes of patients with NPM1-mutated myeloid neoplasms(MNs)with less than 20%bone marrow blasts[1].展开更多
Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereo...Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereotactic body radiotherapy(SBRT),and immunotherapy(IO)and explore their significance in the treatment response of patients with unresectable HCC.Methods:This is a prospective biomarker study of patients with unresectable HCC.The treatment was sequential TACE,SBRT(27.5-40 Gy/5 fractions),and IO.The treatment response was assessed according to modified Re-sponse Evaluation Criteria in Solid Tumors(mRECIST)by magnetic resonance imaging(MRI)after 6 months of treatment.Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts,in-cluding leukocytes,lymphocytes,neutrophils,monocytes,eosinophils,basophils,and platelets.Peripheral blood samples were collected at baseline and after TACE,SBRT,and IO for T-lymphocyte subtyping by flow cytometry.Generalized estimation equation was employed for longitudinal analyses.Results:A total of 35 patients with unresectable HCC were enrolled:23 patients in the exploratory cohort and 12 in the validation cohort.STIE circulating cells,especially lymphocytes,were heterogenous at baseline and changed differentially after TACE,SBRT,and IO in both cohorts.SBRT caused the greatest reduction of 0.7×10^(9)/L(95%CI:0.3×10^(9)/L-1.0×10^(9)/L,P<0.001)in lymphocytes;less reduction was associated with significantly better treatment response.The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+T cells(P=0.010),type 1 T helper(Th1)cells(P=0.007),and Th1/Th17 ratios(P=0.001)were significantly higher in responders,while regulatory T(Treg)cells(P=0.002),Th17 cells(P=0.047),and Th2/Th1 ratios(P=0.028)were significantly higher in non-responders.After treatment with TACE,SBRT and IO,T-lymphocyte lineage also changed differentially.More reductions were observed in CD25^(+)CD8^(+)T cells and CD127^(+)CD8^(+)T cells after SBRT in non-responders,while increases in natural killer T(NKT)cells after SBRT(10.4%vs.3.4%,P=0.001)and increases in the lymphocyte counts were noted during IO in responders.Conclusions:STIE cells are significant for treatment response,can be reshaped differentially after TACE,SBRT,and IO.The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25^(+)CD8^(+)T cells,CD127^(+)CD8^(+)T cells,and NKT cells,which also have significant effects on the ultimate treatment response after TACE-SBRT-IO(ClinicalTrails.gov identifier:GCOG0001/NCT05061342).展开更多
Photodynamic therapy(PDT)not only directly eradicates tumor cells but also boosts immunogenicity,promoting antigen presentation and immune cell infiltration.However,the robust antioxidant defense mechanisms within tum...Photodynamic therapy(PDT)not only directly eradicates tumor cells but also boosts immunogenicity,promoting antigen presentation and immune cell infiltration.However,the robust antioxidant defense mechanisms within tumor cells significantly weaken the efficacy of photodynamic immunotherapy.Herein,a supramolecular hybrid nanoassembly is constructed by exploring the synergistic effects of the photodynamic photosensitizer(pyropheophorbide a,PPa)and the ferroptosis inducer(erastin).The erastinmediated inhibition of system X_(c)−significantly downregulates glutathione(GSH)expression,amplifying intracellular oxidative stress,leading to pronounced cell apoptosis,and promoting the release of damageassociated molecular patterns(DAMPs).Additionally,the precise cooperation of PPa and erastin enhances ferroptosis efficiency,exacerbating the accumulation of lipid peroxides(LPOs).Ultimately,LPOs serve as a“find me”signal,while DMAPs act as an“eat me”signal,collectively promoting dendritic cell maturation,enhancing infiltration of the cytotoxic T lymphocytes,and eliciting a robust immune response.This study opens new horizons for enhancing tumor immunotherapy through simultaneous ferroptosis-PDT.展开更多
Appendiceal mucinous neoplasms(AMNs)are rare tumors originating from mucin-producing epithelial cells of the appendix.They can exhibit both benign and malignant behavior.They are often incidentally discovered during a...Appendiceal mucinous neoplasms(AMNs)are rare tumors originating from mucin-producing epithelial cells of the appendix.They can exhibit both benign and malignant behavior.They are often incidentally discovered during appendectomy.Clinical presentation ranges from asymptomatic to mimicking acute appendicitis.Histologically,noninvasive AMNs are classified as low-grade AMNs(LAMNs)or high-grade AMNs(HAMNs),whereas invasive tumors are categorized as mucinous adenocarcinomas.Although LAMNs and HAMNs are generally nonmalignant,rupture can lead to pseudomyxoma peritonei(PMP).Surgical resection is the primary diagnostic and therapeutic approach,with intraoperative assessment to prevent rupture.Treatment strategies vary based on findings and include appendectomy,right hemicolectomy,and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.Histological diagnosis relies on mucin detection,and immunohistochemical markers such as cytokeratin 20(diffusely positive),cytokeratin 7(often negative),mucin 5AC,and special ATrich sequence-binding protein 2 assist in characterization.Molecular profiling frequently identifies KRAS,GNAS,and TP53 mutations.KRAS mutations are generally associated with a favorable prognosis,whereas GNAS and TP53 mutations correlate with poorer survival outcomes.These findings highlight the potential role of molecular profiling in guiding treatment strategies for AMN and PMP.展开更多
Objective Hepatocellular carcinoma(HCC)is sensitive to ferroptosis,a new form of programmed cell death that occurs in most tumor types.However,the mechanism through which ferroptosis modulates HCC remains unclear.This...Objective Hepatocellular carcinoma(HCC)is sensitive to ferroptosis,a new form of programmed cell death that occurs in most tumor types.However,the mechanism through which ferroptosis modulates HCC remains unclear.This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy.Methods Using clinicopathological parameters and bioinformatic techniques,we comprehensively examined the expression of FANCD2 macroscopically and microcosmically.We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death.Results FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration.As an independent risk factor for HCC,a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade.Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism.Conclusion To the best of our knowledge,this is the first study to comprehensively elucidate the oncogenic role of FANCD2.FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC;hence,it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.展开更多
Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a ...Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.展开更多
基金supported by the National Science Foundation of China(No.82172726)the Youth Project of Science and Technology Department of Shanxi Province(No.202203021212105)the Research Project Supported by the Shanxi Scholarship Council of China(2021-156).
文摘Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells,reducing the overall tumor burden.Increasing evidence suggests that conventional therapies possess significant immunomodulatory properties in addition to their established direct tumoricidal effects.Emerging immunotherapies have revolutionized the clinical management of various cancer types.Conventional therapy and immunotherapy have demonstrated remarkable clinical efficacy,leading to numerous ongoing clinical investiga-tions exploring their potential synergistic effects.However,trials investigating the combination of conventional therapy and immunotherapy have shown limited synergistic therapeutic efficacy.This unsatisfactory clinical outcome may be attributed to the suboptimal design of the combination approach and the inadequate understanding of the mechanisms and impacts of radiotherapy,chemotherapy,targeted ther-apy regimens(including dosing,timing,and administration route),and surgery on both cancer cells and the host immune system.Here,we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of conventional therapy alone or in combination with immunotherapy.We proposed that optimizing the dosing,timing,and route of administration of conventional therapies can enhance the synergistic efficacy of combination therapies,thus offering significant clinical advantages.
文摘Neuroendocrine neoplasms(NENs)are relatively rare tumors that arise from peptidergic neurons and neuroendocrine cells.NENs are highly heterogeneous and can occur in any part of the body,with a particular prevalence in the digestive system.NENs consist of a range of tumor types and the biological behaviors exhibit significant differences.NENs are classified into well-differentiated neuroendocrine tumors(NETs)and poorly differentiated neuroendocrine carcinomas(NECs).NETs can be further classified and graded into the following three categories:low-grade NETs,grade 1(NET G1);intermediate-grade NET G2;and high-grade NET G3.NECs include large cell-type NEC(LCNEC)and small cell-type NEC(SCNEC),both of which are considered high grade.Currently,the main treatments for advanced NENs are biological treatments,targeted therapy,chemotherapy,and newer treatments that are still under development,such as immunotherapy and peptide receptor radionuclide therapy(PRRT).However,owing to the rarity of NENs,pharmaceutical company investment is limited and few phase Ⅲ studies have targeted advanced NENs.Most current research consists of investigator-initiated phase Ⅰ and Ⅱ clinical trials or largescale retrospective studies.NEN treatment should be chosen carefully because it is cumbersome and complicated,as indicated above.Herein,we comprehensively summarize the clinical application status and research progress for advanced NEN treatment regimens,especially for advanced NETs,which may help to create awareness on NENs among medical professionals across specialties.
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 National Natural Science Foundation of China,No.82004298Jiangsu Graduate Research and Practice Innovation Program,China,No.KYCX23_2090.
文摘BACKGROUND Recently,several endoscopic techniques have been used to improve the R0 resection rate of rectal neuroendocrine neoplasms(R-NENs).However,none of these methods can achieve 100%complete resection(CR),particularly in the vertical direction.Endoscopic full-thickness resection(EFTR)has proven to be an effective method for the treatment of submucosal tumors but is seldom utilized in the eradication of R-NENs.AIM To review cases of R-NENs removed using EFTR and to evaluate the safety and efficacy of this technique.METHODS This retrospective cohort study enrolled 160 patients with pathologically confirmed R-NENs,including 132 who underwent endoscopic submucosal dissection(ESD)and 28 who underwent EFTR.Lesions were categorized as<1 cm,1-2 cm,and>2 cm in size.CR rate,en bloc resection rate,operation time,and complications were evaluated.Subgroup analyses and follow-up were also performed.RESULTS EFTR achieved 100%CR rates for lesions<1 cm and 1-2 cm,compared with 67.0%and 50.0%,respectively,in the ESD group.En bloc resection and successful removal of the R-NENs were achieved in all patients.Meanwhile,EFTR showed performance comparable to ESD in terms of operation time,hospitalization cost,and postoperative adverse events,except for a one-day longer hospital stay.We also analyzed the invasion depth of R-NENs based on full-thickness specimens.The data showed that 80%of lesions(<1 cm)and 85.7%of lesions(1-2 cm)had invaded the SM3 level or deeper at the time of resection.For ESD specimens,46.6%(<1 cm)and 89.3%(1-2 cm)of lesions had infiltrated more than 2000μm beneath the muscularis mucosae.CONCLUSION EFTR has shown superior performance in the resection of small R-NENs compared with that of ESD.
基金Supported by National Key Technology Research and Developmental Program of China,No.2022YFC2704400 and No.2022YFC2704405.
文摘BACKGROUND Mitochondrial genes are involved in tumor metabolism in ovarian cancer(OC)and affect immune cell infiltration and treatment responses.AIM To predict prognosis and immunotherapy response in patients diagnosed with OC using mitochondrial genes and neural networks.METHODS Prognosis,immunotherapy efficacy,and next-generation sequencing data of patients with OC were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.Mitochondrial genes were sourced from the MitoCarta3.0 database.The discovery cohort for model construction was created from 70% of the patients,whereas the remaining 30% constituted the validation cohort.Using the expression of mitochondrial genes as the predictor variable and based on neural network algorithm,the overall survival time and immunotherapy efficacy(complete or partial response)of patients were predicted.RESULTS In total,375 patients with OC were included to construct the prognostic model,and 26 patients were included to construct the immune efficacy model.The average area under the receiver operating characteristic curve of the prognostic model was 0.7268[95% confidence interval(CI):0.7258-0.7278]in the discovery cohort and 0.6475(95%CI:0.6466-0.6484)in the validation cohort.The average area under the receiver operating characteristic curve of the immunotherapy efficacy model was 0.9444(95%CI:0.8333-1.0000)in the discovery cohort and 0.9167(95%CI:0.6667-1.0000)in the validation cohort.CONCLUSION The application of mitochondrial genes and neural networks has the potential to predict prognosis and immunotherapy response in patients with OC,providing valuable insights into personalized treatment strategies.
基金supported by the National Natural Science Foundation of China(82104596)the Shenzhen Key Medical Discipline Construction Fund&Sanming Project of Medicine in Shenzhen(SZSM202111002)+1 种基金the Medicine-Engineering Interdisciplinary Research Foundation of Shenzhen University(2023YG019)the Shenzhen Science and Technology Program(GJHZ20220913143005010)。
文摘Neuroendocrine neoplasms(NENs)are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system.Gastroenteropancreatic NENs(GEP-NENs)are the most common subtype of NENs.Historically,GEP-NENs have been regarded as infrequent and slow-growing malignancies;however,recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades.In addition,an increasing number of studies have proven that GEP-NENs result in a limited life expectancy.These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed.Therefore,there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs.In this review,we have summarized the limitations and recent advancements in our comprehension of the epidemiology,clinical presentations,pathology,molecular biology,diagnosis,and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.
文摘Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.
基金Supported by the National Natural Science Foundation of China,No.82072732.
文摘BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.
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supported by grants from the National Natural Science Foundation of China(Grant Nos.81672638 and W2421095)National Natural Science Foundation of Shandong Province(Grant No.ZR2024LMB011)Collaborative Academic Innovation Project of Shandong Cancer Hospital(Grant No.GF003)。
文摘The principal breast cancer treatment approach has long been surgical removal of the primary breast lesions and regional lymph nodes,particularly the axillary lymph nodes.However,the advent of minimally invasive diagnostic techniques,such as sentinel lymph node biopsy(SLNB),has markedly diminished the extent of surgery required for regional lymph nodes.
基金funded by start-up funds from the University of Chicago.
文摘Bladder cancer remains a significant global health challenge,requiring repeated treatments and surveillance and potentially morbid therapies,particularly in advanced and recurrent stages.Exosomes,small extracellular vesicles central to intercellular communication,have emerged as innovative tools in cancer diagnostics,prognosis,and therapy.Their role in modulating the immune response and the tumor microenvironment makes them particularly attractive for cancer immunotherapy.This review provides a comprehensive overview of exosome biology,with a focus on their role in immune modulation and potential therapeutic applications.We explore the progress and challenges of exosome-based immunotherapy in cancer,followed by a discussion on the current state of bladder cancer immunotherapy.Additionally,we highlight the roles of exosomes in bladder cancer,emphasizing their diagnostic and prognostic applications.Despite promising preclinical studies and a growing number of clinical trials in other cancers,exosome-based therapies remain underexplored in bladder cancer.We discuss the current clinical trials related to exosomes in bladder cancer and propose their potential future role in immunotherapy.Finally,we address the challenges and opportunities in translating exosome-based therapies from bench to bedside,emphasizing the need for further preclinical and clinical investigations.This review emphasized the potential of exosome-based immunotherapy as a transformative approach for bladder cancer diagnosis and treatment.
基金supported by the Natural Scientific Foundation of Zhejiang Province,China(Grant No.LTGY23H160007).
文摘Objective:Immune checkpoint inhibitors(ICIs)have demonstrated substantial efficacy in patients with advanced non-small cell lung cancer(NSCLC).However,the optimal duration of ICI therapy remains unclear,and limited real-world data are available.The aim of this study was to evaluate the relationship between ICI therapy duration and overall survival(OS)in patients who achieved varying best overall response(BOR)during ICI treatment,and to compare patients treated for 6 to 18 months vs.at least 18 months.Methods:This retrospective cohort study included adult patients diagnosed with advanced NSCLC who received ICI therapy at the Zhejiang Cancer Hospital between 2017 and 2022.Data collection ended on May 1,2024,and statistical analysis was performed between May and June 2024.Results:Using strict entry criteria,we screened 487 patients with advanced NSCLC and identified 134 eligible patients.Among these patients,the median durations of immunotherapy and follow-up were 24.57 months and 43.60 months,respectively.The objective response rate(ORR)was 58.2%,and the median progression-free survival(PFS)was 10.6 months.Median OS was not reached.At the last follow-up,54 patients had no disease progression,and 118 patients remained alive.Patients treated with ICI therapy for≥18 months had superior survival to those treated for 6 to 18 months(P=0.039).Further analysis revealed that the survival benefit was associated with BOR during ICI therapy.Specifically,patients achieving complete response/partial response(CR/PR)who received≥18 months of ICI therapy had a trend toward longer median OS than those treated for 6 to 18 months,but the difference did not reach statistical significance(P=0.177).Patients with stable disease(SD)who received≥18 months of ICI therapy had a statistically longer median OS than those treated for 6 to 18 months(P=0.019).Among patients treated with ICIs for≥18 months,24 continued with ICI-based therapy and achieved a median PFS2 of 6.67 months,an ORR of 33.3%,and a disease control rate(DCR)of 83.3%.Conclusions:This study provides real-world evidence and novel insights into the need for continuing ICI therapy beyond 18 months in patients with advanced NSCLC who do not exhibit progressive disease.For patients achieving SD during ICI therapy,a treatment duration of at least 18 months appears appropriate.For patients achieving CR/PR,treatment decisions should be individualized according to patient-specific circumstances.However,owing to the retrospective study design,potential selection bias and confounding factors might have influenced the results.Therefore,our findings require further validation in prospective clinical studies.
文摘Perivascular epithelioid cell tumors(PEComas)are a diverse group of mesenchymal neoplasms.While they have been described throughout the genitourinary system,PEComas are quite rare within the bladder.We present the case of a 37-year-old male who presented in clot retention and was found to have a bladder PEComa.Staging images seemingly demonstrated solid tumor confinement to the bladder and pelvis.Intraoperative pathology revealed peritoneal metastasis.The patient underwent a pelvic mass excision and partial cystectomy.The patient had plans for adjuvant chemotherapy,but later returned to the hospital and passed away from acute hypoxic respiratory failure.
文摘To the Editor,We have read the article by Gener-Ricos et al.titled"NPM1-mutated myeloid neoplasms are a unique entity not defined by bone marrow blast percentage",published in Cancer[1].This retrospective,cross-sectional pilot study provides valuable insights into the clinicopathological features and treatment outcomes of patients with NPM1-mutated myeloid neoplasms(MNs)with less than 20%bone marrow blasts[1].
基金supported by the Shenzhen Science and Technology Program(grant number:KQTD20180411185028798).
文摘Background:The role of systemic tumor immune environment(STIE)is unclear in hepatocellular carcinoma(HCC).This study aimed to exam the cells in the STIE,their changes after transarterial chemoembolisation(TACE),stereotactic body radiotherapy(SBRT),and immunotherapy(IO)and explore their significance in the treatment response of patients with unresectable HCC.Methods:This is a prospective biomarker study of patients with unresectable HCC.The treatment was sequential TACE,SBRT(27.5-40 Gy/5 fractions),and IO.The treatment response was assessed according to modified Re-sponse Evaluation Criteria in Solid Tumors(mRECIST)by magnetic resonance imaging(MRI)after 6 months of treatment.Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts,in-cluding leukocytes,lymphocytes,neutrophils,monocytes,eosinophils,basophils,and platelets.Peripheral blood samples were collected at baseline and after TACE,SBRT,and IO for T-lymphocyte subtyping by flow cytometry.Generalized estimation equation was employed for longitudinal analyses.Results:A total of 35 patients with unresectable HCC were enrolled:23 patients in the exploratory cohort and 12 in the validation cohort.STIE circulating cells,especially lymphocytes,were heterogenous at baseline and changed differentially after TACE,SBRT,and IO in both cohorts.SBRT caused the greatest reduction of 0.7×10^(9)/L(95%CI:0.3×10^(9)/L-1.0×10^(9)/L,P<0.001)in lymphocytes;less reduction was associated with significantly better treatment response.The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+T cells(P=0.010),type 1 T helper(Th1)cells(P=0.007),and Th1/Th17 ratios(P=0.001)were significantly higher in responders,while regulatory T(Treg)cells(P=0.002),Th17 cells(P=0.047),and Th2/Th1 ratios(P=0.028)were significantly higher in non-responders.After treatment with TACE,SBRT and IO,T-lymphocyte lineage also changed differentially.More reductions were observed in CD25^(+)CD8^(+)T cells and CD127^(+)CD8^(+)T cells after SBRT in non-responders,while increases in natural killer T(NKT)cells after SBRT(10.4%vs.3.4%,P=0.001)and increases in the lymphocyte counts were noted during IO in responders.Conclusions:STIE cells are significant for treatment response,can be reshaped differentially after TACE,SBRT,and IO.The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25^(+)CD8^(+)T cells,CD127^(+)CD8^(+)T cells,and NKT cells,which also have significant effects on the ultimate treatment response after TACE-SBRT-IO(ClinicalTrails.gov identifier:GCOG0001/NCT05061342).
基金financially supported by the National Natural Science Foundation of China(No.82161138029)the Basic Research Projects of Liaoning Provincial Department of Education(No.LJKZZ20220109)the Shenyang Youth Science and Technology Innovation Talents Program(No.RC210452).
文摘Photodynamic therapy(PDT)not only directly eradicates tumor cells but also boosts immunogenicity,promoting antigen presentation and immune cell infiltration.However,the robust antioxidant defense mechanisms within tumor cells significantly weaken the efficacy of photodynamic immunotherapy.Herein,a supramolecular hybrid nanoassembly is constructed by exploring the synergistic effects of the photodynamic photosensitizer(pyropheophorbide a,PPa)and the ferroptosis inducer(erastin).The erastinmediated inhibition of system X_(c)−significantly downregulates glutathione(GSH)expression,amplifying intracellular oxidative stress,leading to pronounced cell apoptosis,and promoting the release of damageassociated molecular patterns(DAMPs).Additionally,the precise cooperation of PPa and erastin enhances ferroptosis efficiency,exacerbating the accumulation of lipid peroxides(LPOs).Ultimately,LPOs serve as a“find me”signal,while DMAPs act as an“eat me”signal,collectively promoting dendritic cell maturation,enhancing infiltration of the cytotoxic T lymphocytes,and eliciting a robust immune response.This study opens new horizons for enhancing tumor immunotherapy through simultaneous ferroptosis-PDT.
文摘Appendiceal mucinous neoplasms(AMNs)are rare tumors originating from mucin-producing epithelial cells of the appendix.They can exhibit both benign and malignant behavior.They are often incidentally discovered during appendectomy.Clinical presentation ranges from asymptomatic to mimicking acute appendicitis.Histologically,noninvasive AMNs are classified as low-grade AMNs(LAMNs)or high-grade AMNs(HAMNs),whereas invasive tumors are categorized as mucinous adenocarcinomas.Although LAMNs and HAMNs are generally nonmalignant,rupture can lead to pseudomyxoma peritonei(PMP).Surgical resection is the primary diagnostic and therapeutic approach,with intraoperative assessment to prevent rupture.Treatment strategies vary based on findings and include appendectomy,right hemicolectomy,and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.Histological diagnosis relies on mucin detection,and immunohistochemical markers such as cytokeratin 20(diffusely positive),cytokeratin 7(often negative),mucin 5AC,and special ATrich sequence-binding protein 2 assist in characterization.Molecular profiling frequently identifies KRAS,GNAS,and TP53 mutations.KRAS mutations are generally associated with a favorable prognosis,whereas GNAS and TP53 mutations correlate with poorer survival outcomes.These findings highlight the potential role of molecular profiling in guiding treatment strategies for AMN and PMP.
基金supported by Beijing Science and Technology Commission(grant number Z211100002921059)National Science and Technology Major Projects of China(2017ZX10201201-001-006,2017ZX10201201-002-006,and 2018ZX10715-005-003-005)+5 种基金Digestive Medical Coordinated Development Center of Beijing Hospital Authority(XXZ0302 and XXT28)National Key R&D Program China(2022YFC2603505)Beijing Hospital Authority Clinical Medicine Development with Special Funding Support(XMLX 202127)High-Level Public Health Technical Personnel Training Program of Beijing the Municipal Health Commission(2022-3-050)Capital Health Research and Development of Special(2022-1-2172)HBV infection,Clinical Cure and Immunology Joint Laboratory for Clinical Medicine Capital Medical University.
文摘Objective Hepatocellular carcinoma(HCC)is sensitive to ferroptosis,a new form of programmed cell death that occurs in most tumor types.However,the mechanism through which ferroptosis modulates HCC remains unclear.This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy.Methods Using clinicopathological parameters and bioinformatic techniques,we comprehensively examined the expression of FANCD2 macroscopically and microcosmically.We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death.Results FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration.As an independent risk factor for HCC,a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade.Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism.Conclusion To the best of our knowledge,this is the first study to comprehensively elucidate the oncogenic role of FANCD2.FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC;hence,it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
基金supported by the Henan Provincial Science and Technology Research Project(grant number 221100310100 to Z.L.and X.H.).
文摘Human microbiota constitute a complex and dynamic community that interacts with the innate immunity of the host at various anatomical sites,influencing both physiological and pathological states.In individuals with a genetic predisposition,disruptions to the“innate immunity‒microbiota”axis appear to rewire immune responses within the tumor microenvironment(TME),thereby driving cancer pathogenesis.This review summarizes the intricate crosstalk between the microbiota and innate immunity in both healthy and cancerous states,focusing on the modulation of immune recognition and polarization during tumor progression,including immune escape,barrier disruption,chronic inflammatory transformation,and angiogenesis in the initiation phase,as well as the regulation of local invasion,vascular invasion,and pre-metastatic ecological niche formation involved in the metastatic phase.This review also highlights recent advances and challenges in leveraging microbiota for cancer immunotherapy,covering innovations in bacteriophages,genetically engineered probiotics,and bioinformatic applications.Moreover,this review proposes potential approaches to enhance therapeutic efficacy by targeting innate immunity‒microbiota interactions.Further mechanistic insights into these interactions may pave the way for developing innovative microbiota-based cancer immunotherapies.
