Third-line treatment for metastatic colorectal cancer(mCRC)refers to subsequent therapeutic interventions following the failure or intolerance of first-and second-line treatments.This represents a critical challenge in clinical practice and a core focus of translational medicine research in recent years.With advancements in molecular typing technologies and the emergence of novel therapies,the third-line treatment strategy has evolved from traditional chemotherapy toward precision targeting and immunotherapy.A comprehensive literature search was conducted across PubMed,ClinicalTrials.gov database and American Society of Clinical Oncology(ASCO),European Society for Medical Oncology(ESMO)conference abstracts.Phase Ⅲ randomized controlled trials,phase Ⅰ/Ⅱ frontier clinical studies,and authoritative reviews were included,with an emphasis on data related to survival benefits,drug resistance mechanisms,and biomarkers.This review provided an in-depth analysis of significant progress in third-line treatment strategies for mCRC,encompassing standard therapies[regorafenib,fruquintinib,trifluridine/tipiracil,anti-epidermal growth factor receptor(EGFR)rechallenge therapy],targeted therapies(e.g.,BRAF V600E inhibitors,ERBB2 amplification inhibitors,KRAS G12C inhibitors)and immunotherapies[microsatellite instability-high(MSI-H)/deficient mismatch repair(dMMR),microsatellite stable(MSS)/proficient mismatch repair(pMMR)and target-immune combination therapies].Notable breakthroughs have been achieved in targeted therapies.Anti-EGFR rechallenge therapy extended the median overall survival(OS)to 17.3 months in RAS/BRAF wild-type patients identified through dynamic circulating tumor DNA(ctDNA)monitoring.However,drug resistance remains complex,with high secondary mutation rates necessitating further optimization of dynamic monitoring systems.For BRAF V600E mutations,triple therapy(encorafenib+binimetinib+cetuximab)demonstrated a median OS of 9.3 months[hazard ratio(HR)=0.52],surpassing conventional treatments.The combination of KRAS G12C inhibitor adagrasib with cetuximab achieved an objective response rate(ORR)of 34%and a median OS of 15.9 months,though tumor resistance continued to pose challenges.In the realm of immunotherapy,dual immunotherapy(nivolumab+ipilimumab)yielded a 4-year OS rate of 71%in MSI-H/dMMR patients.For MSS patients,immune-targeted combination strategies(e.g.,cabozantinib+atezolizumab)increased the ORR to 27.6%.Emerging therapies include artificial intelligence platforms for precision medicine,gut microbiota-based biomarkers and fecal microbiota transplantation,as well as advancements in chimeric antigen receptor-T(CAR-T)cell therapy.By summarizing the current status and progress of third-line treatment for mCRC,this review aims to inform clinical decision-making and guide future research directions.

Objective:This study aimed to retrospectively analyze the incidence and influencing factors of tricuspid regurgitation (TR) in the short term after pacemaker lead implantation at the Second Affiliated Hospital of Zhejiang University School of Medicine, so as to provide evidence for understanding pacemaker lead-related TR.Methods:Consecutive patients who underwent single- or dual-chamber permanent pacemaker implantation between June 2019 and December 2023 in the Department of Cardiology were enrolled. General clinical data and relevant parameters were collected. Changes in TR severity before and shortly after the procedure were assessed using echocardiography. TR progression was defined as an increase by one grade or more, and TR improvement as a decrease by one grade or more. Logistic regression analysis was employed to identify factors associated with TR progression.Results:A total of 219 patients were included (128 males, 91 females), with a mean age of 69.7 ± 11.2 years. The median follow-up time was 99 (26, 199) days. TR remained unchanged in 114 patients (52.1%), improved in 46 (21.0%)—including 36 (16.4%) with one-grade reduction, 9 (4.1%) with two-grade reduction, and 1 (0.5%) with three-grade reduction—and progressed in 59 patients (26.9%). Among those with progression, 51 (23.3%) had mild-to-moderate TR worsening by one grade, and 8 (3.7%) had moderate or worse TR worsening by at least two grades. Notably, one case involved lead perforation of the leaflet and two cases had lead impingement. Compared with the non-progression group ( n = 114), pacemaker indication (AV block vs. sick sinus syndrome), baseline left atrial diameter, pulmonary artery systolic pressure (PASP), and the severity of mitral regurgitation (MR) and TR were significantly associated with TR progression or improvement (all P < 0.05). Ordinal logistic regression analysis identified preoperative TR severity [ OR=10.57 (3.77–29.68), P < 0.001] and pacemaker indication [ OR=0.452 (0.222–0.918), P = 0.028] as independent predictors of postoperative TR progression. Patients with AV block were more likely to receive left bundle branch pacing ( P < 0.001), which may contribute to their lower risk of TR. Conclusions:Short-term progression of TR after pacemaker implantation is relatively common, although severe TR remains rare. Preoperative TR severity and pacemaker indication are independent predictors of short-term TR progression. The use of physiological pacing modalities may help reduce the incidence of TR following pacemaker lead implantation.

Objective:To investigate the feasibility of transcatheter edge-to-edge repair (TEER) using a short-clip strategy for patients with moderate-to-severe or greater degenerative mitral regurgitation caused by commissural prolapse.Methods:This retrospective study included patients with severe mitral regurgitation secondary to commissural prolapse who underwent TEER at the Second Affiliated Hospital of Zhejiang University School of Medicine between September 2022 and July 2024. Preoperative clinical and imaging data, intraoperative details, procedural outcomes, and 1-month postoperative follow-up results were collected.Results:A total of 19 patients were enrolled, aged (74.1±6.1) years, including 12 males. Among them, 10 patients had external commissural prolapse, and 9 patients had internal commissural prolapse. Preoperatively, all patients exhibited severe mitral regurgitation (4+), with an effective regurgitant orifice area of (0.55±0.17) cm2, left atrial volume of (104.77±36.57) ml, left ventricular end-diastolic volume of (102.29±32.47) ml, left ventricular end-diastolic dimension of (5.34±0.59) mm, and prolapse width of (1.18±0.34) cm. All procedures utilized short clips (NTR or NTW clips) to target the prolapsed commissural region and were completed successfully without intraoperative complications. At 1-month follow-up, no mortality, stroke, single-leaflet device attachment, myocardial infarction, or unplanned mitral reintervention occurred. Mitral regurgitation severity improved to ≤2+ in all patients, with left atrial volume of (74.49±33.83) ml, left ventricular end-diastolic volume of (85.90±18.05) ml, and left ventricular end-diastolic dimension of (4.93±0.37) mm (all P<0.05). Conclusion:The short-clip strategy, focusing on precise clip placement at the commissural interface, is feasible and effective for TEER in patients with severe mitral regurgitation due to commissural prolapse.

Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

COMPERA 2.0 risk stratification has been demonstrated to be useful in patients with precapillary pulmonary hypertension (PH). However, its suitability for patients at risk for post-capillary PH or PH associated with left heart disease (PH-LHD) is unclear. To investigate the use of COMPERA 2.0 in patients with severe aortic stenosis (SAS) undergoing transcatheter aortic valve replacement (TAVR), who are at risk for post-capillary PH, a total of 327 eligible SAS patients undergoing TAVR at our institution between September 2015 and November 2020 were included in the study. Patients were classified into four strata before and after TAVR using the COMPERA 2.0 risk score. The primary endpoint was all-cause mortality. Survival analysis was performed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression model. The study cohort had a median (interquartile range) age of 76 (70‒80) years and a pulmonary arterial systolic pressure of 33 (27‒43) mmHg (1 mmHg=0.133 kPa) before TAVR. The overall mortality was 11.9% during 26 (15‒47) months of follow-up. Before TAVR, cumulative mortality was higher with an increase in the risk stratum level (log-rank, both P<0.001); each increase in the risk stratum level resulted in an increased risk of death (hazard ratio (HR) 2.53, 95% confidential interval (CI) 1.54‒4.18, P<0.001), which was independent of age, sex, estimated glomerular filtration rate (eGFR), hemoglobin, albumin, and valve type (HR 1.76, 95% CI 1.01‒3.07, P=0.047). Similar results were observed at 30 d after TAVR. COMPERA 2.0 can serve as a useful tool for risk stratification in patients with SAS undergoing TAVR, indicating its potential application in the management of PH-LHD. Further validation is needed in patients with confirmed post-capillary PH by right heart catheterization.
Humans ; Aortic Valve Stenosis/complications* ; Aged ; Hypertension, Pulmonary/mortality* ; Male ; Female ; Transcatheter Aortic Valve Replacement ; Aged, 80 and over ; Risk Assessment/methods* ; Proportional Hazards Models ; Kaplan-Meier Estimate ; Retrospective Studies

Transcatheter aortic valve replacement (TAVR) has emerged as the standard treatment for severe aortic stenosis, demonstrating comparable efficacy to traditional surgery in low and intermediate-risk patients. However, the bioprosthetic valves utilized in TAVR have a limited lifespan, and bioprosthetic valve failure, including calcification, rupture or infection may develop, leading to poor clinical outcomes. Elevated blood pressure has been identified as a key factor in aortic valve calcification, and its role in bioprosthetic valve failure is gaining increasing attention. Hypertension may accelerate the calcification process and exacerbate valve failure due to increased mechanical stress on the valve, activation of the renin-angiotensin system, and enhanced thrombus formation. Furthermore, elevated blood pressure interacts with prosthesis mismatch and paravalvular leak, jointly affecting valve durability. This review explores the impact of elevated blood pressure on bioprosthetic valve calcification and failure after TAVR, and emphasizes the importance of blood pressure control, optimized preoperative assessment, and appropriate valve selection in reducing valve failures.
Humans ; Transcatheter Aortic Valve Replacement/adverse effects* ; Calcinosis/etiology* ; Bioprosthesis ; Heart Valve Prosthesis/adverse effects* ; Prosthesis Failure ; Aortic Valve Stenosis/surgery* ; Aortic Valve/surgery* ; Hypertension/physiopathology*

Tricuspid regurgitation associated with cardiac implantable electronic devices (CIED) constitutes a significant subset of secondary tricuspid regurgitation, characterized by a multifactorial etiology involving pacing lead-mediated mechanical interference and CIED-related systemic factors. The pathogenesis of CIED-related tricuspid regurgitation encompasses direct mechanical trauma or functional disruption of the tricuspid valve apparatus by pacing leads, pacing mode-induced hemodynamic alterations, and clinical risk factors such as permanent atrial fibrillation, apical pacing, and high right ventricular pacing burden. The natural progression and clinical outcomes of CIED-related tricuspid regurgitation parallel those of tricuspid regurgitation stemming from other etiologies. Advanced imaging modalities, including echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging, enable precise diagnosis and longitudinal assessment of CIED-related tricuspid regurgitation. Management strategies emphasize multidisciplinary collaboration as well as integration of preventive approaches-such as refined lead implantation techniques and tailored pacing modalities-with therapeutic interventions ranging from pharmacotherapy to surgical valve repair or replacement. This article reviews the current understanding of CIED-related tricuspid regurgitation to provide a reference for clinical practice and research.
Tricuspid Valve Insufficiency/diagnosis* ; Humans ; Defibrillators, Implantable/adverse effects* ; Pacemaker, Artificial/adverse effects*

Third-line treatment for metastatic colorectal cancer(mCRC)refers to subsequent therapeutic interventions following the failure or intolerance of first-and second-line treatments.This represents a critical challenge in clinical practice and a core focus of translational medicine research in recent years.With advancements in molecular typing technologies and the emergence of novel therapies,the third-line treatment strategy has evolved from traditional chemotherapy toward precision targeting and immunotherapy.A comprehensive literature search was conducted across PubMed,ClinicalTrials.gov database and American Society of Clinical Oncology(ASCO),European Society for Medical Oncology(ESMO)conference abstracts.Phase Ⅲ randomized controlled trials,phase Ⅰ/Ⅱ frontier clinical studies,and authoritative reviews were included,with an emphasis on data related to survival benefits,drug resistance mechanisms,and biomarkers.This review provided an in-depth analysis of significant progress in third-line treatment strategies for mCRC,encompassing standard therapies[regorafenib,fruquintinib,trifluridine/tipiracil,anti-epidermal growth factor receptor(EGFR)rechallenge therapy],targeted therapies(e.g.,BRAF V600E inhibitors,ERBB2 amplification inhibitors,KRAS G12C inhibitors)and immunotherapies[microsatellite instability-high(MSI-H)/deficient mismatch repair(dMMR),microsatellite stable(MSS)/proficient mismatch repair(pMMR)and target-immune combination therapies].Notable breakthroughs have been achieved in targeted therapies.Anti-EGFR rechallenge therapy extended the median overall survival(OS)to 17.3 months in RAS/BRAF wild-type patients identified through dynamic circulating tumor DNA(ctDNA)monitoring.However,drug resistance remains complex,with high secondary mutation rates necessitating further optimization of dynamic monitoring systems.For BRAF V600E mutations,triple therapy(encorafenib+binimetinib+cetuximab)demonstrated a median OS of 9.3 months[hazard ratio(HR)=0.52],surpassing conventional treatments.The combination of KRAS G12C inhibitor adagrasib with cetuximab achieved an objective response rate(ORR)of 34%and a median OS of 15.9 months,though tumor resistance continued to pose challenges.In the realm of immunotherapy,dual immunotherapy(nivolumab+ipilimumab)yielded a 4-year OS rate of 71%in MSI-H/dMMR patients.For MSS patients,immune-targeted combination strategies(e.g.,cabozantinib+atezolizumab)increased the ORR to 27.6%.Emerging therapies include artificial intelligence platforms for precision medicine,gut microbiota-based biomarkers and fecal microbiota transplantation,as well as advancements in chimeric antigen receptor-T(CAR-T)cell therapy.By summarizing the current status and progress of third-line treatment for mCRC,this review aims to inform clinical decision-making and guide future research directions.

[Objective]To investigate the effect of secreted frizzled related protein 1(SFRP1)via Wnt/β-catenin signaling pathway on calcification of vascular smooth muscle cell.[Methods]Primary human aortic vascular smooth muscle cells were transfected with SFRP1-specific small interfering RNA(siSFRP1)to knock down SFRP1 expression,transfected with lentiviral vector Lenti-Sfrp1 to overexpress SFRP1,and stimulated with 3 mmol/L sodium dihydrogen phosphate(Pi)to establish a cellular vascular calcification model.In vivo,a mouse model of acute vascular calcification was established using vitamin D3(VD3)treatment.The SFRP1 inhibitor WAY-316606 was administered intraperitoneally(0.5 mg/kg daily for 7 days).Aortic calcification was quantified by micro-computed tomography(micro-CT).Western blot analysis was performed to detect the expression of osteogenic differentiation markers(RUNX2 and BMP2),vascular smooth muscle cell contractile marker SM22α,and β-catenin protein in the Wnt signaling pathway.The severity of vascular calcification was evaluated through calcium content measurement and Alizarin Red staining.These approaches were employed to investigate the effect of SFRP1 on VSMC calcification.[Results]In the primary human vascular smooth muscle cell calcification model and the acute vascular calcification model,the expression of SFRP1 protein was significantly down-regulated(0.30±0.02,P=0.02;0.15±0.03,P=0.04).The expression of RUNX2(2.91±0.38,P＜0.05)was significantly up-regulated and SM22α(0.48±0.08,P＜0.05)were significantly down-regulated by small interfering RNA(siRNA),whereas the Wnt/β-catenin signaling pathway was also significantly activated(2.01±0.11,P=0.003).In vivo,inhibition of SFRP1 exacerbated aortic calcification and significantly up-regulated the expression of BMP2(3.11±0.55,P=0.04)and β-catenin(3.97±0.44,P=0.03).Lentiviral overexpression of SFRP1 significantly downregulated RUNX2(1.34±0.04,P=0.02)and β-catenin(1.06±0.06,P=0.04)expression,while upregulating SM22α(0.74±0.03,P=0.03).Quantitative alizarin red staining and calcium content assays demonstrated that SFRP1 overexpression significantly inhibited vascular smooth muscle cell calcification(1.36±0.08,P=0.000 6;1.51±0.03,P=0.002 1).[Conclusion]SFRP1 attenuates vascular smooth muscle cell calcification via the Wnt/β-catenin signaling pathway.

Objective:To investigate the feasibility of transcatheter edge-to-edge repair (TEER) using a short-clip strategy for patients with moderate-to-severe or greater degenerative mitral regurgitation caused by commissural prolapse.Methods:This retrospective study included patients with severe mitral regurgitation secondary to commissural prolapse who underwent TEER at the Second Affiliated Hospital of Zhejiang University School of Medicine between September 2022 and July 2024. Preoperative clinical and imaging data, intraoperative details, procedural outcomes, and 1-month postoperative follow-up results were collected.Results:A total of 19 patients were enrolled, aged (74.1±6.1) years, including 12 males. Among them, 10 patients had external commissural prolapse, and 9 patients had internal commissural prolapse. Preoperatively, all patients exhibited severe mitral regurgitation (4+), with an effective regurgitant orifice area of (0.55±0.17) cm2, left atrial volume of (104.77±36.57) ml, left ventricular end-diastolic volume of (102.29±32.47) ml, left ventricular end-diastolic dimension of (5.34±0.59) mm, and prolapse width of (1.18±0.34) cm. All procedures utilized short clips (NTR or NTW clips) to target the prolapsed commissural region and were completed successfully without intraoperative complications. At 1-month follow-up, no mortality, stroke, single-leaflet device attachment, myocardial infarction, or unplanned mitral reintervention occurred. Mitral regurgitation severity improved to ≤2+ in all patients, with left atrial volume of (74.49±33.83) ml, left ventricular end-diastolic volume of (85.90±18.05) ml, and left ventricular end-diastolic dimension of (4.93±0.37) mm (all P<0.05). Conclusion:The short-clip strategy, focusing on precise clip placement at the commissural interface, is feasible and effective for TEER in patients with severe mitral regurgitation due to commissural prolapse.