The phase 3 SYMPATICO study included an open-label cohort to evaluate the efficacy and safety of first-line ibrutinib plus venetoclax in patients with non-blastoid mantle cell lymphoma (MCL) ≥65 years (n=65), or ≥18 years with a TP53 mutation (TP53m) (n=11). Eligible patients received oral ibrutinib 560 mg once daily and venetoclax (5-week ramp-up to 400 mg once daily) for 2 years, then single-agent ibrutinib 560 mg until disease progression or unacceptable toxicity. In total, 78 patients were enrolled. With median time on study of 40.5 months (range, 0.6+ to 46.9), the complete response (CR) rate was 69% (95% CI, 58-79), and the overall response rate was 95% (95% CI, 87-99). The median duration of response was 37.1 months (95% CI, 30.3-not estimable [NE]). Median progression-free survival (mPFS) was 40.2 months (95% CI, 29.4-NE); median overall survival (OS) was not reached (3-year OS rate, 79% [95% CI, 68-86]). In patients ≥65 years, CR rates were 76% (no TP53m) and 44% (with TP53m), mPFS was 40.2 and 22.0 months, and 3-year OS was 85% and 66%, respectively. In adult patients <65 years (with TP53m), the CR rate was 73%, mPFS was 15.4 months, and 3-year OS was 73%. The most common treatment-emergent adverse events were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). First-line ibrutinib plus venetoclax showed promising efficacy, with high CR rates and durable remissions, in patients with previously untreated non-blastoid MCL and may be an option for patients ≥65 years or patients of any age with TP53m. NCT03112174.
Chronic inflammation is a prolonged immune response that leads to the development of numerous diseases, including arthritis, cardiovascular disorders, and metabolic syndromes. Currently, synthetic anti-inflammatory medications are widely used to treat chronic inflammation due to their high efficacy. However, their long-term use is often associated with serious side effects. This led to an urgent need to explore the anti-inflammatory drugs that are more efficient and exhibit few or no adverse effects. Several studies have revealed the anti-inflammatory properties of various plants. However, most focus primarily on listing anti-inflammatory plants and their phytoconstituents, with limited scientific validation. In addition, no compiled data is available that includes comprehensive pre-clinical and clinically validated studies of anti-inflammatory plants and their phytoconstituents. The current study aims to provide a comprehensive overview of chronic inflammation and its management, addressing the challenges of synthetic anti-inflammatory medications, and investigating the potential of plants and their phytoconstituents as anti-inflammatory agents, with scientific validation through preclinical and clinical studies. Literature was searched, analyzed, and compiled from PubMed, ScienceDirect, and Google Scholar databases. The search terms used included anti-inflammatory plants, phytoconstituents, in-vitro and in-vivo, anti-inflammatory drugs, inflammation mechanism, etc., and several combinations of these keywords. A total of 297 publications published between August 1978 and February 2026 were included in this review. Overall, this review provides a detailed mechanistic explanation of plant-derived anti-inflammatory drugs for the treatment of chronic inflammation.
Endoglin (ENG) is expressed in liver sinusoidal endothelial cells (LSECs), where it regulates endothelial activation and inflammation. The 7-ketocholesterol (7-K), a cholesterol oxidation product, accumulates in the liver and induces endothelial dysfunction. ENG has been shown to play an important role in adhesion processes in other endothelial models but its role in LSECs upon 7-K exposure remains unclear. We hypothesized that 7-K treatment of LSECs would confirm the critical role of ENG in endothelial activation, potentially outweighing the contributions of the cell adhesion molecules VCAM-1 and ICAM-1. Human LSECs were exposed to 25 µM 7-K. Protein expression and monocyte adhesion were assessed by flow cytometry, and soluble ENG was measured by ELISA. 7-K reduced ENG expression, while ICAM-1 was markedly upregulated. 7-K increased monocyte adhesion to LSECs, which was abrogated by ICAM-1, but not by ENG neutralization. We showed that 7-K promotes a pro-inflammatory phenotype defined by ICAM-1, rather than ENG. Thus, we propose that individual roles of ENG, ICAM-1, and VCAM-1 must be carefully considered when studying endothelial dysfunction.
The rising wave of antimicrobial resistant organisms, together with the lack of novel group of antibacterial agents, represents a major concern in modern medicine. This study aims to investigate the anti-staphylococcal potential of two semi-synthetic derivatives of naturally occurring nitrogen-containing molecules (1 nm and 2 nm). The two semi-synthetic analogues were evaluated against reference bacterial strains and clinical bacterial isolates. Furthermore, the most active compound, 1 nm, was subjected to synergistic activity screening with the commercial antibiotics against MRSA. The toxicity profile of 1 nm was further explored using in vitro (HepG2 and HK-2 cells) and in vivo (Galleria mellonella) models, accompanied by an insight into its in silico physicochemical characteristics and cytotoxicity. Our results suggest that this derivative possesses promising activity against clinically relevant staphylococci, while showing a favourable safety and bioavailability profile. In addition, this compound showed synergistic or additive effects in combination with several clinically important antibiotics. 1 nm demonstrates promising adjuvant anti-staphylococcal activity, with a favourable safety profile and an additive interaction with the last-resort antibiotic linezolid, supporting its potential to mitigate resistance development within combination strategies.
Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for metastatic renal cell carcinoma (mRCC). Nivolumab monotherapy remains an established option in previously treated patients; however, real-world data (RWD) from Central and Eastern Europe are limited. We conducted a retrospective multicenter cohort study using data from the RENIS II registry, including 501 patients with mRCC treated with nivolumab in the second or later line between 2013 and 2025 across the Czech Republic and Slovakia. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), safety, and exploratory analyses of baseline inflammatory indices (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]). Median OS was 24.2 months and median PFS was 8.6 months. The ORR was 28.8% and the DCR was 61.2% in the response-evaluable population. Grade 3/4 adverse events were recorded in 11.4% of patients. In exploratory analyses, higher baseline NLR, PLR, and SII were associated with inferior survival in univariable analyses. In multivariable models, NLR and PLR remained independently associated with OS and PFS, whereas SII did not retain independent prognostic significance. In this large multicenter real-world cohort, nivolumab monotherapy demonstrated consistent clinical activity and manageable toxicity in previously treated mRCC, with outcomes comparable to those reported in clinical trials and other European real-world studies. Baseline inflammatory indices, particularly NLR and PLR, showed potential prognostic value and warrant further investigation.
The development of bioactive peptides derived from food is crucial for alleviating nonalcoholic fatty liver disease. As a traditional meat product, Jinhua ham is rich in various bioactive peptides and has anti-inflammatory and liver-protective effects. This study aims to isolate novel dual-function peptides with anti-inflammatory and hepatoprotective properties from Jinhua ham hydrolysates. Potential target peptides were identified through mass spectrometry and computational virtual screening, followed by molecular docking and molecular dynamics simulations. In vitro, 1 mg/mL of NWRPPQPIK (NW-9) reduced AST, ALT, IL-1β, IL-6, and TNF-α levels by 51.66%, 54.08%, 24.66%, 33.71%, and 15.79%, respectively. In vivo, NW-9 also demonstrated therapeutic effects. This is because NW-9 can alleviate liver inflammatory damage caused by the cGAS-STING pathway. These findings provide a theoretical basis for the development of Jinhua ham-derived dual-function peptides with anti-inflammatory and hepatoprotective properties in the functional food industry, further expanding the high-value utilization of food-derived bioactive peptides.
To evaluate the association between bevacizumab use and fistula occurrence in patients with metastatic or persistent cervical cancer (CC) treated with definitive chemoradiotherapy (CRT). We retrospectively analyzed 101 patients with FIGO stage IIB-IVB CC treated with curative-intent CRT between 2017 and 2023. The primary outcome was the incidence of fistula formation, with a focus on the impact of bevacizumab exposure. Fistulas occurred in 7 of 101 patients (6.9%). Among the 13 patients treated with bevacizumab, 4 (30.8%) developed fistulas compared with 3 (3.4%) of 88 not receiving bevacizumab. Univariable analysis showed significant associations with bevacizumab use (OR = 12.59, 95% CI: 2.43-65.38, p = 0.003), and FIGO stage IVB (OR = 21.90, p = 0.001). In multivariable analysis, bevacizumab (AOR = 13.5, 95% CI: 1.84-99.5, p = 0.011) and FIGO stage IV (AOR = 26.7, 95% CI: 2.59-274.4, p = 0.006) remained independent predictors. No fistulas occurred after 2021, coinciding with institutional discontinuation of bevacizumab in metastatic or persistent disease after CRT (p = 0.043). Bevacizumab use and FIGO stage IV disease were associated with increased risk of fistula formation after definitive CRT. These findings highlight the need for careful treatment planning when considering bevacizumab in previously irradiated patients, particularly in the current era of multimodal therapy.
Prognosis in metastatic renal cell carcinoma (mRCC) treated with PD-1 blockade remains difficult to estimate early during therapy. Routine laboratory markers of systemic inflammation and metabolic stress are widely available, yet single-marker approaches may not reflect coordinated early inflammatory-metabolic dynamics. In a multicenter real-world cohort of previously treated mRCC patients receiving nivolumab monotherapy, we applied a prespecified day-28 (1-month) landmark framework. Using baseline (BL) and month-1 (Mo1) LDH and complete blood count (CBC)-derived indices (NLR, PLR, SII) as systemic inflammatory and metabolic markers, we engineered BL, Mo1, and early relative change features (log2[Mo1/BL]), standardized them within the phenotype-eligible cohort, and derived early inflammatory-metabolic trajectory phenotypes via unsupervised k-means clustering (k = 3). Phenotypes were labeled post hoc as IM-Quiescent (P1), IM-Quiescent-to-Inflamed (P2), and IM-Inflamed-Persistent (P3). OS and PFS were analyzed from the landmark using Kaplan-Meier and multivariable Cox models. Durable benefit was assessed as 24-month OS (OS24) using multivariable logistic regression. The overall cohort included 498 patients; 329 were phenotype-eligible (P1 n = 142; P2 n = 69; P3 n = 118). Survival differed across phenotypes (log-rank OS p = 0.002; PFS p = 0.001). In multivariable Cox models (reference P1), P3 was associated with worse outcomes (OS HR 1.63, 95% CI 1.09-2.45; p = 0.019; PFS HR 1.92, 95% CI 1.36-2.73; p < 0.001), whereas P2 was not statistically supported versus P1 (OS HR 1.30, 95% CI 0.82-2.07; p = 0.262; PFS HR 1.21, 95% CI 0.82-1.79; p = 0.336). OS24 rates differed across phenotypes and phenotype remained associated with OS24 after covariate adjustment. Early inflammatory-metabolic trajectory phenotypes derived from routine systemic inflammatory and metabolic markers within a day-28 landmark framework were clinically interpretable and associated with OS, PFS, and durable benefit in nivolumab-treated mRCC. External validation and prospective evaluation in contemporary ICI-based regimens are warranted.
Glioblastoma (GBM) is a highly aggressive brain tumor with limited prognostic markers to predict patient outcomes reliably. This study investigates the perioperative levels of tryptophan, kynurenine, and neopterin in patients with GBM to assess their potential as biomarkers for prognosis. Twenty-four patients with supratentorial GBM and 24 age- and gender-matched healthy controls were included. Blood and urine samples were collected at four time points: preoperatively, three days postoperatively, prior to adjuvant therapy, and post-adjuvant therapy. Analytical measurements of tryptophan, kynurenine, and neopterin levels were conducted using liquid chromatography-tandem mass spectrometry, and statistical analyses were performed to determine their correlation with survival outcomes. The analysis revealed significant perioperative fluctuations in neopterin, kynurenine and tryptophan levels in GBM patients. Moreover, a trend (p = 0.08) of an association between preoperatively obtained blood level of kynurenine and survival probability was observed supporting further validation of kynurenine-pathway biomarkers in larger, molecularly annotated cohorts.
Atopic dermatitis (AD) is primarily a TH2-driven pathology, yet seasonal factors may activate additional immune pathways. This study examined seasonal variation in plasma cytokines in adults with AD treated with dupilumab (N = 20), AD patients without systemic therapy (N = 15), and healthy controls (N = 34). Cytokines (interleukin [IL]-17A, thymic stromal lymphopoietin (TSLP), interferon (IFN)γ, tumor necrosis factor (TNFα), IL-2, IL-6, IL-12p70, IL-23, and IL-31) were measured during summer and winter under unstimulated and phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated conditions. Dupilumab-treated patients showed significant winter increases in stimulated IFNγ, TNFα, IL-2, IL-6, and TSLP, indicating preserved inducible TH1/innate and alarmin activity. Untreated AD patients displayed winter elevation of stimulated IL-6 and unstimulated IFNγ, while healthy controls showed broad winter up-regulation of stimulated TH1/innate cytokines. Higher winter cytokine levels tended to occur in dupilumab-treated patients with scoring atopic dermatitis (SCORAD) > 10 (evaluation of severity AD - scoring of atopic dermatitis). The findings obtained here suggest that seasonal environmental factors modulate immune responses even under biologic therapy, supporting season-aware, individualized AD management. Winter up-regulation under dupilumab: Stimulated interferon (IFN)γ, tumor necrosis factor (TNF)α, interleukin (IL)-2, IL-6, and TSLP increased in winter among dupilumab-treated atopic dermatitis (AD) patients, indicating compensatory immune activation beyond TH2 blockade.Functional capacity revealed by stimulation: The unstimulated vs. stimulated design uncovered latent, inducible immune activity that may contribute to subclinical inflammation or seasonal flares.AD patients without systemic therapy: Stimulated IL-6 and IFNγ unstimulated rose in winter.Controls show seasonality: Healthy subjects exhibited strong winter increases in stimulated TH1/innate cytokines (IFNγ, TNFα, IL-2, and IL-23) and higher unstimulated IL-6, with lower IL-12p70 and IL-31.Clinical signal: Higher winter cytokines tended to occur in dupilumab-treated patients with scoring atopic dermatitis (SCORAD0 > 10 (non-significant due to variability).
Older adults with metastatic triple-negative breast cancer (mTNBC) remain underrepresented in clinical trials. Although sacituzumab govitecan (SG) improved outcomes in the phase III ASCENT trial, real-world data in older populations are limited. We conducted a retrospective multinational study across 18 oncology centers in Central Europe, including patients with mTNBC treated with SG between August 2021 and May 2025. Patients were stratified by age at SG initiation: <65 versus ≥65 years. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment modifications and safety. Among 303 patients, 76 (25.1%) were aged ≥65 years. Older patients had more comorbidities, more prior palliative treatment lines and more frequent ECOG performance status ≥1. In unadjusted analyses, patients aged ≥65 years had longer median OS (12.8 vs. 10.9 months; HR 0.70, 95% CI 0.49-0.99; p = 0.045) and PFS (5.4 vs. 4.1 months; HR 0.73, 95% CI 0.54-0.97; p = 0.031). ORR, DCR, treatment modifications and grade ≥3 neutropenia were comparable between groups. In multivariable analyses, age was not independently associated with OS or PFS. In this selected real-world cohort, patients aged ≥65 years receiving SG had outcomes at least comparable to younger patients, without apparent excess severe toxicity. Survival differences were likely influenced by baseline disease characteristics and patient selection rather than chronological age itself.
Rural general practitioners (GPs) play a vital role in providing healthcare to populations in remote areas, yet there is a significant shortage of doctors willing to work in these regions. Despite the critical need, a strong preference for urban practices persists among young GPs in Europe, exacerbating the lack of healthcare providers in rural settings. Understanding the motivation factors influencing young GPs' decisions to work in rural areas is essential to address this workforce distribution problem. This study aims to identify the main motivating factors that drive young GPs to work in rural areas across four European countries. Additionally, the study seeks to propose strategies to enhance recruitment of young GPs in rural healthcare settings. A key informant survey was conducted across four member countries of the European Rural and Isolated Practitioners Association (EURIPA). The EURIPA Motivating young EuropeAn DOctors for rural Work (MEADOW) study utilized a semi-structured questionnaire. The survey targeted young GPs in Denmark, Norway, Turkey, and the Czech Republic, collecting data from 350 respondents. Our survey revealed that 64.14% of young GPs expressed an interest in rural practice, with major motivating factors including accessibility of schooling for their children, income profitability, and employment opportunities for partners. The study highlights that financial incentives alone are insufficient to motivate young GPs to work in rural areas. Instead, a comprehensive approach that includes improving rural medical education, ensuring access to quality schools for children, and providing employment opportunities for partners is crucial. Addressing these multifaceted needs can enhance rural recruitment and retention efforts across Europe.
Post hoc analysis of the PULSAR Phase 3 trial (NCT04423718) to describe whether dosing interval outcomes were associated with key baseline disease characteristics. Exploratory post hoc analysis of PULSAR, a 96-week, double-masked, active-controlled, randomized clinical trial in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) treated with aflibercept 8 mg or aflibercept 2 mg. For the main analysis, patients receiving aflibercept 8 mg were grouped according to their last assigned dosing interval at Weeks 48 and 96. Patients with treatment-naïve nAMD who were randomly assigned to receive aflibercept 8 mg in PULSAR. Aflibercept 8 mg was administered every 12 weeks (8q12) or 16 weeks (8q16) following 3 initial monthly injections. Dosing intervals could be shortened in Year 1 based on prespecified disease activity criteria, whereas in Year 2, both interval shortening and extension were allowed. Patients were monitored every 4 weeks but assessed for interval modification at dosing visits only. Baseline best-corrected visual acuity (BCVA), central retinal thickness (CRT), and macular neovascularization (MNV) area were assessed in patients grouped by their last assigned dosing interval (Q8, Q12, Q16, Q20, or Q24) at Weeks 48 and 96. In 86.6% and 78.4% of patients assigned to the 8q12 and 8q16 arms in PULSAR, respectively, randomized dosing intervals were maintained or extended through Week 96. In the 8q12 arm, no trends were observed in baseline BCVA, CRT, and MNV area across groups based on patients' last assigned dosing intervals. In the 8q16 arm, no trends were observed in baseline BCVA across treatment arms; however, patients with shorter last assigned dosing intervals (Q8 and Q12) at Weeks 48 and 96 tended to have a greater baseline CRT or MNV area compared with patients with longer dosing intervals (Q16 to Q24). Overall, findings from this PULSAR post hoc analysis of key baseline characteristics in patients grouped by dosing interval suggest that the aflibercept 8q12 and 8q16 regimens were suitable for most patients across a broad range of baseline BCVA, CRT, and MNV area values, with a large proportion of patients able to achieve and maintain extended dosing intervals through Week 96.
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The management of locally-advanced, resectable head and neck squamous cell carcinoma (HNSCC) is undergoing a major shift driven by the integration of neoadjuvant immunotherapy (nIO). The rationale for nIO lies in its administration within an immunologically active, treatment-naïve microenvironment that enhances immune priming and anti-tumor response. Despite encouraging clinical data, including the pivotal KEYNOTE-689 trial and multiple phase II studies, methodological heterogeneity in trial design, endpoint definitions, and response criteria currently hampers data comparability and the establishment of new standards of care. This expert narrative review proposes a structured framework for standardizing clinical, pathologic, imaging, and translational endpoints in HNSCC nIO trials, highlighting harmonized definitions of pathologic response, practical reporting templates, and methods to evaluate immune priming. Standardization of response evaluation, biomarker integration, and trial methodology is essential to accelerate the translation of neoadjuvant immunotherapy into routine clinical practice for HNSCC.
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Diosmin, a flavonoid with documented vascular-protective properties, together with the closely related compounds diosmetin and diosmetin-7-O-glucoside, has not previously been subjected to a systematic comparative biophysical characterization. In this study, we performed an integrated biophysical comparison of these three structurally related flavonoids to delineate how structural differences translate into distinct patterns of metal-ion coordination, membrane interaction and hemoglobin engagement, thereby providing a mechanistic context for their behavior in complex erythrocyte- and simplified hemoglobin-based redox systems. All three compounds exhibited low direct radical-scavenging activity in the DPPH• assay and showed differences in predicted lipophilicity and metal-ion interactions. Diosmetin, the most lipophilic derivative, selectively chelated Cu2+/Cu+, while diosmin showed the strongest chelation of both Fe2+ and Fe3+; none of the tested flavonoids reduced iron ions. Diosmetin inhibited rat intestinal α-glucosidase, and both diosmetin and diosmin inhibited lipoxygenase with comparable potency. In intact human erythrocytes, all flavonoids did not cause hemolysis and did not alter osmotic resistance within the concentration range tested, but they differentially affected cell morphology and response to Fe3+-induced oxidative stress. Diosmin and diosmetin-7-O-glucoside predominantly induced echinocyte formation, whereas diosmetin favored stomatocytes and, at the highest concentration, partially reduced Fe3+-induced hemolysis. Measurements in erythrocyte-mimetic liposomes showed no effect of any compound on acyl chain order, while diosmetin induced a pronounced decrease in membrane dipole potential, in contrast to the modest changes observed for diosmin, indicating different modes of interaction with the lipid headgroup region. All three flavonoids quenched the hemoglobin tryptophan fluorescence via a static mechanism, with a similar quenching efficiency but differing binding constants. ATR-FTIR spectroscopy did not reveal detectable alterations in the overall secondary-structure content of hemoglobin. Collectively, the results demonstrate systematic differences among diosmetin, diosmetin-7-O-glucoside and diosmin in metal-ion coordination, membrane-related effects and hemoglobin interactions, providing a comparative biophysical basis for distinguishing their activities. Based on these results, diosmetin appears to be a particularly interesting candidate for further biophysical and functional investigation.
Garden nasturtium (Tropaeolum majus L.) is a rich source of bioactive compounds, particularly glucotropaeolin, and is increasingly used in functional foods. Maintaining glucosinolate stability during processing is critical for ensuring consistent bioactivity. This study systematically investigated the kinetics and mechanism of glucotropaeolin degradation in edible extracts obtained from seeds, leaves, and flower buds under typical processing and storage conditions. Glucotropaeolin hydrolysis was primarily driven by myrosinase, producing benzyl isothiocyanate, which then degraded to form benzyl thiocarbamate and 1,3-dibenzyl-2-thiourea. Untreated or lyophilised extracts showed rapid glucotropaeolin degradation, whereas boiling-induced myrosinase inactivation substantially improved glucotropaeolin stability. Additionally, an analysis of commercial garden nasturtium extracts revealed surprisingly low levels of glucotropaeolin and benzyl isothiocyanate, highlighting the impact of industrial processing. These findings provide insight into the mechanism of glucotropaeolin stability and highlight processing strategies for preserving bioactive glucosinolates, supporting the development of functional foods with predictable bioactive profiles.
Aim: Chemotherapeutic resistance is a leading cause of cancer-related mortality worldwide. It has been suggested to be at least partly driven by the activity of uridine diphosphate glucuronosyltransferases (UGTs). However, this hypothesis is primarily supported by indirect evidence with potential confounding factors arising from the use of multienzymatic models among other things. Here we present new HepG2 models transduced with UGT1A1 or UGT2B7 that provide mechanistic insights into the potential role of UGTs in resistance to SN-38, etoposide, and epirubicin. Methods: The new cellular models were characterised by immunofluorescence, quantitative real-time PCR, and doubling-time assessment. Possible differences in chemotherapeutic efficacy were evaluated using comparative ATP viability assays and an inhibitor-based verification study. Drug combination assays were conducted to determine whether dual-activity modulation could combat enzyme-mediated resistance, using the quantitative Chou-Talalay method to detect synergistic effects. Finally, an advanced physiologically relevant model based on proliferating primary upcyte hepatocytes was characterised and used to verify the results obtained with the transduced models. Results: The comparative ATP viability assays and verification studies using the UGT inhibitors atazanavir and diclofenac confirmed that both UGT enzymes significantly reduced the tested drugs' pharmacodynamic activity. Drug combination experiments then showed that UGT1A1 activity can be synergistically targeted by nilotinib and regorafenib via a new dual-activity modulation approach. Finally, the role of UGT1A1 in resistance to SN-38 was confirmed in a complex model based on primary upcyte hepatocytes. Conclusion: After in vivo confirmation, our findings could potentially be translated into effective and safe combination regimens for oncology patients.
Evidence supporting the use of conduction system pacing (CSP) in bradycardia is currently predominantly based on observational data. We performed a meta-analysis of recent propensity-score matched (PSM) studies and randomized controlled trials (RCTs) evaluating outcomes of CSP and right ventricular pacing (RVP) in bradycardia indications. We systematically searched three databases for eligible studies. Risk ratios (RRs) and mean differences (MDs) with their 95% confidence intervals (CI) were pooled using a random-effects model. Subgroup analyses of RCTs were performed for key outcomes. Fifteen studies (8 RCTs, 7 PSM) comprising 6,064 patients were included. Compared to RVP, CSP significantly reduced heart failure hospitalizations (RR:0.31; 95% CI:0.21-0.46; p < 0.001) and the need for cardiac resynchronization therapy (CRT) upgrades (RR:0.31; 95% CI:0.12-0.78; p = 0.01), while modestly improving left ventricular ejection fraction (MD:3.98%; 95% CI:2.22-5.74; p < 0.001) and resulting in narrower QRS durations (MD:-27.3 ms; 95% CI:-35.9 to -18.6; p < 0.001). These findings were consistent in sub-analyses of RCTs. CSP was associated with reduction of all-cause mortality in the overall analysis (RR:0.51; 95% CI:0.34-0.78; p = 0.002), but not in the RCT and PSM subgroups. No significant differences between groups were observed for cardiovascular mortality (RR:0.49; 95% CI:0.23-1.04; p = 0.06), procedural complications, or atrial fibrillation. CSP was associated with longer procedural and fluoroscopy times. CSP significantly reduces the risk of heart failure hospitalizations and the need for CRT upgrades compared to RVP in patients with bradycardia indications. Ongoing, large-scale RCTs are needed to verify the effect of CSP on mortality and its long-term safety.