BACKGROUND:Metastatic clear-cell renal cell carcinoma (m-ccRCC) with pancreatic and/or thyroid metastases (PM/TM) is sensitive to vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Optimal first-line therapy for these patients (VEGFR-TKI-monotherapy, immune checkpoint inhibitor (ICPI) combinations (ipilimumab/nivolumab) or ICPI/VEGFR-TKI-combinations) remains unknown. MATERIALS AND METHODS:We studied (A) the specific impact of axitinib and/or pembrolizumab dose reductions and treatment interruptions on response in patients treated with axitinib/pembrolizumab, (B) tumor shrinkage in individual PM upon VEGFR-TKIs and ICPIs, (C) the optimal first-line therapy in m-ccRCC patients with PM/TM in terms of tumor shrinkage, response rate (RR), time-to-progression (TTP) and cancer-specific-survival (CSS) and (D) explored molecular features of PM. RESULTS:We describe 5 cases of m-ccRCC patients with PM, treated with first-line axitinib/pembrolizumab, in whom tumor response was clearly linked to axitinib administration and dose rather than pembrolizumab. In 119 individual PM, tumor shrinkage was the highest with ICPI/VEGFR-TKI-combinations followed by VEGFR-TKIs-monotherapy and lowest with ICPIs without VEGFR-TKIs (p < 0.0001). In 40 patients with PM/TM, median maximal tumor shrinkage was -54%, -39% and 0%, respectively (p = 0.04). RR was 83% with ICPI/VEGFR-TKI-combinations, 69% with VEGFR-TKI-monotherapy and 22% with ipilimumab/nivolumab (p = 0.01). Median TTP was not reached, 19 and 27 months, respectively (p = 0.07). Median CSS was not similarly impacted by first-line therapy. PM displayed high AXL-expression and higher infiltration by M2-like anti-inflammatory macrophages compared to other metastatic sites. CONCLUSION:In m-ccRCC patients with PM/TM, first-line therapy with VEGFR-TKIs or ICPI/VEGFR-TKI-combinations leads to improved RR and tumor shrinkage, compared to ipilimumab/nivolumab, but not to CSS benefit in the current analysis. PM displayed high AXL-expression and higher infiltration by M2-like anti-inflammatory macrophages compared to other metastatic sites.
BACKGROUND:The atherogenic index of plasma (AIP) and inflammatory indices may reflect the burden of atherosclerosis. This study evaluated their predictive value for obstructive coronary artery disease (CAD) in patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS:This retrospective study included 624 NSTEMI patients undergoing coronary angiography. Patients were classified as having obstructive or non-obstructive CAD. Demographic, clinical, laboratory, and echocardiographic characteristics were compared. Independent predictors were identified using multivariable logistic regression, and discriminative performance was assessed by receiver operating characteristic analysis. RESULTS:The obstructive CAD group was significantly older (64.3 ± 12.3 vs. 57.4 ± 14.2 years; p < 0.001) with higher prevalence of males (63.3% vs. 50.8%; p = 0.003), hypertension (52.1% vs. 30.2%; p < 0.001), and diabetes mellitus (47.6% vs. 28.9%; p < 0.001). Inflammatory markers were markedly elevated: NLR [4.2 vs. 1.9; p < 0.001], PLR [140.9 vs. 119.1; p < 0.001], SII [1113.3 vs. 520.1; p < 0.001], and CRP [0.4 vs. 0.2 mg/dL; p < 0.001]. AIP was significantly higher [0.71 vs. 0.46; p < 0.001]. ROC analysis demonstrated that NLR (AUC = 0.764) and SII (AUC = 0.738) had the highest discriminative ability, while AIP showed limited performance (AUC = 0.563). In multivariable analysis, independent predictors included age (OR = 1.031), hypertension (OR = 1.645), diabetes (OR = 1.547), PLR (OR = 1.004), CRP (OR = 1.156), and AIP (OR = 2.413; all p < 0.05). CONCLUSION:AIP was independently associated with obstructive CAD beyond traditional risk factors and inflammatory indices, despite modest standalone discriminative ability. These findings are hypothesis-generating and require prospective validation with clinical outcomes before routine clinical implementation.
OBJECTIVES:To quantify the concordance and stability of symptomatic, echocardiographic and renal trajectories after sodium-glucose cotransporter 2 inhibitor (SGLT2i) initiation and examine their association with subsequent events. METHODS:This day-210 landmark analysis included 618 adults with heart failure, baseline left ventricular ejection fraction (LVEF) <50%, and paired New York Heart Association (NYHA) class, LVEF and estimated glomerular filtration rate (eGFR) measurements on days 150-210. Domains were cross-classified rather than treated as equivalent causal components. Repeat classification was assessed by day 365. Death or heart-failure hospitalisation on days 211-365 was analysed with multivariable Cox regression; fixed-horizon Firth logistic regression and continuous, threshold, weighting and co-intervention analyses tested robustness. RESULTS:Discordant trajectories occurred in 368/618 patients (59.5%). Among 209 with repeat assessment, 181 (86.6%) retained the same classification (κ=0.74). Outcome status was complete in 576 patients, with 33 events. Non-concordance was associated with the time-to-event outcome (adjusted hazard ratio 4.27, 95% confidence interval 1.61-11.32; p = 0.004); the fixed-horizon Firth estimate was concordant (odds ratio 4.27, 95% confidence interval 1.64-11.13; p = 0.003). NYHA improvement contributed most of the prognostic signal. Adding non-concordance to a conventional baseline model increased the area under the curve from 0.752 to 0.790, but the bootstrap interval for the increment included zero. CONCLUSION:Trajectories were frequently discordant and usually stable to day 365. Their association with events was non-causal, driven predominantly by symptomatic change and of uncertain incremental predictive value.
OBJECTIVES:To review the literature concerning the antimicrobial treatment of Whipple's disease and to highlight consequences of diagnostic delay (including inappropriate use of immunosuppressants). This in the context of two illustrative case reports in which the standard treatment regimen of intravenous (IV) ceftriaxone for two weeks followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) was either ineffective or poorly tolerated. METHODS:A narrative review of the literature on antimicrobial treatment and the interplay of Whipple's disease with immunosuppressants was conducted alongside the clinical case descriptions. RESULTS:A review of the literature identified two principal treatment strategies in use: the standard IV ceftriaxone/TMP-SMX regimen and the doxycycline/hydroxychloroquine oral-only combination. Debate regarding optimal approach is ongoing, however several studies report on the failure or relapse of the standard IV regimen. Diagnostic delay and inappropriate use of immunosuppressants can lead to severe complications. CONCLUSION:In patients with Whipple's disease who fail or cannot tolerate the standard IV regimen, combination of doxycycline and hydroxychloroquine represents a viable and effective alternative in patients without cerebral involvement. Clinical awareness of this condition and its treatment options is essential for a timely diagnosis and appropriate management.
OBJECTIVE:Pioglitazone and dipeptidyl peptidase-4 inhibitors (DPP-4is) are used to treat type 2 diabetes mellitus (T2DM), yet their influence on gout risk remains unclear. This study aimed to examine whether the incidence of newly diagnosed gout differed between pioglitazone users and DPP-4i users among patients with T2DM. METHODS:We conducted a retrospective cohort study using data from the TriNetX. Patients with T2DM aged 20-84 years were selected. The pioglitazone and DPP-4i cohorts were matched 1:1 using propensity score matching based on demographic and clinical characteristics. The primary endpoint was incident gout. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the 'Compare Outcomes' module within the TriNetX. RESULTS:After propensity score matching and using post-matching 6-month lag exclusion, 120,095 patients in the pioglitazone group and 120,211 patients in the DPP-4i group were included. During the maximum follow-up period of 5 years, 1,948 cases of gout occurred in the pioglitazone group and 1,877 in the DPP-4i group, corresponding to cumulative incidence of 1.622% and 1.561%, respectively. The Cox proportional hazards analysis indicated a modestly higher incidence of gout among pioglitazone users compared with DPP-4i users (HR, 1.085; 95% CI, 1.018-1.156). CONCLUSION:Pioglitazone use is associated with a modestly higher incidence of gout compared with DPP-4i use in patients with T2DM; however, the small absolute risk difference and observational design warrant cautious interpretation.
OBJECTIVES:Due to increased life expectancy, patients with chronic respiratory failure treated with home ventilation have an increasing likelihood of requiring surgery in their lifetime. Evidence on the safety and feasibility of surgery in this population is scarce. METHODS:Retrospective analysis of all surgical procedures under general anaesthesia in patients included in the chronic home ventilation registry at Ghent University Hospital. RESULTS:Between 1 October 2006 and 1 March 2022, 128 surgical procedures were performed on 53 (female: 25) patients with a median age of 52 yr, BMI of 25 kg/m2, Charlson Comorbidity Index of 2 and FVC of 1.12 L (34%). 21 patients were ventilated via tracheostomy. The most common cause of respiratory failure was neuromuscular disease and tetraplegia (28 patients). Most procedures were minor (e.g. tracheostomy revisions), but 30 non-elective or emergency procedures (including 7 laparotomies) were registered. Respiratory complications occurred in 25 procedures (19%) and were associated with length of stay (p < 0.001) and hospital mortality (p = 0.029). Four patients (8%) died, all after emergency surgery, with one death deemed not attributable to the underlying respiratory failure (intracerebral haemorrhage). The ARISCAT score (median: 19; range: 0-86) was significantly associated with respiratory complications, length of stay, and hospital mortality (all p < 0.05). CONCLUSION:Surgery is feasible in chronically ventilated patients, though the risk of respiratory complications and death after surgery, particularly if non-elective, is not negligible. The ARISCAT score was associated with outcomes and appears to be a valuable tool for risk assessment in this population.
OBJECTIVES:Tumour treating fields (TTF) improve survival in newly diagnosed glioblastoma (GBM) in randomized trials, but real-world impact in Belgium remains unclear due to limited access and lack of reimbursement. This study evaluates progression-free survival (PFS) and overall survival (OS) in Belgian patients with newly diagnosed GBM treated with TTF alongside standard therapy. METHODS:We conducted a retrospective single-centre cohort study at UZ Leuven including patients with histologically confirmed newly diagnosed GBM treated with TTF between April 2019 and July 2026. TTF was initiated during adjuvant temozolomide. Clinical, molecular and treatment data were extracted from institutional records. Primary outcomes were PFS and OS from diagnosis. Kaplan-Meier survival analyses were performed, including subgroup analyses by MGMT status, device adherence (>75%), and extent of resection. RESULTS:Twenty-eight patients were analysed (median age 52 years; 71% male). MGMT promoter methylation was present in 29% and gross total resection was achieved in 50%. Adherence exceeded 75% in 96%. Median PFS was 6.8 months and median OS 24.6 months, comparing favourably with EF-14 outcomes. ECOG status predicted survival (p = 0.04). Survival was not associated with MGMT status or adherence. Gross total resection showed a clinically meaningful association with improved OS (30.7 vs 8.2 months; p = 0.07). Treatment was well tolerated. CONCLUSION:In this real-world Belgian cohort, TTF with standard therapy yielded survival outcomes consistent with or exceeding pivotal trials. While clinical benefit appears evident, implementation remains challenged by financial costs. Further prospective Belgian studies are needed to assess cost-effectiveness and quality-of-life impact.
BACKGROUND:Cardiovascular disease (CVD) remains a leading cause of mortality worldwide. Emerging evidence indicates that environmental and occupational risk factors (EORF) are significantly associated with its onset. However, the current global burden of CVD attributable to these exposures remains unclear. METHOD:Using data from the Global Burden of Disease (GBD) Study, we estimated the number of deaths, disability-adjusted life years (DALYs), age-standardized death and DALY rates attributable to EORF from 1990 to 2021. Estimates were stratified by sex, region, and year. Additionally, we assessed the association between the EORF-related CVD burden and sociodemographic index (SDI). RESULT:We found that CVD mortality due to EORF increased from 4.42million in 1990 to 6.44 million in 2021 (95% UI: 4.99-7.77), representing a 45.7% increase, while DALYs rose from 103million in 1990 to 138 million in 2021 (95% UI: 109-165), marking a 34.0% rise. During this period, age-standardized death and DALY rates globally showed a downward trend, decreasing by 38.5% and 38.9% respectively. At the national and regional levels, Western Australia and high SDI regions in Australia demonstrated significant improvements in EORF-related CVD burden. Additionally, men exhibit higher CVD burdens compared to women. CONCLUSION:Our findings indicate that the overall burden of CVD attributable to EORF has increased substantially in the current population, highlighting significant room for improvement in prevention and control strategies. There is an urgent need to implement effective interventions targeting major EORF to mitigate the global CVD burden associated with these modifiable risks.
BACKGROUND AND AIMS:The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS:In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS:Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS:The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.
BACKGROUND AND AIMS:Low-dose mineralocorticoid receptor antagonists (MRAs) are guideline-recommended heart failure (HF) therapies. However, MRAs increase aldosterone production, and the sub-saturating doses utilized may allow continued mineralocorticoid receptor (MR) stimulation. The aim of the current analysis was to understand how baseline and change in aldosterone concentrations during MRA therapy impacts MR activity and clinical outcomes. METHODS:HF cohorts with MRA exposure and plasma aldosterone concentrations available were included in patient-level, pooled cohort analyses [DOSE, CARRESS-HF, MDR, and TOPCAT (n = 1019)]. In the MDR cohort (n = 136), urine sodium to potassium ratio was utilized to quantitate MR activity. The relationship of pre-MRA aldosterone concentration, MRA use, and clinical outcomes were meta-analysed utilizing the above pooled cohorts in addition to the EARLIER (n = 300) and EPHESUS (n = 453) trials. RESULTS:MRA use was associated with significantly higher median aldosterone concentrations [MRA = 310 (interquartile range, IQR 180, 533) pg/mL vs no MRA = 174 (IQR 106, 299) pg/mL, P < .001] in the pooled cohort. In the MDR cohort, higher aldosterone was correlated with higher MR activity, with a similar relationship on MRA (r = -.52, P < .001) vs off MRA (r = -.44, P < .001, P interaction = .65), differing only in that higher aldosterone concentrations were required on MRA to achieve the same level of MR activity. In patients with high pre-MRA aldosterone, new MRA initiation reduced MR activity, but MRA initiation increased MR activity in patients with low pre-MRA aldosterone [median change in urine Na/K with high aldosterone =1.4 (IQR 1.1, 2.9) vs low aldosterone = -.9 (IQR -2.1, -.1), P < .001]. In the pooled cohort, the association between MRA use and clinical outcomes was dependent on pre-MRA aldosterone concentration (P interaction = .005). In patients with high pre-MRA aldosterone, MRA was associated with substantially improved clinical outcomes [hazard ratio (HR) .63, 95% confidence interval (CI) .42-.92, P = .02]. However, in patients with low pre-MRA aldosterone, MRA use was associated with worse clinical outcomes (HR 1.66, 95% CI 1.12-2.45, P = .01). CONCLUSIONS:Low-dose MRAs significantly increase aldosterone but inadequately block MR activity (measured by urine Na/K) at these new higher aldosterone concentrations. In patients with high pre-MRA aldosterone, MRA use is associated with improved MR activity and clinical outcomes. However, in patients with lower pre-MRA aldosterone concentrations, MRA use is associated with worsened MR activity and clinical outcomes. MRAs remain guideline-directed HF medications with established population level benefit, but these hypothesis-generating findings indicate additional research is warranted to understand if outcomes can be further improved.
BACKGROUND AND AIMS:Familial hypercholesterolaemia (FH) leads to life-long exposure to high low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease. Evidence supporting initiation of cholesterol-lowering medication (CLM) in childhood to lower this cumulative cholesterol burden and cardiovascular sequelae is sparse. This study assessed the long-term impact of contemporary management of FH on LDL-C and cardiovascular events. METHODS:Observational prospective cohort study (SAFEHEART) including children/adolescents (age <18 years) with genetically confirmed heterozygous FH (FH-Ch), their non-affected children and adolescents' relatives (non-FH-Ch), and FH parents (FH-P). Impact of CLM, LDL-C burden, and cardiovascular events were assessed. RESULTS:Overall, 348 FH-Ch, 165 non-FH-Ch and 288 FH-P were included (49.8% female; median untreated LDL-C: 5.46, 2.63, and 7.19 mmol/L, respectively). Median follow-up was 12.4 years (interquartile range 9.6-15.3). At follow-up, 84.5% FH-Ch, 4.2% non-FH-Ch, and 95.1% FH-P were receiving CLM. FH-Ch started therapy at a median age of 14.5, vs. 36.1 years in their FH-P. Latest on-treatment LDL-C was 3.00 mmol/L in FH-Ch (median change: -2.60 mmol/L, -47.4%) and 2.44 mmol/L in FH-P (-4.72 mmol/L, -67.6%); LDL-C among non-FH-Ch (not on CLM) was 2.72 mmol/L. By age 30-40 years, median LDL-C burden over life was 5909.0 and 10 206.8 mg/dL*years among FH-Ch and FH-P, respectively. By age 39 years, rate of cardiovascular events was 0.0%, 0.3% and 5.2% among non-FH-Ch, FH-Ch, and FH-P, respectively. CONCLUSIONS:Treatment of FH from childhood/adolescence reduces the cumulative LDL-C burden compared with later onset treatment from adulthood in affected parents and permits attainment of LDL-C levels close to non-FH individuals; this finding was associated with the observation of a reduction in the cardiovascular risk of young FH patients. These findings support FH as a paediatric condition requiring early-life detection and treatment. STUDY REGISTRATION NUMBER:ClinicalTrials.gov, NCT02693548.
BACKGROUND AND AIMS:Adults with congenital heart disease tend to develop both cardiac and noncardiac age-related comorbidities earlier in life than the general population, suggesting accelerated biological ageing. Epigenetic clocks estimate biological age based on DNA methylation profiles. This study investigated whether adults with congenital heart disease display accelerated epigenetic ageing and whether the degree of age acceleration relates to disease complexity. METHODS:A total of 120 patients with congenital heart disease (age 29-50 years, 58 females) and 120 age- and sex-matched healthy controls were included. Patients were divided into simple, moderate, and complex disease complexity groups (n = 40 per group). Epigenetic age was estimated using the Horvath, Hannum, Zhang, GrimAge2, and PhenoAge clocks, whereas the pace of ageing was assessed using DunedinPACE. RESULTS:Compared to healthy controls, patients with moderate and complex congenital heart disease exhibit significant age acceleration with PhenoAge (+3.0 years, P = .019; +5.5 years, P < .001) and GrimAge2 (+2.1 years, P = .045; +2.3 years, P = .022) and a higher pace of ageing (P = .008 and P = .016, respectively). No significant differences were detected between healthy controls and patients with simple disease. CONCLUSIONS:Accelerated epigenetic ageing is observed in adults with moderate and complex congenital heart disease, while individuals with simple disease show ageing patterns comparable to healthy peers. These findings provide biological evidence of premature ageing in congenital heart disease and suggest a lifelong systemic vulnerability. Integrating biological ageing metrics into follow-up strategies may enable earlier detection of age-related complications and support interventions to preserve long-term healthspan.
BACKGROUND AND AIMS:Frailty is associated with cardiovascular disease (CVD) through shared pathophysiology and risk factors, and frailty is a known modifiable risk factor for CVD. Statins reduce CVD risk and have anti-inflammatory properties that may lower the risk of frailty, though this has not been comprehensively examined. METHODS:Older US veterans (aged ≥67 years) who were statin naïve and received regular care in the Veteran Affairs (VA) medical system from 2002 to 2018 were included. Veterans who were frail at baseline based on a validated 31-item VA-Frailty Index (VA-FI) were excluded (scores >0.2). Data were linked to Medicare and Medicaid. Overlap propensity score weighting (PSW) was used to address confounding by indication. Cox regression models were fit to examine the association of statin use with the composite outcome of incident frailty with censoring at death. Similar analyses were conducted on pre-frail veterans (VA-FI score of 0.1-0.2). RESULTS:Of 987 301 veterans included in the study population (age 72 ± 6 years; 98% men; 87% white), 290 729 initiated statins during the study period. During a mean follow-up of 5.3 (SD 4.1) years, 636 195 incident frailty events occurred, representing unadjusted event rates of 153.1 events per 1000 person-years among statin initiators and 111.4 events per 1000 person-years in non-initiators. After PSW, new statin initiators were less likely to experience incident frailty (hazard ratio 0.76, 95% confidence interval 0.75-0.76) compared to non-initiators. Similar results were seen in pre-frail veterans. CONCLUSIONS:Statin initiation was associated with a significantly lower risk of incident frailty or death among older US veterans including those who were pre-frail at baseline.
BACKGROUND:The role of statins in individuals older than 75 years, particularly those with frailty, remains unclear. Recent studies suggest survival benefits of chronic statin use, independent of cardiovascular status. However, survival effects of statins during acute hospitalisation in geriatric patients are unknown. OBJECTIVE:To examine the association between in-hospital statin exposure and all-cause in-hospital mortality among patients admitted to an acute geriatric ward. METHODS:A retrospective observational cohort study of patients ≥ 75 years admitted to a geriatric ward was conducted between 9 December 2022 and 24 July 2023. Exposure was defined as statin administration on day 2 after admission. Patients were followed until death or discharge. The outcome was in-hospital all-cause mortality. Multivariable logistic regression models were adjusted for age, sex, comorbidity burden, and functional status measured by handgrip strength. Sensitivity analyses included additional adjustment for, or stratification by, prior atherosclerotic cardiovascular disease (ASCVD) and systemic inflammation assessed by C-reactive protein (CRP). RESULTS:Among 545 patients, in-hospital statin use was associated with a 6.3% absolute risk reduction or 49% adjusted odds reduction (OR 0.5, 95% CI [0.3-1.0]) for in-hospital mortality compared with non-use. Additional adjustment for ASCVD (OR 0.5, 95% CI [0.3-1.1]) or CRP (OR 0.6, 95% CI [0.3-1.2]) yielded similar results. Mortality reductions were comparable in secondary and primary prevention subgroups (OR 0.5 and 0.6, respectively). No significant interactions were observed. CONCLUSIONS:In-hospital statin exposure was associated with lower in-hospital mortality among acutely hospitalised older adults. Prospective randomized studies are warranted to assess causality and inform clinical practice.
OBJECTIVES:This article aims to highlight proteinuria and nephrotic syndrome as significant yet under-recognized adverse events of VEGF pathway inhibition by tyrosine kinase inhibitors (TKIs), illustrated in the treatment of radioiodine-refractory differentiated thyroid cancer. METHODS:This report presents a case of recurring (nephrotic range) proteinuria in a patient with radioiodine-refractory differentiated thyroid cancer treated sequentially with lenvatinib, sorafenib and cabozantinib. In the discussion, an overview of the existing literature is provided through a PubMed search. RESULTS:Reported incidence of proteinuria varies across VEGFR-targeted TKIs in clinical trials. However, direct comparisons between agents should be interpreted cautiously. The underlying pathophysiology is multifactorial, involving hypertension, endothelial injury, and direct podocyte damage, often resulting in focal segmental glomerulosclerosis, minimal change disease or non-thrombotic hyaline glomerular microangiopathy. Timely recognition and monitoring are essential, as early discontinuation or dose adjustment can lead to partial or full reversibility of renal damage. Switching to TKIs with a different nephrotoxic profile may be a feasible strategy to maintain oncological benefit while minimising renal risk. Nonetheless, given the limited evidence, this approach requires cautious implementation in selected cases. CONCLUSION:Proteinuria and nephrotic syndrome are an important class effect of VEGFR-directed TKIs. Regular monitoring, early detection, and timely dose adjustments or treatment switches are essential to minimize irreversible renal damage while maintaining oncological benefit.
BACKGROUND AND AIMS:The 2021 ESC guidelines on cardiovascular (CV) disease prevention recommend the SMART-REACH lifetime risk model to guide treatment decisions in patients with established atherosclerotic CV disease. The aim was to develop the SMART-REACH2 model for estimating lifetime risk of recurrent CV events and treatment benefits in patients with established atherosclerotic CV disease, with systematic recalibration to the four European and other global risk regions. METHODS:SMART-REACH2 was derived in 8708 individuals aged 40-90 years with coronary, cerebrovascular, peripheral artery disease and/or abdominal aortic aneurysm from the UCC-SMART cohort. Sex-stratified, cause-specific Cox models for recurrent CV events and non-CV death were fitted using age as timescale and routinely available predictors. Recurrent CV events were defined as a composite of myocardial infarction, stroke, or CV death. Recalibration was based on representative cohorts per risk region. External validation was performed in 2 085 780 patients from 54 countries; model performance was assessed by calibration plots and Harrell's C-statistic. RESULTS:In the derivation cohort, 2057 recurrent CV events occurred over a median follow-up of 8.5 years (25th-75th: 4.3-13.0). In external validation, 307 706 events occurred. The pooled C-statistic was 0.68 (95% confidence interval 0.66-0.69) and ranged from 0.66 (0.64-0.69) for European low-risk region up to 0.72 (0.66-0.78) for Latin America, with adequate calibration across risk regions. Performance was consistent across sexes and CV disease subtypes. Using SMART-REACH2, estimated potential gains in CV disease-free life expectancy for a 50-year-old example patient receiving intensified preventive treatment (15 mmHg systolic blood pressure and 1.0 mmol/L low-density lipoprotein cholesterol reduction) ranged from 2 years in the low-risk region to 4.4 years in the very-high-risk region. CONCLUSIONS:The updated SMART-REACH2 model accounts for geographical and sex-specific variations and allows estimation of short-term and lifetime risk of recurrent CV events and treatment benefits, facilitating shared decision-making as recommended by guidelines.
BACKGROUND AND AIMS:Atherosclerosis (AS) and abdominal aortic aneurysm (AAA) are both metabolism-associated vascular diseases, yet the role of lipid metabolic disturbances in their pathogenesis remains largely unknown. This study aimed to clarify the differential impact of lipid metabolic disturbances and their underlying mechanisms in AS and AAA. METHODS:Lipidomic analysis was performed to identify lipid metabolic differences between AS and AAA in various mouse models and different human cohorts. A multi-omics approach, integrated with functional assays, was utilized to elucidate the downstream mechanisms underlying disease-specific lipid metabolic features. Machine learning models were developed based on lipidomic features to differentiate AS from AAA. RESULTS:Lipidomic analysis of mouse models and human samples revealed a predominant enrichment of neutral lipids (e.g. triglycerides and cholesterol esters) in AS, in contrast to phosphoglycerides in AAA. Consistently, large-scale longitudinal data from the UK Biobank showed strong positive associations of triglycerides, cholesterol, and fatty acid with the future risk of coronary atherosclerotic disease, while phosphoglycerides were negatively associated with the risk of AAA. Integrated transcriptomic and metabolomic analyses identified fatty acid metabolism, particularly Acadm-mediated fatty acid β-oxidation (FAO) pathway, as the most significantly altered lipid metabolic pathway contributing to the lipid metabolic differences between AS and AAA. Consistently, targeted restoration of the Acadm-mediated FAO pathway inhibited AS by reducing lipotoxic metabolites and preserving mitochondrial homeostasis but had little impact on AAA. Further validation with lipid droplets autophagy-tethering compound (LD·ATTEC), which selectively eliminates intracellular lipid droplets, significantly alleviated AS progression and improved FAO with no significant change observed in AAA. Finally, predictive models were developed based on lipidomic features using machine learning algorithms, facilitating accurate differentiation between these two vascular diseases. CONCLUSIONS:These findings define previously unrecognized distinct lipid metabolic characteristics in the pathogenesis of AS vs AAA, providing a basis for differential diagnosis and targeted treatments.
