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: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.
AIMS:Continuous subcutaneous insulin infusion (CSII) is standard care in paediatric type 1 diabetes (T1D). This study evaluated 11-year trends in CSII adoption, device evolution, indications, discontinuation, and metabolic outcomes in a paediatric diabetes centre. METHODS:We conducted a retrospective cohort study of children and adolescents with T1D followed from 2013 to 2024. Data included age at diagnosis and pump initiation, prior insulin regimen, device type, HbA1c, acute complications, and reasons for discontinuation or switching. Time to pump discontinuation was analysed using Cox regression. RESULTS:CSII adoption increased to 41% of the centre's cohort by 2024. Devices evolved from 100% standalone pumps in 2013 to 54% hybrid closed-loop systems in 2024. At initiation, 36% started CSII within the first week after diagnosis, 58% transitioned from twice-daily injections, and 6% from multiple daily injections. Reasons for initiation included lifestyle considerations (51%), avoiding injections (21%), and suboptimal glycaemic control (13%). Mean HbA1c improved modestly over 5 years, with rare severe hypoglycaemia or ketoacidosis. CSII discontinuation occurred in 11%, mainly patient-driven, while 37% were physician-driven due to non-compliance. Older age at pump initiation was associated with discontinuation (HR 1.422, 95% CI 1.224-1.651; p < 0.001). Device switching occurred in 21%, mostly to access newer features. CONCLUSIONS:CSII adoption increased substantially over the study period, accompanied by a shift toward hybrid closed-loop systems and stable metabolic outcomes. Early initiation at diagnosis was feasible and safe. These real-world findings highlight the importance of education, adherence support, and multidisciplinary care in optimizing long-term paediatric CSII use.
OBJECTIVES:The coexistence of chronic arthritis - here defined as rheumatoid arthritis, spondyloarthritis and gout - and end-stage renal disease (ESRD) is clinically relevant, underscoring the need for safe medication choices and dosage adjustments. However, drug use in dialysis patients is challenging, as it requires balancing treatment efficacy - potentially reduced by drug removal during dialysis - with the risks associated with impaired renal function, such as overdose and drug toxicity. In the absence of evidence-based guidelines, this paper aims to summarize the existing literature and offer a descriptive guide for the use of DMARDs and gout therapy in ESRD patients with chronic arthritis. METHODS:A literature search using three different databases (Cochrane, PubMed and Embase) was conducted, yielding 41 articles. RESULTS:In patients with ESRD, methotrexate is contraindicated, leflunomide appears safe and effective, sulfasalazine and hydroxychloroquine are not recommended because of inconsistent data. Biological DMARDs are considered safe and effective, with existing evidence likely applicable to the entire class. Limited data exist for targeted synthetic DMARDs. However, apremilast appears relatively safe, whereas JAK inhibitors are generally not recommended because of an increased cardiovascular risk. For gout patients on dialysis, urate-lowering therapy is often required. It is recommended to initiate treatment with a lower dose of allopurinol or febuxostat, both of which are effective and well tolerated. Colchicine also appears to be safe at low doses in patients on hemodialysis. CONCLUSION:Treatment decisions in ESRD patients with chronic arthritis should be individualized, with strict monitoring.
OBJECTIVES:Periodontal disease, characterized by subgingival biofilm dysbiosis and Porphyromonas gingivalis (P. gingivalis) colonization, has been increasingly implicated in Alzheimer's disease (AD) pathogenesis. This review systematically delineates the pathophysiological mechanisms underlying the periodontal-AD nexus, highlighting olfactory dysfunction (OD) and salivary gland hypofunction as putative prodromal biomarkers for periodontal disease-associated AD progression. METHODS:PubMed/MEDLINE database was systematically searched for English-language articles published between January 1994 and March 2025. Search terms encompassed periodontal disease, Porphyromonas gingivalis, Alzheimer's disease, neuroinflammation, olfactory dysfunction, salivary gland hypofunction, blood-brain barrier, microglial activation, and cognitive decline. RESULTS:Periodontal disease compromises blood-brain barrier integrity via bacterial translocation, systemic pro-inflammatory mediator dissemination, and peripheral immune cell activation, thereby potentiating microglial polarization and neuroinflammatory cascades integral to early AD neuropathology. Both OD and salivary gland hypofunction demonstrate robust associations with periodontal disease severity and constitute sensitive biomarkers for prodromal AD. CONCLUSIONS:Periodontal disease-mediated neuroinflammation constitutes a pivotal mechanistic pathway linking oral dysbiosis to AD onset. OD and salivary gland hypofunction emerge as promising early diagnostic indicators for periodontal disease-associated AD susceptibility, warranting prospective clinical validation.
OBJECTIVES:Influenza infections affect around 20% of the population annually, generally causing a mild viral syndrome, but occasionally leading to severe complications or death. Influenza vaccines, with quadrivalent influenza vaccines (QIV) as the newest generation, decrease the likelihood of infection and complications. Because both influenza infections and vaccinations impose costs on patients and on the broader society, the health gains of vaccination programs should be weighed against their financial impact. This review summarises the literature on cost-effectiveness analyses for quadrivalent influenza vaccinations compared with non-vaccination, in the general European population since 2012. METHODS:We conducted a systematic review of the literature on cost-effectiveness analyses that compared quadrivalent influenza vaccination with non-vaccination. RESULTS:The eight included studies found that QIVs were cost-effective in 18/19 analyses at a willingness-to-pay threshold of 35 000 euro/QALY and in 15/19 analyses at 20 000 euro/QALY. Herd immunity was a major factor, as a large part of the observed cost-effectiveness gains occurred not in the targeted population for vaccination (children) but in the generations of their (grand)parents . CONCLUSIONS:This review suggests that vaccination programs with quadrivalent influenza programs are cost-effective compared with no influenza vaccination, regardless of the modelling assumptions. Their implementation should always be based on multiple factors, such as cost-effectiveness, the latest recommendations on optimal effectiveness for each influenza season, and ethical considerations. These results may have been influenced by the clinical and epidemiological validity of the data used by the included studies and the limited number of included analyses, most of which were industry funded.
OBJECTIVES:To assess the prevalence of anti-aminoacyl tRNA synthetase antibodies (anti-ARS) in a large cohort of untreated early rheumatoid arthritis (RA) patients compared to healthy controls. METHODS:The baseline serum samples of patients with early RA (n = 332) included in the multicentre CareRA trial, a completed interventional trial in untreated early RA, and healthy controls (n = 72) were screened for anti-ARS antibodies with a commercial dot immunoassay (DIA). Radiolabelled protein immunoprecipitation (IP) was performed to confirm the presence of suspected anti-ARS antibodies, in addition to HEp-2 indirect immunofluorescence and a commercial line immunoassay (LIA). RESULTS:Anti-ARS antibodies (anti-PL12 n = 2, anti-OJ n = 1) were detected in 0.9% of early RA patients using a DIA, of which one anti-PL12-positive sample was also positive on LIA. Presence of these anti-ARS antibodies could, however, not be confirmed by protein immunoprecipitation. No anti-ARS antibodies were detected in the healthy control group. CONCLUSION:We report that the presence of anti-ARS antibodies cannot be confirmed by IP in a multicentre cohort of untreated early RA patients. Anti-ARS autoantibodies should not routinely be evaluated in patients with early RA. Sensitivity and specificity issues with DIA and LIA for anti-ARS should be considered in the interpretation of anti-ARS testing.
OBJECTIVES:Medication reviews (MRs) in nursing homes (NHs) are valuable but time-consuming. Electronic screening tools can assist community pharmacists by detecting potential drug-related problems (pDRPs). This study aimed to evaluate the implementation of electronic tools (GheOP³S-tool and EBMeDS®CMR) to facilitate MR in NH residents and to explore the overall clinical and economic impact of this MR process. METHODS:A pilot study was conducted in one NH (January-July 2024). For each included resident (life expectancy of ≥3 months, excluding short-stays and general practitioner (GP) refusals), a 3-step MR was performed: 1) medication record analysis by a pharmacist using GheOP3S-tool and EBMeDS®CMR, and additional implicit screening, 2) interdisciplinary meeting (with pharmacist, GP, nurse) to discuss pDRPs and interventions, and 3) 3-month follow-up. Primary outcomes included the number, type, and resolution rate of pDRPs per screening method. Secondary outcomes were changes in medication use (number, fall risk-increasing drugs (FRIDs), Drug Burden Index (DBI)), and medication costs. RESULTS:Fifty-four residents were included (mean age 84.7 ± 8.9 years, 66.7% female). The electronic tools detected 508 pDRPs: 41.7% only by GheOP³S-tool, 29.5% only by EBMeDS®CMR, and 28.7% by both. The pharmacist appended 252 pDRPs. Of the 603 recommendations formulated, 48.4% were accepted and 37.5% implemented. The overall resolution rate was 40.1%. At follow-up, significant reductions were observed in number of medications, FRIDs, DBI, and medication costs. CONCLUSION:GheOP³S-tool and EBMeDS®CMR detected a considerable proportion of complementary pDRPs. A substantial part of pDRPs was appended by the pharmacist, highlighting the importance of combining explicit and implicit screening.
