Anna Ungvari’s research while affiliated with Semmelweis University and other places

Treatment delay in breast cancer care represents a significant concern in oncology, potentially impacting patient survival outcomes. While various factors can contribute to delayed treatment initiation, the quantitative relationship between specific delay intervals and survival remains incompletely understood in breast cancer management. Our study aims to explore the impact of treatment delays on survival outcomes in breast cancer. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases, covering publications from 2000 to 2025. From an initial 6222 records, 18 eligible studies comprising 25 cohorts were included. Hazard ratios (HRs) for all-cause and breast cancer–specific mortality were extracted or calculated for treatment delays of 4, 8, and 12 weeks. Random-effects meta-analyses were performed, and heterogeneity and publication bias were assessed using I ² statistics, funnel plots, and Egger’s test. This meta-analysis revealed progressively increasing mortality risks with longer treatment delays. For all-cause mortality, HRs increased from 1.12 (95% CI 1.08–1.15) at 4 weeks to 1.25 (95% CI 1.17–1.33) at 8 weeks, and 1.39 (95% CI 1.26–1.53) at 12 weeks. Breast cancer–specific mortality showed more pronounced effects, with HRs of 1.20 (95% CI 1.06–1.36), 1.43 (95% CI 1.11–1.84), and 1.71 (95% CI 1.18–2.49) for 4-, 8-, and 12-week delays, respectively. Analyses combining both survival outcomes demonstrated consistent risk elevation across all time intervals (4 weeks: HR = 1.12, 95% CI 1.09–1.16; 8 weeks: HR = 1.26, 95% CI 1.18–1.34; 12 weeks: HR = 1.41, 95% CI 1.29–1.55). While heterogeneity was significant ( I ² = 54–92%), no substantial publication bias was detected. Delays in initiating breast cancer treatment are associated with significantly worse survival, particularly for cancer-specific mortality. Each additional 4-week delay increases the hazard of death by over 10%, underscoring the urgency of minimizing delays in diagnosis-to-treatment pathways. These findings have critical implications for healthcare systems, clinical decision-making, and public health policy.

Gait alterations are recognized as early markers of age-related decline and cognitive impairment. Dual-task assessments, which impose cognitive load while walking, provide valuable insights into gait control limitations and cognitive-motor interactions in aging populations. This study evaluates age-related and cognitive load-induced changes in gait parameters, with a particular focus on asymmetry, and aims to optimize the gait assessment protocol for the Semmelweis Study framework. The Semmelweis Study is a large-scale workplace cohort investigating the determinants of unhealthy aging and promoting healthy brain aging by identifying risk factors and protective mechanisms influencing vascular, metabolic, and neurocognitive decline. As part of this initiative, gait analysis is emerging as a critical tool for assessing functional aging, detecting early signs of mobility and cognitive impairment, and contributing to biological age assessment. A cross-sectional analysis was conducted on adults aged 23 to 87 years using a pressure-sensitive walkway system. Participants were evaluated under single-task conditions (normal walking) and dual-task conditions (walking while performing a concurrent cognitive task). Spatiotemporal gait parameters, asymmetry indices, and dual-task costs were analyzed to assess age-related changes in gait performance and cognitive-motor interactions. Aging was associated with significant reductions in gait speed, step length, and stride length, along with a corresponding increase in gait asymmetry. Dual-task conditions exacerbated these alterations, indicating age-related impairments in cognitive-motor integration. Asymmetry indices were sensitive to aging effects, suggesting their potential as biomarkers for functional decline. The dual-task cost on gait was significantly greater in older adults, reinforcing the interplay between cognitive and motor systems in aging. Age-related gait alterations, particularly under cognitive load, underscore the importance of comprehensive gait assessments in aging research. Our findings contribute to the optimization of the Semmelweis Study gait assessment protocol by identifying key gait parameters that capture functional decline and biological aging. Integrating dual-task gait analysis into large-scale epidemiological studies has the potential to enhance early detection of brain health decline, refine biological age estimation, and guide targeted interventions to support healthy aging and neuromotor resilience.

Aging is a complex biological process that detrimentally affects the brain and cerebrovascular system, contributing to the pathogenesis of age-related diseases like vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). While cell-autonomous mechanisms that occur within cells, independent of external signals from neighboring cells or systemic factors, account for some aspects of aging, they cannot explain the entire aging process. Non-autonomous, paracrine and endocrine, pathways also play a crucial role in orchestrating brain and vascular aging. The systemic milieu modulates aging through pro-geronic and anti-geronic circulating factors that mediate age-related decline or confer rejuvenative effects. This review explores the impact of systemic factors on cerebrovascular and brain aging, with a particular focus on findings from heterochronic parabiosis, blood exchange, and plasma transfer experiments. We discuss how these factors influence fundamental cellular and molecular processes of aging and impact cerebrovascular endothelial function, neurovascular coupling mechanisms, blood–brain barrier integrity, neuroinflammation, capillary density, and amyloid pathologies, with significant consequences for cognitive function. Additionally, we address the translational potential and challenges of modifying the systemic milieu to promote brain health and prevent age-related cognitive impairment.

Timely initiation of treatment is a core principle of oncologic care, especially for aggressive cancers such as lung cancer. However, the real-world impact of short-term delays in treatment initiation on survival outcomes in lung cancer remains unclear. This meta-analysis evaluates the association between treatment delays of 4, 8, and 12 weeks and all-cause mortality in lung cancer patients. A systematic search was conducted in PubMed, Scopus, and Web of Science for studies published between 2000 and 2025. Of 5360 screened records, 15 studies were included, comprising 16 cohorts for overall survival of lung cancer patients. Hazard ratios (HRs) for 4-, 8-, and 12-week treatment delays were estimated using random-effects meta-analyses. Heterogeneity was measured with the I ² statistic, and publication bias was assessed using funnel plots and Egger’s test. No significant association was found between treatment delay and survival at any of the time points. Pooled HRs were 1.00 (95% CI, 0.99–1.02) for a 4-week delay, 1.01 (95% CI, 0.99–1.03) for an 8-week delay, and 1.01 (95% CI, 0.98–1.05) for a 12-week delay. Despite high heterogeneity ( I ² = 97%), no evidence of publication bias was detected. This meta-analysis found no significant impact of short-term treatment delays (up to 12 weeks) on mortality in lung cancer patients. These findings challenge the assumption that brief delays universally worsen outcomes and underscore the importance of individualized treatment planning and prioritization.

Depression is a prevalent but often underrecognized comorbidity among cancer patients. Emerging evidence suggests that psychological distress may adversely impact cancer outcomes, but the magnitude of its effect on survival remains unclear. This meta-analysis evaluates the association between depression diagnosed after cancer diagnosis and cancer-specific and all-cause mortality across major cancer types. A systematic search of PubMed, Web of Science, Google Scholar, and the Cochrane Library was conducted to identify cohort studies examining the impact of depression on cancer mortality. Studies were included if they assessed clinically diagnosed depression or depressive symptoms using validated scales and reported hazard ratios (HRs) for mortality outcomes. A random-effects meta-analysis was performed to pool HR estimates, with heterogeneity assessed via Cochran’s Q and I ² statistics. Funnel plots and Egger’s test were used to evaluate publication bias. A total of 65 cohort studies were included. Depression was associated with significantly increased cancer-specific mortality in colorectal cancer (HR 1.83, 95% CI 1.47–2.28), breast cancer (HR 1.23, 95% CI 1.13–1.34), lung cancer (HR 1.59, 95% CI 1.36–1.86), and prostate cancer (HR 1.74, 95% CI 1.36–2.23). When considering mixed cancer types, depression was linked to a 38% increased risk of cancer mortality (HR 1.38, 95% CI 1.20–1.60). Significant heterogeneity was observed across studies ( I ² range 56–98%), suggesting variations in study populations and methodologies. Sensitivity analyses confirmed the robustness of the findings, and trial sequential analysis indicated sufficient evidence for a conclusive association. Depression after cancer diagnosis is associated with a significantly increased risk of cancer-specific mortality across multiple cancer types. These findings highlight the urgent need for integrating routine mental health screening and interventions into oncology care. Future research should focus on mechanistic pathways and targeted interventions to mitigate the negative impact of depression on cancer survival.

Cancer remains a major global health challenge, and growing evidence suggests that physical activity is a key modifiable factor that may improve survival outcomes in cancer patients. However, a comprehensive, large-scale synthesis of the effects of post-diagnosis physical activity across multiple cancer types remains lacking. This meta-analysis aims to systematically evaluate the association between physical activity and survival in patients diagnosed with breast, lung, prostate, colorectal, and skin cancers. We conducted a comprehensive search in PubMed, Web of Science, Scopus, and Cochrane Library for studies on physical activity and cancer survival. Eligible studies (January 2000–November 2024) included adults (≥ 18 years) with breast, lung, prostate, colorectal, or skin cancer. Only prospective cohort and case–control studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall or cancer-specific mortality were included, with a minimum sample size of 100 and at least six months of follow-up. Meta-analysis was performed using metaanalysisonline.com, applying random-effects models and assessing heterogeneity via the I2 statistic. Sensitivity analyses and publication bias (Egger’s test, funnel plots) were evaluated. The meta-analysis included 151 cohorts with almost 1.5 million cancer patients. Post-diagnosis physical activity was associated with significantly lower cancer-specific mortality across all five cancer types. The greatest benefit was observed in breast cancer, with a pooled hazard ratio (HR) of 0.69 (95% CI: 0.63–0.75), followed by prostate cancer (HR: 0.73, 95% CI: 0.62–0.87). Lung cancer patients who engaged in physical activity had a 24% lower risk of cancer-specific death (HR: 0.76, 95% CI: 0.69–0.84), while colorectal cancer patients experienced a similar benefit (HR: 0.71, 95% CI: 0.63–0.80). In skin cancer, physical activity was associated with a non-significant reduction in mortality (HR: 0.86, 95% CI: 0.71–1.05). These findings provide robust evidence supporting the survival benefits of post-diagnosis physical activity in cancer patients, particularly for breast, prostate, lung, and colorectal cancers. The results underscore the potential for incorporating structured physical activity interventions into oncological care to improve long-term patient outcomes.

Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a prominent manifestation of this instability, characterized by the non-malignant expansion of hematopoietic stem cell clones that harbor somatic mutations. CHIP is well-established as a contributor to atherosclerosis and cardiovascular disease through its promotion of chronic inflammation. Given that aging is also a major risk factor for cerebral small vessel disease (CSVD) and VCID, it is likely that the same aging processes driving large artery atherosclerosis in CHIP carriers also impair small vessels, including the cerebral microvasculature. While the role of CHIP in large vessel disease is well-documented, its specific contributions to cerebrovascular aging and microvascular dysfunction remain poorly understood. This review explores the potential role of CHIP in age-related cerebrovascular pathologies, with a particular focus on its contribution to CSVD. We discuss how CHIP-related mutations can promote inflammation and oxidative stress, potentially leading to endothelial dysfunction, dysregulation of cerebral blood flow (CBF), blood–brain barrier (BBB) disruption, microvascular inflammation, and cerebral microhemorrhages. Given the potential implications for VCID, elucidating these mechanisms is critical for developing targeted therapies aimed at reducing the burden of cognitive decline in aging populations. This review aims to highlight the current knowledge gaps and encourage further research into the intersection of CHIP, CSVD, and cognitive aging.

Sleep disorders, particularly insomnia and obstructive sleep apnea, are increasingly implicated as significant contributors to cognitive decline, dementia, and neurodegenerative diseases such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID). However, the extent and specificity of these associations remain uncertain. This meta-analysis evaluates the impact of common sleep disorders on the risk of developing dementia and cognitive decline. A comprehensive search of the literature was conducted to identify prospective cohort studies assessing sleep disorders and dementia risk. Studies reporting risk estimates for dementia, AD, or cognitive decline associated with obstructive sleep apnea, insomnia, and other sleep disorders (e.g., restless legs syndrome, circadian rhythm sleep disorders, excessive daytime sleepiness) were included. Meta-analyses were performed using a random-effects model to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Thirty-nine cohort studies were included, with subgroup analyses showing significant associations between all-cause dementia and obstructive sleep apnea (HR 1.33, 95% CI 1.09–1.61), insomnia (HR 1.36, 95% CI 1.19–1.55), and other sleep disorders (HR 1.33, 95% CI 1.24–1.43). Obstructive sleep apnea increased the risk for AD (HR 1.45, 95% CI 1.24–1.69), though its association with vascular dementia did not reach statistical significance (HR 1.35, 95% CI 0.99–1.84). Insomnia was significantly associated with increased risk for both vascular dementia (HR 1.59, 95% CI 1.01–2.51) and AD (HR 1.49, 95% CI 1.27–1.74). This meta-analysis highlights the critical role of sleep disorders in dementia risk, emphasizing the need for early detection and management of sleep disturbances. Targeted interventions could play a pivotal role in reducing dementia risk, particularly among high-risk populations.

Increasing evidence suggests that red and processed meat consumption may elevate the risk of colorectal cancer (CRC), yet the magnitude and consistency of this association remain debated. This meta-analysis aims to quantify the relationship between red and processed meat intake and the risk of CRC, colon cancer, and rectal cancer using the most comprehensive set of prospective studies to date. We conducted a comprehensive search in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases from 1990 to November 2024, to identify relevant prospective studies examining red, processed, and total meat consumption in relation to colorectal, colon, and rectal cancer risk. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted for each study and pooled using a random-effects model to account for variability among studies. Statistical evaluation was executed using the online platform MetaAnalysisOnline.com. A total of 60 prospective studies were included. Red meat consumption was associated with a significantly increased risk of colon cancer (HR = 1.22, 95% CI 1.15–1.30), colorectal cancer (HR = 1.15, 95% CI 1.10–1.21), and rectal cancer (HR = 1.22, 95% CI 1.07–1.39). Processed meat consumption showed similar associations with increased risk for colon cancer (HR = 1.13, 95% CI 1.07–1.20), colorectal cancer (HR = 1.21, 95% CI 1.14–1.28), and rectal cancer (HR = 1.17, 95% CI 1.05–1.30). Total meat consumption also correlated with an elevated risk of colon cancer (HR = 1.22, 95% CI 1.11–1.35), colorectal cancer (HR = 1.17, 95% CI 1.12–1.22), and rectal cancer (HR = 1.28, 95% CI 1.10–1.48). This meta-analysis provides robust evidence that high consumption of red and processed meats is significantly associated with an increased risk of colorectal, colon, and rectal cancers. These findings reinforce current dietary recommendations advocating for the limitation of red and processed meat intake as part of cancer prevention strategies.

Aging is associated with a progressive decline in circulating insulin-like growth factor- 1 (IGF- 1) levels in humans, which has been implicated in the pathogenesis of sarcopenia. IGF- 1 is an anabolic hormone that plays a dual role in maintaining skeletal muscle health, acting both directly on muscle fibers to promote growth and indirectly by supporting the vascular network that sustains muscle perfusion. However, the microvascular consequences of IGF- 1 deficiency in aging muscle remain poorly understood. To elucidate how impaired IGF- 1 input affects skeletal muscle vasculature, we examined the effects of endothelial-specific IGF- 1 receptor (IGF- 1R) deficiency using a mouse model of endothelial IGF- 1R knockdown (VE-Cadherin-CreER T2 /Igf1r f/f mice). These mice exhibited significantly reduced skeletal muscle endurance and attenuated hyperemic response to acetylcholine, an endothelium-dependent vasodilator. Additionally, they displayed microvascular rarefaction and impaired nitric oxide-dependent vasorelaxation, indicating a significant decline in microvascular health in skeletal muscle. These findings suggest that endothelial IGF- 1R signaling is critical for maintaining microvascular integrity, muscle perfusion, and function. Impaired IGF- 1 input to the microvascular endothelium may contribute to reduced muscle blood flow and exacerbate age-related sarcopenia. Enhancing vascular health by modulating IGF- 1 signaling could represent a potential therapeutic strategy to counteract age-related muscle decline.