Early Effects of Modern Radiotherapy for Lung Cancer on Endothelial Damage and Myocardial Fibrosis: A Prospective Single-Center Study
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SUBMITTER: Sławinski G
PROVIDER: S-EPMC11204135 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:BackgroundLung disease as major cause for morbidity in patients with cystic fibrosis (CF) starts early in life. Its large phenotypic heterogeneity is partially explained by the genotype but other contributing factors are not well delineated. The close relationship between mucus, inflammation and infection, drives morpho-functional alterations already early in pediatric CF disease, The TRACK-CF cohort has been established to gain insight to disease onset and progression, assessed by lung function testing and imaging to capture morpho-functional changes and to associate these with risk and protective factors, which contribute to the variation of the CF lung disease progression.Methods and designTRACK-CF is a prospective, longitudinal, observational cohort study following patients with CF from newborn screening or clinical diagnosis throughout childhood. The study protocol includes monthly telephone interviews, quarterly visits with microbiological sampling and multiple-breath washout and as well as a yearly chest magnetic resonance imaging. A parallel biobank has been set up to enable the translation from the deeply phenotyped cohort to the validation of relevant biomarkers. The main goal is to determine influencing factors by the combined analysis of clinical information and biomaterials. Primary endpoints are the lung clearance index by multiple breath washout and semi-quantitative magnetic resonance imaging scores. The frequency of pulmonary exacerbations, infection with pro-inflammatory pathogens and anthropometric data are defined as secondary endpoints.DiscussionThis extensive cohort includes children after diagnosis with comprehensive monitoring throughout childhood. The unique composition and the use of validated, sensitive methods with the attached biobank bears the potential to decisively advance the understanding of early CF lung disease.Ethics and trial registrationThe study protocol was approved by the Ethics Committees of the University of Heidelberg (approval S-211/2011) and each participating site and is registered at clinicaltrials.gov (NCT02270476).
| S-EPMC9853074 | biostudies-literature
Project description:In non-small cell lung cancer (NSCLC), pathologic complete response (pCR) following radiotherapy treatment has been shown to be an independent prognostic factor for long-term survival, progression-free survival and locoregional control. PCR is considered a surrogate to therapeutic efficacy, years before survival data are available, and therefore can be used to guide treatment plans and additional therapeutic interventions post-surgical resection. Given the extensive fibrotic changes induced by radiotherapy in the lung, radiological assessment of response can potentially misrepresent pathologic response. The optimal timing for assessment of pathologic response after conventionally fractionated radiotherapy and stereotactic ablative radiotherapy (SABR) remains poorly understood. In this review, we summarize recent literature on pathologic response after radiotherapy for early stage and locally advanced NSCLC, we discuss current controversies around radiobiological considerations, and we present upcoming trials that will provide insight into current knowledge gaps.
| S-EPMC6795577 | biostudies-literature
Project description:BackgroundBreast radiotherapy (RT) induces diffuse myocardial changes, which may increase the incidence of heart failure with preserved ejection fraction. This study aimed to evaluate the early signs of diffuse fibrosis after RT and their evolution during a six-year follow-up.MethodsThirty patients with early-stage left-sided breast cancer were studied with echocardiography and electrocardiography (ECG) at baseline, after RT, and at three-year and six-year follow-up visits. Echocardiography analysis included an off-line analysis of integrated backscatter (IBS). ECG was analysed for fragmented QRS (fQRS). In addition, cardiac magnetic resonance (CMR) imaging was performed at the six-year control. The left ventricle 16-segment model was used in cardiac imaging, and respective local radiation doses were analysed.ResultsRegional myocardial reflectivity in inferoseptal segments increased by 2.02 (4.53) dB (p = 0.026) and the percentage of leads with fQRS increased from 9.2 to 16.4% (p = 0.002) during the follow-up. In CMR imaging, abnormal extracellular volume (ECV) and T1 mapping values were found with anteroseptal and apical localization in a median of 3.5 (1.00-5.75) and 3 (1.25-4.00) segments, respectively. A higher left ventricle radiation dose was associated with an increased likelihood of having changes simultaneously in CMR and echocardiography (OR 1.26, 95% Cl. 1.00-1.59, p = 0.047).ConclusionsAfter radiotherapy, progressive changes in markers of diffuse myocardial fibrosis were observed in a multimodal manner in ECG and echocardiography. Changes in echocardiography and abnormal values in CMR were localized in the septal and apical regions, and multiple changes were associated with higher radiation doses.
| S-EPMC10373367 | biostudies-literature
Project description:BackgroundPostoperative radiotherapy (PORT) is an important treatment for lung cancer patients with poor prognostic features, but accurate delineation of the clinical target volume (CTV) and organs at risk (OARs) is challenging and time-consuming. Recently, deep learning-based artificial intelligent (AI) algorithms have shown promise in automating this process.ObjectiveTo evaluate the clinical utility of a deep learning-based auto-segmentation model for AI-assisted delineating CTV and OARs in patients undergoing PORT, and to compare its accuracy and efficiency with manual delineation by radiation oncology residents from different levels of medical institutions.MethodsWe previously developed an AI auto-segmentation model in 664 patients and validated its contouring performance in 149 patients. In this multi-center, validation trial, we prospectively involved 55 patients and compared the accuracy and efficiency of 3 contouring methods: (i) unmodified AI auto-segmentation, (ii) fully manual delineation by junior radiation oncology residents from different medical centers, and (iii) manual modifications based on AI segmentation model (AI-assisted delineation). The ground truth of CTV and OARs was delineated by 3 senior radiation oncologists. Contouring accuracy was evaluated by Dice similarity coefficient (DSC), Hausdorff distance (HD), and mean distance of agreement (MDA). Inter-observer consistency was assessed by volume and coefficient of variation (CV).ResultsAI-assisted delineation achieved significantly higher accuracy compared to unmodified AI auto-contouring and fully manual delineation by radiation oncologists, with median HD, MDA, and DCS values of 20.03 vs. 21.55 mm, 2.57 vs. 3.06 mm, 0.745 vs. 0.703 (all P<0.05) for CTV, respectively. The results of OARs contours were similar. CV for OARs was reduced by approximately 50%. In addition to better contouring accuracy, the AI-assisted delineation significantly decreased the consuming time and improved the efficiency.ConclusionAI-assisted CTV and OARs delineation for PORT significantly improves the accuracy and efficiency in the real-world setting, compared with pure AI auto-segmentation or fully manual delineation by junior oncologists. AI-assisted approach has promising clinical potential to enhance the quality of radiotherapy planning and further improve treatment outcomes of patients with lung cancer.
| S-EPMC11579590 | biostudies-literature
Project description:Pentraxin 3 (PTX3) is a main component of the innate immune system by inducing complement pathway activation, acting as an inflammatory mediator, coordinating the functions of macrophages/dendritic cells and promoting apoptosis/necrosis. Additionally, it has been found in fibrotic regions co-localizing with collagen. In this work, we wanted to investigate the predictive role of PTX3 in myocardial damage and fibrosis of Duchenne muscular dystrophy (DMD). DMD is an X-linked recessive disease caused by mutations of the dystrophin gene that affects muscular functions and strength and accompanying dilated cardiomyopathy. Here, we expound the correlation of PTX3 cardiac expression with age and Toll-like receptors (TLRs)/interleukin-1 receptor (IL-1R)-MyD88 inflammatory markers and its modulation by the so-called alarmins IL-33, high-mobility group box 1 (HMGB1), and S100β. These findings suggest that cardiac levels of PTX3 might have prognostic value and potential in guiding therapy for DMD cardiomyopathy.
| S-EPMC7248204 | biostudies-literature
Project description:BackgroundAdverse cardiac remodeling with a myocardial fibrosis as a key pathophysiologic component may be associated to worse survival in aortic stenosis (AS) patients. Therefore, with the application of advanced cardiac imaging we aim to investigate left ventricular myocardial fibrosis in severe AS patients undergoing aortic valve replacement (AVR) and determine its impact with post-intervention clinical outcomes.MethodsIn a prospective, observational, cohort study patients with severe AS scheduled either for surgical or transcatheter AVR will be recruited from two tertiary heart centers in Denmark and Lithuania. All patients will receive standard of care in accordance with the current guidelines and will undergo additional imaging testing before and after AVR: echocardiography with deformation analysis and cardiovascular magnetic resonance (CMR) with T1 parametric mapping. Those undergoing surgical AVR will also have a myocardial biopsy sampled at the time of a surgery for histological validation. Patients will be recruited over a 2-year period and followed up to 2 years to ascertain clinical outcomes. Follow-up CMR will be performed 12 months following AVR, and echocardiography with deformation analysis will be performed 3, 12, and 24 months following AVR. The study primary outcome is a composite of all-cause mortality and major adverse cardiovascular events.DiscussionDespite continuous effort of research community there is still a lack of early predictors of left ventricular decompensation in AS, which could improve patient risk stratification and guide the optimal timing for aortic valve intervention, before irreversible left ventricular damage occurs. Advanced cardiac imaging and CMR derived markers of diffuse myocardial fibrosis could be utilized for this purpose. FIB-AS study is intended to invasively and non-invasively assess diffuse myocardial fibrosis in AS patients and investigate its prognostic significance in post-interventional outcomes. The results of the study will expand the current knowledge of cardiac remodeling in AS and will bring additional data on myocardial fibrosis and its clinical implications following AVR.Ethics/disseminationThe study has full ethical approval and is actively recruiting patients. The results will be disseminated through scientific journals and conference presentations.Trial registrationClinicalTrials.govNCT03585933. Registered on 02 July 2018.
| S-EPMC7278169 | biostudies-literature
Project description:RationaleNeutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown.ObjectivesTo measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF.MethodsWe measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects.Measurements and main resultsChildren with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes.ConclusionsNE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.
| S-EPMC6444666 | biostudies-literature
Project description:BackgroundPatients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain.Methods211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified.ResultsPatients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls - 13.9 ± 2.0%, total cohort - 11.6 ± 3.0%; subgroup - 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22-1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54-2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) - 0.2 (- 0.3 to - 0.08), MPR (β (95% CI) - 0.5 (- 0.8 to - 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (- 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73).ConclusionsMyocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.
| S-EPMC10863286 | biostudies-literature
Project description:ObjectivesIn cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters.MethodsLevels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1-5 using a targeted high-performance liquid chromatography-tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression.ResultsA total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB4 and 6-trans-LTB4 positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB4 was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction.ConclusionsOur data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression.
| S-EPMC11403467 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
| S-EPMC10503802 | biostudies-literature