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Elevated FDG uptake in non-tumorous lung regions does not predict immune checkpoint inhibitor–related pneumonitis in lung cancer patients
Get PDFBackground:
Predictors for checkpoint inhibitor-related pneumonitis (cinrPneumonitis) are desperately needed. This study aimed to investigate the pretreatment standardized uptake value (SUV) on [18F]FDG-PET/CT of non-tumorous lung tissue as a predictive imaging marker for the development of cinrPneumonitis in 239 patients with lung cancer.
Methods:
All patients with lung cancer receiving [18F]Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) prior to immune checkpoint inhibitor (ICI) therapy were included and retrospectively analyzed. Pretreatment SUVMEAN, SUVMAX, SUV95, SUV normalized by lean body mass (SULMEAN, SULMAX) and clinical variables were compared for patients with and without cinrPneumonitis. Logistic regression analyses were performed to identify the predictive value of pretreatment SUV for the development of cinrPneumonitis.
Results:
A total of 239 patients were included, of whom 41 (17.2%) developed cinrPneumonitis. The pretreatment radioligand uptake (SUVMEAN, SUVMAX, SUV95, SULMEAN and SULMAX) was not significantly elevated in patients who developed cinrPneumonitis. Logistic regression using sex, age, body mass index and chronic obstructive pulmonary disease as covariables additionally showed no significant association between pretreatment radioligand uptake and the risk of cinrPneumonitis. However, an increased likelihood of developing cinrPneumonitis (relative risk = 1.979; p = 0.027) was shown in patients who received thoracic radiation during ICI therapy.
Conclusion:
This is the largest study on the association of pretreatment radioligand uptake of the non-tumorous lung and the risk of a cinrPneumonitis. Our results showed no significant association between elevated pretreatment radioligand uptake of non-tumorous lung tissue on FDG-PET/CT and the development of cinrPneumonitis
Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U
Get PDFAtypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the GLI1 transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (MBP), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET
HLA-A∗03:01 as predictive genetic biomarker for glatiramer acetate treatment response in multiple sclerosis: a retrospective cohort analysis
No full textBackground
Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment.
Methods
T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis.
Findings
Common GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or in HLA-DRB1∗15:01 backgrounds, within CD8+ effector- or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA’s clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A∗03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A∗03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47–0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45–0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16–0.88], p = 0.0246), but no positive association with DRB1∗15:01.
Interpretation
HLA-A∗03:01 carrying patients with MS specifically benefit from GA treatment and GA significantly outperforms IFN in these patients. Therefore, determining HLA-A∗03:01 status before choosing a platform treatment for MS, would allow for a personalised treatment decision between GA and IFN.
Funding
German Research Foundation, National Institutes of Health, National Multiple Sclerosis Society, Valhalla Foundation, Westridge Foundation, Mayer Foundation, German Federal Ministry of Education and Research
Werkzeug, Medium oder Partner:in?
No full textIn dieser Arbeit wird die aktuelle Debatte über den Einsatz von Large Language Models (LLMs) in der Analyse qualitativer Daten systematisch untersucht. Dazu wird der Einsatz der LLMs nach den Anwendungsbereichen Zusammenfassungen, semantische Suche, KI-gestütztes Kodieren, Forschungswerkstätten und Post-Coding-Verfahren kategorisiert und anhand der methodologischen Grundlagen qualitativer Forschung sowie forschungspraktischer Erfahrungen reflektiert. Im Zentrum steht die Frage nach der Rollenverteilung zwischen Forschenden und der Künstlichen Intelligenz (KI). Da LLMs zwar keine passiven Werkzeuge darstellen, zugleich aber durch die Leitfunktion der Forschenden gerahmt bleiben, werden sie hier als interpretative Medien eingeordnet. Diese Konzeptualisierung ermöglicht eine angemessene Reflexion sowohl der Interaktion mit der KI als auch der Distanz zum Datenmaterial. Die Analyse zeigt, dass eine gezielte Unterstützung einzelner Arbeitsschritte durch LLMs grundsätzlich möglich ist. Sie setzt jedoch eine kohärente methodische und methodologische Fundierung, explizite Reflexionsphasen zur Wahrung der Datennähe, Kriterien zur Überprüfung der KI-Outputs und eine besondere Sensibilität für forschungsethische Prinzipien voraus
Provenance and selective quarrying of New Kingdom Nubian sandstones on Sai Island, Sudan: Insights from ilmenite alterations and matrix compositions
No full textThis study examines the mineralogical composition and alteration products of ilmenite and the matrix in Nubian sandstones from Temple A and ancient quarries on Sai Island (northern Sudan) for insights into their provenance. We characterized the grains and their diagenetic alteration products via polarized light microscopy, scanning electron microscopy (SEM), and Raman spectroscopy. All samples, deriving from Late Bronze Age contexts (c. 15th–14th cent. BCE), are dominated by quartz (>90 %), minor feldspar (<10 %), and rare lithoclasts (<5%). Depending on the amount of matrix (5–50 %), the sandstones are classified as quartz arenites or quartz wackes. Generally, temple sandstones are moderately sorted, smaller-grained (250 μm to 310 μm), and lighter colored, compared to quarry samples, which are (very) poorly sorted, larger-grained (190 μm to 750 μm), and darker. All sandstone samples bear ilmenite alteration products (pseudorutile, rutile, anatase, hematite, Fe-hydroxides) and have matrices composed of kaolinite and illite, indicating similar weathering, diagenetic, and burial histories. The grains derive from a pluton and the Fe-Ti-oxide assemblage before alteration was consistently ilmenite with minor rutile and hematite, which suggests a late-stage magmatic source with comparable temperature and oxygen fugacity conditions for all samples. The results indicate that all investigated samples likely originate from the same or closely related stratigraphic units. The mineralogical homogeneity precludes precise attribution of temple blocks to specific quarries, however, the difference between moderately sorted temple and (very) poorly sorted quarry sandstones could be explained by selective quarrying by ancient builders to ensure aesthetic and material consistency in construction
Validation of POD24 as a robust early clinical indicator of poor survival in mantle cell lymphoma from 1280 patients on clinical trials, a LYSA study
No full textIn mantle cell lymphoma, early progression of disease has been associated with short overall survival. The impact of clinical, pathological, and treatment strategies on the risk of early relapse has not been assessed in a large cohort of patients. We performed a pooled analysis of patients recruited in France from six randomized first-line MCL trials. Among 1386 treated MCL patients, 1280 were evaluable for POD24 status: 299 (23.4%) with a POD24 event and 981 (76.6%) without. Patients with a POD24 event had a median OS of 9.3 months (95% CI 8.4-11.8) versus not reached (95% CI 97.8-NR) for those without POD24 events. The median post-relapse OS of patients with a late relapse was also significantly longer at 49.4 months (HR = 0.39; 95% CI 0.31-0.48; P 30%) were significantly associated with the risk of POD24, independent of ASCT. Among responding patients at end-of-induction (n = 1105) who had received ASCT, anti-CD20 maintenance was associated with a decreased risk of POD24 (OR = 0.37; 95% CI 0.1-1.0). Using this large data set of patients in clinical trials, we confirm that POD24 status is strongly associated with subsequent OS in MCL. Rituximab maintenance provided significant protection against the risk of POD24, independent of ASCT. Progression within 2 years should be considered as a primary endpoint in future studies
Multiple System Atrophy Without Dysautonomia
Get PDFBackground and Objectives
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by 3 core symptom complexes: parkinsonism, cerebellar syndrome, and dysautonomia. Recent Movement Disorder Society (MDS) criteria allow for the clinical diagnosis of MSA based solely on motor symptoms, without requiring dysautonomia. This study aimed to evaluate the frequency and disease trajectory of MSA patients without dysautonomia compared with those with autonomic involvement.
Methods
A multicenter cohort of autopsy-confirmed patients with MSA was analyzed for demographic characteristics, symptom onset, and progression of parkinsonism, cerebellar syndrome, and dysautonomia. Clinical data were collected through standardized chart reviews across participating centers and categorized using the MDS-MSA criteria. Patients were grouped according to their initial symptom complex and tracked for the evolution of additional symptoms. Analyses included time to development of further symptom complexes, age at symptom onset, disease duration, and phenotype at the last recorded visit. Patients with motor symptoms only were matched to patients with similar demographics but with dysautonomia. Statistical methods included ANOVA, t tests, Welch t tests, and χ2 tests, with significance set at p < 0.05.
Results
Among 140 patients (mean age at onset 62.3 ± 8.9 years; 44% female), 81 (58%) initially presented without dysautonomia (57 with parkinsonism only, 17 with cerebellar syndrome only, 7 with both). At final follow-up, 12 patients (9%) had not developed dysautonomia. These patients showed significantly longer disease duration (mean 8.1 ± 2.1 years) than matched patients with dysautonomia (mean 6.3 ± 2.6 years; p = 0.035). Overall, 51% of patients developed all 3 symptom complexes. Patients with cerebellar onset progressed more rapidly to multisystem involvement than those with parkinsonian onset (mean interval to second symptom: 2.0 vs 3.4 years; p < 0.05).
Discussion
The MDS-MSA criteria expand the diagnostic scope by identifying a motor-only subgroup with a distinct and potentially slower disease course. These findings underscore the importance of including motor-only patients in natural history and interventional studies. Limitations include retrospective data collection and potential variability in symptom documentation
Thyroid volume—new reference values for defining thyroid enlargement
Get PDFObjective: Upper reference values for thyroid volume are 25 mL for men and 18 mL for women. Thyroid volume alters with age, body weight, body height, and iodine status, which is not considered in the current limits. The aim was to develop reference equations, considering age, body weight, and height to calculate individual reference values for thyroid volume.
Design: This cross-sectional study used data from 3 independent cohorts (SHIP-START, SHIP-TREND, and KORA-F4) in Germany. SHIP-START-0, a population-based health survey, was carried out in Northern Germany, from 1997 to 2001. SHIP-TREND-0, a second independent sample of the same study region, was carried out between 2008 and 2012. KORA-F4, a population-based health survey, was conducted between 2006 and 2008 in Southern Germany.
Methods: A total of 11 549 individuals (51% women) were included in the data analysis. Eight thousand six-hundred and six individuals (45% women) were used as the thyroid-healthy reference population when developing equations. Sex-stratified quantile regression models for the 95th percentile using age, body weight, and height as explanatory variables were performed.
Results: The overall reference value was 38.7 mL for men and 28.6 mL for women. According to the established cut-offs, 34% of the overall population would have had goitre compared with 7% when using our equations.
Conclusion: Upper reference values for thyroid volume are too low for an adult, previously iodine-deficient population and do not consider age, body weight, and height. Using individualised equations reduces the prevalence of thyroid enlargement substantially and can lead to a decrease in overdiagnoses and the use of medical resources
Air pollution, greenspace, and metabolic syndrome in older Czech and Swiss populations
Get PDFBackground: The prevalence of metabolic syndrome (MetS) has increased rapidly, with considerable variation between European countries. The study examined the relationship between air pollutants, greenspace, and MetS and its components in the Czech and Swiss populations.
Methods: Cross-sectional data from the Czech Health, Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) (n = 4,931) and the Swiss cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) (n = 4,422) cohorts included participants aged 44-73 years. MetS was defined as abdominal obesity plus two additional components (hypertension, diabetes, low high-density lipoprotein cholesterol, and elevated triglycerides). Annual mean concentrations of PM10, PM2.5, NO2, and greenspace (defined as the annual mean of normalized difference vegetation index within 500 m) were assigned to the individual residential level. We estimated odds ratios (OR) using multivariable logistic regressions with cluster-robust standard error, controlling for multiple confounders.
Results: The prevalence of MetS was significantly higher in the Czech (51.1%) compared with Swiss (35.8%) population as were the concentration means of PM10 and PM2.5. In HAPIEE, a 5 μg/m3 increase in PM2.5 was associated with 14% higher odds of MetS (OR = 1.14; 95% confidence interval [CI] = 1.01, 1.28). In SAPALDIA, no evidence was found for the associations between air pollutants and MetS (e.g. OR = 1.01; 95% CI = 0.90, 1.13 for PM2.5). No protective effects of normalized difference vegetation index on MetS were observed. Upon inspection of MetS components, PM2.5 and PM10 exposures were associated with higher odds of hypertension and elevated triglycerides in HAPIEE only, while PM2.5, PM10, and NO2 were associated with higher odds of diabetes in SAPALDIA only.
Conclusion: Individuals with higher exposures to PM2.5 may be at higher risk of MetS. The differential associations with MetS components between the cohorts deserve further investigation