Large-Scale Plasma Proteome Epitome Profiling is an Efficient Tool for the Discovery of Cancer Biomarkers.

Current proteomic technologies focus on the quantification of protein levels, while little effort is dedicated to the development of system approaches to simultaneously monitor proteome variability and abundance. Protein variants may display different immunogenic epitopes detectable by monoclonal antibodies. Epitope variability results from alternative splicing, posttranslational modifications, processing, degradation, and complex formation and possesses dynamically changing availability of interacting surface structures that frequently serve as reachable epitopes and often carry different functions. Thus, it is highly likely that the presence of some of the accessible epitopes correlates with function under physiological and pathological conditions. To enable the exploration of the impact of protein variation on the immunogenic epitome first, here, we present a robust and analytically validated PEP technology for characterizing immunogenic epitopes of the plasma. To this end, we prepared mAb libraries directed against the normalized human plasma proteome as a complex natural immunogen. Antibody producing hybridomas were selected and cloned. Monoclonal antibodies react with single epitopes, thus profiling with the libraries is expected to profile many epitopes which we define by the mimotopes, as we present here. Screening blood plasma samples from control subjects (n = 558) and cancer patients (n = 598) for merely 69 native epitopes displayed by 20 abundant plasma proteins resulted in distinct cancer-specific epitope panels that showed high accuracy (AUC 0.826-0.966) and specificity for lung, breast, and colon cancer. Deeper profiling (≈290 epitopes of approximately 100 proteins) showed unexpected granularity of the epitope-level expression data and detected neutral and lung cancer-associated epitopes of individual proteins. Biomarker epitope panels selected from a pool of 21 epitopes of 12 proteins were validated in independent clinical cohorts. The results demonstrate the value of PEP as a rich and thus far unexplored source of protein biomarkers with diagnostic potential.

The virtual aging brain: Causal inference supports interhemispheric dedifferentiation in healthy aging.

The mechanisms of cognitive decline and its variability during healthy aging are not fully understood, but have been associated with reorganization of white matter tracts and functional brain networks. Here, we built a brain network modeling framework to infer the causal link between structural connectivity and functional architecture and the consequent cognitive decline in aging. By applying in-silico interhemispheric degradation of structural connectivity, we reproduced the process of functional dedifferentiation during aging. Thereby, we found the global modulation of brain dynamics by structural connectivity to increase with age, which was steeper in older adults with poor cognitive performance. We validated our causal hypothesis via a deep-learning Bayesian approach. Our results might be the first mechanistic demonstration of dedifferentiation during aging leading to cognitive decline.

Malignant pleural effusions for cancer genotyping: A matter of trans-pleural traffic of cell-free tumor DNA.

Body cavity fluids accumulating in progressive malignancies are potential subjects of regular clinical testing for cancer-related features. Besides the cellular component, the supernatant of the fluid proved to gain diagnostic impact as the cell-free DNA (cfDNA) fraction ideally reflects general molecular features of the related tumorous process, e.g. in lung carcinoma. Thus, malignant pleural effusions can be used for lung cancer genetic profiling and this might remain the only source for testing in critical cases. The cfDNA concentration of the pleural effusion depends on many factors in both benign and malignant conditions. Further to direct pleural metastatic spread, the redirection of tissue lymphatic circulation, tumor angiogenesis, inflammatory processes and other variables may contribute to or enhance the enrichment of the effusion tumor DNA from the earliest stages of carcinogenesis. Our review addresses the traffic of cfDNA in the pleural space and the diagnostic utility of effusion cfDNA from the perspective of the complex pleural pathophysiology.

Pathway-Specific Genetic Risk for Alzheimer's Disease Differentiates Regional Patterns of Cortical Atrophy in Older Adults.

Brain aging is highly variable and represents a challenge to delimit aging from disease processes. Moreover, genetic factors may influence both aging and disease. Here we focused on this issue and investigated effects of multiple genetic loci previously identified to be associated with late-onset Alzheimer's disease (AD) on brain structure of older adults from a population sample. We calculated a genetic risk score (GRS) using genome-wide significant single-nucleotide polymorphisms from genome-wide association studies of AD and tested its effect on cortical thickness (CT). We observed a common pattern of cortical thinning (right inferior frontal, left posterior temporal, medial occipital cortex). To identify CT changes by specific biological processes, we subdivided the GRS effect according to AD-associated pathways and performed follow-up analyses. The common pattern from the main analysis was further differentiated by pathway-specific effects yielding a more bilateral pattern. Further findings were located in the superior parietal and mid/anterior cingulate regions representing 2 unique pathway-specific patterns. All patterns, except the superior parietal pattern, were influenced by apolipoprotein E. Our step-wise approach revealed atrophy patterns that partially resembled imaging findings in early stages of AD. Our study provides evidence that genetic burden for AD contributes to structural brain variability in normal aging.

The influence of bilingualism on gray matter volume in the course of aging: a longitudinal study.

Background: Bilingualism is associated with higher gray matter volume (GMV) as a form of brain reserve in brain regions such as the inferior frontal gyrus (IFG) and the inferior parietal lobule (IPL). A recent cross-sectional study reported the age-related GMV decline in the left IFG and IPL to be steeper for bilinguals than for monolinguals. The present study aimed at supporting this finding for the first time with longitudinal data. Methods: In the current study, 200 participants aged 19 to 79 years (87 monolinguals, 113 sequential bilinguals, mostly native German speakers with variable second language background) were included. Trajectories of GMV decline in the bilateral IFG and IPL were analyzed in mono- and bilinguals over two time points (mean time interval: 3.6 years). For four regions of interest (left/right IFG and left/right IPL), mixed Analyses of Covariance were conducted to assess (i) GMV changes over time, (ii) GMV differences for language groups (monolinguals/bilinguals), and (iii) the interaction between time point and language group. Corresponding analyses were conducted for the two factors of GMV, surface area (SA) and cortical thickness (CT). Results: There was higher GMV in bilinguals compared to monolinguals in the IPL, but not IFG. While the left and right IFG and the right IPL displayed a similar GMV change in mono- and bilinguals, GMV decline within the left IPL was significantly steeper in bilinguals. There was greater SA in bilinguals in the bilateral IPL and a steeper CT decline in bilinguals within in the left IPL. Conclusion: The cross-sectional observations of a steeper GMV decline in bilinguals could be confirmed for the left IPL. Additionally, the higher GMV in bilinguals in the bilateral IPL may indicate that bilingualism contributes to brain reserve especially in posterior brain regions. SA appeared to contribute to bilinguals' higher GMV in the bilateral IPL, while CT seemed to account for the steeper structural decline in bilinguals in the left IPL. The present findings demonstrate the importance of time as an additional factor when assessing the neuroprotective effects of bilingualism on structural features of the human brain.

Characterization of the angular gyrus in an older adult population: a multimodal multilevel approach.

The angular gyrus (AG) has been associated with multiple cognitive functions, such as language, spatial and memory functions. Since the AG is thought to be a cross-modal hub region suffering from significant age-related structural atrophy, it may also play a key role in age-related cognitive decline. However, the exact relation between structural atrophy of the AG and cognitive decline in older adults is not fully understood, which may be related to two aspects: First, the AG is cytoarchitectonically divided into two areas, PGa and PGp, potentially sub-serving different cognitive functions. Second, the older adult population is characterized by high between-subjects variability which requires targeting individual phenomena during the aging process. We therefore performed a multimodal (gray matter volume [GMV], resting-state functional connectivity [RSFC] and structural connectivity [SC]) characterization of AG subdivisions PGa and PGp in a large older adult population, together with relations to age, cognition and lifestyle on the group level. Afterwards, we switched the perspective to the individual, which is especially important when it comes to the assessment of individual patients. The AG can be considered a heterogeneous structure in of the older brain: we found the different AG parts to be associated with different patterns of whole-brain GMV associations as well as their associations with RSFC, and SC patterns. Similarly, differential effects of age, cognition and lifestyle on the GMV of AG subdivisions were observed. This suggests each region to be structurally and functionally differentially involved in the older adult's brain network architecture, which was supported by differential molecular and genetic patterns, derived from the EBRAINS multilevel atlas framework. Importantly, individual profiles deviated considerably from the global conclusion drawn from the group study. Hence, general observations within the older adult population need to be carefully considered, when addressing individual conditions in clinical practice.

[Personalized medicine and healthcare: where are we now, where should we go?] / Személyre szabott orvoslás és egészségügy: hol tartunk, merre menjünk?

The authors of this manuscript are representatives of different subdisciplines of medicine, all of them are experienced researchers. As of their origin, they are practicing doctors from the primary care and from the clinical/hospital setting, diagnostics experts, researchers from healthcare management, health economics, representatives of patients' rights and patient organizations. They are all devoted to the implementation of personalized medicine and personalized healthcare in Hungary. The current manuscript - also meant to be a keynote message provoking further discussion in the medical community - is devoted to correcting for two false ideas. One is that personalized medicine is not yet ready for practical applications, it is merely a research area of futurologists. The other false idea is that only (or mainly) the lack of financial resources hinders the introduction of personalized healthcare in Hungary. Orv Hetil. 2023; 164(6): 202-209.

Nintedanib plus Docetaxel after Immune Checkpoint Inhibitor Failure in Patients with Advanced Non-Small-Cell Lung Cancer: A Case Series.

Advances in the treatment of non-small-cell lung cancers (NSCLCs) lacking an actionable driver mutation have included the approval of immunotherapies, such as monotherapy or in combination with chemotherapy. However, limited evidence exists to guide clinical decision-making after progression with immunotherapy. The vascular endothelial growth factor (VEGF) signaling pathway promotes tumor angiogenesis and the development of an immunosuppressive tumor microenvironment (TME). Anti-VEGF treatment is postulated to favor an immunosupportive TME through an "angio-immunogenic switch." Nintedanib, an anti-VEGF receptor treatment, is approved in the EU and other countries, in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma NSCLC after failure of first-line chemotherapy. We present a case series from 5 patients treated with nintedanib plus docetaxel, after chemotherapy and immunotherapy, during routine clinical practice in Austria and Hungary. Four patients were treated with nintedanib plus docetaxel as a second- or third-line treatment after chemotherapy and immunotherapy, and a fifth patient received immunotherapy before and after nintedanib plus docetaxel. Although these patients would typically have a poor prognosis, each achieved a partial response with nintedanib plus docetaxel, with response duration from 8 months to over 30 months. Adverse events were manageable. The fifth patient case shows that nintedanib does not preclude later-line immunotherapy or chemotherapy, supporting the angio-immunogenic switch hypothesis. Overall, the case studies indicate that nintedanib plus docetaxel is an effective and well tolerated treatment, after sequential or combined chemo-immunotherapy for advanced NSCLC, and is compatible with a rechallenge with immunotherapy.

Multimodal investigation of the association between shift work and the brain in a population-based sample of older adults.

Neuropsychological studies reported that shift workers show reduced cognitive performance and circadian dysfunctions which may impact structural and functional brain networks. Here we tested the hypothesis whether night shift work is associated with resting-state functional connectivity (RSFC), cortical thickness and gray matter volume in participants of the 1000BRAINS study for whom information on night shift work and imaging data were available. 13 PRESENT and 89 FORMER night shift workers as well as 430 control participants who had never worked in shift (NEVER) met these criteria and were included in our study. No associations between night shift work, three graph-theoretical measures of RSFC of 7 functional brain networks and brain morphology were found after multiple comparison correction. Preceding multiple comparison correction, our results hinted at an association between more years of shift work and higher segregation of the visual network in PRESENT shift workers and between shift work experience and lower gray matter volume of the left thalamus. Extensive neuropsychological investigations supplementing objective imaging methodology did not reveal an association between night shift work and cognition after multiple comparison correction. Our pilot study suggests that night shift work does not elicit general alterations in brain networks and affects the brain only to a limited extent. These results now need to be corroborated in studies with larger numbers of participants.

EGFR T790M Mutation Detection in Patients With Non-Small Cell Lung Cancer After First Line EGFR TKI Therapy: Summary of Results in a Three-Year Period and a Comparison of Commercially Available Detection Kits.

EGFR mutation in non-small cell lung cancer (NSCLC) offers a potential therapeutic target for tyrosine kinase inhibitor (TKI) therapy. The majority of these cases, however eventually develop therapy resistance, mainly by acquiring EGFR T790M mutation. Recently, third-generation TKIs have been introduced to overcome T790M mutation-related resistance. Cell free circulating tumor DNA (liquid biopsy) has emerged as a valuable alternative method for T790M mutation detection during patient follow up, when a tissue biopsy cannot be obtained for analysis. In this study, we summarized our experience with Super-ARMS EGFR Mutation Detection Kit (AmoyDx) on 401 samples of 242 NSCLC patients in a 3-year period in Hungary, comprising 364 plasma and 37 non-plasma samples. We also compared the performance of two commercially available detection kits, the cobas EGFR Mutation test v2 (Roche) and the Super-ARMS EGFR Mutation Detection Kit (AmoyDx). The same activating EGFR mutation was detected with the AmoyDx kit as in the primary tumor in 45.6% of the samples. T790M mutation was identified in 48.1% of the samples containing activating EGFR mutation. The detection rate of T790M mutation was not dependent on the DNA concentration of the plasma sample and there was no considerable improvement in mutation detection rate after a second, subsequent plasma sample. The concordance of EGFR activating mutation detection was 89% between the two methods, while this was 93% for T790M mutation detection. The AmoyDx kit, however showed an overall higher detection rate of T790M mutation compared to the cobas kit (p = 0.014). T790M mutation was detected at 29.8% of the patients if only plasma samples were available for analysis, while the detection rate was 70.2% in non-plasma samples. If the activating EGFR was detected in the plasma samples, the detection rate of T790M mutation was 42.4%. Although non-plasma samples provided a superior T790M mutation detection rate, we found that liquid biopsy can offer a valuable tool for T790M mutation detection, when a tissue biopsy is not available. Alternatively, a liquid biopsy can be used as a screening test, when re-biopsy should be considered in case of wild-type results.

Underlying reasons for post-mortem diagnosed lung cancer cases - A robust retrospective comparative study from Hungary (HULC study).

Objective: The Hungarian Undiagnosed Lung Cancer (HULC) study aimed to explore the potential reasons for missed LC (lung cancer) diagnosis by comparing healthcare and socio-economic data among patients with post-mortem diagnosed LC with those who were diagnosed with LC during their lives. Methods: This nationwide, retrospective study used the databases of the Hungarian Central Statistical Office (HCSO) and National Health Insurance Fund (NHIF) to identify patients who died between January 1, 2019 and December 31, 2019 and were diagnosed with lung cancer post-mortem (population A) or during their lifetime (population B). Patient characteristics, socio-economic factors, and healthcare resource utilization (HCRU) data were compared between the diagnosed and undiagnosed patient population. Results: During the study period, 8,435 patients were identified from the HCSO database with LC as the cause of death, of whom 1,203 (14.24%) had no LC-related ICD (International Classification of Diseases) code records in the NHIF database during their lives (post-mortem diagnosed LC population). Post-mortem diagnosed LC patients were significantly older than patients diagnosed while still alive (mean age 71.20 vs. 68.69 years, p<0.001), with a more pronounced age difference among female patients (difference: 4.57 years, p<0.001), and had significantly fewer GP (General Practitioner) and specialist visits, X-ray and CT scans within 7 to 24 months and 6 months before death, although the differences in GP and specialist visits within 7-24 months did not seem clinically relevant. Patients diagnosed with LC while still alive were more likely to be married (47.62% vs. 33.49%), had higher educational attainment, and had more children, than patients diagnosed with LC post-mortem. Conclusions: Post-mortem diagnosed lung cancer accounts for 14.24% of total lung cancer mortality in Hungary. This study provides valuable insights into patient characteristics, socio-economic factors, and HCRU data potentially associated with a high risk of lung cancer misdiagnosis.

Cell-free DNA From Pleural Effusion Samples: Is It Right for Molecular Testing in Lung Adenocarcinoma?

Pathogenic molecular features gained specific significance in therapeutic decisions in lung carcinoma in the past decade. Initial and follow up genetic testing requres appropriate amounts and quality of tumor derived DNA, but tumor sampling, especially for disease monitoring is generally limited. Further to the peripheral blood (PB), samples from pleural fluid, accumulating in diverse lung processes might serve as an alternative source for cell-free DNA (cfDNA) for genetic profiling. In our study, cfDNA isolated from the pleural effusion and from the PB, and genomic DNA (gDNA) obtained from tissue/cellular samples were analyzed and compared from altogether 65 patients with pulmonary disease, including 36 lung adenocarcinomas. The quantity of effusion cfDNA yield appeared to be significantly higher compared to that from simultaneously collected PB plasma (23.2 vs. 4.8 ng/µl, p < 0.05). Gene mutations could be safely demonstrated from the effusion cfDNA fraction obtained from adenocarcinoma patients, 3/36 EGFR, 9/36 KRAS and 1/36 BRAF gene variants were detected. In this series, 9/13 samples showed an effusion+/plasma-mutational status, while only 1/13 samples presented with the opposite findings (effusion-/plasma+). gDNA analysis from sediment cell blocks from the identical effusion sample was surprisingly ineffective for lung adenocarcinoma profiling due to the low DNA yield. In conclusion, the cell free supernatant of pleural effusions appears to concentrate cancer derived cfDNA and seems to be particularly suitable for serial genotyping of pulmonary adenocarcinoma.

When your brain looks older than expected: combined lifestyle risk and BrainAGE.

Lifestyle may be one source of unexplained variance in the great interindividual variability of the brain in age-related structural differences. While physical and social activity may protect against structural decline, other lifestyle behaviors may be accelerating factors. We examined whether riskier lifestyle correlates with accelerated brain aging using the BrainAGE score in 622 older adults from the 1000BRAINS cohort. Lifestyle was measured using a combined lifestyle risk score, composed of risk (smoking, alcohol intake) and protective variables (social integration and physical activity). We estimated individual BrainAGE from T1-weighted MRI data indicating accelerated brain atrophy by higher values. Then, the effect of combined lifestyle risk and individual lifestyle variables was regressed against BrainAGE. One unit increase in combined lifestyle risk predicted 5.04 months of additional BrainAGE. This prediction was driven by smoking (0.6 additional months of BrainAGE per pack-year) and physical activity (0.55 less months in BrainAGE per metabolic equivalent). Stratification by sex revealed a stronger association between physical activity and BrainAGE in males than females. Overall, our observations may be helpful with regard to lifestyle-related tailored prevention measures that slow changes in brain structure in older adults.

Pulmonary Toxicity of Hodgkin Lymphoma Treatment: A Prospective Single-Center Study.

BACKGROUND: Standard bleomycin-containing first-line therapy and/or irradiation may cause pulmonary toxicity in Hodgkin lymphoma (HL) patients. Our aim was to prospectively assess effects of chest irradiation, bleomycin administration, and other factors on lung function in the treatment of patients with HL. METHODS: Pulmonary function of newly diagnosed HL patients was assessed via a St. George Respiratory Questionnaire, dynamic inhalation lung scintigraphy, spirometry, and an assessment of the diffusion capacity of the lung for carbon monoxide (DLCO) before, during, and after treatment. RESULTS: This prospective study was conducted at the University of Debrecen. The study included 84 patients with classical HL. Most patients received standard doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Both intramuscular and intravenous administrations of bleomycin were used. Brentuximab vedotin combination chemotherapy was administered to 12 patients. Mediastinal involved-field irradiation therapy (IFRT) was used to treat 16 patients. Lung scintigraphy revealed pulmonary toxicity more sensitively than DLCO. Intravenous bleomycin administration decreased diethylenetriamine pentaacetic acid clearance. Intramuscular bleomycin had the lowest level of pulmonary toxicity among considered treatments. Currently used, mediastinal IFRT had a lower level of pulmonary toxicity than bleomycin. The current prospective evaluation confirmed previous results that determined that cumulative bleomycin dose and administration are major risk factors for pulmonary toxicity, while the currently used treatment method, mediastinal irradiation, was determined to be relatively safe for treating for HL patients. CONCLUSION: We agree with decreasing bleomycin dosage and number of cycles administered and we do not recommend avoiding mediastinal IFRT, unless multiple pulmonary risk factors are present.

Age and Gender Specific Lung Cancer Incidence and Mortality in Hungary: Trends from 2011 Through 2016.

Objective: No assessment was conducted describing the age and gender specific epidemiology of lung cancer (LC) prior to 2018 in Hungary, thus the objective of this study was to appraise the detailed epidemiology of lung cancer (ICD-10 C34) in Hungary based on a retrospective analysis of the National Health Insurance Fund database. Methods: This longitudinal study included patients aged ≥20 years with LC diagnosis (ICD-10 C34) between January 1, 2011 and December 31, 2016. Patients with different cancer-related codes 6 months before or 12 months after LC diagnosis or having any cancer treatment other than lung cancer protocols were excluded. Results: Lung cancer incidence and mortality increased with age, peaking in the 70-79 age group (375.0/100,000 person-years) among males, while at 60-69 age group for females (148.1/100,000 person-years). The male-to-female incidence rate ratio reached 2.46-3.01 (p < 0.0001) among the 70-79 age group. We found 2-11% decrease in male incidence rate at most age groups, while a significant 1-3% increase was observed in older females (>60) annually during the study period. Conclusion: This nationwide epidemiology study demonstrated that LC incidence and mortality in Hungary decreased in younger male and female population, however we found significant increase of incidence in older female population, similar to international trends. Incidence rates peaked in younger age-groups compared to Western countries, most likely due to higher smoking prevalence in these cohorts, while lower age LC incidence could be attributed to higher competing cardiovascular risk resulting in earlier mortality in smoking population.

Improvement in Lung Cancer Survival: 6-Year Trends of Overall Survival at Hungarian Patients Diagnosed in 2011-2016.

Objective: Lung cancer is one of the most common cancers worldwide and its survival is still poor. The objective of our study was to estimate long-term survival of Hungarian lung cancer patients at first time based on a nationwide review of the National Health Insurance Fund database. Methods: Our retrospective, longitudinal study included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between January 1, 2011 and December 31, 2016. Survival rates were evaluated by year of diagnosis, patient gender and age, and morphology of lung cancer. Results: 41,854 newly diagnosed lung cancer patients were recorded. Mean age at diagnosis varied between 64.7 and 65.9 years during study period. One- and 5-year overall survival rates for the total population were 42.2 and 17.9%, respectively. Survival was statistically associated with gender, age and type of lung cancer. Female patients (n = 16,362) had 23% better survival (HR: 0.77, 95% confidence interval (CI): 0.75-0.79; p < 0.001) than males (n = 25,492). The highest survival rates were found in the 20-49 age cohort (5Y = 31.3%) and if the cancer type was adenocarcinoma (5Y = 20.5%). We measured 5.3% improvement (9.2% adjusted) in lung cancer survival comparing the period 2015-2016 to 2011-2012 (HR: 0.95 95% CI: 0.92-0.97; p = 0.003), the highest at females <60 year (0.86 (adjusted HR was 0.79), interaction analysis was significant for age and histology types. Conclusion: Our study provided long-term Lung cancer survival data in Hungary for the first time. We found a 5.3% improvement in 5-year survival in 4 years. Women and young patients had better survival. Survival rates were comparable to-and at the higher end of-rates registered in other East-Central European countries (7.7%-15.7%).

Increase in the Length of Lung Cancer Patient Pathway Before First-Line Therapy: A 6-Year Nationwide Analysis From Hungary.

Objective: This study aimed to examine the characteristics of the lung cancer (LC) patient pathway in Hungary during a 6-years period. Methods: This nationwide, retrospective study included patients newly diagnosed with LC (ICD-10 C34) between January 1, 2011, and December 31, 2016, using data from the National Health Insurance Fund (NHIF) of Hungary. The following patient pathway intervals were examined: system, diagnostic and treatment interval by age, gender, tumor type, study year and first-line LC therapy. Results: During the 6-years study period, 17,386 patients had at least one type of imaging (X-ray or CT/MRI) prior to diagnosis, and 12,063 had records of both X-ray and CT/MRI. The median system interval was 64.5 days, and it was 5 days longer among women, than in men (68.0 vs. 63.0 days). The median system interval was significantly longer in patients with adenocarcinoma compared to those with squamous cell carcinoma or small cell lung cancer (70.4 vs. 64.0 vs. 48.0 days, respectively). Patients who received surgery as first-line treatment had significantly longer median system intervals compared to those receiving chemotherapy (81.4 vs. 62.0 days). The median system interval significantly increased from 62.0 to 66.0 days during the 6-years study period. Conclusion: The LC patient pathway significantly increased in Hungary over the 6-years study period. There were no significant differences in the length of the whole LC patient pathway according to age, however, female sex, surgery as first-line treatment, and adenocarcinoma were associated with longer system intervals.

Significant Regional Differences in Lung Cancer Incidence in Hungary: Epidemiological Study Between 2011 and 2016.

Objective: Hungary has one of the highest incidences and mortality rates of lung cancer (LC), therefore the objective of this study was to analyse and compare LC incidence and mortality rates between the main Hungarian regions. Methods: This nationwide, retrospective study used data from the National Health Insurance Fund and included patients aged ≥20 years who were diagnosed with lung cancer (ICD-10 C34) between Jan 1, 2011 and Dec 31, 2016. Age-standardized incidence and mortality rates were calculated and compared for the main regions. Results: The highest incidence rate in males was recorded in Northern Hungary (146.8/100,000 person-years [PY]), while the lowest rate was found in Western Transdanubia (94.7/100,000 PY in 2011). All rates showed a declining trend between 2011 and 2016, with the largest decrease in the Northern Great Plain (-20.0%; p = 0.008). LC incidence and mortality rates in women both showed a rising tendency in all regions of Hungary, reaching the highest in Central Hungary (59.86/100,000 PY in 2016). Lung cancer incidence and mortality rates in males correlated with the level of education and smoking prevalence (p = 0.006 and p = 0.01, respectively) in the regions. A correlation with GDP per capita and Health Development Index (HDI) index could also be observed in the Hungarian regions, although these associations were not statistically significant. No correlations could be detected between these parameters among females. Conclusion: This analysis revealed considerable differences in the epidemiology of LC between the 7 main Hungarian regions. LC incidence and mortality rates significantly correlated with smoking and certain socioeconomic factors in men, but not in women. Further research is needed to explain the regional differences.

White Matter Microstructure Underlies the Effects of Sleep Quality and Life Stress on Depression Symptomatology in Older Adults.

Sleep complaints are the most prevalent syndromes in older adults, particularly in women. Moreover, they are frequently accompanied with a high level of depression and stress. Although several diffusion tensor imaging (DTI) studies reported associations between sleep quality and brain white matter (WM) microstructure, it is still unclear whether gender impacts the effect of sleep quality on structural alterations, and whether these alterations mediate the effects of sleep quality on emotional regulation. We included 389 older participants (176 females, age = 65.5 ± 5.5 years) from the 1000BRAINS project. Neuropsychological examinations covered the assessments of sleep quality, depressive symptomatology, current stress level, visual working memory, and selective attention ability. Based on the DTI dataset, the diffusion parameter maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated and normalized to a population-specific FA template. According to the global Pittsburgh Sleep Quality Index (PSQI), 119 poor sleepers (PSQI: 10∼17) and 120 good sleepers (PSQI: 3∼6) were identified. We conducted a two by two (good sleepers/poor sleepers) × (males/females) analysis of variance by using tract-based spatial statistics (TBSS) and JHU-ICBM WM atlas-based comparisons. Moreover, we performed a voxel-wise correlation analysis of brain WM microstructure with the neuropsychological tests. Finally, we applied a mediation analysis to explore if the brain WM microstructure mediates the relationship between sleep quality and emotional regulation. No significant differences in brain WM microstructure were detected on the main effect of sleep quality. However, the MD, AD, and RD of pontine crossing tract and bilateral inferior cerebellar peduncle were significant lower in the males than females. Voxel-wise correlation analysis revealed that FA and RD values in the corpus callosum were positively related with depressive symptomatology and negatively related with current stress levels. Additionally, we found a significantly positive association between higher FA values in visual-related WM tracts and better outcomes in a visual pattern recognition test. Furthermore, a mediation analysis suggested that diffusion metrics within the corpus callosum partially mediated the associations between poor sleep quality/high stress and depressive symptomatology.

Eight pillars of oncorheumatology: Crossroads between malignancies and musculoskeletal diseases.

ONCORHEUMATOLOGY: RELATIONSHIP BETWEEN MALIGNANCIES AND MUSCULOSKELETAL DISEASES: Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.