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Kristina Hagenström,1 Kristin Sauer,1 Nicole Mohr,1 Marleen Dettmann,1 Gerd Glaeske,2 Jana Petersen,1 Claudia Garbe,1 Tim Steimle,3 Matthias Augustin1 1German Center for Health Services Research in Dermatology (CVderm), Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; 2Research Center on Inequality and Social Policy, University of Bremen, Bremen, Germany; 3Techniker Krankenkasse, Hamburg, GermanyCorrespondence: Kristina HagenströmGerman Center for Health Services Research in Dermatology (CVderm), Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE), Martinistraße 52, Hamburg, 20246, GermanyTel +49 (0) 40 7410 554 28Fax +49 (0) 40 7410 553 48Email k.hagenstroem@uke.deBackground: Information on the prevalence of atopic dermatitis (AD) varies greatly, and so far, only a few studies describe the healthcare of patients with AD in Germany.Objective: The aim of the study is to describe the prevalence and medications of people with AD in Germany.Methods: Health insurance data for the year 2019 were examined. Prevalence rates, the severity of disease, comorbidities and pharmaceutical supply were analyzed. Insured persons with AD were identified with at least one outpatient or inpatient International Classification Code of Diseases (L20).Results: In 2019, 4.21% [95% CI 4.21− 4.22%] of insured persons had AD (3.6 million). Women were affected slightly more frequently than men (4.74% [95% CI 4.73− 4.74%] and 3.64% [95% CI 3.64− 3.65%]). Adolescents and children under the age of 15 had the highest prevalence of AD compared to other age groups (9.44% [95% CI 9.42− 9.46%]). Majority of the insured persons with AD were affected by a mild to moderate form of the disease. The most common co-morbidity was infections of the skin (RR 5.00 [95% CI 4.97− 5.02%]). Some patients were treated by a dermatologist, while others by a general practitioner, 39.10% and 36.74%, respectively. Of the anti-inflammatory drugs, systemic glucocorticosteroids preparations were used most frequently and were most frequently prescribed by the general practitioner. With a total of 42,841 prescriptions (1.53%), methotrexate (third-line treatment option) was prescribed more frequently than ciclosporin with 19,628 prescriptions (0.70%) or azathioprine with 25,696 prescriptions (0.92%). Ciclosporin (first-line treatment option) was prescribed much more frequently by a dermatologist (44.00% versus 14.32% by general practitioner). The biological dupilumab was prescribed 30,801 times (1,10%) and was also primarily prescribed by a dermatologist (66.67%).Conclusion: The present results reveal that a specialist treats approximately one-third of the patients with AD and that there is still a drug undersupply in some cases, especially concerning innovative drugs.Keywords: epidemiology, frequency of illness, pharmaceutical supply, neurodermatitis, statutory health insurance

Abstract: Given the poor outcome of refractory and relapsing T-cell acute lymphoblastic leukemia (T-ALL), identifying prognostic markers is still challenging. Using single nucleotide polymorphism (SNP) array analysis, we provide a comprehensive analysis of genomic imbalances in a cohort of 317 newly diagnosed patients with T-ALL including 135 children and 182 adults with respect to clinical and biological features and outcomes. SNP array results identified at least 1 somatic genomic imbalance in virtually all patients with T-ALL (∼96%). Del(9)(p21) (∼70%) and UPD(9)p21)/CDKN2A/B (∼28%) were the most frequent genomic imbalances. Unexpectedly del(13)(q14)/RB1/DLEU1 (∼14%) was the second most frequent copy number variant followed by del(6)(q15)/CASP8AP2 (∼11%), del(1)(p33)/SIL-TAL1 (∼11%), del(12)(p13)ETV6/CDKN1B (∼9%), del(18)(p11)/PTPN2 (∼9%), del(1)(p36)/RPL22 (∼9%), and del(17)(q11)/NF1/SUZ12 (∼8%). SNP array also revealed distinct profiles of genomic imbalances according to age, immunophenotype, and oncogenetic subgroups. In particular, adult patients with T-ALL demonstrated a significantly higher incidence of del(1)(p36)/RPL22, and del(13)(q14)/RB1/DLEU1, and lower incidence of del(9)(p21) and UPD(9p21)/CDKN2A/B. We determined a threshold of 15 genomic imbalances to stratify patients into high- and low-risk groups of relapse. Survival analysis also revealed the poor outcome, despite the low number of affected cases, conferred by the presence of chromothripsis (n = 6, ∼2%), del(16)(p13)/CREBBP (n = 15, ∼5%) as well as the newly-identified recurrent gain at 6q27 involving MLLT4 (n = 10, ∼3%). Genomic complexity, del(16)(p13)/CREBBP and gain at 6q27 involving MLLT4, maintained their significance in multivariate analysis for survival outcome. Our study thus demonstrated that whole genome analysis of imbalances provides new insights to refine risk stratification in T-ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, and as #FRALLE 2000T trial., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients., (© 2022. The Author(s).)

T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis. Adenylate kinase 2 (AK2) is a mitochondrial kinase involved in adenine nucleotide homeostasis recently reported as essential in normal T-cell development, as defective AK2 signaling pathway results in a severe combined immunodeficiency with a complete absence of T-cell differentiation. In this study, we show that AK2 is constitutively expressed in T-ALL to varying levels, irrespective of the stage of maturation arrest or the underlying oncogenetic features. T-ALL cell lines and patient T-ALL-derived xenografts present addiction to AK2, whereas B-cell precursor ALL cells do not. Indeed, AK2 knockdown leads to early and massive apoptosis of T-ALL cells that could not be rescued by the cytosolic isoform AK1. Mechanistically, AK2 depletion results in mitochondrial dysfunction marked by early mitochondrial depolarization and reactive oxygen species production, together with the depletion of antiapoptotic molecules (BCL-2 and BCL-XL). Finally, T-ALL exposure to a BCL-2 inhibitor (ABT-199 [venetoclax]) significantly enhances the cytotoxic effects of AK2 depletion. We also show that AK2 depletion disrupts the oxidative phosphorylation pathway. Combined with pharmaceutical inhibition of glycolysis, AK2 silencing prevents T-ALL metabolic adaptation, resulting in dramatic apoptosis. Altogether, we pinpoint AK2 as a genuine and promising therapeutic target in T-ALL., (© 2021 by The American Society of Hematology.)