Die Entwicklung und Validierung eines Prognosescores für Patienten mit chronischer myeloischer Leukämie unter Einbeziehung der zytogenetischen Remission als einer zeitabhängigen Kovariablen

Ziel vorliegender Arbeit war die Entwicklung eines Prognosesystems für Überlebenswahrscheinlichkeiten von Patienten, deren Primärtherapie auf Interferon (IFN)-alpha basiert. In Erweiterung eines bereits existierenden, validierten Prognosesytems, dem New CML-Score, welcher sich auf ausschließlich zum Diagnosezeitpunkt erhobene Baselinevariablen stützt, sollten dabei Therapieverlaufsdaten zur zytogenetischen Remission die Prognoseergebnisse weiter verfeinern. Der New CML-Score diskriminiert drei Risikogruppen (Niedrigrisiko, mittleres Risiko, Hochrisiko) mit statistisch signifikant unterschiedlichen Überlebenswahrscheinlichkeiten (www.pharmacoepi.de). Alle in der IFN-alpha-Ära üblicherweise (d.h. zu 90%) erfassten und bereits von der Entwicklung des New CML-Scores als (potenziell) prognostisch relevant bekannten Baselineparameter wurden bei der Modellentwicklung berücksichtigt: Alter, Geschlecht, Hämoglobin, Leukozytenzahl, Blasten, Basophile, Eosinophile (alle drei aus dem peripheren Blut), Thrombozytenzahl und Milzvergrößerung. Die zytogenetische Remission (ZR) wurde mit Hilfe der beiden dichotomen Ereignisvariablen „Erreichen einer ersten partiellen ZR (1-35% Ph-positive Metaphasen)“ und / oder „Erreichen einer ersten kompletten ZR (0% Ph-positive Metaphasen)“ modelliert, da beide Resultate zu signifikant günstigeren Überlebenswahrscheinlichkeiten geführt hatten. Das neue Prognosesystem identifizierte vier Risikogruppen (Niedrigstrisiko, niedrigeres Risiko, höheres Risiko und Höchstrisiko). Angesichts der hohen Überlebenswahrscheinlichkeiten der Niedrigstrisikogruppe wurde das Ziel, mit einem neuen Prognosesystem im Therapieverlauf eine Patientengruppe zu finden, die von einem Behandlungsbeginn mit IFN-alpha besonders profitieren könnte – ohne dabei die Patienten mit initialem Höchstrisiko außer Acht zu lassen – erreicht. Die deutliche, statistisch signifikante Trennung dieser unterschiedlichsten Risikogruppen wurde durch eine von der Modellentwicklung unabhängige Validierungsstichprobe bestätigt. Das neue Prognosesystem gibt ein methodisches Beispiel für die Entwicklung und Validierung eines Prognosesystems unter Berücksichtigung von Informationen aus dem Therapieverlauf. Dabei war es insbesondere möglich, die Gewinnung eines von einer festen Landmark unabhängigen Prognosesystem aufzuzeigen, dessen Risikogruppen über die ersten beiden Therapiejahre, während derer die zytogenetische Remission im Brennpunkt steht, zu jedem frei wählbaren Entscheidungszeitpunkt auf dieselbe Weise leicht berechnet werden können. Die maximal zwei Risikogruppenwechsel in ausschließlich günstigere Stadien unterstützen die einfache Anwendbarkeit des Prognosesystems und die Interpretierbarkeit der Überlebenswahrscheinlichkeiten seiner Risikogruppen. Für die Patienten ist das Ausschließen einer Risikogruppenverschlechterung psychologisch von positiver Bedeutung. Nach (früher) Stabilisierung der Überlebenskurve zur Niedrigstrisikogruppe können mit Hilfe von Simon-Makuch-Kurven die Überlebenswahrscheinlichkeiten aller vier Risikogruppen – ohne einschränkende Landmark – jederzeit nach dem aktuellsten Informationsstand berechnet werden. Für immer noch viele mit IFN-alpha als Primärtherapie behandelte Patienten sind die prognostizierten Überlebenswahrscheinlichkeiten der Niedrigstrisikogruppe von Bedeutung

High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, -7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20-30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory

CXCL13 and CXCL9 CSF Levels in Central Nervous System Lymphoma-Diagnostic, Therapeutic, and Prognostic Relevance

Background: Diagnostic delay and neurologic deterioration are still a problem for the treatment of rapidly progressing CNS lymphoma (CNSL); there is an unmet need for a diagnostic test with a high diagnostic yield and limited risk, minimizing the time to the initiation of effective treatment. Methods: In this prospective monocentric study, we analyzed the utility of CXCL13 and CXCL9 as diagnostic, therapeutic and prognostic biomarkers for CNSL. Cerebrospinal fluid (CSF) from 155 consecutive patients admitted with brain lesions of various origins was collected. Levels of CXCL13 and CXCL9 were analyzed by ELISA. Additionally, CSF was analyzed during CNSL disease course (relapse, remission, progress) in 17 patients. Results: CXCL13 and CXCL9 CSF levels were significantly increased in patients with CNSL compared to control patients with lesions of other origin. Using logistic regression and a minimal-p-value approach, a cut-off value of 80 pg/ml for CXCL13 shows high sensitivity (90.7%) and specificity (90.1%) for the diagnosis of active CNSL. CXCL9 at a cut-off value of 84 pg/ml is less sensitive (61.5%) and specific (87.1%). Both cytokines correlate with the clinical course and response to therapy. Conclusions: Our results confirm the excellent diagnostic potential of CXCL13 and introduce CXCL9 as a novel albeit less powerful marker for PCNSL

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence

The impact of lockdown stress and loneliness during the COVID-19 pandemic on mental health among university students in Germany

The COVID-19 pandemic led to a shutdown of universities in Germany. In a longitudinal design, we compared mental health (depression, anxiety, somatic complaints) of university students in Germany before (June to August 2019) and in the course of the COVID-19 pandemic (June 2020) and determined the impact of pandemic-related stress and loneliness on students’ mental health in self-report online surveys. We investigated 443 participants (mean age 22.8 years), among them 77% female, and 10.4% medical students. A small increase of depression mean scores was observed (F(1,420) = 5.21; p = .023), anxiety and somatic complaints have not significantly changed. There was a medium increase in loneliness from pre-pandemic scores to the pandemic situation (F(1,423) = 30.56; p < .001). Analyzed with regression analyses, current loneliness and pre-pandemic distress represented the strongest associations with mental health during the pandemic. Additionally, health-related concerns during the pandemic were associated with symptoms of depression [b = 0.21; 95%CI(0.08; 0.34); t = 3.12; p = .002], anxiety [b = 0.07; 95%CI(0.01; 0.12); t = 2.50; p = .013], somatic complaints [b = 0.33; 95%CI(0.18; 0.47); t = 4.49; p < .001], and loneliness [b = 0.10; 95%CI(0.03; 0.17); t = 2.74; p = .006]. Social stress due to the pandemic situation was associated with loneliness [b = 0.38; 95%CI(0.32; 0.45); t = 11.75; p < .001]. The results imply that university students represent a risk group for psychosocial long-term ramifications of the pandemic

Antecedents and moderation effects of maladaptive coping behaviors among German university students

Prolonging working hours and presenteeism have been conceptualized as self-endangering coping behaviors in employees, which are related to health impairment. Drawing upon the self-regulation of behavior model, the goal achievement process, and Warr's vitamin model, we examined the antecedents and moderation effects regarding quantitative demands, autonomy, emotion regulation, and self-motivation competence of university students' self-endangering coping behaviors (showing prolonging working hours and presenteeism). Results from a cross-sectional survey of 3,546 German university students indicate that quantitative demands are positively related and autonomy has a u-shape connection with self-endangering coping. Emotion regulation was shown to be a protective factor for prolonging working hours. Moreover, self-motivation moderated the relationship between quantitative demands and prolonging of working hours, but not in the assumed direction. Self-motivation showed a systematic positive relationship with prolonging of working hours, but no relationship with presenteeism. Autonomy moderated the relationship of quantitative demands with both self-endangering behaviors. We found no moderating effects for emotion regulation of quantitative demands or autonomy and self-endangering behaviors. Besides further practical implications, the results suggest that lecturers should design their courses accordingly with less time pressure and university students should be trained in the use of autonomy

Potential risk groups and psychological, psychosocial, and health behavioral predictors of pharmacological neuroenhancement among university students in Germany

Aiming to develop and implement intervention strategies targeting pharmacological neuroenhancement (PN) among university students more specifically, we (1) assessed the prevalence of PN among German university students, (2) identified potential sociodemographic and study-related risk groups, and (3) investigated sociodemographic, psychological, study-related psychosocial, general psychosocial and health behavior related factors predicting the 12-month prevalence of PN. Therefore, a cross-sectional online survey was administered to students of the University of Mainz, Germany. A binary logistic regression with stepwise inclusion of the five variable groups was performed to predict PN. A total number of 4351 students out of 31,213 registered students (13.9%) participated in the survey, of which N = 3984 answered the question concerning PN. Of these, 10.4% had used one substance for PN at least once in the past 12 months. The regression analysis revealed 13 variables that were significantly related to the 12-month prevalence of PN. Specifically, the group of health behavior related variables showed the strongest relationship with PN. Therefore, an approach to the prevention of PN should be multifactorial so that it addresses social conditions, as well as education on substance use and healthy behaviors in terms of non-pharmacological strategies as alternatives of PN

Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6~months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6~months to 2.99~years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5~mg with dose escalation to 67.5~mg) or placebo for 12~months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.)

ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia

Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis