High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL. METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete. FINDINGS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications. INTERPRETATION: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials. FUNDING: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

Age-adjusted high-dose chemotherapy followed by autologous stem cell transplantation or conventional chemotherapy with R-MP as first-line treatment in elderly primary CNS lymphoma patients - the randomized phase III PRIMA-CNS trial.

BACKGROUND: Older primary central nervous system lymphoma (PCNSL) patients have an inferior prognosis compared to younger patients because available evidence on best treatment is scarce and treatment delivery is challenging due to comorbidities and reduced performance status. High-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) after high-dose methotrexate (MTX)-based immuno-chemotherapy has become an increasingly used treatment approach in eligible elderly PCNSL patients with promising feasibility and efficacy, but has not been compared with conventional chemotherapy approaches. In addition, eligibility for HCT-ASCT in elderly PCNSL is not well defined. Geriatric assessment (GA) may be helpful in selecting patients for the best individual treatment choice, but no standardized GA exists to date. A randomized controlled trial, incorporating a GA and comparing age-adapted HCT-ASCT treatment with conventional chemotherapy is needed. METHODS: This open-label, multicenter, randomized phase III trial with two parallel arms will recruit 310 patients with newly diagnosed PCNSL > 65 years of age in 40 centers in Germany and Austria. The primary objective is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with rituximab, MTX, procarbazine (R-MP) followed by maintenance with procarbazine in terms of progression free survival (PFS). Secondary endpoints include overall survival (OS), event free survival (EFS), (neuro-)toxicity and quality of life (QoL). GA will be conducted at specific time points during the course of the study. All patients will be treated with a pre-phase rituximab-MTX (R-MTX) cycle followed by re-assessment of transplant eligibility. Patients judged transplant eligible will be randomized (1:1). Patients in arm A will be treated with 3 cycles of R-MP followed by maintenance therapy with procarbazine for 6 months. Patients in arm B will be treated with 2 cycles of MARTA (R-MTX/AraC) followed by busulfan- and thiotepa-based HCT-ASCT. DISCUSSION: The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach. TRIAL REGISTRATION: German clinical trials registry DRKS00024085 registered March 29, 2023.

Attentional Lapses of Adults with Attention Deficit Hyperactivity Disorder in Tasks of Sustained Attention.

Adults with attention deficit hyperactivity disorder (ADHD) show attentional dysfunction such as distractibility and mind-wandering, especially in lengthy tasks. However, fundamentals of dysfunction are ambiguous and relationships of neuropsychological test parameters with self-report measures of ADHD symptoms are marginal. We hypothesize that basic deficits in sustaining attention explain more complex attentional dysfunction in persons with ADHD and relate to ADHD symptoms. Attentional function was analyzed by computing ex-Gaussian parameters for 3 time Blocks in a 20 min test of sustained alertness. Changes in performance across these blocks were analyzed by comparing adult persons with ADHD (n = 24) with healthy matched controls (n = 24) and correlated with neuropsychological measures of selective and divided attention as well as self-report measures of ADHD symptoms. We found a significantly steeper increase in the number of slow responses (ex-Gaussian parameter τ) in persons with ADHD with time on task in basic sustained alertness. They also performed significantly worse in tasks of sustained selective and divided attention. However, after controlling for an increase in τ during the alertness task, significant differences between groups disappeared for divided and partly selective attention. Increases in τ in the sustained alertness task correlated significantly with self-report measures of ADHD symptoms. Our results provide evidence that very basic deficits in sustaining attention in adults with ADHD are related to infrequent slow responses (=attentional lapses), with changes over time being relevant for more complex attentional function and experienced ADHD symptoms in everyday life.

Intraindividual variability in inhibitory function in adults with ADHD--an ex-Gaussian approach.

OBJECTIVE: Attention deficit disorder (ADHD) is commonly associated with inhibitory dysfunction contributing to typical behavioral symptoms like impulsivity or hyperactivity. However, some studies analyzing intraindividual variability (IIV) of reaction times in children with ADHD (cADHD) question a predominance of inhibitory deficits. IIV is a measure of the stability of information processing and provides evidence that longer reaction times (RT) in inhibitory tasks in cADHD are due to only a few prolonged responses which may indicate deficits in sustained attention rather than inhibitory dysfunction. We wanted to find out, whether a slowing in inhibitory functioning in adults with ADHD (aADHD) is due to isolated slow responses. METHODS: Computing classical RT measures (mean RT, SD), ex-Gaussian parameters of IIV (which allow a better separation of reaction time (mu), variability (sigma) and abnormally slow responses (tau) than classical measures) as well as errors of omission and commission, we examined response inhibition in a well-established GoNogo task in a sample of aADHD subjects without medication and healthy controls matched for age, gender and education. RESULTS: We did not find higher numbers of commission errors in aADHD, while the number of omissions was significantly increased compared with controls. In contrast to increased mean RT, the distributional parameter mu did not document a significant slowing in aADHD. However, subjects with aADHD were characterized by increased IIV throughout the entire RT distribution as indicated by the parameters sigma and tau as well as the SD of reaction time. Moreover, we found a significant correlation between tau and the number of omission errors. CONCLUSIONS: Our findings question a primacy of inhibitory deficits in aADHD and provide evidence for attentional dysfunction. The present findings may have theoretical implications for etiological models of ADHD as well as more practical implications for neuropsychological testing in aADHD.

Age effects on preattentive and early attentive auditory processing of redundant stimuli: is sensory gating affected by physiological aging?

The frontal hypothesis of aging predicts an age-related decline in cognitive functions requiring inhibitory or attentional regulation. In Alzheimer's disease, preattentive gating out of redundant information is impaired. Our study aimed to examine changes associated with physiological aging in both pre- and early attentive inhibition of recurrent acoustic information. Using a passive double-click paradigm, we recorded mid-latency (P30-P50) and late-latency (N100 and P200) evoked potentials in healthy young (26 ± 5 years) and healthy elderly subjects (72 ± 5 years). Physiological aging did not affect auditory gating in amplitude measures. Both age groups exhibited clear inhibition in preattentive P50 and attention-modulated (N100) components, whereas P30 was not attenuated. Irrespective of age, the magnitude of inhibition differed significantly, being most pronounced for N100 gating. Inhibition of redundant information seems to be preserved with physiological aging. Early attentive N100 gating showed the maximum effect. Further studies are warranted to evaluate sensory gating as a suitable biomarker of underlying neurodegenerative disease.

Development of brain synchronisation within school-age--individual analysis of resting (α) coherence in a longitudinal data set.

OBJECTIVE: Given evidence that synchronisation of neuronal activity may be a correlate of cognition, we examined EEG coherence as function of age and inter-electrode distance in healthy children and adolescents in order to elucidate basic information for a better understanding of developmental disorders associated with deficits in cognitive functions. METHODS: Based on a 64-channel eyes closed resting EEG we combined local and global coherence measures in order to reduce volume conduction and reference effects. We used a two point longitudinal design in order to analyze intraindividual change during school-age (n=40; 6-18 years). Coherence was analyzed within individually adjusted frequency bands and around iPF (= individual alpha peak frequency). RESULTS: Both local and global resting coherence was largest in the alpha range and particularly around iPF. Local synchronisation was larger in the left compared with the right hemisphere. Controlling for increases in iPF, synchronisation increased with age, with global changes being most pronounced in the alpha range. Moreover age-related changes suggest an earlier development in girls. CONCLUSIONS: Our data provides evidence that both local and global functional integration increases during normal development within school-age. SIGNIFICANCE: This general pattern - combined with more specific effects of sex and frequency - may help to specify deviations in developmental disorders.

Maturation of P300 amplitude and short-term learning as reflected by P300 habituation between trial blocks in children.

Although numerous studies concerning P300 have been reported in adults, few have focused on the normal development of children, particularly in relation to habituation. The aim of this study was to investigate maturation of the P300 component and its habituation (short-term automatic learning) in a sample of healthy children and adolescents. Four models of maturation of the P300 (linear, quadratic or two different linear regressions for the pre-pubertal and pubertal age groups as well as age-inverse) were applied and compared, in order to find the most adequate model according to the Bayesian Information Criterion. A visual oddball paradigm was presented to 81 healthy children and adolescents aged 6-18 years. Three blocks, each with 200 trials were recorded to assess between-block habituation. The data was best fitted to (a) an age-inverse relation between P300 latency and age, and (b) a linear relationship between P300 amplitude and age. An age-dependent effect of habituation was detected in the P300 amplitude, where a considerable amplitude decline was found in the younger children and no significant change for adolescents. Our results support the hypothesis that younger children show stronger habituation effects because they activate a larger neuronal pool from which unnecessary neurons can be excluded during short-term learning. In contrast, in adolescents, these neurons may have already been eliminated as a consequence of pruning, thus reducing habituation effects. Future studies are required to test this hypothesis because our data do not permit alternative explanations to be discarded.

Individual analysis of EEG background-activity within school age: impact of age and sex within a longitudinal data set.

OBJECTIVES: Quantitative EEG can monitor changes in brain function during development and may help to understand developmental disorders. However, current EEG-databases are primarily based on standardized frequency bands which disregard age-related changes in alpha peak frequency (PF) and therefore complicate the interpretation of spectral estimates in the theta and alpha range. METHODS: We used a two point longitudinal design in order to analyze intraindividual changes in 40 healthy children and adolescents with age (T1: 6-18 years; interval approximately 4 years). Using a 64-channel eyes closed resting EEG we calculated absolute/relative power in individualized frequency bands (IFB: delta, theta, alpha1/2 and beta) based on PF. RESULTS: PF increased with age, with changes being larger for children than adolescents. Controlling for changes in PF, changes in absolute/relative alpha1/2 power and in absolute beta power were minor. Relative beta power, however, increased while absolute/relative delta and theta power decreased massively. Sex-differences in PF did not reach significance. However, boys exhibited larger changes during adolescence than girls for all absolute power measures except alpha. CONCLUSION: Normal EEG development during school-age is mainly based on an absolute decrease of slow frequency activity and increases of PF which may be interpreted in terms of a reorganization of the EEG towards a higher frequency oscillatory scale rather than a maturation of the theta-alpha1/2 band power sequence. Age-related changes differed between boys and girls suggesting a different developmental timing for the sexes. In future studies a combined analysis of PF and IFB may help to specify deviations in developmental disorders.