Search

BackgroundSIOP-CNS-GCT-II European trial was opened for the treatment of patients of any age with central nervous system germ cell tumour (CNS-GCT). Four courses of pre-irradiation chemotherapy were delivered. The influence of patient age on chemotherapy related acute toxicity (CRAT) was assessed.MethodsCRAT was analysed according to age-groups: children (aged ≤11 years), adolescents (aged 12-17 years), adults (aged ≥18 years) and to chemotherapy type: CarboPEI (alternating etoposide-carboplatin/etoposide-ifosfamide) for non-metastatic germinoma; PEI (cisplatin-etoposide-ifosfamide) for standard-risk non-germinomatous GCT (NGGCT); PEI and high-dose PEI (HD-PEI), for high-risk or poorly responsive NGGCTs.Results296 patients were assessable for CRAT: 105 children, 121 adolescents, 70 adults (max age: 41 years). Median cumulative doses/m² of chemotherapy were similar among age-groups. The proportion of germinoma over NGGCT (and accordingly use of CarboPEI chemotherapy) was higher in the adult groups (79%) versus the other two groups (62%). Delay in chemotherapy ≥7 days was noticed in 27%, 38%, and 19% of children, adolescents, and adults, respectively. Grade ≥3 haematological and non-haematological adverse events (AEs) were observed in 94%/31%, 97%/36%, and 77%/21% of children, adolescents, and adults, respectively. No toxic death was reported. Grade ≥3 AEs and delayed chemotherapies were significantly rarer in adults when compared with adolescents, even when adjusted on chemotherapy type: odds ratio: 0.1 [95%CI 0.02-0.4], and 0.2 [95%CI 0.1-0.4] in the group treated with CarboPEI.ConclusionAdult patients can be treated safely with a chemotherapy intensive protocol, with even less toxicity than that observed in adolescents. Further work is required to understand age-related differences regarding toxicity.

Summary: Background: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. Methods: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. Findings: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients’ subgroups. Interpretation: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. Funding: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.

In China, there is enormous development potential for resource recovery from sewage sludge. Government plans indicate that there will be greater investment in sewage sludge treatment, recycling and associated new technologies. Expert interviews and an expert workshop with representatives of German firms and institutions were held in order to identify barriers to and possible measures for the dissemination of technologies geared towards the utilisation of sewage sludge, such as anaerobic digestion, thermal hydrolysis and hydrothermal carbonisation. The following measures were identified as crucial: influence and support for the development of suitable regulations for sewage sludge in China, improvement in the processes and practices within specialised authorities, improved knowledge transfer, the development of appropriate business or operator models and persuasion of decision-makers within public authorities. German companies cannot implement most of these measures easily. HIGHLIGHTS For business development, it is crucial to have strong ties with Chinese partners.; Operator models require great commitment and most of the German companies are not suitable due to their size or ownership structure.; Transition school literature was helpful to develop an understanding of barriers and measures concerning resource-efficient handling of sewage sludge in China.;

We study the expressiveness and succinctness of history-deterministic pushdown automata (HD-PDA) over finite words, that is, pushdown automata whose nondeterminism can be resolved based on the run constructed so far, but independently of the remainder of the input word. These are also known as good-for-games pushdown automata. We prove that HD-PDA recognise more languages than deterministic PDA (DPDA) but not all context-free languages (CFL). This class is orthogonal to unambiguous CFL. We further show that HD-PDA can be exponentially more succinct than DPDA, while PDA can be double-exponentially more succinct than HD-PDA. We also study HDness in visibly pushdown automata (VPA), which enjoy better closure properties than PDA, and for which we show that deciding HDness is ExpTime-complete. HD-VPA can be exponentially more succinct than deterministic VPA, while VPA can be exponentially more succinct than HD-VPA. Both of these lower bounds are tight. We then compare HD-PDA with PDA for which composition with games is well-behaved, i.e. good-for-games automata. We show that these two notions coincide, but only if we consider potentially infinitely branching games. Finally, we study the complexity of resolving nondeterminism in HD-PDA. Every HDPDA has a positional resolver, a function that resolves nondeterminism and that is only dependant on the current configuration. Pushdown transducers are sufficient to implement the resolvers of HD-VPA, but not those of HD-PDA. HD-PDA with finite-state resolvers are determinisable.

Abstract Background Characterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS). Patients and methods Patients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial. Results Compared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.

Abstract Volatile organic compounds play an essential role in every domain of life, with diverse functions. In this study, we use novel secondary electrospray ionisation high-resolution Orbitrap mass spectrometry (SESI-Orbitrap MS) to monitor the complete yeast volatilome every 2.3 s. Over 200 metabolites were identified during growth in shake flasks and bioreactor cultivations, all with their unique intensity profile. Special attention was paid to ethanol as biotech largest product and to acetaldehyde as an example of a low-abundance but highly-volatile metabolite. While HPLC and Orbitrap measurements show a high agreement for ethanol, acetaldehyde could be measured five hours earlier in the SESI-Orbitrap MS. Volatilome shifts are visible, e.g. after glucose depletion, fatty acids are converted to ethyl esters in a detoxification mechanism after stopped fatty acid biosynthesis. This work showcases the SESI-Orbitrap MS system for tracking microbial physiology without the need for sampling and for time-resolved discoveries during metabolic transitions.

Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.

Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P

We introduce good-for-games $\omega$-pushdown automata ($\omega$-GFG-PDA). These are automata whose nondeterminism can be resolved based on the input processed so far. Good-for-gameness enables automata to be composed with games, trees, and other automata, applications which otherwise require deterministic automata. Our main results are that $\omega$-GFG-PDA are more expressive than deterministic $\omega$- pushdown automata and that solving infinite games with winning conditions specified by $\omega$-GFG-PDA is EXPTIME-complete. Thus, we have identified a new class of $\omega$-contextfree winning conditions for which solving games is decidable. It follows that the universality problem for $\omega$-GFG-PDA is in EXPTIME as well. Moreover, we study closure properties of the class of languages recognized by $\omega$-GFG- PDA and decidability of good-for-gameness of $\omega$-pushdown automata and languages. Finally, we compare $\omega$-GFG-PDA to $\omega$-visibly PDA, study the resources necessary to resolve the nondeterminism in $\omega$-GFG-PDA, and prove that the parity index hierarchy for $\omega$-GFG-PDA is infinite. This is a corrected version of the paper arXiv:2001.04392v6 published originally on January 7, 2022.

In central northern Namibia, challenges in water governance related to scarcity meet needs in capacity development on municipal levels. Reuse of treated water in agriculture forms a technical innovation in urbanizing arid regions, because it potentially contributes to both improving water availability and reducing pollution from waste water in arid regions. Governing this transformative approach entails a complexity of processes and actors at different levels and in a range of sectors. The aim of this research is to assess the potential of an informal municipal partnership to (a) support capacity development in implementation of innovation in urban water systems (here: water reuse), and (b) compensate for lack of coordination in governance. Establishing a municipal partnership for wastewater treatment was part of a living lab approach analyzing the potential for water reuse, in collaboration of an interdisciplinary team of researchers, municipal decision-makers, engineers and farmers. Findings show the potential and limitations in capacity development in municipal water governance by means of an informal partnership. The lessons learnt on establishing an informal municipal partnership for learning and capacity development in water governance provide valuable insights for water governance in both research and practice, in particular but not limited to the field of water reuse as means of transforming socio-hydrological relations toward sustainability. The research thus contributes to research on water reuse governance, and to transformative research on water in social-ecological systems.

Based on three pilot- and demonstration-scale projects investigating agricultural irrigation practices with reclaimed water, risks associated with these water reuse practices are highlighted and processes and strategies to minimize associated microbial risks were evaluated. A number of treatment processes and combinations were tested regarding their efficacy for pathogen removal, representing the biggest threat to the quality of products from reuse irrigation practices. In addition, the importance of regrowth potential and different methods for monitoring risks associated with pathogens were discussed. One method for online monitoring is flow cytometry. The results of an exemplary quantitative microbial risk assessment (QMRA) were discussed to determine the significance of microbial risks. Multi-barrier approaches comprised of technical and administrative barriers can reduce the risks of water reuse significantly. Quality management also needs to address all stakeholders involved in a reuse project, starting from source control in the sewershed to marketing of the final products. In addition, environmental risks of water reuse need to be addressed by quality management as well. HIGHLIGHTS Multi-barrier approaches comprised of technical and administrative barriers can reduce the risks of water reuse significantly.; A number of treatment processes and combinations were tested regarding their efficacy for pathogen removal (ultrafiltration, ozone, UV, ponds, biological processes, and biofilters).; Flow cytometry as a method for online monitoring is discussed.; The importance of regrowth potential is shown.; An exemplary QMRA is carried out, differentiating between risks from bacteria, viruses, and protozoa.;

Treated wastewater is expected to constitute an essential part of the urban water cycle as an additional water resource in water-scarce or densely populated regions in the future. As decisions on the implementation of water recycling measures should always consider local conditions, the project ‘MULTI-ReUse: Modular treatment and monitoring for wastewater reuse’ has developed a comprehensive sustainability assessment tool, designed to support decision-makers in examining the technical feasibility, economic viability, ecological compatibility and social acceptance of alternative service water supply solutions at local level. This article describes the structure of this sustainability assessment tool and its underlying multi-criteria assessment approach based on 23 evaluation criteria. Already in the development phase, the tool was tested in a German and a Namibian case study. Both case studies are presented with a special focus on the technologies used and the results of the analysis with the sustainability assessment tool. Case study testing proved that the tool is applicable in various environmental and societal settings with widely differing climatic conditions, limited resource availability, for varying feed water qualities and water quality requirements. The comprehensive, straightforward assessment approach enabled the local users to identify the most sustainable supply system or strategy for their decision case. HIGHLIGHTS The paper presents a multi-criteria assessment approach based on 23 evaluation criteria that can be used to assess the technical feasibility, economic viability, ecological compatibility and social acceptance of alternative service water supply solutions at local level.; Assessment results from two different case studies comparing different solutions for industrial and agricultural water reuse are presented.;

Water-saving agricultural practices can reduce negative environmental impacts in water-scarce regions all over the world. This study deals with an innovation that combines hydroponic crop production and municipal wastewater reuse for irrigation purposes. The research question was what impacts such hydroponic water reuse systems have on product confidence, economic viability, groundwater recharge, biodiversity and landscape quality. It should also be clarified under which conditions and with which measures these systems can be sustainable. To answer these questions, a number of generic hydroponic water reuse systems were modeled and assessed using a Bayesian Belief Network that included both numerical values and expert knowledge. The hydroponic water reuse systems with the most positive overall impacts are small-scale food production systems (tomatoes) equipped with lighting and heating whose products are marked with a quality label or with a label for regional products. The systems are located in a former industrial area. In addition, a wetland system and landscape integration are implemented as landscaping measures. Hydroponic systems can be operated economically viable, their products have a high level of product confidence and their ecological impacts can be positive. No tradeoffs have to be accepted between economic, social and ecological goals. HIGHLIGHTS The study shows that hydroponic water reuse systems can be operated economically viable, that their products have a high level of product confidence and that their ecological effects can be positive if appropriate landscaping measures are taken.; Landscaping as well as acceptance measures should be carried out to accompany hydroponic crop production to improve its social and ecological impacts.;

Intelligence in its decisions is a trait that people have grown to expect from a cyber−physical system, in particular that it makes the right choices at runtime, that is, those that allow it to fulfill its tasks, even in case of faults or unexpected interactions with its environment. Analyzing how to continuously achieve the currently desired (and possibly continuously changing) goals and adapting its behavior to reach these goals is undoubtedly a serious challenge. This becomes even more challenging if the atomic actions a system can implement become unreliable due to faulty components or some exogenous event out of its control. Herein, a solution for the presented challenge is proposed. In particular, it is shown how to adopt a lightweight diagnosis concept to cope with such situations. The approach is based on rules coupled with means for rule selection that is based on previous information regarding success or failure of rule executions. Furthermore, Java‐based framework of the lightweight diagnosis concept is presented, and the results obtained from an experimental evaluation considering several application scenarios are discussed. At the end, a qualitative comparison with other related approaches that should help the readers decide which approach works best for them is presented. An interactive preprint version of the article can be found here: https://www.authorea.com/doi/full/10.22541/au.163578445.51350502.

Nature-based solutions (NBS) can protect, manage and restore natural or modified ecosystems. They are a multidisciplinary, integrated approach to address societal challenges and some natural hazards effectively and adaptively, simultaneously providing human well-being and biodiversity benefits. NBS applications can be easily noticed in circular cities, establishing an urban system that is regenerative and accessible. This paper aims to offer a review on NBS for urban water management from the literature and some relevant projects running within the COST Action ‘Implementing nature-based solutions for creating a resourceful circular city’. The method used in the study is based on a detailed tracking of specific keywords in the literature using Google Scholar, ResearchGate, Academia.edu, ScienceDirect and Scopus. Based on this review, three main applications were identified: (i) flood and drought protection; (ii) the water-food-energy nexus; and (iii) water purification. The paper shows that NBS provide additional benefits, such as improving water quality, increasing biodiversity, obtaining social co-benefits, improving urban microclimate, and the reduction of energy consumption by improving indoor climate. The paper concludes that a systemic change to NBS should be given a higher priority and be preferred over conventional water infrastructure.

Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in trial CoALL 08-09 (clinicaltrials gov. identifier: NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2,500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 randomized patients per arm reaching MRD-negativity (c2 test P=0.03, leftsided P [Fisher’s exact test]=0.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 [P=0.96]; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 [P=0.59]), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.

Abstract: We conducted a clinical trial and report the long-term outcome of 773 children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03 (from the Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia). In a 2-step stratification, patients were allocated to receive either low- or high-risk treatment, based on initial white blood cell count, age, and immunophenotype. A second stratification was performed according to the results of in vitro pharmacosensitivity toward prednisolone, vincristine, and asparaginase (PVA score) and in vivo response after induction therapy (minimal residual disease [MRD]). Therapy was reduced for both risk groups in patients with a low PVA score or negative MRD result, and intensified in patients with a high PVA score. Overall outcome improved significantly compared with the predecessor CoALL 06-97 trial, with identical therapy backbone despite treatment reduction in 15.8% of patients (10-year probability of event-free survival, 83.5% vs 73.9%; overall survival, 90.7% vs 83.8%). Outcome for patients in the reduced treatment arms was superior to that of patients in the standard arms, associated with a profound reduction in frequency and severity of infectious complications. Importantly, we observed a lack of correlation between in vitro and in vivo drug response, as well as a lower predictive value of in vitro drug testing, reflecting an intrinsic limitation of this methodology that prevents its use for treatment stratification in future trials. In conclusion, it might be possible to reduce chemotherapy in children with acute lymphoblastic leukemia selected by stringent in vivo measurement of MRD without jeopardizing overall outcome.

Linear Temporal Logic (LTL) is the standard specification language for reactive systems and is successfully applied in industrial settings. However, many shortcomings of LTL have been identified in the literature, among them the limited expressiveness, the lack of quantitative features, and the inability to express robustness. There is work on overcoming these shortcomings, but each of these is typically addressed in isolation. This is insufficient for applications where all shortcomings manifest themselves simultaneously. Here, we tackle this issue by introducing logics that address more than one shortcoming. To this end, we combine the logics Linear Dynamic Logic, Prompt-LTL, and robust LTL, each addressing one aspect, to new logics. For all combinations of two aspects, the resulting logic has the same desirable algorithmic properties as plain LTL. In particular, the highly efficient algorithmic backends that have been developed for LTL are also applicable to these new logics. Finally, we discuss how to address all three aspects simultaneously.

With regard to water supply constraints, water reuse has already become an indispensable water resource. In many regions of southern Africa, so-called waste stabilisation ponds (WSP) represent a widespread method of sewage disposal. Since capacity bottlenecks lead to overflowing ponds and contamination, a concept was designed and piloted in order to upgrade a plant and reuse water in agriculture. Using a social–ecological impact assessment (SEIA), the aim of this study was to identify and evaluate intended and unintended impacts of the upgrading of an existing WSP to reuse water for livestock fodder production. For this purpose, semistructured expert interviews were conducted. In addition, a scenario analysis was carried out regarding a sustainable operation of the water reuse system. The evaluation of the impacts has shown that intended positive impacts clearly outweigh the unintended ones. The scenario analysis revealed the consequences of an inadequate management of the system and low fodder demand. Furthermore, the analysis showed that good management of such a system is of fundamental importance in order to operate the facility, protect nature and assist people. This allows subsequent studies to minimize negative impacts and replicate the concept in regions with similar conditions.

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time polymerase chain reaction (RQ-PCR) in bone marrow applying a cut-off of 10 copies NPM-ALK/104 copies of ABL1 identifies very high-risk patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation and to validate digital polymerase chain reaction (dPCR) as an alternative method. Among 91 patients whose bone marrow was analyzed by RQ-PCR, more than 10 normalized copy-numbers correlated with stage III/IV disease, mediastinal and visceral organ involvement and low anti-ALK antibody titers. The cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of NPM-ALK was 61±12% compared to 21±5% for the remaining 73 patients (P=0.0002). Results in blood correlated with those in bone marrow (r=0.74) in 70 patients for whom both materials could be tested. Transcripts were quantified by RQ-PCR and dPCR in 75 bone marrow and 57 blood samples. Copy number estimates using dPCR and RQ-PCR correlated in 132 samples (r=0.85). Applying a cut-off of 30 copies NPM-ALK/104 copies ABL1 for quantification by dPCR, almost identical groups of patients were separated as those separated by RQ-PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Blood can substitute for bone marrow. Quantification of minimal disease by dPCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.

ABL-class fusions other than BCR-ABL1 characterize around 2–3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10−4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

Abstract Second malignant neoplasms pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for second malignant neoplasms in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma. 3590 patients

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin–Frankfurt–Münster (ALL-BFM) trials between 1995–2016 and 1995–2007, respectively. Patients received four courses MTX (5 g/m2 each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m2 in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m2 MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients vs. 516 in 1,089 NDS-patients, P

Die Digitalisierung in der Siedlungswasserwirtschaft kann dazu beitragen, die Aufgaben, die sich für Wasserversorgung und Abwasserbeseitigung aufgrund des demografischen und klimatischen Wandels ergeben, besser anzugehen. Gleichzeitig können sich durch Cyberangriffe die Risiken für einen Ausfall dieser Kritischen Infrastrukturen vergrößern. Aspekte der Cybersicherheit werden im Wassersektor jedoch noch nicht hinreichend berücksichtigt. Entsprechende Regularien und Maßnahmen zielen alleine auf die Ausfallsicherheit der Infrastrukturen ab und vernachlässigen dabei die Versorgungssicherheit der Bevölkerung. Die Aufmerksamkeit der Politik auf große Wasserunternehmen und Versorgungsgebiete ignoriert Sicherheitslücken bei kleinen und mittleren Betrieben. Kooperationen zwischen mehreren Wasserunternehmen könnten ein geeignetes Mittel sein, diesbezüglich Synergieeffekte zu erzeugen.

Abstract. Aberrant activation of key signaling-molecules is a hallmark of acute myeloid leukemia (AML) and may have prognostic and therapeutic implications. AML summarizes several disease entities with a variety of genetic subtypes. A comprehensive model spanning from signal activation patterns in major genetic subtypes of pediatric AML (pedAML) to outcome prediction and pre-clinical response to signaling inhibitors has not yet been provided. We established a high-throughput flow-cytometry based method to assess activation of hallmark phospho-proteins (phospho-flow) in 166 bone-marrow derived pedAML samples under basal and cytokine stimulated conditions. We correlated levels of activated phospho-proteins at diagnosis with relapse incidence in intermediate (IR) and high risk (HR) subtypes. In parallel, we screened a set of signaling inhibitors for their efficacy against primary AML blasts in a flow-cytometry based ex vivo cytotoxicity assay and validated the results in a murine xenograft model. Certain phospho-signal patterns differ between genetic subtypes of pedAML. Some are consistently seen through all AML subtypes such as pSTAT5. In IR/HR subtypes high levels of GM-CSF stimulated pSTAT5 and low levels of unstimulated pJNK correlated with increased relapse risk overall. Combination of GM-CSF/pSTAT5high and basal/pJNKlow separated three risk groups among IR/HR subtypes. Out of 10 tested signaling inhibitors, midostaurin most effectively affected AML blasts and simultaneously blocked phosphorylation of multiple proteins, including STAT5. In a mouse xenograft model of KMT2A-rearranged pedAML, midostaurin significantly prolonged disease latency. Our study demonstrates the applicability of phospho-flow for relapse-risk assessment in pedAML, whereas functional phenotype-driven ex vivo testing of signaling inhibitors may allow individualized therapy.

Abstract We compared 24 primary pediatric T‐cell acute lymphoblastic leukemias (T‐ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient‐derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome‐wide chromatin accessibility (ATAC‐Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T‐ALL‐derived PDX models.

Abstract: Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.

Abstract Background Deletions of 6q15–16.1 are recurrently found in pediatric T-cell acute lymphoblastic leukemia (T-ALL). This chromosomal region includes the mitogen-activated protein kinase kinase kinase 7 (MAP3K7) gene which has a crucial role in innate immune signaling and was observed to be functionally and prognostically relevant in different cancer entities. Therefore, we correlated the presence of MAP3K7 deletions with clinical parameters in a cohort of 327 pediatric T-ALL patients and investigated the function of MAP3K7 in the T-ALL cell lines CCRF-CEM, Jurkat and MOLT-4. Methods MAP3K7 deletions were detected by multiplex ligation-dependent probe amplification (MLPA). T-ALL cell lines were transduced with adeno-associated virus (AAV) vectors expressing anti-MAP3K7 shRNA or a non-silencing shRNA together with a GFP reporter. Transduction efficiency was measured by flow cytometry and depletion efficiency by RT-PCR and Western blots. Induction of apoptosis was measured by flow cytometry after staining with PE-conjugated Annexin V. In order to assess the contribution of NF-κB signaling to the effects of MAP3K7 depletion, cells were treated with TNF-α and cell lysates analyzed for components of the NF-κB pathway by Western blotting and for expression of the NF-κB target genes BCL2, CMYC, FAS, PTEN and TNF-α by RT-PCR. Results MAP3K7 is deleted in approximately 10% and point-mutated in approximately 1% of children with T-ALL. In 32 of 33 leukemias the deletion of MAP3K7 also included the adjacent CASP8AP2 gene. MAP3K7 deletions were associated with the occurrence of SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and outcome. Depletion of MAP3K7 expression in T-ALL cell lines by shRNAs slowed down proliferation and induced apoptosis, but neither changed protein levels of components of NF-κB signaling nor NF-κB target gene expression after stimulation with TNF-α. Conclusions This study revealed that the recurrent deletion of MAP3K7/CASP8AP2 is associated with SIL-TAL1 fusions and a mature immunophenotype, but not with response to treatment and risk of relapse. Homozygous deletions of MAP3K7 were not observed, and efficient depletion of MAP3K7 interfered with viability of T-ALL cells, indicating that a residual expression of MAP3K7 is indispensable for T-lymphoblasts.

What is a finite-state strategy in a delay game? We answer this surprisingly non-trivial question and present a very general framework for computing such strategies: they exist for all winning conditions that are recognized by automata with acceptance conditions that satisfy a certain aggregation property. Our framework also yields upper bounds on the complexity of determining the winner of such delay games and upper bounds on the necessary lookahead to win the game. In particular, we cover all previous results of that kind as special cases of our uniform approach.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels

Quantitative extensions of parity games have recently attracted significant interest. These extensions include parity games with energy and payoff conditions as well as finitary parity games and their generalization to parity games with costs. Finitary parity games enjoy a special status among these extensions, as they offer a native combination of the qualitative and quantitative aspects in infinite games: The quantitative aspect of finitary parity games is a quality measure for the qualitative aspect, as it measures the limit superior of the time it takes to answer an odd color by a larger even one. Finitary parity games have been extended to parity games with costs, where each transition is labeled with a nonnegative weight that reflects the costs incurred by taking it. We lift this restriction and consider parity games with costs with arbitrary integer weights. We show that solving such games is in NP $\cap$ coNP, the signature complexity for games of this type. We also show that the protagonist has finite-state winning strategies, and provide tight pseudo-polynomial bounds for the memory he needs to win the game. Naturally, the antagonist may need infinite memory to win. Moreover, we present tight bounds on the quality of winning strategies for the protagonist. Furthermore, we investigate the problem of determining, for a given threshold $b$, whether the protagonist has a strategy of quality at most $b$ and show this problem to be EXPTIME-complete. The protagonist inherits the necessity of exponential memory for implementing such strategies from the special case of finitary parity games.

Thromboembolism is a serious complication of induction therapy for childhood acute lymphoblastic leukemia. We prospectively compared the efficacy and safety of antithrombotic interventions in the consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acute lymphoblastic leukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low molecular weight heparin (enoxaparin) or activity-adapted antithrombin throughout induction therapy. The primary objective of the study was to determine whether enoxaparin or antithrombin reduces the incidence of thromboembolism as compared to unfractionated heparin. The principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of thromboembolism (8.0%) compared with those randomized to enoxaparin (3.5%; P=0.011) or antithrombin (1.9%; P

Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia (AML) have poor survival. We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (

Energy games are infinite two-player games played in weighted arenas with quantitative objectives that restrict the consumption of a resource modeled by the weights, e.g., a battery that is charged and drained. Typically, upper and/or lower bounds on the battery capacity are part of the problem description. Here, we consider the problem of determining upper bounds on the average accumulated energy or on the capacity while satisfying a given lower bound, i.e., we do not determine whether a given bound is sufficient to meet the specification, but if there exists a sufficient bound to meet it. In the classical setting with positive and negative weights, we show that the problem of determining the existence of a sufficient bound on the long-run average accumulated energy can be solved in doubly-exponential time. Then, we consider recharge games: here, all weights are negative, but there are recharge edges that recharge the energy to some fixed capacity. We show that bounding the long-run average energy in such games is complete for exponential time. Then, we consider the existential version of the problem, which turns out to be solvable in polynomial time: here, we ask whether there is a recharge capacity that allows the system player to win the game. We conclude by studying tradeoffs between the memory needed to implement strategies and the bounds they realize. We give an example showing that memory can be traded for bounds and vice versa. Also, we show that increasing the capacity allows to lower the average accumulated energy.

We consider the optimization variant of the realizability problem for Prompt Linear Temporal Logic, an extension of Linear Temporal Logic (LTL) by the prompt eventually operator whose scope is bounded by some parameter. In the realizability optimization problem, one is interested in computing the minimal such bound that allows to realize a given specification. It is known that this problem is solvable in triply-exponential time, but not whether it can be done in doubly-exponential time, i.e., whether it is just as hard as solving LTL realizability. We take a step towards resolving this problem by showing that the optimum can be approximated within a factor of two in doubly-exponential time. Also, we report on a proof-of-concept implementation of the algorithm based on bounded LTL synthesis, which computes the smallest implementation of a given specification. In our experiments, we observe a tradeoff between the size of the implementation and the bound it realizes. We investigate this tradeoff in the general case and prove upper bounds, which reduce the search space for the algorithm, and matching lower bounds.

We consider the synthesis of distributed implementations for specifications in Prompt Linear Temporal Logic (PROMPT-LTL), which extends LTL by temporal operators equipped with parameters that bound their scope. For single process synthesis it is well-established that such parametric extensions do not increase worst-case complexities. For synchronous systems, we show that, despite being more powerful, the distributed realizability problem for PROMPT-LTL is not harder than its LTL counterpart. For asynchronous systems we have to consider an assume-guarantee synthesis problem, as we have to express scheduling assumptions. As asynchronous distributed synthesis is already undecidable for LTL, we give a semi-decision procedure for the PROMPT-LTL assume-guarantee synthesis problem based on bounded synthesis.

Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients’ anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients’ immune response.

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0–10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).

We continue the investigation of parameterized extensions of Linear Temporal Logic (LTL) that retain the attractive algorithmic properties of LTL: a polynomial space model checking algorithm and a doubly-exponential time algorithm for solving games. Alur et al. and Kupferman et al. showed that this is the case for Parametric LTL (PLTL) and PROMPT-LTL respectively, which have temporal operators equipped with variables that bound their scope in time. Later, this was also shown to be true for Parametric LDL (PLDL), which extends PLTL to be able to express all omega-regular properties. Here, we generalize PLTL to systems with costs, i.e., we do not bound the scope of operators in time, but bound the scope in terms of the cost accumulated during time. Again, we show that model checking and solving games for specifications in PLTL with costs is not harder than the corresponding problems for LTL. Finally, we discuss PLDL with costs and extensions to multiple cost functions.