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Supplementary Data 1. This supplementary data comprises a step-by-step description on how our gene-expression based classification models were generated and validated

Supplementary Figure 1. Highlights the EFS and OS for the cohort of neuroblastoma patients with MYCN-amplified disease (n=114, Fig 1a) and for th subcohort of patients >18 months of age with stage 4, MYCN non-amplified disease (n=102, fig. 1b). F, favorable; UF, unfavorable.

Purpose: To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression–based classification and established prognostic markers.Experimental Design: Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4 × 44 K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n = 634) by Kaplan–Meier estimates and Cox regression analyses.Results: The best-performing classifier predicted patient outcome with an accuracy of 0.95 (sensitivity, 0.93; specificity, 0.97) in the validation cohort. The highest potential clinical value of this predictor was observed for current low-risk patients [5-year event-free survival (EFS), 0.84 ± 0.02 vs. 0.29 ± 0.10; 5-year overall survival (OS), 0.99 ± 0.01 vs. 0.76 ± 0.11; both P < 0.001] and intermediate-risk patients (5-year EFS, 0.88 ± 0.06 vs. 0.41 ± 0.10; 5-year OS, 1.0 vs. 0.70 ± 0.09; both P < 0.001). In multivariate Cox regression models for low-risk/intermediate-risk patients, the classifier outperformed risk assessment of the current German trial NB2004 [EFS: hazard ratio (HR), 5.07; 95% confidence interval (CI), 3.20–8.02; OS: HR, 25.54; 95% CI, 8.40–77.66; both P < 0.001]. On the basis of these findings, we propose to integrate the classifier into a revised risk stratification system for low-risk/intermediate-risk patients. According to this system, we identified novel subgroups with poor outcome (5-year EFS, 0.19 ± 0.08; 5-year OS, 0.59 ± 0.1), for whom we propose intensified treatment, and with beneficial outcome (5-year EFS, 0.87 ± 0.05; 5-year OS, 1.0), who may benefit from treatment de-escalation.Conclusions: Combination of gene expression–based classification and established prognostic markers improves risk estimation of patients with low-risk/intermediate-risk neuroblastoma. We propose to implement our revised treatment stratification system in a prospective clinical trial. Clin Cancer Res; 21(8); 1904–15. ©2014 AACR.See related commentary by Attiyeh and Maris, p. 1782

Supplementary Table 1. Clinical co-variates for the 709 patients who participated in the study. This supplementary table comprises detailed information on clinical co-variates for all 709 neuroblastoma patients who participated in the study.

Supplementary Table 2. External performance validation of the top five classifiers. This supplementary table comprises the external performance metrics of the top five classifiers. Indicated are the values for classification accuracy, sensitivity , specificity and Matthew's correlation coefficient (MCC) in the prediction of 325 patients of the test set who fulfilled the criteria for classifier training (Favorable, n=187; Unfavorable, n=138).

Supplementary Table 4. Transcripts that contribute to the SVM_th10 classifier. This supplementary table highlights the transcripts that constitute the SVM_th10 classifier. Indicated for each feature are the Oligo-ID, the Gene symbols, the Entrez gene IDs, the RefSeq IDs, the Gene IDs and the Transcript IDs.

Legends to Supplementaries. This documents comprises the legends to the supplementary figures and tables

Supplementary Data 2. This supplementary data comprises the r-algorithm scripts required to perform the both model selection and validation as described in the step-by-step protocol

Objectives The aim of this study was to compare the second trimester thymus-thorax-ratio (TTR) between fetuses born preterm (study group) and those born after 37 weeks of gestation were completed (control group). Methods This study was conducted as a retrospective evaluation of the ultrasound images of 492 fetuses in the three vessel view. The TTR was defined as the quotient of a.p. thymus diameter and a.p. thoracic diameter. Results Fetuses that were preterm showed larger TTR (p Conclusions In our study, fetuses affected by PTB showed enlarged thymus size. These findings led us to hypothesize, that inflammation and immunomodulatory processes are altered early in pregnancies affected by PTB. However, TTR alone is not able to predict PTB.

Whereas the theory of confirmatory adaptive designs is well understood for uncensored data, implementation of adaptive designs in the context of survival trials remains challenging. Commonly used adaptive survival tests are based on the independent increments structure of the log-rank statistic. This implies some relevant limitations: On the one hand, essentially only the interim log-rank statistic may be used for design modifications (such as data-dependent sample size recalculation). Furthermore, the treatment arm allocation ratio in these classical methods is assumed to be constant throughout the trial period. Here, we propose an extension of the independent increments approach to adaptive survival tests that addresses some of these limitations. We present a confirmatory adaptive two-sample log-rank test that allows rejection regions and sample size recalculation rules to be based not only on the interim log-rank statistic, but also on point-wise survival rate estimates, simultaneously. In addition, the possibility is opened to adapt the treatment arm allocation ratio after each interim analysis in a data-dependent way. The ability to include point-wise survival rate estimators in the rejection region of a test for comparing survival curves might be attractive, e.g., for seamless phase II/III designs. Data-dependent adaptation of the allocation ratio could be helpful in multi-arm trials in order to successively steer recruitment into the study arms with the greatest chances of success. The methodology is motivated by the LOGGIC Europe Trial from pediatric oncology. Distributional properties are derived using martingale techniques in the large sample limit. Small sample properties are studied by simulation.

Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure.

Successive multicenter studies for pediatric low-grade glioma (LGG) in Germany were accompanied by a doubling of annual recruitment over 2 decades. We investigated whether this increase conveyed a change of epidemiologic characteristics or survival.Participating centers reported 4634 patients with the radiologic/histologic diagnosis of LGG (1996-2018), rising from 109 to 278/year. Relating these numbers to all pediatric CNS tumors registered at the German Childhood Cancer Registry, the LGG fraction and annual crude incidence rates increased (32% to 51%; 0.94 to 2.12/100,000 children/adolescents15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 1836 (LGG-registry) patients with similar distribution of tumor-sites, histology, and dissemination. 5-year overall survival was 96%-98% at median observation time of 8.1 years. Acknowledging unequal follow-up periods, 589/899 (66%), 1089/1582 (69%), and 1387/1836 (76%) patients remained under observation, while 1252/4317 received adjuvant treatment with decreasing frequency of front-line radiotherapy from 16% to 5%.Pediatric LGG incidence rates in Germany are now comparable to other European countries. The rise in patient numbers followed implementation of standard-of-care treatment protocols, but did not result in relevant changes of epidemiologic or clinical parameters or survival. Shifts in patient distribution between treatment arms reflect growing acceptance of the LGG therapy algorithm.In den vergangenen 20 Jahren hat sich die jährliche Patientenrekrutierung in den aufeinanderfolgenden multizentrischen Studien für pädiatrische niedrig-gradige Gliome (LGG) in Deutschland verdoppelt. Wir haben untersucht, ob sich mit dieser Zunahme auch epidemiologische Merkmale oder das Überleben verändert haben.Zwischen 1996 und 2018 meldeten die teilnehmenden Zentren insgesamt 4634 Patienten mit der radiologischen/histologischen Diagnose eines LGG. Die Zahl stieg von anfangs 109 bis 278 Patienten pro Jahr. Gleichzeitig stieg der Anteil der LGGs an allen am Deutschen Kinderkrebsregister gemeldeten pädiatrischen Hirntumoren von 32 auf 51%, die jährliche Inzidenz erhöhte sich von 0,94 auf 2,12/100 000 Kinder/Jugendliche15 Jahre. Die aufeinanderfolgenden LGG-Studien rekrutierten 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004) und 1836 (LGG-Register) Patienten mit vergleichbarer Verteilung von Tumorsitz, Histologie und Disseminierung. Das 5-Jahres-Überleben lag bei einer medianen Nachbeobachtungszeit von 8,1 Jahren zwischen 96 und 98%. Unter Berücksichtigung der ungleich langen Follow-up-Zeit wurden 589/899 (65,5%), 1089/1582 (68,8%) und 1387/1836 (75,5%) Patienten bislang beobachtet, während 1252/4317 eine adjuvante Therapie erhielten. Dabei sank der Anteil der primären Radiotherapie von 16 auf 5%.Die Rekrutierung pädiatrischer LGG ist dank Implementierung verbindlicher Therapiestandards in Deutschland gestiegen, ohne zu relevanten Veränderungen epidemiologischer oder klinischer Merkmale oder des Überlebens zu führen. Die Inzidenz ist mit anderen europäischen Ländern vergleichbar. Verschiebungen der Patientenzuteilung zwischen den Therapiearmen spiegeln die zunehmende Akzeptanz des LGG-Therapie-Algorithmus wider.Successive multicenter studies for pediatric low-grade glioma (LGG) in Germany were accompanied by a doubling of annual recruitment over 2 decades. We investigated whether this increase conveyed a change of epidemiologic characteristics or survival.Participating centers reported 4634 patients with the radiologic/histologic diagnosis of LGG (1996–2018), rising from 109 to 278/year. Relating these numbers to all pediatric CNS tumors registered at the German Childhood Cancer Registry, the LGG fraction and annual crude incidence rates increased (32% to 51%; 0.94 to 2.12/100,000 children/adolescents15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 1836 (LGG-registry) patients with similar distribution of tumor-sites, histology, and dissemination. 5-year overall survival was 96%-98% at median observation time of 8.1 years. Acknowledging unequal follow-up periods, 589/899 (66%), 1089/1582 (69%), and 1387/1836 (76%) patients remained under observation, while 1252/4317 received adjuvant treatment with decreasing frequency of front-line radiotherapy from 16% to 5%.Pediatric LGG incidence rates in Germany are now comparable to other European countries. The rise in patient numbers followed implementation of standard-of-care treatment protocols, but did not result in relevant changes of epidemiologic or clinical parameters or survival. Shifts in patient distribution between treatment arms reflect growing acceptance of the LGG therapy algorithm.In den vergangenen 20 Jahren hat sich die jährliche Patientenrekrutierung in den aufeinanderfolgenden multizentrischen Studien für pädiatrische niedrig-gradige Gliome (LGG) in Deutschland verdoppelt. Wir haben untersucht, ob sich mit dieser Zunahme auch epidemiologische Merkmale oder das Überleben verändert haben.Zwischen 1996 und 2018 meldeten die teilnehmenden Zentren insgesamt 4634 Patienten mit der radiologischen/histologischen Diagnose eines LGG. Die Zahl stieg von anfangs 109 bis 278 Patienten pro Jahr. Gleichzeitig stieg der Anteil der LGGs an allen am Deutschen Kinderkrebsregister gemeldeten pädiatrischen Hirntumoren von 32 auf 51%, die jährliche Inzidenz erhöhte sich von 0,94 auf 2,12/100 000 Kinder/Jugendliche15 Jahre. Die aufeinanderfolgenden LGG-Studien rekrutierten 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004) und 1836 (LGG-Register) Patienten mit vergleichbarer Verteilung von Tumorsitz, Histologie und Disseminierung. Das 5-Jahres-Überleben lag bei einer medianen Nachbeobachtungszeit von 8,1 Jahren zwischen 96 und 98%. Unter Berücksichtigung der ungleich langen Follow-up-Zeit wurden 589/899 (65,5%), 1089/1582 (68,8%) und 1387/1836 (75,5%) Patienten bislang beobachtet, während 1252/4317 eine adjuvante Therapie erhielten. Dabei sank der Anteil der primären Radiotherapie von 16 auf 5%.Die Rekrutierung pädiatrischer LGG ist dank Implementierung verbindlicher Therapiestandards in Deutschland gestiegen, ohne zu relevanten Veränderungen epidemiologischer oder klinischer Merkmale oder des Überlebens zu führen. Die Inzidenz ist mit anderen europäischen Ländern vergleichbar. Verschiebungen der Patientenzuteilung zwischen den Therapiearmen spiegeln die zunehmende Akzeptanz des LGG-Therapie-Algorithmus wider.

BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.

We examined the potential of thermal evaporation for the controlled production of aerosols for the administration of drugs to the lungs. A novel volumetric heater was designed and fabricated allowing better control of the heating power transferred to the solvent compared to conventional coil heaters that are commonly used in e-cigarettes. The whole silicon chip is used as a resistive heater. Therefore, we call this approach a volumetric heater. We demonstrate that the vapor production of the volumetric heater can be controlled over a wide dynamic range by varying the heater temperature. [2020-0105]

The one-sample log-rank test allows to compare the survival of a single sample with a prefixed reference survival curve. It naturally applies in single-arm phase IIa trials with time-to-event endpoint. Several authors have described that the original one-sample log-rank test is conservative when sample size is small and have proposed strategies to correct the conservativeness. Here, we propose an alternative approach to improve the one-sample log-rank test. Our new one-sample log-rank statistic is based on the unique transformation of the underlying counting process martingale such that the moments of the limiting normal distribution have no shared parameters. Simulation results show that the new one-sample log-rank test gives type I error rate and power close to the nominal levels also when sample size is small, while relevantly reducing the required sample size to achieve the desired power as compared to current approaches to design studies to compare the survival outcome of a sample with a reference.

Expansion of magnetic resonance imaging T2- or T1-tumor lesion volume after radiation therapy (RT) may indicate pseudoprogression (PsPD). The differentiation between true progression and PsPD is a clinical challenge and underinvestigated in pediatric low-grade glioma (LGG). We evaluated radiologic criteria for PsPD after front-line RT and investigated the frequency and duration of PsPD after 3 RT-modalities within the framework of the German pediatric multicenter LGG-studies.Baseline and follow-up magnetic resonance imaging scans of 136 patients (72 male [52.9%], median age at start of RT of 11.3 years [range, 0.8-25.9]) of the Society for Pediatric Oncology-LGG 2004 study and LGG-registry cohorts (Definite PsPD was radiologically determined in 54 of 136 (39.7%) without differences in frequency between RT-modalities: IS 22 of 48 versus XRT 24 of 54 versus PBT 11 of 20; P = .780. Definite PsPD occurred at median 6.3 months (IS 7.2 months; XRT 4.4 months; PBT 6.5 months) after RT-initiation and persisted for median 7.2 months (IS 8.5 months; XRT 7 months; PBT 7.4 months). Appearance of necrosis within the focal tumor-associated T2 lesion proved to be a relevant associated predictor of definite PsPD (P.001).PsPD is frequent after irradiation of pediatric LGG and independent of the RT modality (IS vs XRT vs PBT). Adequate identification of PsPD versus true progression is imperative to prevent unneeded salvage treatment.

Time-to-event endpoints show an increasing popularity in phase II cancer trials. The standard statistical tool for such one-armed survival trials is the one-sample log-rank test. Its distributional properties are commonly derived in the large sample limit. It is however known from the literature, that the asymptotical approximations suffer when sample size is small. There have already been several attempts to address this problem. While some approaches do not allow easy power and sample size calculations, others lack a clear theoretical motivation and require further considerations. The problem itself can partly be attributed to the dependence of the compensated counting process and its variance estimator. For this purpose, we suggest a variance estimator which is uncorrelated to the compensated counting process. Moreover, this and other present approaches to variance estimation are covered as special cases by our general framework. For practical application, we provide sample size and power calculations for any approach fitting into this framework. Finally, we use simulations and real world data to study the empirical type I error and power performance of our methodology as compared to standard approaches.

Background The prognosis of patients with recurrences from stage 4 neuroblastoma is not uniformly dismal. The evaluation of new therapies therefore needs to consider the individual risks of the treated patients. This study aims to define clinically useful risk criteria. Patients and Methods Inclusion criteria were: first recurrence of neuroblastoma stage 4 aged ≥18 months and enrollment in first line trials between 1997 and 2016. Patients were randomized into a training set (N = 310) and an independent validation set (N = 159). The primary endpoint was secondary event‐free survival. The individual treatment elements the patients received during initial and recurrent disease were analyzed as binary and time‐dependent variables. A five‐step multiple time‐dependent Cox regression analysis was performed on the training set to identify prognostic variables adjusted for the individual frontline treatment. The selected variables resulted in a prognostic index (PI) and were used to build a risk score system. The score was validated with the validation set. Results Of the 469 patients, 372 were treated with curative intent and 97 with palliative intent. The PI included the variables number of recurrence organs (hazard ratio [HR] = 2.27), time to recurrence (HR = 2.03), liver metastasis at diagnosis (HR = 1.77), first recurrence at site of the primary tumor (HR = 1.55), and age (HR = 1.29). Three risk groups were built and confirmed in the validation set. The scoring system was likewise useful for the curatively or palliatively treated subgroups. Conclusion A new risk score system for patients with first recurrence of stage 4 neuroblastoma aged ≥18 months at diagnosis is proposed., The prognostic index of each patient with first recurrence of stage 4 neuroblastoma aged >18 months at first diagnosis can be calculated. If a characteristic is present, use the indicated figure. If absent, use 0. The sum indicates the related risk group.

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.

Background Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce. Methods We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36). Results Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment. Conclusions The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.

Confirmatory adaptive designs comprise a range of statistical methods that allow to modify the sample size of an ongoing trial in a data-dependent way without compromising control of the type I error rate. For short-term endpoints (e.g., 3-month response rate), comprehensive methodology of adaptive designs exists. However, clinical trials in oncology often have a special focus on long-term outcome and therefore often choose a time-to-event endpoint as the primary endpoint. Typical examples are progression-free survival (PFS) or overall survival (OS). But subtle statistical problems arise when adaptively analysing survival trials. Classical designs for survival trials are therefore commonly limited to a single primary endpoint, which combines the occurrence of progression, toxicities, deaths, and other events of potential interest into a single statistical measure (composite endpoint). However, the complexity of oncological diseases can be mapped more accurately using multi-stage models, where the occurrence of progressions, toxicities and deaths is modelled jointly instead of combining them into a single composite endpoint. We present and discuss adaptive design methodology for single-arm phase II survival trials for testing hypotheses on the joint distribution of several time-to-event endpoints in the context of multi-state models. We illustrate the methodology using the example of adaptive hypothesis tests for the joint distribution of progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model. The methodology is motivated from application in pediatric oncology.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.

First-line treatment of pediatric low-grade glioma using surgery, radio- or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP-LGG 2004 study (2004-2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow-up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment-lines, accompanied by up to 4 tumor-reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first-line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (

Brain invasion (BI) in meningiomas impacts WHO grading and therefore adjuvant treatment. However, BI is rare and neurosurgical sampling and neuropathological analyses are not standardised. Moreover, associations with imaging findings are sparsely known. Associations between BI and findings on preoperative MRI were investigated in 617 meningioma patients. BI was strongly correlated with other high-grade criteria (p.05, each). High-grade histology (p=.033) but not BI (p=.354) was associated with tumour location. Irregular tumour shape (OR: 3.33, 95%CI 1.33-8.30; p=.007), heterogeneous contrast enhancement (OR: 2.82, 95%CI 1.19-6.70; p=.015) and peritumoural edema (OR: 1.005 per ccm, 95%CI 1.001-1.008); p=.011) were associated with BI. Multivariable analyses identified only increasing edema volume (OR: 1.005 per ccm, 95%CI 1.002-1.009; p=.010) as a predictor for BI, independent of other histopathological high-grade criteria. We finally provide a new model to estimate the risk of BI using routine preoperative MRI. Several imaging characteristics were identified as predictors for BI. Consideration in clinical routine can increase the accuracy of the detection in neuropathological analyses.

BACKGROUND Near-infrared spectroscopy (NIRS) can be used to measure tissue oxygen saturation (StO2) in different sites and in a wide range of clinical scenarios. Peripheral regional anaesthesia induces vascular changes causing increased arterial blood flow and venodilatation, but its effect on StO2 is still under debate. This is especially so for patients undergoing arteriovenous fistula surgery, wherein latest data suggest an improved outcome under brachial plexus block (BPB) compared with local anaesthesia, but no data are available. OBJECTIVE The aim of this study was to investigate changes in StO2 following BPB prior to arteriovenous fistula surgery using NIRS. DESIGN A prospective observational study. SETTING A secondary teaching hospital from August 2016 to March 2017. PATIENTS Fifteen patients undergoing arteriovenous fistula surgery. INTERVENTION Ultrasound-guided BPB in 15 patients undergoing arteriovenous fistula surgery. OUTCOME MEASURES StO2 at baseline and compared with baseline and the contralateral arm following BPB measured using NIRS of the thenar eminence (NIRSth). RESULTS Baseline values of StO2 assessed by NIRSth were 42.6 ± 7.7% in the arteriovenous fistula arm and 42.7 ± 9.7% in the contralateral arm. There was no significant difference between the two. Five minutes after BPB, there was a significant increase in StO2 of the blocked arm, compared with the control arm expressed as difference of absolute values (7.1 ± 9.7%). At 60 min, an absolute difference of 21.0 ± 13.5% was reached. The absolute increase in StO2 of the blocked arm compared with baseline reached significance after 5 min (8.8 ± 4.6%) and increased up to 23.2 ± 8.2% after 60 min. CONCLUSION NIRSth indicates that BPB significantly increases StO2 of the arteriovenous fistula arm in patients undergoing haemodialysis. TRIAL REGISTRATION Clinicaltrials.gov: NCT03044496.

BACKGROUND: Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables. METHODS: A cohort of 695 neuroblastoma patients was divided into a discovery set (n = 75) for multigene predictor generation, a training set (n = 411) for risk score development, and a validation set (n = 209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score. RESULTS: The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9 ± 3.4 vs 63.6 ± 14.5 vs 31.0 ± 5.4; P

Summary Traditional designs in phase IIa cancer trials are single-arm designs with a binary outcome, for example, tumor response. In some settings, however, a time-to-event endpoint might appear more appropriate, particularly in the presence of loss to follow-up. Then the one-sample log-rank test might be the method of choice. It allows to compare the survival curve of the patients under treatment to a prespecified reference survival curve. The reference curve usually represents the expected survival under standard of the care. In this work, convergence of the one-sample log-rank statistic to Brownian motion is proven using Rebolledo's martingale central limit theorem while accounting for staggered entry times of the patients. On this basis, a confirmatory adaptive one-sample log-rank test is proposed where provision is made for data dependent sample size reassessment. The focus is to apply the inverse normal method. This is done in two different directions. The first strategy exploits the independent increments property of the one-sample log-rank statistic. The second strategy is based on the patient-wise separation principle. It is shown by simulation that the proposed adaptive test might help to rescue an underpowered trial and at the same time lowers the average sample number (ASN) under the null hypothesis as compared to a single-stage fixed sample design.

Background and Purpose Blend sign (BS) and black hole sign (BHS) on non-contrast computed tomography (NCCT) and spot sign (SS) on CT-angiography (CTA) are indicators of early hematoma expansion in spontaneous intracerebral hemorrhage (ICH). However, their independent contributions to outcome have not been well explored. Methods In this retrospective study, inclusion criteria were: 1) spontaneous ICH and 2) NCCT and CTA performed on admission within 6 hours after onset of symptoms. Discharge outcome was dichotomized as good (modified Rankin Scale [mRS] 0-3) and poor (mRS 4-6) outcomes. The impacts of BHS, BS and SS on outcome were assessed in univariate and multivariable logistic regression models. Results Of 182 patients with spontaneous ICH, 26 (14.3%) presented with BHS, 37 (20.3%) with BS and 39 (21.4%) with SS. There was a substantial correlation between SS and BS (κ=0.701) and a moderate correlation between SS and BHS (κ=0.424). In univariable logistic regression, higher baseline hematoma volume (P

Objective: To evaluate segmental left (LV-S) and right (RV-S) ventricular strain as well as longitudinal mechanical myocardial dyssynchrony as a time difference between peaks in strain of both ventricles in fetuses (two-chamber-dyssynchrony, 2C-DYS) using speckle tracking echocardiography (STE). The aim of our study was to evaluate the influence of data acquisition on the results of STE measurement using different ultrasound probes. Methods: We prospectively recorded cardiac cycles of four-chamber views of 56 normal fetuses with three different ultrasound probes and analyzed them offline with speckle tracking imaging software. Furthermore, we looked at a possible influence of heartbeat variability (beat-to-beat variability). Results: The evaluation of the parameters was feasible with all three probes in 53 cases. There was no influence of heartbeat variability and no noticeable differences in 2C-DYS, LV-S and RV-S in all cases and for all three probes determined. Conclusion: Assessment of strain and dyssynchrony using STE with three different probes is comparable. Further research is needed to validate dyssynchrony as a predictor for fetal outcome.

Intraoperative Hypotonie ist im klinischen Alltag keine Seltenheit. Obwohl ein Zusammenhang mit erhohter perioperativer Morbiditat und Letalitat zu bestehen scheint, wird sie oft zu spat oder gar nicht therapiert. Dabei gibt es eine Vielzahl an Pradiktoren und technischen Hilfsmitteln, um Risikopatienten zu identifizieren und das perioperative Management durch ein adaquates Monitoring und eine fruhzeitige Therapie zu optimieren.

Background and Purpose— Significant early hematoma growth in patients with intracerebral hemorrhage is an independent predictor of poor functional outcome. Recently, the novel blend sign (BS) has been introduced as a new imaging sign for predicting hematoma growth in noncontrast computed tomography. Another parameter predicting increasing hematoma size is the well-established spot sign (SS) visible in computed tomographic angiography. We, therefore, aimed to clarify the association between established SS and novel BS and their values predicting a secondary neurological deterioration. Methods— Retrospective study inclusion criteria were (1) spontaneous intracerebral hemorrhage confirmed on noncontrast computed tomography and (2) noncontrast computed tomography and computed tomographic angiography performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (secondary neurological deterioration versus no secondary deterioration). As secondary neurological deterioration, we defined (1) early hemicraniectomy under standardized criteria or (2) secondary decrease of Glasgow Coma Scale of >3 points, both within the first 48 hours after symptom onset. Results— Of 182 patients with spontaneous intracerebral hemorrhage, 37 (20.3%) presented with BS and 39 (21.4%) with SS. Of the 81 patients with secondary deterioration, 31 (38.3%) had BS and SS on admission. Multivariable logistic regression analysis identified hematoma volume (odds ratio, 1.07 per mL; P ≤0.001), intraventricular hemorrhage (odds ratio, 3.08; P =0.008), and the presence of BS (odds ratio, 11.47; P ≤0.001) as independent predictors of neurological deterioration. Conclusions— The BS, which is obtainable in noncontrast computed tomography, shows a high correlation with the computed tomographic angiography SS and is a reliable predictor of secondary neurological deterioration after spontaneous intracerebral hemorrhage.

Neurocognitive deficits are frequent in childhood brain tumor survivors and affect mental intelligence, psychomotor and executive abilities. The differential impact of factors such as disease (location, histology) or treatment (local (LI) vs. craniospinal irradiation (CSI)) on these parameters is not fully understood. Between 2007–2011 and 2013–2017 300 testings were performed on-site by one neuropsychologist. Of these, 274 tests from n=208 children with medulloblastoma (MB), ependymoma (EP) and supratentorial embryonal tumors (SET)

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL×1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

Background Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. Patients and methods An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1–21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. Results Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65–5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. Conclusion While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. Clinical Trials.gov number NCT number 03042429.

Background The aim of this study was to compare transabdominal and transcervical chorionic villus sampling (CVS) as well as amniocentesis (AC) with respect to their rates of premature delivery and fetal growth restriction. Methods We retrospectively evaluated the mentioned procedures of invasive prenatal testing performed in a single center between 2001 and 2016. Seven hundred and ninety-nine cases of AC and 719 cases of CVS were included, of which 400 were performed transvaginally. Only singleton pregnancies with a normal karyotype and delivery after 24 + 0 weeks of gestation were included. Fetal growth restriction was defined as birth weight below the 10th percentile. Premature delivery was defined as delivery before 37 + 0 weeks of gestation. Data were compared to a control group without an invasive procedure. Results The frequency of premature delivery was 8.5% after transabdominal CVS, 6.3% after transcervical CVS and 10.5% after AC as compared to 10.8% in the control group. The frequency of fetal growth restriction was 8.2% after transabdominal CVS 6.8% after transcervical CVS and 8.4% after AC as compared to 9.7% in the control group. Conclusion Our study supports that the three different methods of invasive prenatal testing do not lead to a higher risk of either premature delivery or fetal growth restriction when compared to controls. We found no difference in risk profile among the three techniques.

Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2–16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.

In asthmatic airways secondary ciliary dyskinesia contributes to impaired mucociliary clearance. To investigate underlying mechanisms, we studied the effects of cytokines associated with asthma phenotype on the ciliary beat frequency (CBF) in a cell culture model of ciliated human respiratory epithelial cells. Nasal respiratory epithelial cells of 21 patients were used to prepare multicellular cells (spheroids) in the presence of the T helper (TH) 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13, and the TH1 cytokine interferon gamma (IFN-γ). CBF was determined by high-speed video microscopy. Addition of IL-4 and IL-13 and IL-4 + IL-13 decreased the mean CBF by 17, 21, and 22%, respectively, compared with untreated controls. Addition of IL-5 and IL-9 lead to an increase in mean CBF (20 and 10%, respectively). Lower concentrations of IFN-γ (0.1 and 1 ng/ml) decreased mean CBF and higher concentrations (10 ng/ml) increased CBF by 6%. Addition of IFN-γ to IL-13 reversed the effect of IL-13 on the CBF of spheroids. Cytokines directly influence the ciliary function of respiratory epithelium and contribute to the impaired mucociliary clearance in asthmatic disease. Our study encourages further research to investigate IFN-γ as a treatment option in diseases with impaired mucociliary clearance like asthma.

Background and Purpose: Computed tomography perfusion (CTP) has a high diagnostic value in the detection of acute ischemic stroke in the anterior circulation. However, the diagnostic value in suspected posterior circulation (PC) stroke is uncertain, and whole brain volume perfusion is not yet in widespread use. We therefore studied the additional value of whole brain volume perfusion to non-contrast CT (NCCT) and CT angiography source images (CTA-SI) for infarct detection in patients with suspected acute ischemic PC stroke. Methods: This is a retrospective review of patients with suspected stroke in the PC in a database of our stroke center (n = 3,011) who underwent NCCT, CTA and CTP within 9 h after stroke onset and CT or MRI on follow-up. Images were evaluated for signs and pc-ASPECTS locations of ischemia. Three imaging models - A (NCCT), B (NCCT + CTA-SI) and C (NCCT + CTA-SI + CTP) - were compared with regard to the misclassification rate relative to gold standard (infarction in follow-up imaging) using the McNemar's test. Results: Of 3,011 stroke patients, 267 patients had a suspected stroke in the PC and 188 patients (70.4%) evidenced a PC infarct on follow-up imaging. The sensitivity of Model C (76.6%) was higher compared with that of Model A (21.3%) and Model B (43.6%). CTP detected significantly more ischemic lesions, especially in the cerebellum, posterior cerebral artery territory and thalami. Conclusions: Our findings in a large cohort of consecutive patients show that CTP detects significantly more ischemic strokes in the PC than CTA and NCCT alone.