A graph neural network framework for causal inference in brain networks.

A central question in neuroscience is how self-organizing dynamic interactions in the brain emerge on their relatively static structural backbone. Due to the complexity of spatial and temporal dependencies between different brain areas, fully comprehending the interplay between structure and function is still challenging and an area of intense research. In this paper we present a graph neural network (GNN) framework, to describe functional interactions based on the structural anatomical layout. A GNN allows us to process graph-structured spatio-temporal signals, providing a possibility to combine structural information derived from diffusion tensor imaging (DTI) with temporal neural activity profiles, like that observed in functional magnetic resonance imaging (fMRI). Moreover, dynamic interactions between different brain regions discovered by this data-driven approach can provide a multi-modal measure of causal connectivity strength. We assess the proposed model's accuracy by evaluating its capabilities to replicate empirically observed neural activation profiles, and compare the performance to those of a vector auto regression (VAR), like that typically used in Granger causality. We show that GNNs are able to capture long-term dependencies in data and also computationally scale up to the analysis of large-scale networks. Finally we confirm that features learned by a GNN can generalize across MRI scanner types and acquisition protocols, by demonstrating that the performance on small datasets can be improved by pre-training the GNN on data from an earlier study. We conclude that the proposed multi-modal GNN framework can provide a novel perspective on the structure-function relationship in the brain. Accordingly this approach appears to be promising for the characterization of the information flow in brain networks.

Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

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.

[Age-related characteristics of the efficacy of different glucocorticosteroids in the therapy of acute lymphoblastic leukemia].

AIM: To determine predictors for decision-making on a differential approach to choosing glucocorticosteroids (GCS) for children and adolescents with acute lymphoblastic leukemia (ALL). SUBJECTS AND METHODS: The analysis covered 1064 primary patients aged to 1 to 18 years with ALL who had been registered at the clinics of Russia and Belorussia in April 2002 to November 2006. Before induction therapy, the patients were randomized into a dexamethasone (DEXA) 6 mg/m2 group (n=539) and a methylprednisolone (MePRED) 60 mg/m2 one (n=525). RESULTS: The entire group showed no statistically significant differences in survival rates between the patients receiving DEXA or MePRED. However, an analysis of age groups revealed the benefits of DEXA in children younger than 14 years (the event-free survival (EFS) was 76±2 and 71±2%, respectively (p=0.048); the overall survival (OS) was 81±2 and 77±2%, respectively (p=0.046); therapy-induced mortality was 6.4% (DEXA) andl 1.1% (MePRED) (p=0.01 4); the rate of isolated extramedullary relapses was 1.5% (DEXA) and 4.4% (MePRED) (p=0.009). At the same time, EFS and OS in 14-to-18-year-old adolescents were statistically significantly higher than in those who used MePRED (EFS, 65±6 and 52±6%, respectively (p=0.087); OS, 72±6 and 61±6%, respectively; (p=0.l 7). CONCLUSION: The findings suggest that it is possible that the choice of a GCS for ALL therapy must be also based on a patient's age. There is a need for further studies of this matter in prospective randomized multicenter trials in children and adolescents.

Higher fibrinogen concentrations for reduction of transfusion requirements during major paediatric surgery: A prospective randomised controlled trial.

BACKGROUND: Hypofibrinogenaemia is one of the main reasons for development of perioperative coagulopathy during major paediatric surgery. The aim of this study was to assess whether prophylactic maintenance of higher fibrinogen concentrations through administration of fibrinogen concentrate would decrease the volume of transfused red blood cell (RBCs). METHODS: In this prospective, randomised, clinical trial, patients aged 6 months to 17 yr undergoing craniosynostosis and scoliosis surgery received fibrinogen concentrate (30 mg kg(-1)) at two predefined intraoperative fibrinogen concentrations [ROTEM(®) FIBTEM maximum clot firmness (MCF) of <8 mm (conventional) or <13 mm (early substitution)]. Total volume of transfused RBCs was recorded over 24 h after start of surgery. RESULTS: Thirty children who underwent craniosynostosis surgery and 19 children who underwent scoliosis surgery were treated per protocol. During craniosynostosis surgery, children in the early substitution group received significantly less RBCs (median, 28 ml kg(-1); IQR, 21 to 50 ml kg(-1)) compared with the conventional fibrinogen trigger of <8 mm (median, 56 ml kg(-1); IQR, 28 to 62 ml kg(-1)) (P=0.03). Calculated blood loss as per cent of estimated total blood volume decreased from a median of 160% (IQR, 110-190%) to a median of 90% (IQR, 78-110%) (P=0.017). No significant changes were observed in the scoliosis surgery population. No bleeding events requiring surgical intervention, postoperative transfusions of RBCs, or treatment-related adverse events were observed. CONCLUSIONS: Intraoperative administration of fibrinogen concentrate using a FIBTEM MCF trigger level of <13 mm can be successfully used to significantly decrease bleeding, and transfusion requirements in the setting of craniosynostosis surgery, but not scoliosis. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT01487837.

Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: prognostic relevance of early and late assessment.

The prognosis for children with high-risk relapsed acute lymphoblastic leukemia (ALL) is poor. Here, we assessed the prognostic importance of response during induction and consolidation treatment prior to hematopoietic stem cell transplantation (HSCT) aiming to evaluate the best time to assess minimal residual disease (MRD) for intervention strategies and in future trials in high-risk ALL relapse patients. Included patients (n=125) were treated uniformly according to the ALL-REZ BFM (Berlin-Frankfurt-Münster) 2002 relapse trial (median follow-up time=4.8 years). Patients with MRD ⩾10(-3) after induction treatment (76/119, 64%) or immediately preceding HSCT (19/71, 27%) had a significantly worse probability of disease-free survival 10 years after relapse treatment begin, with 26% (±6%) or 23% (±7%), respectively, compared with 58% (±8%) or 48% (±7%) for patients with MRD <10(-3). Conventional intensive consolidation treatment reduced MRD to <10(-3) before HSCT in 63% of patients, whereas MRD remained high or increased in the rest of this patient group. Our data support that MRD after induction treatment can be used to quantify the activity of different induction treatment strategies in phase II trials. MRD persistence at ⩾10(-3) before HSCT reflects a disease highly resistant to conventional intensive chemotherapy and requiring prospective controlled investigation of new treatment strategies and drugs.

Musculoskeletal pain: a new algorithm for differential diagnosis of a cardinal symptom in pediatrics.

Musculoskeletal pain (MSP) is a common childhood complaint associated with multiple differential diagnoses, including cancer. Considering the expanding spectrum of diagnostics, evaluat-ing a young patient with MSP is a challenge today, particularly for non-specialists in a primary care setting. Since childhood cancer is rare and most cardinal symptoms mimic rather non-serious diseases, misdiagnosis is not uncommon, but of significant prognostic relevance. To build the appropriate bridge between primary and secon-dary care for a child presenting with MSP, thereby preventing treatment delay and longterm sequelae, initial evaluation should follow a comprehensive, multidisciplinary, systematic and stepwise approach, which unites the patient's individual anamnestic, psychosocial, and clinical charac-teristics. After a systematic review of the literature, we generated multidisciplinarily quality-assured recommendations for efficient, rational and cost-effective primary care assessment of pediatric MSP. The algorithm promotes the identification and structured interpretation of the patient's individual clinical clues. It should serve the primary care physician to recognize when further intervention, rather than reassurance and follow-up, is needed using the minimum amount of testing to make an appropriate, prompt diagnosis in the clinical situation "child presenting with MSP". A German version of this algorithm has been published in the Guideline-Portal of The Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF) in November 2013.

Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

Key treatment questions in childhood acute lymphoblastic leukemia: results in 5 consecutive trials performed by the ALL-BFM study group from 1981 to 2000.

Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.

ALL-REZ BFM--the consecutive trials for children with relapsed acute lymphoblastic leukemia.

The BFM studies for relapsed childhood acute lymphoblastic leukemia (ALL) were started in 1983, at a time when cure rates for ALL were still lower and the number of children with ALL relapse equaled about the number of children with newly diagnosed neuroblastoma. Today, relapses have become relatively rare events in ALL although, because of the frequency of ALL, they are still a significant cause of death in children and adolescents. With currently used treatment modalities, cure rates of about 50% after relapse can be achieved, and, together with the improved results of front-line therapy, the survival rate of childhood ALL is now about 90%. Most children with extramedullary and late bone marrow (BM) relapses achieve a second CR; remission rates in patients with high-risk features, however, remain still unsatisfactory. With improved techniques allogeneic hematopoietic stem cell transplant (HSCT) has become a relatively safe treatment but is not necessary for all patients as postremission therapy. HSCT is not required in children with isolated extramedullary and late BM relapses with rapid response to induction therapy measured by molecular techniques (minimal residual disease, MRD) but absolutely indicated in patients with early BM relapses and systemic relapses of T-cell ALL. For patients with insufficient response innovative therapies such as small molecules or targeted immunological or pharmacological approaches are urgently required. Efforts have to be made, therefore, in order to detect potential biological or molecular targets, which can be used for individualized, more effective and hopefully less toxic therapies in the future.

Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.

Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.

A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia.

OBJECTIVES: Aqueous Viscum album L. extracts are widely used for anti-cancer therapies. Due to their low solubility, triterpenes (which are known to act on cancers), do not occur in aqueous extracts in significant amounts. Using cyclodextrins, we have found it possible to solubilize mistletoe triterpene acids and to determine their effects on acute lymphoblastic leukaemia (ALL) in vitro and in vivo. MATERIALS AND METHODS: A C.B-17/SCID model of pre-B ALL (NALM-6) was used to test efficacy and mechanisms of treatment with lectin- and triterpene acid containing preparations in vivo. Cytotoxicity of increasing concentrations of V. album L. preparations was assessed in vitro. Apoptosis was determined using mitochondrial membrane potential measurements, annexin V/PI, western blot analyses and caspase inhibitor assays. RESULTS: Solubilized triterpene acid- or lectin-containing V. album L. extracts inhibited cell proliferation and demonstrated cytotoxic properties in vitro. Annexin V/PI and mitochondrial membrane potential assays indicated that dose-dependent induction of apoptosis was the main mechanism. Combination (viscumTT) of lectin- (viscum) and triterpene-containing (TT) extracts resulted in greatest induction of apoptosis. Furthermore, caspase activity demonstrated that these extracts were able to induce apoptosis through both caspase-8 and -9 dependent pathways. In vivo experimentation showed that treatment of mice with viscumTT combination prolonged mean survival to 50.5 days compared to 39.3 days in the phosphate-buffered saline group. CONCLUSION: Here for the first time, we have demonstrated that either solubilized triterpene acids or lectins and combinations thereof, induce dose-dependent apoptosis in the ALL cell line NALM-6 via caspase-8 and -9 dependent pathways.

Low inhibin B levels alone are not a reliable marker of dysfunctional spermatogenesis in childhood cancer survivors.

Hormone and semen analyses were carried out to examine the diagnostic value of hormones and hormone combinations as markers of spermatogenesis in male patients who had received oncological treatment in childhood. Hormone analyses from 73 participants and spermiograms from 42 participants were evaluated. Spearman's correlation coefficients and measures of diagnostic accuracy were calculated for the hormone and semen analysis values. Inhibin B levels of <80 ml/ml, follicle-stimulating hormone (FSH) levels of >10 IU l(-1) and a combination of the two parameters showed positive predictive values for azoospermia of 0.423, 0.6154 and 0.6667 respectively. While 32% of the 73 participants showed a combination of abnormal inhibin B and FSH values, which strongly indicates impaired spermatogenesis, 31% of the 42 spermiogram results revealed azoospermia. The hormone and semen analyses showed that approximately one-third of the participants had fertility impairment. Inhibin B alone thus does not reflect spermatogenesis as well as inhibin B in combination with FSH in patients who have undergone cancer treatment in childhood. Both parameters should therefore be evaluated in paediatric cancer follow-up programmes to allow better identification of treatment regimens that cause persistent azoospermia in male childhood cancer survivors.

Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.

High reliability of scrotal ultrasonography in the management of childhood primary testicular neoplasms.

BACKGROUND: The role for testis-sparing surgery in the treatment of primary intratesticular lesions in childhood is growing. The reliability of scrotal ultrasonograpy (US) in the management of these lesions is still controversial. PATIENTS: Between 1991 and 2007, 383 children and adolescents presented with testicular abnormalities. Ultrasound results and records of patients with primary testicular neoplasms were analyzed. RESULTS: 12 of 383 patients (3.1%) had a histologically proven primary intratesticular neoplasm. Scrotal US was highly sensitive for the detection of these lesions. Patients' mean age at initial US was 6 years (9 prepubertal, 3 juvenile patients). The most frequent symptom was a painless unilateral scrotal mass (75%). Tumor markers or testosterone were elevated in 6/12 boys. Histology was intratesticular germ cell in 7, sexcord stromal tumor in 4 and capillary hemangioma in 1 patient. US correctly distinguished between benign and malignant lesions in all cases. When combined with clinical symptoms, US predicted 75% of histologies. After including hormone and tumor marker levels, a correct preoperative diagnosis was made for all boys with germ cell, and for 75% of boys with sexcord stromal tumor. CONCLUSION: Scrotal US is highly sensitive for the detection of childhood primary intratesticular tumors and, when combined with clinical data, highly reliable for differential diagnosis. It may help clinicians to decide when to opt for testis-sparing surgery.

Evaluation of interim PET response criteria in paediatric Hodgkin's lymphoma--results for dedicated assessment criteria in a blinded dual-centre read.

BACKGROUND: The aim of this study was to evaluate the use and reliability of the new positron emission tomography (PET)-based response criteria for interim positron emission tomography (iPET) in patients with paediatric Hodgkin's lymphoma (pHL). Particular emphasis was put on interobserver variability and on identification of a visual cut-off defining patients with very low risk for relapse. PATIENTS AND METHODS: The iPET scans of 39 pHL patients were evaluated in two independent centres by two PET-experienced specialists in nuclear medicine (blinded read, centre consensus) each. The iPET scans were interpreted using a 5-point scale and were compared with the outcome. Cohen's kappa-test (κ) was used to analyse the interobserver agreement. RESULTS: Concordant ratings were assessed in 19 patients with iPET-negative findings, in 11 patients with iPET-positive findings and in 2 patients with inconclusive ratings. A 'substantial agreement' between attended centres was achieved (κ = 0.748). All patients suffering relapse were concordantly identified, taking mediastinal blood pool structures (MBPS) as visual cut-off between PET-positive and PET-negative findings, respectively. All pHL patients with uptake lower than or equal to MBPS remained in complete remission. CONCLUSION(S): The iPET interpretation assured low interobserver variability. High sensitivity for identification of pHL patients suffering relapse is achieved if [18F]-fluorodeoxyglucose uptake above the MBPS value is rated as a PET-positive finding.

Autologous purified peripheral blood SCT in childhood low-risk relapsed ALL.

The treatment of childhood B-cell-precursor ALL after isolated-extramedullary or late relapse is controversial. Most approaches are based on chemotherapy or allogeneic transplantation. The aim of this report is to assess the long-term outcome of children with 'low-risk' relapsed ALL treated according to a prospective purified auto-transplantation protocol. From January 1997 to March 2004, at a single pediatric Center, 30 ALL consecutive children, lacking an HLA-identical sibling, were treated according to the autologous purified peripheral blood stem cell protocol after isolated-extramedullary (7) or late medullary (24) relapse. After the 'DIAVE' mobilizing regimen a median of 11.6 × 10(6)CD34+/Kg (range 3.9-27.4) were collected. Leukaphereses were depleted by 99% of CD19+cells (range 98-100) by means of a double step immunological purification. The conditioning regimen included TBI. No early severe complications nor transplant-related deaths occurred; late effects, as expected, mostly consisted in endocrinological issues and were assessed at a median follow-up of 8.5 years. Five-year-EFS and survival were 68.5% (s.e. 7.9) and 85.7% (s.e. 5.9), respectively, for the 35 eligible patients and 70.0% (s.e. 8.4) and 86.7% (s.e. 6.2) for the 30 patients actually transplanted as per protocol. The outcome of this series favorably compares with historical data regarding both autologous transplantation and standard salvage chemotherapy.