The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk ...individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited.
We ...conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.
Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval CI, 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.
Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).
The interplay and longitudinal associations between positive and negative illness-related experiences in childhood cancer survivors and their families remain unclear. Therefore, benefit finding, ...cancer-related worries, depressive symptoms, and life satisfaction were prospectively investigated in childhood cancer survivors and parents. Directionality of effects and interactions between benefit finding and cancer-related worries in predicting general well-being were examined.
Childhood cancer survivors (n = 125 at T1; aged 14-25), mothers (n = 133 at T1), and fathers (n = 91 at T1) completed two annual questionnaires on benefit finding, cancer-related worries, depressive symptoms, and life satisfaction. Cross-lagged panel analyses including benefit finding, cancer-related worries, their interaction, and depressive symptoms or life satisfaction were conducted in survivors, mothers, and fathers.
Relatively high stability coefficients were found for all study variables. In survivors, cancer-related worries predicted relative increases in depressive symptoms and benefit finding over time. Benefit finding predicted relative increases in life satisfaction over time and buffered negative effects of cancer-related worries on life satisfaction. In mothers and fathers, positive correlated change at T2 (the correlation between residuals at T2) indicated that relative change in benefit finding over time was positively related to relative change in cancer-related worries.
Benefit finding was related both to positive well-being and negative illness experiences, which calls for more research to unravel the different functions of benefit finding over time. Clinicians should be encouraged to attend to positive illness experiences along with more negative ones to obtain a more nuanced view on the illness experiences of survivors and their families.
Long-term sequelae are well-known in childhood brain tumor survivors, but motor functioning remains poorly described. This cross-sectional study aimed to assess objective motor functioning, ...patient-specific risk factors, and parental perceptions. Fifty-two childhood brain tumor patients (pilocytic astrocytoma, medulloblastoma, and other types) who were at least 6 months out of treatment were evaluated. Mean age at testing was 11.7 years. Objective motor functioning was assessed with the Movement Assessment Battery for Children (MABC-2-NL) and/or Bruininks-Oseretsky test of motor proficiency (BOT-2). Functional walking capacity was assessed with the 6-min walk test (6MWT). Parent-reported motor functioning was addressed using the ABILHAND-Kids, ABILOCO-Kids questionnaires, and a standardized anamnesis. Patients showed impaired motor functioning in all domains (
p
< 0.001). Regarding risk factors, younger age at diagnosis (< 5 year) was significantly associated with lower scores on body coordination (
p
= 0.006). Adjuvant treatment resulted in lower scores for fine manual control of the BOT-2 (
p
= 0.024) and balance of MABC-2-NL (
p
= 0.036). Finally, questionnaires revealed an underestimation of motor problems as perceived by the parents. In conclusion, many children who are in follow-up for a brain tumor show impaired motor functioning on multiple aspects, with younger age at diagnosis and adjuvant treatment as specific risk factors. Based on the questionnaires and anamnesis, motor problems appear to be underestimated by the parents.
Conclusion
: These findings point to the need for timely prospective screening of motor functioning. Based on a screening assessment, adequate rehabilitation programs can be applied in childhood brain tumor survivors, aiming to reduce the adverse impact on their daily lives, both for functional activities and cardiovascular fitness.
What is Known:
•
A pediatric brain tumor and its treatment are associated with potential long-term motor sequelae.
•
Test assessments could enable us to objectify motor functioning of these patients.
What is New:
•
Pediatric brain tumors survivors show lower motor performance compared to the norm, which is often underestimated by parents.
•
Younger age at diagnosis and adjuvant treatment could be specific risk factors.
Abstract Neurocognitive sequelae are known to be induced by cranial radiotherapy and central-nervous-system-directed chemotherapy in childhood Acute Lymphoblastic Leukemia (ALL) and brain tumor ...patients. However, less evidence exists for solid non-CNS-tumor patients. To get a better understanding of the potential neurotoxic mechanisms of non-CNS-directed chemotherapy during childhood, we performed a comprehensive literature review of this topic. Here, we provide an overview of preclinical and clinical studies investigating neurotoxicity associated with chemotherapy in the treatment of pediatric solid non-CNS tumors. Research to date suggests that chemotherapy has deleterious biological and psychological effects, with animal studies demonstrating histological evidence for neurotoxic effects of specific agents and human studies demonstrating acute neurotoxicity. Although the existing literature suggests potential neurotoxicity throughout neurodevelopment, research into the long-term neurocognitive sequelae in survivors of non-CNS cancers remains limited. Therefore, we stress the critical need for neurodevelopmental focused research in children who are treated for solid non-CNS tumors, since they are at risk for potential neurocognitive impairment.
Abstract
Spi-1 Proto-Oncogene (SPI1)
fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that
SPI1
...fusions in combination with activating
NRAS
mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the
NRAS
mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within
Transcription factor 7
(
TCF7)-SPI1
or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the
TCF7-SPI1
fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of
SPI1
targets. Together, our results reveal an example where
TCF7-SPI1
leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.
Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum ...activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients.
Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation.
Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours 13%; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 27%; apparent volume of distribution 1150 L 34%; and apparent clearance 15.4 L/h 24% (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day).
Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.
Medulloblastoma is a malign posterior fossa brain tumor, mostly occurring in childhood. The CNS-directed chemoradiotherapy treatment can be very harmful to the developing brain and functional ...outcomes of these patients. However, what the underlying neurotoxic mechanisms are remain inconclusive. Hence, this review summarizes the existing literature on the association between advanced neuroimaging and neurocognitive changes in patients that were treated for pediatric medulloblastoma. The PubMed/Medline database was extensively screened for studies investigating the link between cognitive outcomes and multimodal magnetic resonance (MR) imaging in childhood medulloblastoma survivors. A behavioral meta-analysis was performed on the available IQ scores. A total of 649 studies were screened, of which 22 studies were included. Based on this literature review, we conclude medulloblastoma patients to be at risk for white matter volume loss, more frequent white matter lesions, and changes in white matter microstructure. Such microstructural alterations were associated with lower IQ, which reached the clinical cut-off in survivors across studies. Using functional MR scans, changes in activity were observed in cerebellar areas, associated with working memory and processing speed. Finally, cerebral microbleeds were encountered more often, but these were not associated with cognitive outcomes. Regarding intervention studies, computerized cognitive training was associated with changes in prefrontal and cerebellar activation and physical training might result in microstructural and cortical alterations. Hence, to better define the neural targets for interventions in pediatric medulloblastoma patients, this review suggests working towards neuroimaging-based predictions of cognitive outcomes. To reach this goal, large multimodal prospective imaging studies are highly recommended.
Long-term follow-up (LTFU) care for childhood, adolescent, and young adult (CAYA) cancer survivors is essential to preserve health and quality of life (QoL). Evidence-based guidelines are needed to ...inform optimal surveillance strategies, but many topics are yet to be addressed by the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG). Therefore, the PanCareFollowUp Recommendations Working Group collaborated with stakeholders to develop European harmonised recommendations in anticipation of evidence-based IGHG guidelines.
The PanCareFollowUp Recommendations Working Group, consisting of 23 late effects specialists, researchers, and survivor representatives from nine countries, collaborated in the first Europe-wide effort to provide unified recommendations in anticipation of evidence-based guidelines. A pragmatic methodology was used to define recommendations for topics where no evidence-based IGHG recommendations exist. The objective was to describe the surveillance requirements for high-quality care while balancing the different infrastructures and resources across European health care systems. The process included two face-to-face meetings and an external consultation round involving 18 experts from 14 countries.
Twenty-five harmonised recommendations for LTFU care were developed collaboratively and address topics requiring awareness only (n = 6), awareness, history and/or physical examination (n = 9), or additional surveillance tests (n = 10).
The PanCareFollowUp Recommendations, representing a unique agreement across European stakeholders, emphasise awareness among survivors and health care providers in addition to tailored clinical evaluation and/or surveillance tests. They include existing IGHG guidelines and additional recommendations developed by a pragmatic methodology and will be used in the Horizon 2020–funded PanCareFollowUp project to improve health and QoL of CAYA cancer survivors.
•Long-term follow-up care is important for survivors of childhood cancer.•Evidence-based guidelines to direct care are essential, but lacking for many topics.•We developed harmonised surveillance recommendations to bridge the gap.•Survivor representatives were involved in the formulation of recommendations.
With the increase of survival rates of pediatric cancer patients, the number of children facing potential cognitive sequelae has grown. Previous adult studies suggest that white matter (WM) ...microstructural changes may contribute to cognitive impairment. This study aims to investigate WM microstructure in childhood bone and soft tissue sarcoma. Differences in (micro‐)structure can be investigated using diffusion MRI (dMRI). The typically used diffusion tensor model (DTI) assumes Gaussian diffusion, and lacks information about fiber populations. In this study, we compare WM structure of childhood bone and soft tissue sarcoma survivors (n = 34) and matched controls (n = 34), combining typical and advanced voxel‐based models (DTI and NODDI model, respectively), as well as recently developed fixel‐based models (for estimations of intra‐voxel differences, apparent fiber density AFD and fiber cross‐section FC). Parameters with significant findings were compared between treatments, and correlated with subscales of the WAIS‐IV intelligence test, age at diagnosis, age at assessment and time since diagnosis. We encountered extensive regions showing lower fractional anisotropy, overlapping with both significant NODDI parameters and fixel‐based parameters. In contrast to these diffuse differences, the fixel‐based measure of AFD was reduced in the cingulum and corpus callosum only. Furthermore, AFD of the corpus callosum was significantly predicted by chemotherapy treatment and correlated positively with time since diagnosis, visual puzzles and similarities task scores. This study suggests altered WM structure of childhood bone and soft tissue sarcoma survivors. We conclude global chemotherapy‐related changes, with particular vulnerability of centrally located WM bundles. Finally, such differences could potentially recover after treatment.
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