Publications by authors named "Anne Uyttebroeck"

102 Publications

Upregulation of miR181a/miR212 Improves Myogenic Commitment in Murine Fusion-Negative Rhabdomyosarcoma.

Front Physiol 2021 6;12:701354. Epub 2021 Aug 6.

Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium.

Fusion-negative rhabdomyosarcoma (FN-RMS) is the most common soft tissue sarcoma of childhood arising from undifferentiated skeletal muscle cells from uncertain origin. Currently used therapies are poorly tumor-specific and fail to tackle the molecular machinery underlying the tumorigenicity and uncontrolled proliferation of FN-RMS. We and other groups recently found that microRNAs (miRNA) network contributes to myogenic epigenetic memory and can influence pluripotent stem cell commitments. Here, we used the previously identified promyogenic miRNAs and tailored it to the murine FN-RMS. Subsequently, we addressed the effects of miRNAs by performing syngeneic transplant of pre-treated FN-RMS cell line in C57Bl/6 mice. miRNA pre-treatment affects murine FN-RMS cell proliferation as showed by bioluminescence imaging analysis, resulting in better muscle performances as highlighted by treadmill exhaustion tests. In conclusion, in our study we identified a novel miRNA combination tackling the anti-myogenic features of FN-RMS by reducing proliferation and described novel antitumorigenic therapeutic targets that can be further explored for future pre-clinical applications.
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http://dx.doi.org/10.3389/fphys.2021.701354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378536PMC
August 2021

European PanCareFollowUp Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer.

Eur J Cancer 2021 Sep 29;154:316-328. Epub 2021 Jul 29.

Princess Máxima Centre for Paediatric Oncology, Heidelberglaan 25, Utrecht, 3584 CS, the Netherlands.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.ejca.2021.06.004DOI Listing
September 2021

Identity formation in adolescent and emerging adult cancer survivors: a differentiated perspective and associations with psychosocial functioning.

Psychol Health 2021 Jul 26:1-18. Epub 2021 Jul 26.

Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium.

Objective: Identity formation was investigated in adolescent and emerging adult cancer survivors from a (neo-)Eriksonian perspective by comparing survivors to control participants. In survivors, associations between identity and clinical/demographical variables and general and illness-specific functioning were investigated.

Design: Childhood cancer survivors ( = 125; : 19.54; 47% male) were matched on age and gender with healthy controls (2:1).

Main Outcome Measures: All participants completed identity questionnaires. Survivors reported on demographics, well-being (depressive symptoms, life satisfaction, physical functioning), and illness-specific experiences (PTSS, illness centrality, cancer self-identity, benefit finding, cancer-related worries). Medical records provided clinical information.

Results: Survivors did not differ from controls on identity synthesis or confusion or on the identity statuses resulting from cluster analysis on the identity dimensions (achievement, foreclosure, moratorium, diffusion). Identity synthesis related to better well-being and illness experiences, whereas confusion related to worse well-being and illness experiences. Youth in moratorium and diffusion reported lower well-being and more negative illness experiences. Associations between identity and demographical and clinical characteristics were inconsistent.

Conclusions: This study revealed no significant differences in identity formation between cancer survivors and controls. However, survivors who struggle in their identity quest should be identified as they are at risk for poorer well-being and negative illness experiences.
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http://dx.doi.org/10.1080/08870446.2021.1955116DOI Listing
July 2021

Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia.

Nat Commun 2021 07 6;12(1):4164. Epub 2021 Jul 6.

Children's Cancer Institute, UNSW Sydney, Lowy Cancer Research Centre, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1038/s41467-021-24442-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260768PMC
July 2021

The European multistakeholder PanCareFollowUp project: novel, person-centred survivorship care to improve care quality, effectiveness, cost-effectiveness and accessibility for cancer survivors and caregivers.

Eur J Cancer 2021 Aug 18;153:74-85. Epub 2021 Jun 18.

Princess Máxima Centre for Paediatric Oncology, Heidelberglaan 25, Utrecht, 3584 CS, the Netherlands.

Background: The majority of childhood cancer survivors are at risk of treatment-related adverse health outcomes. Survivorship care to mitigate these late effects is endorsed, but it is not available for many adult survivors of childhood cancer in Europe. The PanCareFollowUp project was initiated to improve their health and quality of life (QoL) by facilitating person-centred survivorship care.

Methods: The PanCareFollowUp consortium was established in 2018, consisting of 14 project partners from ten European countries, including survivor representatives. The consortium will develop two PanCareFollowUp Interventions, including a person-centred guideline-based model of care (Care Intervention) and eHealth lifestyle coaching (Lifestyle Intervention). Their development will be informed by several qualitative studies and systematic reviews on barriers and facilitators for implementation and needs and preferences of healthcare providers (HCPs) and survivors. Implementation of the PanCareFollowUp Care Intervention as usual care will be evaluated prospectively among 800 survivors from Belgium, Czech Republic, Italy and Sweden for survivor empowerment, detection of adverse health conditions, satisfaction among survivors and HCPs, cost-effectiveness and feasibility. The feasibility of the PanCareFollowUp Lifestyle Intervention will be evaluated in the Netherlands among 60 survivors.

Results: Replication manuals, allowing for replication of the PanCareFollowUp Care and Lifestyle Intervention, will be published and made freely available after the project. Moreover, results of the corresponding studies are expected within the next five years.

Conclusions: The PanCareFollowUp project is a novel European collaboration aiming to improve the health and QoL of all survivors across Europe by developing and prospectively evaluating the person-centred PanCareFollowUp Care and Lifestyle Interventions.
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http://dx.doi.org/10.1016/j.ejca.2021.05.030DOI Listing
August 2021

Brain network hubs and cognitive performance of survivors of childhood infratentorial tumors.

Radiother Oncol 2021 08 5;161:118-125. Epub 2021 Jun 5.

Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Belgium.

Background: Childhood infratentorial tumor patients frequently suffer from long-term cognitive deficits. As each constituent of their treatment can lead to neurotoxicity, cascade effects can lead to profound reorganization of the underlying brain network, the so-called 'connectome'. However, to date, few studies have assessed the relationship between brain network topology, the functional role of network hubs (i.e. highly connected regions), and neurocognitive outcomes in adult survivors of childhood infratentorial tumors.

Methods: In this cross-sectional study, childhood infratentorial tumor survivors (n = 21: pilocytic astrocytoma (n = 8), ependymoma (n = 1) and medulloblastoma (n = 12)) and healthy controls (n = 21) were recruited. Using multishell diffusion-weighted MRI, microstructural organization and topology of supratentorial white matter was investigated; using a voxel-based approach, a fixel-based analysis, and a graph theoretical approach. In addition, neurocognitive subscales of the WAIS-IV intelligence test, and their relationship with nodal strength and network efficiency metrics were assessed.

Results: Similar to earlier studies, we observed widespread decreases in fractional anisotropy (FA) in patients compared to controls, based on voxel-based analyses. In addition, the fixel-based analyses dissociated macro- from microstructural changes, which were encountered in in infratentorial versus supratentorial brain areas, respectively. Finally, regional reorganization (i.e. differences in local efficiency) occurred mainly in hubs, which suggests a specific vulnerability of these areas. These hubs were not only mostly affected, but also most strongly correlated with the intelligence subscales.

Conclusion: This study suggests that network hubs are functionally important for intellectual outcomes in infratentorial tumor survivors. Furthermore, these regions could be the primary targets of treatment toxicity. Validation of this specific hypothesis in larger samples is required.
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http://dx.doi.org/10.1016/j.radonc.2021.05.028DOI Listing
August 2021

Methylene tetrahydrofolate reductase A1298C polymorphisms influence the adult sequelae of chemotherapy in childhood-leukemia survivors.

PLoS One 2021 30;16(4):e0250228. Epub 2021 Apr 30.

Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium.

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087097PMC
April 2021

Age- and Intravenous Methotrexate-Associated Leukoencephalopathy and Its Neurological Impact in Pediatric Patients with Lymphoblastic Leukemia.

Cancers (Basel) 2021 Apr 16;13(8). Epub 2021 Apr 16.

Department of Pediatric Oncology, KU Leuven, 3000 Leuven, Belgium.

Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population are still inconclusive. FLAIR-MRI scans were acquired at the end of treatment in children who were treated for ALL/LBL, which were quantitatively analyzed for LE. Voxels were assigned to the lesion segmentation if indicated by two raters. Logistic and linear regression models were used to test whether lesion presence and size were predicted by risk factors such as age at diagnosis, gender, intrathecal (IT-) or intravenous (IV-)MTX dose, CNS invasion, and acute neurological events. Patients with a pre-existing neurological condition or low-quality MR scan were excluded from the analyses. Of the 129 patients, ten (8%) suffered from CNS invasion. Chemotherapy-associated neurological events were observed in 13 patients (10%) during therapy, and 68 patients (53%) showed LE post-treatment. LE was more frequent in cases of lower age and higher cumulative IV-MTX doses, while the extent of LE and neurological symptoms were associated only with IV-MTX doses. Neurological events were not significantly associated with LE, even though symptomatic patients demonstrated a higher ratio of LE ( = 9/13) than asymptomatic patients ( = 59/116). This study suggests leukoencephalopathy frequently occurs in both symptomatic and asymptomatic leukemia patients. Younger children and patients treated with higher cumulative IV-MTX doses might need more regular screening for early detection and follow-up of associated sequelae.
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http://dx.doi.org/10.3390/cancers13081939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073318PMC
April 2021

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Department of Pediatric Hematology, Oncology and BMT, University Hospital Muenster, 48149 Münster, Germany.

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.
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http://dx.doi.org/10.3390/cancers13092075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123268PMC
April 2021

Primary post-transplant lymphoproliferative disorder of the central nervous system: characteristics, management and outcome in 25 paediatric patients.

Br J Haematol 2021 Jun 25;193(6):1178-1184. Epub 2021 Mar 25.

Department of Pediatric Hematology and Oncology, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.

Primary central nervous system (CNS) post-transplant lymphoproliferative disorder (PTLD) in childhood is rare. Twenty-five patients were retrieved from nine European Intergroup for Childhood Non-Hodgkin's Lymphoma and/or international Berlin-Frankfurt-Münster Study Group members. Types of allografts included kidney (n = 11), liver (n = 4), heart (n = 5), bowel (n = 1) and haematopoietic stem cells (n = 4). Eighteen were male, 16 ≥ 10 years old, 21 had monomorphic disease and 24 solid intracranial tumour masses. Four-year event-free and overall survival rates were 50% ± 10% and 74% ± 9% respectively. This report represents the largest paediatric series of CNS PTLD reported to date, showing favourable survival odds following systemic and intrathecal chemotherapy and rituximab administration.
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http://dx.doi.org/10.1111/bjh.17398DOI Listing
June 2021

Burkitt lymphoma in children causing an osteolytic lesion in the mandible: A case report.

Clin Case Rep 2021 Feb 25;9(2):938-943. Epub 2020 Dec 25.

Department of Imaging and Pathology Faculty of Medicine OMFS-IMPATH Research Group Catholic University Leuven Leuven Belgium.

Imaging is the first step in diagnosing a persistent swelling of the jaw. A lymphoma in the jaw typically manifests as a poorly defined osteolytic lesion. A biopsy is mandatory and will result in definite diagnosis.
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http://dx.doi.org/10.1002/ccr3.3703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869388PMC
February 2021

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

Ther Drug Monit 2021 08;43(4):512-518

Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1097/FTD.0000000000000877DOI Listing
August 2021

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

Pediatr Blood Cancer 2021 04 3;68(4):e28903. Epub 2021 Feb 3.

Department of Radiation Oncology, University Hospital Vienna, Vienna, Austria.

Background: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.

Patients, Materials, And Methods: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment.

Results: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient.

Conclusions: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.
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http://dx.doi.org/10.1002/pbc.28903DOI Listing
April 2021

Neuroimaging Biomarkers and Neurocognitive Outcomes in Pediatric Medulloblastoma Patients: a Systematic Review.

Cerebellum 2021 Jun 8;20(3):462-480. Epub 2021 Jan 8.

Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1007/s12311-020-01225-4DOI Listing
June 2021

Scoring system for clinically significant CMV infection in seropositive recipients following allogenic hematopoietic cell transplant: an SFGM-TC study.

Bone Marrow Transplant 2021 06 18;56(6):1305-1315. Epub 2020 Dec 18.

Department of Hematology, Univ. Lille, CHU Lille, F-59000, Lille, France.

In order to identify cytomegalovirus (CMV)-seropositive patients who are at risk of developing CMV infection following first allogeneic hematopoietic cell transplantation (allo-HCT), we built up a scoring system based on patient/donor characteristics and transplantation modalities. To this end, 3690 consecutive patients were chronologically divided into a derivation cohort (2010-2012, n = 2180) and a validation cohort (2013-2014, n = 1490). Haploidentical donors were excluded. The incidence of first clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) at 1, 3, and 6 months in the derivation cohort was 13.8%, 38.5%, and 39.6%, respectively. CMV-seropositive donor, unrelated donor (HLA matched 10/10 or HLA mismatched 9/10), myeloablative conditioning, total body irradiation, antithymocyte globulin, and mycophenolate mofetil significantly and independently affected the incidence of 3-month infection. These six factors were selected to build up the prognostic model. Four risk groups were defined: low, intermediate-low, intermediate-high, and high-risk categories, with a 3-month predicted incidence of first clinically significant CMV infection in the derivation cohort of 22.2%, 31.1%, 45.4%, and 56.9%, respectively. This score represents a framework for the evaluation of patients who are at risk of developing clinically significant CMV infection following allo-HCT. Prospective studies using this score may be of benefit in assessing the value of anti-CMV prophylaxis in well-defined patient cohorts.
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http://dx.doi.org/10.1038/s41409-020-01178-6DOI Listing
June 2021

Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach.

Pediatr Res 2021 05 17;89(7):1695-1705. Epub 2020 Oct 17.

Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.

Background: Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers.

Methods: Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis.

Results: Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast.

Conclusion: Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML.

Impact: Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
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http://dx.doi.org/10.1038/s41390-020-01199-3DOI Listing
May 2021

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively ( < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
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http://dx.doi.org/10.3390/cancers12102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598675PMC
September 2020

Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Pediatr Blood Cancer 2020 12 23;67(12):e28702. Epub 2020 Sep 23.

Department of Malignant Haematology, Great Ormond Street Hospital for Children NHS Trust, London, UK.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.
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http://dx.doi.org/10.1002/pbc.28702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537044PMC
December 2020

The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia.

Clin Cancer Res 2020 11 21;26(21):5747-5758. Epub 2020 Aug 21.

Center for Human Genetics, KU Leuven, Leuven, Belgium.

Purpose: KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL.

Experimental Design: First, we searched for the most synergistic combination of KPT-8602 with dexamethasone, vincristine, or doxorubicin in both B-ALL and T-ALL cell lines using proliferation and apoptosis as a readout. Next, we validated this synergistic effect by treatment of clinically relevant B- and T-ALL patient-derived xenograft models . Finally, we performed RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the mechanism of synergy.

Results: KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as in three patient-derived ALL xenografts. Compared with single-drug treatment, the drug combination caused increased apoptosis and led to histone depletion. Mechanistically, integration of ChIP-seq and RNA-seq data revealed that addition of KPT-8602 to dexamethasone enhanced the activity of the glucocorticoid receptor (NR3C1) and led to increased inhibition of E2F-mediated transcription. We observed strong inhibition of E2F target genes related to cell cycle, DNA replication, and transcriptional regulation.

Conclusions: Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1315DOI Listing
November 2020

Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia.

Blood 2021 02;137(6):801-811

Center for Human Genetics, KU Leuven, Leuven, Belgium.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia that is most frequent in children and is characterized by the presence of few chromosomal rearrangements and 10 to 20 somatic mutations in protein-coding regions at diagnosis. The majority of T-ALL cases harbor activating mutations in NOTCH1 together with mutations in genes implicated in kinase signaling, transcriptional regulation, or protein translation. To obtain more insight in the level of clonal heterogeneity at diagnosis and during treatment, we used single-cell targeted DNA sequencing with the Tapestri platform. We designed a custom ALL panel and obtained accurate single-nucleotide variant and small insertion-deletion mutation calling for 305 amplicons covering 110 genes in about 4400 cells per sample and time point. A total of 108 188 cells were analyzed for 25 samples of 8 T-ALL patients. We typically observed a major clone at diagnosis (>35% of the cells) accompanied by several minor clones of which some were less than 1% of the total number of cells. Four patients had >2 NOTCH1 mutations, some of which present in minor clones, indicating a strong pressure to acquire NOTCH1 mutations in developing T-ALL cells. By analyzing longitudinal samples, we detected the presence and clonal nature of residual leukemic cells and clones with a minor presence at diagnosis that evolved to clinically relevant major clones at later disease stages. Therefore, single-cell DNA amplicon sequencing is a sensitive assay to detect clonal architecture and evolution in T-ALL.
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http://dx.doi.org/10.1182/blood.2020006996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885827PMC
February 2021

Pediatric randomized trial EORTC CLG 58951: Outcome for adolescent population with acute lymphoblastic leukemia.

Hematol Oncol 2020 Dec 5;38(5):763-772. Epub 2020 Sep 5.

Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, Claude Bernard Lyon I University, Lyon, France.

Over the years, the prognosis of adolescents treated for acute lymphoblastic leukemia (ALL) has improved. However, this age group still represents a challenge with an overall survival (OS) of 60% compared to 85% in younger children. Herein, we report the outcome of adolescents treated in the European Organisation for Research and Treatment of Cancer (EORTC) 58951 clinical trial. EORTC 58951 clinical trial included patients with de novo ALL between 1998 and 2008. For this study, we analyzed data of all adolescents between 15 and under 18. Data from 97 adolescents were analyzed, 70 had B-lineage and 27 had T-lineage ALL. The 8-year event-free survival (EFS) and OS for the B-cell precursor ALL cases were 72.3% (59.4%-81.7%) and 80.8% (67.4%-89.1%), respectively. For the T-lineage, the 8-year EFS and OS were 57.4% (36.1%-74.0%) and 59.0% (36.1%-76.2%), respectively. "B-other" ALL, defined as BCP-ALL lacking any known recurrent genetic abnormalities were more frequent in our adolescent population (52.8%) than in younger children (27.1%). Outcome of adolescents in the EORTC 58951 study is supporting the findings that adolescents have better outcome in pediatric compared to adults' trials. Nevertheless, in pediatric studies, adolescents still have a worse prognosis than younger children. Despite the fact that specific unfavorable characteristics may be linked to the adolescent population, a careful study and characterization of adolescents "B-other" genetic abnormalities in ALL is critical to improve the outcome of this population.
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http://dx.doi.org/10.1002/hon.2791DOI Listing
December 2020

Prevalence of leukoencephalopathy and its potential cognitive sequelae in cancer patients.

J Chemother 2020 Nov 17;32(7):327-343. Epub 2020 Aug 17.

Department of Oncology, KU Leuven, Leuven, Belgium.

Due to the rising use of chemotherapy treatment in cancer patients and growing survival rates, therapy-induced neurotoxic side effects are increasingly reported. Given the ambiguity about the prevalence and severity of leukoencephalopathy, one of such toxic side effects, in non-central nervous system (CNS) cancer patients, we performed a systematic literature search using the PubMed/Medline database to summarize existing literature regarding leukoencephalopathy epidemiology in non-CNS cancer patients and its potential cognitive sequelae. The search was based on the following terms: ('MRI' OR 'T2-weighted MRI' OR 'FLAIR') AND ('cancer' OR 'tumour' OR 'leukaemia' OR 'neoplasms') AND ('chemotherapy' OR 'radiotherapy') AND ('posterior reversible encephalopathy' OR 'leukoencephalopathy' OR 'cerebral ischaemia' OR 'stroke'). Thirty-two studies discussing the occurrence of leukoencephalopathy in cancer patients were included, of which the majority investigated Acute Lymphoblastic Leukaemia (ALL) patients (n = 22).Regularly scanned ALL patients showed a prevalence of leukoencephalopathy between 17 - 87%, and 15 - 83% of patients presented with leukoencephalopathy when only scanned after a CNS event. When diagnosed with posterior reversible encephalopathy syndrome, 100% of patients showed leukoencephalopathy because its diagnosis is based in part on observable lesions. An increased prevalence was observed in ALL patients treated with higher doses of methotrexate (5 g/m MTX, 42 - 87%) when compared to lower doses (< 5 g/m, 32 - 67%). By contrast, in breast cancer patients, white matter lesions were mainly detected in case of neurological symptoms, but not (yet) clearly associated with chemotherapy administration. However, chemotherapy treatment was associated with more infratentorial microbleeds in breast cancer patients . Up to 50% of other (neurologically asymptomatic) solid tumour patients presented white matter lesions, even years after treatment. When cognitive data were investigated, lesioned patients showed lower scores on neurocognitive tests in 50% of studies, years after ending therapy.In conclusion, leukoencephalopathy is well-documented for ALL patients (with a focus on methotrexate), but there is a lack of knowledge for other intravenous chemotherapeutics, other oncological populations, wider age ranges and possible risk factors (e.g. history of CNS event). Furthermore, the long-term neuropsychological impact and potential risk for neurodegenerative processes due to leukoencephalopathy remains inconclusive. Hence, large international databanks, epidemiological and prospective case-control studies are necessary to stratify risk groups for CNS-related side effects.
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http://dx.doi.org/10.1080/1120009X.2020.1805239DOI Listing
November 2020

Stem Cell Transplantation and Vinblastine Monotherapy for Relapsed Pediatric Anaplastic Large Cell Lymphoma: Results of the International, Prospective ALCL-Relapse Trial.

J Clin Oncol 2020 12 30;38(34):3999-4009. Epub 2020 Jul 30.

Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Germany.

Purpose: To analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408) stratified patients according to the time of relapse and CD3 expression to prospectively test reinduction approaches combined with consolidation by allogeneic or autologous hematopoietic stem cell transplantation (SCT) and vinblastine monotherapy.

Patients And Methods: Patients with progression during frontline therapy (very high risk) or a CD3-positive relapse (high risk) were scheduled for allogeneic SCT after reinduction chemotherapy. Patients with a CD3-negative relapse within 1 year after initial diagnosis or prior exposure to vinblastine (intermediate risk) received autologous SCT after carmustine-etoposide-cytarabine-melphalan. This arm was terminated prematurely, and subsequent patients received vinblastine monotherapy instead. Patients with a CD3-negative relapse > 1 year after initial diagnosis (low risk) received vinblastine monotherapy.

Results: One hundred sixteen patients met the inclusion criteria; 105 evaluable patients with CNS-negative disease had a 5-year event-free survival (EFS) of 53% ± 5% and a 5-year overall survival (OS) of 78% ± 4%. Before termination of autologous SCT, EFS rates of patients in the very-high- (n = 17), high- (n = 26), intermediate- (n = 32), and low- (n = 21) risk groups were 41% ± 12%, 62% ± 10%, 44% ± 9%, and 81% ± 9%; the respective OS rates were 59% ± 12%, 73% ± 9%, 78% ± 7%, and 90% ± 6%. Analyzing only the patients in the intermediate-risk group consolidated per protocol by autologous SCT, EFS and OS of 23 patients were 30% ± 10% and 78% ± 9%, respectively. All 5 patients with intermediate risk receiving vinblastine monotherapy after the amendment experienced relapse again.

Conclusion: Shorter time to relapse was the strongest predictor of subsequent relapse. Allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse. For early relapsed ALCL autologous SCT was not effective. Vinblastine monotherapy achieved cure in patients with late relapse; however, it was not effective for early relapses.
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http://dx.doi.org/10.1200/JCO.20.00157DOI Listing
December 2020

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

N Engl J Med 2020 06;382(23):2207-2219

From the Departments of Pediatric and Adolescent Oncology (V.M.-C., C.P.) and Clinical Research (G.V.), INSERM Unité 1015 (V.M.-C.), and the Unit of Biostatistics and Epidemiology and INSERM Unité 1018 (A.A.), Gustave Roussy, Université Paris-Saclay, Villejuif, France; the Department of Pediatric Hematology and Oncology, University of Padua, Padua, Italy (M.P.); the Department of Paediatric Haematology, Oncology, and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge (G.A.A.B.), Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham (K.W.), and the Department of Histopathology, Royal Marsden NHS Foundation Trust, London (A.W.) - all in the United Kingdom; the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (D.A.B.); the Department of Pediatric Hematology and Oncology, University of Valencia, Valencia, Spain (R.F.D.); the Division of Haematology-Oncology, Hospital for Sick Children, Toronto (S.A.); the Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium (A.U.); the Center for Cancer and Immunology Research, Children's National Health System and George Washington University, Washington, DC (C.M.B.); Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (J.Z.); the Department of Pediatric Hematology and Oncology, Semmelweis University, Budapest, Hungary (M.C.); the Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland (B.K.); the Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong (A.K.C.); the Department of Pathology, University of Utah, Salt Lake City (R.R.M.); Children's Hospital of Philadelphia, Philadelphia (P.C.A.); and the National Cancer Institute, Center for Global Health, Rockville, MD (T.G.G.).

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).
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http://dx.doi.org/10.1056/NEJMoa1915315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720281PMC
June 2020

Rare non-Hodgkin lymphoma of childhood and adolescence: A consensus diagnostic and therapeutic approach to pediatric-type follicular lymphoma, marginal zone lymphoma, and nonanaplastic peripheral T-cell lymphoma.

Pediatr Blood Cancer 2020 08 26;67(8):e28416. Epub 2020 May 26.

Department of Pediatric Hematology and Oncology, The Queen Silvia's Hospital for Children and Adolescents, University of Gothenburg, Gothenburg, Sweden.

Pediatric-type follicular (PTFL), marginal zone (MZL), and peripheral T-cell lymphoma (PTCL) account each for <2% of childhood non-Hodgkin lymphoma. We present clinical and histopathological features of PTFL, MZL, and few subtypes of PTCL and provide treatment recommendations. For localized PTFL and MZL, watchful waiting after complete resection is the therapy of choice. For PTCL, therapy is subtype-dependent and ranges from a block-like anaplastic large cell lymphoma (ALCL)-derived and, alternatively, leukemia-derived therapy in PTCL not otherwise specified and subcutaneous panniculitis-like T-cell lymphoma to a block-like mature B-NHL-derived or, preferentially, ALCL-derived treatment followed by hematopoietic stem cell transplantation in first remission in hepatosplenic and angioimmunoblastic T-cell lymphoma.
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http://dx.doi.org/10.1002/pbc.28416DOI Listing
August 2020

Second malignant neoplasms after treatment of non-Hodgkin's lymphoma-a retrospective multinational study of 189 children and adolescents.

Leukemia 2021 02 11;35(2):534-549. Epub 2020 May 11.

Department of Pediatric Hematology and Oncology, University of Padova, Padova, Italy.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.
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http://dx.doi.org/10.1038/s41375-020-0841-xDOI Listing
February 2021

Cortical thinning and altered functional brain coherence in survivors of childhood sarcoma.

Brain Imaging Behav 2021 Apr;15(2):677-688

Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

High-dose chemotherapy is increasingly evidenced to be neurotoxic and result in long-term neurocognitive sequelae. However, research investigating grey matter alterations in childhood cancer patients remains limited. As childhood sarcoma patients receive high-dose chemotherapy, we aimed to investigate cortical brain alterations in adult survivors. We analyzed high-resolution structural (T1-weighted) MRI and resting-state functional MRI (rsfMRI), to derive structural and functional cortical information in survivors of childhood sarcoma, treated with high-dose intravenous chemotherapy (n = 33). These scans were compared to age- and gender- matched controls (n = 34). Cortical volume and thickness were investigated using voxel-based morphometry and vertex-wise surface-based morphometry. Brain regions showing significant group differences in volume or thickness were implemented as seeds of interest to estimate their resting state co-activity with other areas (i.e. functional coherence). We explored whether structural measures were associated with potential risk factors, such as age at diagnosis, and cumulative doses of chemotherapeutic agents (methotrexate, ifosfamide). Finally, we investigated the link between functional regional strength, neurocognitive assessments and daily life complaints. In patients relative to controls we observed lower grey matter volumes in cerebellar and frontal areas, as well as frontal cortical thinning. Cerebellar volume and orbitofrontal thickness appeared dose- and age-related, respectively. Cortical thickness of the parahippocampal area appeared lower, only if the group comparison was not adjusted for depression. This region specifically showed lower functional coherence, which was associated with lower processing speed. This study suggests cortical thinning as well as decreased functional coherence in survivors of childhood sarcoma, which could be important for both long-term attentional functioning and emotional distress in daily life. Frontal areas might be specifically vulnerable during adolescence.
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http://dx.doi.org/10.1007/s11682-020-00276-9DOI Listing
April 2021

Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma.

Blood 2020 05;135(19):1685-1695

Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non-cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non-cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.
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http://dx.doi.org/10.1182/blood.2019003880DOI Listing
May 2020
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