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  • 1
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    The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women
    SAGE Publications ; 2009
    In:  Antiviral Therapy Vol. 14, No. 3 ( 2009-04), p. 443-450
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 14, No. 3 ( 2009-04), p. 443-450
    Abstract: Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting. Methods A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 ±2), the third trimester (week 33 ±2) and post-partum (weeks 4–6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1. Results A total of 37 women were included in the analysis. Mean (±sd) values for saquinavir area under the curve (AUC 0–12h ) were 23.47 h•mg/l (11.92) at week 20 ( n=16), 23.65 h•mg/l (9.07) at week 33 ( n=31) and 25.00 h•mg/l (11.81) post-partum ( n=9). There was no significant difference in the saquinavir AUC 0–12h when comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as 〈 0.10 mg/l) were not observed throughout the study. No major safety concerns were noted. Conclusions Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.1177/135965350901400301
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2009
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  • 2
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    Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’
    Elsevier BV ; 2022
    In:  European Journal of Cancer Vol. 175 ( 2022-11), p. 311-325
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 175 ( 2022-11), p. 311-325
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2022.09.001
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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    detail.hit.zdb_id: 1468190-0
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  • 3
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    Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm
    American Medical Association (AMA) ; 2023
    In:  JAMA Network Open Vol. 6, No. 2 ( 2023-02-03), p. e2254157-
    Details
    In: JAMA Network Open, American Medical Association (AMA), Vol. 6, No. 2 ( 2023-02-03), p. e2254157-
    Abstract: To improve diagnostics of cancer predisposition syndromes (CPSs) in children with cancer, it is essential to evaluate the effect of CPS gene sequencing among all children with cancer and compare it with genetic testing based on clinical selection. However, a reliable comparison is difficult because recent reports on a phenotype-first approach in large, unselected childhood cancer cohorts are lacking. Objective To describe a national children’s cancer center’s experience in diagnosing CPSs before introducing routine next-generation sequencing. Design, Setting, and Participants This retrospective cohort study was conducted at the National Retinoblastoma Treatment Center (Amsterdam, the Netherlands) and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) and included Dutch pediatric patients with a new diagnosis of neoplasm between June 1, 2018, and December 31, 2019. Follow-up was at least 18 months after neoplasm diagnosis. Data analysis was conducted from July 2021 to February 2022. Exposures As part of routine diagnostics, pediatric oncologists and ophthalmologists checked for characteristics of CPSs and selected children for referral to clinical geneticists and genetic testing. Main Outcomes and Measures Detected cancer predisposition syndromes. Results A total of 824 patients (median [range] age at diagnosis 7.5 [0-18.9] years; 361 girls [44%]) were assessed, including 335 children with a hematological neoplasm (41%) and 489 (59%) with a solid tumor. In 71 of 824 children (8.6%), a CPS was identified, of which most (96%) were identified by a phenotype-driven approach. Down syndrome and neurofibromatosis type 1 were the most common CPSs diagnosed. In 42 of 71 patients (59%), a CPS was identified after these children developed a neoplasm. The specific type of neoplasm was the most frequent indicator for genetic testing, whereas family history played a minor role. Conclusions and Relevance In this cohort study of children with a neoplasm, the prevalence of CPSs identified by a phenotype-driven approach was 8.6%. The diagnostic approach for identifying CPSs is currently shifting toward a genotype-first approach. Future studies are needed to determine the diagnostic value, as well as possible disadvantages of CPS gene sequencing among all children with cancer compared with the phenotype-driven approach.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    URL: Article
    DOI: 10.1001/jamanetworkopen.2022.54157
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 4
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    Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Precision Oncology , No. 6 ( 2022-05)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-05)
    Abstract: Gene fusions play a significant role in cancer etiology, making their detection crucial for accurate diagnosis, prognosis, and determining therapeutic targets. Current diagnostic methods largely focus on either targeted or low-resolution genome-wide techniques, which may be unable to capture rare events or both fusion partners. We investigate if RNA sequencing can overcome current limitations with traditional diagnostic techniques to identify gene fusion events. METHODS We first performed RNA sequencing on a validation cohort of 24 samples with a known gene fusion event, after which a prospective pan-pediatric cancer cohort (n = 244) was tested by RNA sequencing in parallel to existing diagnostic procedures. This cohort included hematologic malignancies, tumors of the CNS, solid tumors, and suspected neoplastic samples. All samples were processed in the routine diagnostic workflow and analyzed for gene fusions using standard-of-care methods and RNA sequencing. RESULTS We identified a clinically relevant gene fusion in 83 of 244 cases in the prospective cohort. Sixty fusions were detected by both routine diagnostic techniques and RNA sequencing, and one fusion was detected only in routine diagnostics, but an additional 24 fusions were detected solely by RNA sequencing. RNA sequencing, therefore, increased the diagnostic yield by 38%-39%. In addition, RNA sequencing identified both gene partners involved in the gene fusion, in contrast to most routine techniques. For two patients, the newly identified fusion by RNA sequencing resulted in treatment with targeted agents. CONCLUSION We show that RNA sequencing is sufficiently robust for gene fusion detection in routine diagnostics of childhood cancers and can make a difference in treatment decisions.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00504
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 5
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    EPID-18. TRENDS IN INCIDENCE AND SURVIVAL OF MALIGNANT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN THE NETHERLANDS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii322-iii322
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii322-iii322
    Abstract: Variation in survival of pediatric central nervous system (CNS) tumors is large between countries. Within Europe, the Netherlands had one of the worst reported survival rates of malignant CNS (mCNS) tumors during 2000–2007. METHODS Using the Netherlands Cancer Registry, we evaluated trends in incidence and survival of pediatric mCNS tumors (behavior /3, 5th digit in the morphology code) diagnosed between 1990–2017. RESULTS 839 newly-diagnosed mCNS tumor patients & lt;18 years were registered between 1990–2017. Incidence of mCNS tumors remained stable (average incidence rate, 21.6 per million person-years). However, an increased incidence of malignant gliomas, NOS was found (Estimated Annual Percentage Change (EAPC) 11.6% p & lt;0.001). This appears to be related to a registration shift between 1990–1999 and 2000–2009 as brainstem tumors increased (+25%, n=79) for astrocytomas and other gliomas but decreased (-31%, n=32) for unspecified intracranial and intraspinal neoplasms. Overall, 5-year observed survival (5Y-OS) of mCNS tumors increased from 51% in 1990–1999 to 61% in 2010–2017 (P-for-trend & lt;0.001). This increase was not constant over time, as 5Y-OS for the period 2000–2009 was 47%. The only significant decrease in survival was found for malignant astrocytomas and other gliomas with a 5Y-OS of 56% in 1990–1999 decreasing to 48% in 2010–2017 (P-for-trend & lt;0.001). CONCLUSION Between 1990–2017 incidence of mCNS tumors in the Netherlands remained stable and survival increased. However, a decrease in survival was seen for malignant astrocytomas and other gliomas, which is partially explained by the registration shift of brainstem tumors. The impact of this shift on survival for all mCNS tumors is subject to further research.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.204
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    EPID-01. Differences in first-line treatment but comparable survival outcomes for pediatric brainstem and non-brainstem high-grade gliomas in the Netherlands – a population-based study
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i46-i46
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i46-i46
    Abstract: INTRODUCTION: Pediatric high-grade gliomas (pHGG) are among the most devastating childhood cancers. Due to their limited treatment options and tumor biology, brainstem (BS) pHGG are considered to have worse survival outcomes compared to non-brainstem (NBS) pHGG. METHODS: Detailed clinical data were gathered by trained registrars for all children diagnosed with a pHGG (including radiologically diagnosed brainstem tumors) in the Netherlands for the period 2003-2017. Tumors were grouped into BS and NBS tumors according to the ICD-O-3 topography codes. Differences in treatment characteristics were tested with the Chi-squared, Fisher exact or Mann-Whitney-Wilcoxon test. Median survival time was determined by Kaplan-Meier method. Trends and survival differences were tested with Cox Proportional-Hazards Models. RESULTS: In total, 276 pHGG patients (BS n=166, NBS n=110) were diagnosed during 2003-2017. Differences in first line treatment were found for neurosurgery (25% of BS versus 95% of NBS patients, p & lt;0.001) and systemic therapy (20% of BS versus 70% of NBS, p & lt;0.001). Notable, 10% of BS patients received temozolomide compared to 55% of NBS patients (p & lt;0.001). No significant difference was found for first-line radiotherapy. However, total cumulative dose and number of fractions differed significantly (BS: median 44.8 Gy and 16 fractions; NBS: median 57.4 Gy and 30 fractions, both p & lt;0.001), reflecting hypofractionation regimens in BS pHGG. Survival remained stable over time for both BS (p=0.9) and NBS (p=0.3). Median survival time was comparable between BS (9.7 months) and NBS patients (9.8 months, p=0.6).CONCLUSION: Despite differences in treatment characteristics we found comparable survival outcomes for BS and NBS pHGG. It remains unclear why survival for both BS and NBS pHGG in this retrospective population-based study is substantially inferior to published data. If the underlying reasons can be found in differences in treatment characteristics, data type (hospital-based versus population-based) or incompleteness of non-microscopically verified cases, is subject to further research.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.169
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    THER-02. Pediatric brain tumor cultures reveal differential susceptibility to four oncolytic viruses
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i186-i186
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i186-i186
    Abstract: INTRODUCTION: New therapeutic modalities such as Oncolytic viruses (OVs) are considered possible treatment options for pediatric brain tumors (PBTs) either as monotherapy or as adjuvants to immunotherapies. OVs specifically lyse tumor cells and can induce anti-tumor immune responses. Here, we evaluate the oncolytic potency of different clinically relevant OVs against various PBT entities. METHODS: The effect of four different OVs, Reovirus (R124), Newcastle Disease virus (NDV), Adenovirus (DNX-2401) and Herpes simplex virus-1 (rQNestin 34.5v.1), was assessed on patient-derived cell cultures belonging to four different PBT entities. Cell viability 5 days after virus treatment of diffuse midline gliomas (DMG n=6), atypical teratoid rhabdoid tumors (n=4), glioblastomas (n=1) and ependymomas (n=2) was measured using Cell Titer Glo assay to demonstrate the cytotoxic potency of each virus. RESULTS: Our screenings revealed that DNX-2401, rQNestin and NDV could infect and kill the majority of cell cultures (12 out of 13, 11 out of 13 and 11 out of 13, respectively). rQNestin34.5v.1 required lower amounts of infectious particles per cell (MedianEC50: 0.65±2.7) compared to NDV (3.5±1.7) and DNX-2401 (7.5±14.5), with DMGs being more sensitive for rQNestin34.5v.1 than non-DMGs. R124 was effective in only 6 out of 13 cultures, with DMGs being more resistant with EC50 & gt; 100 (5 out of 6) compared to non-DMG cell lines with EC50 & lt; 8 (5 out of 7). CONCLUSION: All cell lines revealed differential susceptibility to the 4 different OVs with at least one effective OV per cell line. Further analysis of transcriptome and methylome data might uncover genes and pathways which correlate with specific OV susceptibility and provide biomarkers for response prediction. Further investigation is ongoing to interpret how differential susceptibility affects OV-induced anti-tumor immunity.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.696
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 8
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    Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology
    Wiley ; 2020
    In:  Clinical Pharmacology & Therapeutics Vol. 108, No. 3 ( 2020-09), p. 494-505
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 108, No. 3 ( 2020-09), p. 494-505
    Abstract: In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (C min ) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure–efficacy relationship from adults to children and propose target C min values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Article
    DOI: 10.1002/cpt.1808
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2040184-X
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  • 9
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    LGG-15. SINGLE-NUCLEUS AND BULK RNA SEQUENCING OF PEDIATRIC PILOCYTIC ASTROCYTOMAS REVEALS CNS LOCATION-ASSOCIATED TUMOR CELL AND MICROENVIRONMENTAL HETEROGENEITY
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i58-i59
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i58-i59
    Abstract: Pilocytic astrocytomas are the most common pediatric central nervous system (CNS) tumors. While the overall survival is generally favorable, a substantial part of the patients relapse, resulting in long-term complications. Additionally, pilocytic astrocytomas show limited genetic heterogeneity and are often driven by a single molecular event. The role of the tumor microenvironment (TME) in disease progression is yet unknown. Here, we aimed to delineate the composition of the tumor in pilocytic astrocytomas originating from different CNS locations. METHODS We collected 112 tumor samples, out of which a subset (n = 10) was used for single-nucleus RNA-sequencing (10X Genomics). These tumor samples originated from various CNS locations: posterior fossa (n = 64), supratentorial (n = 38) and spinal (n = 10). Clinical characteristics, DNA methylation profiles, whole exome/genome sequencing and bulk RNA sequencing data were available for most of these samples. RESULTS Single-nucleus RNA-sequencing revealed substantial heterogeneity amongst both tumor and TME cells, which mainly associated with tumor location. While a large proportion of tumor cells expressed gene signatures related to oligodendrocyte precursor cells (OLIG1/2, PDGFRA), a subset of tumor cells was characterized by high expression of astrocyte genes (AQP4, GFAP). Moreover, we defined multiple populations of lymphocytes and myeloid cells, with the latter constituting the vast majority of non-neoplastic cells. Deconvolution of the bulk RNA sequencing data showed heterogeneous involvement of the TME. Additionally, the relative abundances of TME cells varied considerably across CNS locations. We are currently correlating the relative proportions of tumor and TME cell populations with clinicopathological data. CONCLUSION Single-nucleus RNA-sequencing demonstrated transcriptional differences in both tumor cell states and TME cell populations, which associated with CNS location. Future research should elucidate the importance of the cellular composition of the tumor in pilocytic astrocytomas.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.225
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 10
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    IMMU-05. Integrative transcriptomic analysis of pilocytic astrocytomas reveals CNS region-associated characteristics
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i81-i82
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i81-i82
    Abstract: BACKGROUND: Recent insights highlight how the initiation and growth of gliomas is governed by interactions between glioma stem-like cells and stromal and immune cells in the tumor microenvironment. For pilocytic astrocytomas, the most common pediatric CNS tumor, this relationship is so far less explored. To this end, we used transcriptomic methods to investigate inter-patient heterogeneity, and the stromal and immune microenvironment of pilocytic astrocytomas. MATERIALS AND METHODS: In this study, we collected clinical data and tissue of 90 pre-treatment pilocytic astrocytomas from different CNS compartments: posterior fossa (n=57), supratentorial (n=23), and spinal (n=10). The median age at primary resection was 8 (0-16) years, and 66% (n=59) of our cohort was male. From 10 of these patients, we collected post-treatment samples after re-growth of the tumor as well. We characterized all samples by bulk RNA-sequencing and DNA methylation profiling, and selected a subset (n=10) samples for single-nucleus RNA-sequencing. RESULTS: Principal component analysis and unsupervised clustering of bulk sequencing data revealed gene expression patterns correlating to the CNS location of the tumor, consistent with prior reports. Using differential expression and functional pathway analysis, we found CNS region-associated enrichment of cell-cycle, developmental, and inflammatory-related pathways. With respect to the glioma immune microenvironment, supratentorial tumors were enriched in gene-sets related to T-cell activation and cytotoxicity, while spinal tumors had lowest expression of immune-related genes. Moreover, spinal tumors were enriched in pathways related to cell division, nucleotide synthesis, and neurodevelopment. To resolve cell-type expression programs of glioma and immune cells in the microenvironment, we collected and analyzed snRNA-seq data of 10 pilocytic astrocytomas, as well as harmonized our findings with a pre-existing dataset from Vladoiu, 2019. CONCLUSION: Our integrative transcriptomic analysis of pilocytic astrocytomas highlights CNS region-associated differences in expression programs of the glioma cells and in the immune cell composition of the tumor microenvironment.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.298
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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