Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous... Show morePaediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous research has provided evidence that genetic variants in TPMT, NUDT15, UGT1A1 and DPYD are associated with toxicity of anticancer drugs. This led to pharmacogenetic guidelines that are integrated into clinical practice in paediatric oncology. Recently, novel genetic variants have been associated with a higher risk of developing chemotherapy-induced toxicity. In this case series, we selected 21 novel variants and genotyped these in nine patients with excessive chemotherapy-induced toxicity using whole exome sequencing or micro-array data. We observed that six out of nine patients carried at least one variant that, according to recent studies, potentially increased the risk of developing methotrexate- or vincristine-induced toxicity. As patient-derived genetic data are becoming widely accessible in paediatric oncology, these variants could potentially enter clinical practice to mitigate chemotherapy-induced toxicity. Show less
Infantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping... Show moreInfantile fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) are locally aggressive tumors primarily occurring in infants. Both IFS and the cellular subtype of CMN show overlapping morphological features and an ETV6-NTRK3 fusion, suggesting a close relationship. An activating alteration of EGFR, based on an EGFR kinase domain duplication (KDD), occurs in a subset of CMNs lacking an NTRK3 rearrangement, especially in the classic and mixed type. So far no EGFR-KDDs have been detected in IFS.We describe four pediatric tumors at the extremities (leg, n = 2; foot and arm n = 1) with histological features of IFS/CMN. Two cases showed classic IFS morphology while two were similar to classic/mixed type CMN. In all cases, an EGFR-KDD was identified without detection of a fusion gene. There were no abnormalities of the kidneys in any of the patients.This is the first description of IFS with an EGFR-KDD as driver mutation, supporting that IFS and CMN are similar lesions with the same morphological and genetic spectrum. Pathologists should be aware of the more fibrous variant of IFS, similar to classic/mixed type CMN. Molecular analyses are crucial to treat these lesions adequately, especially with regard to the administration of tyrosine kinase inhibitors. Show less
Bank, P.C.D.; Jacobs, L.H.J.; Berg, S.A.A. van den; Deutekom, H.W.M. van; Hamann, D.; Molenkamp, R.; ... ; Oosterhuis, W.P. 2021
The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and... Show moreThe in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantlywewould like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs. Show less
Eijkelenboom, A.; Tops, B.B.J.; Berg, A. van den; Brule, A.J.C. van den; Dinjens, W.N.M.; Dubbink, H.J.; ... ; Ligtenberg, M.J.L. 2019
Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications)... Show moreNext-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology. We briefly discuss two common approaches to detect gene copy number gains from NGS data, i.e., the relative coverage and B-allele frequencies. In addition, we provide recommendations for reporting gene copy gains for clinical purposes. In addition to general QC metrics associated with NGS in routine diagnostics, it is recommended to include clinically relevant quantitative parameters of copy number gains in the clinical report, such as (i) relative coverage and estimated copy numbers in neoplastic cells, (ii) statistical scores to show significance (e.g., z-scores), and (iii) the sensitivity of the assay and restrictions of NGS-based detection of copy number gains. Collectively, this information can guide clinical and analytical decisions such as the reliable detection of high-level gene amplifications and the requirement for additional in situ assays in case of borderline results or limited sensitivity. Show less
