Publications by authors named "Ronald R De Krijger"

Background: The 5-year prognosis of non-high-risk neuroblastomas is generally good (>90%). However, a proportion of patients show progression and succumb to their disease. We aimed to identify molecular aberrations (not incorporated in the current risk stratification) associated with overall survival (OS) and/or event-free survival (EFS) in patients diagnosed with non-high-risk neuroblastoma.

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Background: With many rare tumour types, acquiring the correct diagnosis is a challenging but crucial process in paediatric oncology. Historically, this is done based on histology and morphology of the disease. However, advances in genome wide profiling techniques such as RNA sequencing now allow the development of molecular classification tools.

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Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic 'fetal' and WNT-high 'embryonal', displaying divergent WNT signaling patterns.

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Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are the most hereditary tumors known. PPGLs were considered benign, but the fourth edition of the World Health Organisation (WHO) classification redefined all PPGLs as malignant neoplasms with variable metastatic potential. The metastatic rate differs based on histopathology, genetic background, size, and location of the tumor.

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Purpose: Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors.

Methods: We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014.

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Acute lymphoblastic leukemia (ALL) survivors are at risk for developing subsequent neoplasms, but there is limited information on long-term risks and risk factors for both subsequent malignant neoplasms (SMNs) and subsequent non-malignant neoplasms (SNMNs). We analyzed long-term risk and risk factors for SMNs and SNMNs among 3291 5-year ALL survivors from the Dutch Childhood Cancer Survivor Study-LATER cohort (1963-2014). We calculated standardized incidence ratios (SIRs) and cumulative incidences and used multivariable Cox proportional hazard regression analyses for analyzing risk factors.

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Objectives: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) discourages invasive procedures to determine the histology of paediatric renal neoplasms at diagnosis. Therefore, the histological subtype of Wilms' tumours (WT) is unknown at the start of neoadjuvant chemotherapy. MR-DWI shows potential value as a non-invasive biomarker through apparent diffusion coefficients (ADCs).

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Article Synopsis
  • Congenital mesoblastic nephroma is the most common solid kidney tumor in newborns, and MRI is the preferred method for diagnosis, especially in differentiating it from Wilms tumor.
  • This study involved a review of MRI scans from 52 confirmed cases of congenital mesoblastic nephroma, categorizing them into classic, cellular, and mixed types, with a focus on their distinct MRI characteristics.
  • Key findings revealed that the classic type was more homogeneous and smaller, while cellular and mixed types were larger and more heterogeneous, with specific MRI signaling patterns noted across all cases.
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Objective: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.

Methods: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements.

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Article Synopsis
  • - The text discusses
  • extrarenal rhabdoid tumors (ERT)
  • , which are aggressive cancers that often do not respond well to chemotherapy, mainly affecting children but can rarely appear in older individuals, as shown by a case of a
  • 16-year-old
  • diagnosed with a primary liver ERT following flu-like symptoms after COVID vaccination.
  • - This particular case revealed a
  • loss of INI-1 protein
  • expression and highlighted findings from reviewing
  • 53 pediatric and 6 adult cases
  • , focusing on the histological features, treatments, and outcomes associated with these tumors.
  • - The key takeaway emphasizes the challenges of diagnosing liver ERT due to the lack of specific symptoms, leading to delays that can decrease survival rates; thus
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Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations.

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Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time.

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Purpose: Sentinel lymph node (SLN) biopsy is rarely used for thyroid carcinoma staging. This is due to challenges associated with conventional Tc-99m-labeled tracers, often producing a large hotspot at the injection site, potentially hiding nearby SLNs (shine-through effect). The aim of this study was to demonstrate the feasibility and effectiveness of SLN visualization using the new PET tracer [Ga]Ga-tilmanocept.

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Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare aggressive ovarian malignancy mainly affecting children, adolescents, and young adults. Since the discovery of mutations in the SMARCA4 gene in 2014, SCCOHT has become the subject of extensive investigation. However, international uniform treatment guidelines for SCCOHT are lacking and the outcome remains poor.

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Background: The most common thymic tumours, thymomas, are derived from thymic epithelium and are generally low-grade neoplasm. Frankly malignant tumours, thymic carcinomas are rarer still. Exceedingly rare thymic tumours contain a mesenchymal tissue component such as fibrous connective tissue and/or mature fat.

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Article Synopsis
  • Histopathological assessment of Wilms tumors (WT) is essential for determining treatment plans, but variations among pathologists can lead to misdiagnosis.
  • Researchers tested a deep learning AI system to improve the accuracy and consistency of identifying tumor components in WT using images from 72 patients.
  • The AI demonstrated strong performance, achieving a Dice coefficient of 0.85 overall and 0.79 for tumor-related components, indicating it can reliably assist in classifying WT.
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Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches.

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Article Synopsis
  • Adrenal cortical carcinoma (ACC) is a rare type of cancer with varying outcomes, and the Weiss score helps in diagnosing and predicting its prognosis through specific histologic criteria.
  • A study analyzed 79 cases of ACC to determine the impact of Weiss parameters on patient survival, utilizing methods like principal component analysis and multivariate regression.
  • Results indicated that necrosis is the most significant predictor of overall and disease-free survival among Weiss criteria, leading to shorter survival and recurrence times.
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Article Synopsis
  • - Pediatric renal cell carcinoma (RCC) is a rare form of cancer, and MRI is the best imaging method for assessing these tumors, though studies on MRI features have been limited.
  • - In a case series of six patients, most were around 12 years old, with various RCC subtypes identified; tumors generally had a hypo-intense appearance on T2-weighted MRI and well-defined margins.
  • - The study highlights that while distinguishing between RCC subtypes and other renal tumors using MRI is challenging, T2-weighted hypo-intensity may serve as a unique feature for RCC.
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Objective: To review somatic genetic changes in nephrogenic rests (NR), which are considered to be precursor lesions of Wilms tumors (WT).

Methods: This systematic review is written according to the PRISMA statement. PubMed and EMBASE were systematically searched for articles in the English language studying somatic genetic changes in NR between 1990 and 2022.

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Heterozygous germline pathogenic variants (GPVs) in , the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing of in recent years has revealed putative GPVs affecting in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants in Median age at diagnosis was 5 years (range 2 months-26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland.

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Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children's Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels.

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iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content.

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