| 1. |
- Jonkers, Y. M. H., et al.
(författare)
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DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients
- 2007
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 14:3, s. 769-779
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Tidskriftsartikel (refereegranskat)abstract
- The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size 2 cm, Ki67 proliferative index 2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 non-insulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan–Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P0.0004) and tumor-specific death (P0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index 2% were reliable in predicting a poor tumor-free survival in non-insulinoma EPTs (P0.0181, whereas CK19 expression was the most optimal predictor of tumor-specific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in non-insulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.
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| 2. |
- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 3. |
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| 4. |
- da Costa, Cristiana E. T., et al.
(författare)
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No Genomic Aberrations in Langerhans Cell Histiocytosis as Assessed by Diverse Molecular Technologies
- 2009
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 48:3, s. 239-249
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Tidskriftsartikel (refereegranskat)abstract
- The etiology of Langerhans cell histiocytosis (LCH), a disease characterized by uncontrolled proliferation of Langerhans cells, is unknown. Although some believe that LCH is reactive, others support a neoplastic origin. We tested the hypothesis that LCH is neoplastic by investigating potential consistent chromosomal aberrations in LCH cells. We used multiparameter DNA flow cytometry to analyze the DNA ploidy LCH cells in 20 cases, performed karyotype analysis in 31 cases, array-based comparative genomic hybridization (arrayCGH) and single nucleotide polymorphism (SNP) arrays with DNA from flow-sorted CD1a-positive and CD1a-negative cells in 19 cases. Ploidy analysis revealed diploid DNA content in all cases. The karyotype of all patients analyzed was normal, excluding the presence of balanced translocations. ArrayCGH and SNP arrays did not show genome abnormalities. Despite positive TP53 protein immunohistochemical staining, sequencing of exon 5 to 8 of p53 gene showed no alterations in 7 cases. This study strongly suggests that gross chromosomal abnormalities do not cause LCH. Although we cannot exclude cryptic point mutations in as yet unidentified genes, this study of 72 LCH cases shows that LCH may be the result of restricted oligoclonal stimulation rather than unlimited neoplastic proliferation. (c) 2008 Wiley-Liss, Inc.
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| 5. |
- Taïeb, David, et al.
(författare)
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Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants : an international expert Consensus statement
- 2024
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Ingår i: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 20:3, s. 168-184
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Forskningsöversikt (refereegranskat)abstract
- 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. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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| 6. |
- van der Kamp, Ananda, et al.
(författare)
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Artificial Intelligence in Pediatric Pathology: The Extinction of a Medical Profession or the Key to a Bright Future?
- 2022
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Ingår i: Pediatric and Developmental Pathology. - : SAGE PUBLICATIONS INC. - 1093-5266 .- 1615-5742. ; 25:4, s. 380-387
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Forskningsöversikt (refereegranskat)abstract
- Artificial Intelligence (AI) has become of increasing interest over the past decade. While digital image analysis (DIA) is already being used in radiology, it is still in its infancy in pathology. One of the reasons is that large-scale digitization of glass slides has only recently become available. With the advent of digital slide scanners, that digitize glass slides into whole slide images, many labs are now in a transition phase towards digital pathology. However, only few departments worldwide are currently fully digital. Digital pathology provides the ability to annotate large datasets and train computers to develop and validate robust algorithms, similar to radiology. In this opinionated overview, we will give a brief introduction into AI in pathology, discuss the potential positive and negative implications and speculate about the future role of AI in the field of pediatric pathology.
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| 7. |
- van der Kamp, Ananda, et al.
(författare)
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Automated Deep Learning-Based Classification of Wilms Tumor Histopathology
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Wilms tumor (WT) is the most frequent pediatric tumor in children and shows highly variable histology, leading to variation in classification. Artificial intelligence-based automatic recognition holds the promise that this may be done in a more consistent way than human observers can. We have therefore studied digital microscopic slides, stained with standard hematoxylin and eosin, of 72 WT patients and used a deep learning (DL) system for the recognition of 15 different normal and tumor components. We show that such DL system can do this task with high accuracy, as exemplified by a Dice score of 0.85 for the 15 components. This approach may allow future automated WT classification.(1) Background: Histopathological assessment of Wilms tumors (WT) is crucial for risk group classification to guide postoperative stratification in chemotherapy pre-treated WT cases. However, due to the heterogeneous nature of the tumor, significant interobserver variation between pathologists in WT diagnosis has been observed, potentially leading to misclassification and suboptimal treatment. We investigated whether artificial intelligence (AI) can contribute to accurate and reproducible histopathological assessment of WT through recognition of individual histopathological tumor components. (2) Methods: We assessed the performance of a deep learning-based AI system in quantifying WT components in hematoxylin and eosin-stained slides by calculating the Sorensen-Dice coefficient for fifteen predefined renal tissue components, including six tumor-related components. We trained the AI system using multiclass annotations from 72 whole-slide images of patients diagnosed with WT. (3) Results: The overall Dice coefficient for all fifteen tissue components was 0.85 and for the six tumor-related components was 0.79. Tumor segmentation worked best to reliably identify necrosis (Dice coefficient 0.98) and blastema (Dice coefficient 0.82). (4) Conclusions: Accurate histopathological classification of WT may be feasible using a digital pathology-based AI system in a national cohort of WT patients.
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| 8. |
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| 9. |
- Hettmer, Simone, et al.
(författare)
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Genetic testing and surveillance in infantile myofibromatosis : a report from the SIOPE Host Genome Working Group
- 2021
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Ingår i: Familial Cancer. - : Springer. - 1389-9600 .- 1573-7292. ; 20 SI:4, s. 327-336
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Tidskriftsartikel (refereegranskat)abstract
- Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked toPDGFRBgermline variants. SomaticPDGFRBvariants were also detected in solitary and multifocal IM lesions.PDGFRBvariants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRBgermline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.
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| 10. |
- van der Beek, Justine N., et al.
(författare)
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MRI Characteristics of Pediatric Renal Tumors : A SIOP-RTSG Radiology Panel Delphi Study
- 2022
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Ingår i: Journal of Magnetic Resonance Imaging. - : Wiley. - 1053-1807 .- 1522-2586. ; 55:2, s. 543-552
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Tidskriftsartikel (refereegranskat)abstract
- Background: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. Purpose: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. Study Type: Consensus process using a Delphi method. Population: Not applicable. Field Strength/Sequence: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. Assessment: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. Statistical Tests: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. Results: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. Data Conclusion: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. Level of Evidence: 3. Technical Efficacy Stage: 3.
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