scholarly journals Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?

2006 ◽  
Vol 91 (8) ◽  
pp. 2851-2858 ◽  
Author(s):  
Camilo Jiménez ◽  
Gilbert Cote ◽  
Andrew Arnold ◽  
Robert F. Gagel
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Evidence Synthesis ◽  
Germline Mutations ◽  
Potential Effect ◽  
Hereditary Disease ◽  
Mitochondrial Complex ◽  
Hereditary Syndromes ◽  
Sporadic Pheochromocytoma ◽  
Hereditary Pheochromocytoma

Abstract Context: The recent identification of germline mutations of the mitochondrial complex II genes in variants of paraganglioma/pheochromocytoma syndrome has enlarged the number of known causative genes for hereditary pheochromocytoma. A question confronting clinicians is whether they should screen patients with apparently sporadic pheochromocytomas for unsuspected germline mutations of some or all of the seven genes known to cause hereditary paraganglioma or pheochromocytoma (NF1, VHL, RET, MEN1, SDHD, SDHC, and SDHB). A positive answer was suggested by a report that placed the estimate of hereditary disease in apparently sporadic pheochromocytoma as high as 24%. Evidence Acquisition: We applied clinically useful criteria to a review of the literature, defining cases of apparently sporadic pheochromocytoma as those without a suspicious personal or family history, with a focal, unilateral pheochromocytoma, and presenting at age less than 50 yr. Evidence Synthesis: We reduced the overall estimate of unsuspected hereditary pheochromocytoma patients with apparently sporadic pheochromocytoma to approximately 17%. Mutations in only three genes (VHL, SDHB, and SDHD) accounted for almost this entire minority, and unsuspected RET mutation was rare. Costs, coverage by insurance, the potential effect on insurability, and deficient information for populations outside of referral centers should be considered before recommending genetic testing in patients with apparently sporadic presentations of pheochromocytomas. Conclusion: We recommend genetic testing for patients with an apparently sporadic pheochromocytoma under the age of 20 yr with family history or features suggestive of hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For individuals who do not meet these criteria, genetic testing is optional.

scholarly journals Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?

2009 ◽  
Vol 160 (2) ◽  
pp. 227-231 ◽  
Author(s):  
Pascal Pigny ◽  
Catherine Cardot-Bauters ◽  
Christine Do Cao ◽  
Marie Christine Vantyghem ◽  
Bruno Carnaille ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Screening ◽  
Age Of Onset ◽  
Age At Onset ◽  
Hereditary Disease ◽  
Imaging Features ◽  
Systematic Screening ◽  
Bilateral Pheochromocytoma ◽  
Sporadic Pheochromocytoma ◽  
Hereditary Pheochromocytoma

BackgroundAccording to previous studies, around 15% of patients with an apparently sporadic pheochromocytoma and a negative family history had a hereditary disease. This high frequency together with the financial support provided to reference laboratories of molecular genetics by the French government led to a nearly systematic screening in each patient with a pheochromocytoma.ObjectiveTo check the efficiency of systematic genetic screening in patients with apparently sporadic pheochromocytoma, by analysing the 6 years experience of a multidisciplinary team in this field.MethodsOne hundred patients with a pheochromocytoma-only phenotype and no family history were included. Patients with extra-adrenal tumours were excluded. Prevalence of hereditary forms was determined and analyzed according to age at onset, sex. Cost of the genetic analysis was calculated.ResultsA germline mutation in one of the five susceptibility genes (VHL, RET, SDHD, SDHC, SDHB) was identified in eight patients (8%) with an age of onset between 13 and 57 years. Among them, six had a bilateral pheochromocytoma and only two had a unilateral tumour. If the guidelines for genetic screening were age of onset less than 50 or bilateral pheochromocytoma, no patients with a hereditary tumour would be missed and a 24% cost reduction would be achieved.ConclusionsAccording to these data, a genetic predisposition test for hereditary pheochromocytoma seems not recommended in patients with a unilateral adrenal tumour diagnosed after 50 in the absence of familial, clinical, biological or imaging features for a familial disease.

Germline mutations in Brazilian pancreatic carcinoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16749-e16749
Author(s):  
Livia Munhoz Rodrigues ◽  
Simone Maistro ◽  
Maria Lucia Hirata Katayama ◽  
Luiz A.Senna Leite ◽  
Joao Glasberg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Pancreatic Carcinoma ◽  
Germline Mutations ◽  
Family History Of Cancer ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

Burden of genetic testing in an academic biobank by pathological and family history-based criteria in prostate cancer (PCa).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1576-1576
Author(s):  
James Ding ◽  
Emily Feld ◽  
Anh Le ◽  
Pauleen Sanchez ◽  
Jacquelyn Powers ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Language Processing ◽  
Germline Mutations ◽  
Phenotypic Data ◽  
Genotype Information ◽  
Genetic Testing Guidelines ◽  
Testing Criteria

1576 Background: Approximately 5% of localized PCa and 12% of metastatic PCa are associated with germline mutations in DNA repair genes. The National Comprehensive Cancer Network (NCCN) issued genetic testing guidelines to identify PCa patients (pts) likely to harbor a germline DNA repair mutation. The overall burden of this guideline-based, resource-intensive genetic testing is unknown. Using supervised phenotype-genotype information extraction algorithms, we determined the projected genetic testing burden at a single institution adhering to NCCN PCa genetic testing guidelines. Methods: A PCa cohort of 2127 pts was identified from the Penn Medicine BioBank via ICD 9/10 codes. Phenotypic data were extracted from the Penn Medicine Cancer Registry and electronic health record systems via natural language processing and manual chart review. Pts were classified based on 9 germline genetic testing criteria outlined in the NCCN PCa guidelines (Version 4.2019). Results: 895/2127 pts met at least 1 of the 9 NCCN genetic testing criteria, corresponding to a 42.1% overall genetic testing burden. 35.2% qualified for testing via high-risk localized PCa and 6.4% qualified via metastatic disease. Of the pts with localized PCa (n=2014), 15.1% qualified for genetic testing via high Gleason score, 5.1% via high-risk family history, 3.7% via PSA>20ng/mL, 8.7% via Ashkenazi Jewish descent, and 0.8% via intraductal/ductal histology. Conclusions: In this single-center PCa cohort, germline genetic testing was NCCN-guideline recommended for a larger proportion of pts than would otherwise be expected based on previously published reports. Future studies are needed to validate the sensitivity and specificity of these criteria for identifying germline mutations. Our study also highlights a need for novel methods to improve the efficiency of genetic testing for a large cohort. [Table: see text]

Genetic Testing for Germline Mutations of the APC Gene in Patients With Apparently Sporadic Desmoid Tumors but a Family History of Colorectal Carcinoma

2005 ◽  
Vol 48 (6) ◽  
pp. 1275-1281 ◽  
Author(s):  
Wolfgang M. Brueckl ◽  
Wolfgang G. Ballhausen ◽  
Thomas Förtsch ◽  
Klaus Günther ◽  
Wolfgang Fiedler ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Colorectal Carcinoma ◽  
Germline Mutations ◽  
Apc Gene ◽  
Desmoid Tumors ◽  
History Of

scholarly journals MON-300 AIP Gene Germline Mutations in Non-Selected Patients with Apparently Sporadic Pituitary Macrodenomas

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Malgorzata Trofimiuk-Muldner ◽  
Bartosz Domagała ◽  
Grzegorz Sokolowski ◽  
Anna Skalniak ◽  
Jakub Piatkowski ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Clinical Significance ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Tumor Diameter ◽  
Her Family ◽  
Aip Gene ◽  
Acth Secreting ◽  
Pituitary Macroadenomas

Abstract Up to 5% of all pituitary tumors are hereditary (e.g. due to menin or AIP genes germline mutations). AIP gene mutations are more common in subjects with acromegaly, less than 30 years old at the onset of disease, and with FIPA family history. The study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in non-selected patients with pituitary macroadenomas. Material and methods. The study included subsequent 131 patients (57 males, 74 females; median age 42 years (IQR 25 years) diagnosed with pituitary macroadenomas, and with a negative family history of FIPA or MEN1 syndromes. The following tumors were identified: 11 ACTH-secreting, 49 GH-secreting (including 7 pluri-hormonal ones), 6 gonadotropinomas, 23 prolactinomas, 1 TSH-oma, and 43 non-secreting adenomas. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC. Results. An AIP mutation was identified in five of 131 included subjects (3.8%): one diagnosed with Cushing’s disease, two with acromegaly, and two with non-secreting adenomas. In two patients, the identified mutation usually predisposes to ACTH-secreting adenomas, in two patients - mutations of unknown clinical significance were found (usually connected with pituitary adenomas), and the mutation detected in one patient was described as benign. Patients harboring hereditary AIP gene variations did not differ from the rest of the study group in median age at diagnosis (41 vs. 42.5 years, p=0.8), median largest tumor diameter (25 vs. 24 mm, p=0.6), gender distribution (60% of females vs. 56.3%, p=0.8), secreting tumor frequency (60% vs. 67.5%, p=0.7), or acromegaly diagnosis frequency (40% vs.37.3%, p=0.9). 2 of the 5 patients with identified AIP gene mutations agreed for their families to be offered AIP genetic testing: (1) An AIP mutation was found in the asymptomatic mother of one acromegalic female patient. (2) The AIP mutation of unknown clinical significance was detected in the son of a male acromegalic patient with acromegaly, clinically unscreened yet. Conclusions. In our series of apparently sporadic pituitary macroadenomas, AIP gene mutation carriers did not differ substantially from patients with negative genetic testing. A risk factor-centered approach to AIP genetic screening may result in missing germline mutations, therefore, there is a need to establish if such a situation negatively impacts a patient’s and his/her family outcomes.

Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17523-e17523
Author(s):  
Yu Wei ◽  
Yao Zhu ◽  
Junlong Wu ◽  
Dingwei Ye ◽  
Hao Zeng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Cancer Patients ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
History Of ◽  
Repair Genes

e17523 Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.

Effect of access to germline genetic testing on pancreatic cancer precision treatment across disease stage and ethnicity.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16783-e16783
Author(s):  
Edward D. Esplin ◽  
Rebecca Truty ◽  
Shan Yang ◽  
Sarah M. Nielsen ◽  
Margaret Klint ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
African American ◽  
Genetic Testing ◽  
Family History ◽  
Germline Mutations ◽  
Disease Stage ◽  
Family History Of Cancer ◽  
History Of ◽  
History Of Cancer ◽  
Multigene Panel

e16783 Background: PARP inhibitor (PARPi) treatment was recently approved for pancreatic cancer (PaCa) patients with germline mutations in 2 DNA damage repair (DDR) genes. Despite criteria recommending germline multigene panel testing for all PaCa patients, barriers to testing remain, including among underserved populations, which limit access to precision therapies. We initiated a sponsored testing program that increases access to germline genetic testing for PaCa in two ways: 1) offering a comprehensive multigene panel, and 2) removing the barrier of cost. Here we present initial results from this program, including the diagnostic yield in patients across stages of PaCa and clinical utility of the findings. Methods: We retrospectively analyzed de-identified data from 966 PaCa patients tested on an 84 gene panel as part of the program to date. The only inclusion criterion was a willingness to participate in the sponsored program by the patient and the provider who ordered the testing. Data included likely pathogenic (LP) and pathogenic (P) mutations, disease stage and ethnicity. Results: In total, 166 (17%) patients were positive for P/LP germline mutations in 30 genes. Mutation rate by ethnicity was: Caucasian 17%, African American 12%, Hispanic 16%, Ashkenazi Jewish 20%, Asian 3%. Only 25% of patients with P/LP variants reported a family history of cancer. There was no statistical difference in mutation rates by stage (p = 0.11) [Table]. In positive patients, 83 (78%) had mutations conferring potential eligibility for DDR gene-specific precision therapies or clinical treatment trials. 28 (26%) were potentially eligible for olaparib due to BRCA1/2 mutations, 8 (7%) were potentially eligible for pembrolizumab, and 47 (44%) for PARPi clinical trials. Conclusions: This study found 8.5% of all PaCa patients tested are potentially eligible for germline-based precision therapies and/or clinical treatment trials. Of mutation positive patients, 75% did not report a family history of cancer. The positive rate was not statistically different between patients with stage I and stage IV PaCa, underscoring the recommendation to test all patients with PaCa. This program had a 1.5% increased relative uptake among African American patients compared to a standard insurance reimbursement delivery model. These data suggest reducing barriers improves PaCa patient access to genetic information that enables precision therapy. [Table: see text]

A family with pheochromocytoma-paraganglioma inherited tumour syndrome

2016 ◽  
Vol 55 (01) ◽  
pp. 34-40 ◽  
Author(s):  
P. Zschieschang ◽  
V. Prasad ◽  
D. Moskopp ◽  
B. Knie ◽  
M. Plotkin
Keyword(s):  
Early Detection ◽  
Neck Region ◽  
Hereditary Disease ◽  
Head And Neck Region ◽  
Pet Ct ◽  
Highly Sensitive ◽  
Hereditary Pheochromocytoma ◽  
Genetically Determined ◽  
Mass Lesions ◽  
Pet Ct Scan

SummaryAim: Hereditary pheochromocytoma-paraganglioma syndromes are characterized by multiple pheochromocytomas (PCC) and paragangliomas (PGLs), inherited in an autosomal dominant manner. Early detection and removal of tumours may prevent or minimize complications related to mass effects and malignant transformation. Having confirmed the diagnosis, it is important to localize the tumours and reveal their extent preoperatively. This study aimed to introduce 18F-DOPA PET/CT as a highly sensitive noninvasive diagnostic tool for early detection of mass lesions in patients with pheochromocytoma-paraganglioma inherited tumour syndrome and to report about its impact on patient management. Patients, methods: We are currently supervising one of the largest documented families in Germany with genetically determined SDHD gene mutation. We performed 18F-DOPA PET/CT in order to detect tumours in asymptomatic gene carriers and enable subsequent surgical therapy. Results: In seven patients undergoing 12 18F-DOPA PET/CT scans 17 lesions have been detected. Three of these lesions, located in the head and neck region, have had no morphologic correlate in CT and one had also no morphologic correlate in MRI. Of the six histologically analyzed lesions five have been tumors (PGL or PCC) and one has been a nodular hyperplasia. This means the 18F-DOPA PET/CT scan in our study group had a sensitivity of 83%. 18F-DOPA PET/CT investigations lead to change in the management in 5/7 studied patients (70%). Conclusion: The benefits of PET/ CT in detection of pheochromocytoma and paraganglioma are well documented, but we are the first to use this technique for screening of a rare hereditary disease (estimated prevalence 0.3/100 000).

scholarly journals Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two case reports

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Rei Hirose ◽  
Yuya Tsurutani ◽  
Chiho Sugisawa ◽  
Kosuke Inoue ◽  
Sachiko Suematsu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Succinate Dehydrogenase ◽  
Novel Mutation ◽  
Case Reports ◽  
Site Mutation ◽  
Japanese Family ◽  
Paraganglioma Syndrome ◽  
Succinate Dehydrogenase Subunit B ◽  
Hereditary Pheochromocytoma ◽  
Subunit B

Abstract Background Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. Case presentation A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father’s paraganglioma tissues. In silico analysis predicted the mutation as “disease causing.” She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. Conclusions We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

scholarly journals Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

2021 ◽  
Vol 22 (9) ◽  
pp. 4700
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Giuseppe Ciconte ◽  
Ilaria Rivolta ◽  
Valeria Borrelli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Risk Stratification ◽  
Brugada Syndrome ◽  
Electrophysiological Study ◽  
Functional Characterization ◽  
The Family ◽  
Novel Variant ◽  
History Of ◽  
Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

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