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J Med Genet ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494577


INTRODUCTION: Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. MATERIALS AND METHODS: Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. RESULTS: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564). CONCLUSIONS: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Oncologist ; 24(9): e921-e929, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30850560


BACKGROUND: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce. PATIENTS AND METHODS: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed. RESULTS: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA-fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n = 4; posterior fossa ependymoma not further classifiable, n = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n = 1; PF-EPN-A, n = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively. CONCLUSION: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified. IMPLICATIONS FOR PRACTICE: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA-fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients.

Hum Mutat ; 40(5): 649-655, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30740824


Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

Leuk Lymphoma ; : 1-9, 2018 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-29966458


Anthracyclines are integral components of antileukemic treatment. Apart from cardiotoxicity, myelosuppression and infectious complications have been described for doxorubicin (DOX) and daunorubicin (DNR) as predominant side effects, but little is known about their differential toxicities. To address the question whether DNR is associated with a lower rate of infectious complications compared with DOX, 307 children with newly diagnosed acute lymphoblastic leukemia, enrolled in trial CoALL 08-09, were randomized to receive either DOX 30 mg/m2 (n = 153) or DNR 36 mg/m2 (n = 154) in delayed intensification. Hematologic toxicities and stomatitis were less frequent in the DNR group resulting in a significantly lower rate of infections in the DNR arm (27% vs. 59%, p < .0001). Survival was equal in both arms (95% SE 2%) (p = .55), with an insignificant difference in the relapse rate (RR 0.12 (SE = 0.03) in the DOX arm vs. 0.16 (SE = 0.04) in the DNR arm; p = .37; Hazard ratio 1.3; 95% confidence interval 0.7-2.6). In conclusion, DNR given in delayed intensification is associated with a lower incidence of infectious complications without loss of efficacy.

Eur Radiol ; 24(1): 128-35, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23979106


OBJECTIVES: To analyse the development of MRI-guided vacuum-assisted biopsy (VAB) in Switzerland and to compare the procedure with stereotactically guided and ultrasound-guided VAB. METHODS: We performed a retrospective analysis of VABs between 2009 and 2011. A total of 9,113 VABs were performed. Of these, 557 were MRI guided. RESULTS: MRI-guided VAB showed the highest growth rate (97 %) of all three procedures. The technical success rates for MRI-guided, stereotactically guided and ultrasound-guided VAB were 98.4 % (548/557), 99.1 % (5,904/5,960) and 99.6 % (2,585/2,596), respectively. There were no significant differences (P = 0.12) between the MRI-guided and the stereotactically guided procedures. The technical success rate for ultrasound-guided VAB was significantly higher than that for MRI-guided VAB (P < 0.001). There were no complications using MRI-guided VAB requiring open surgery. The malignancy diagnosis rate for MRI-guided VAB was similar to that for stereotactically guided VAB (P = 0.35). CONCLUSION: MRI-guided VAB is a safe and accurate procedure that provides insight into clinical breast findings. KEY POINTS: • Three vacuum-assisted breast biopsy (VAB) procedures were compared. • Technical success rates were high for all three VAB procedures. • Medical complications were relatively low using all three VAB procedures. • The use of MRI-guided vacuum-assisted breast biopsy is growing.

Biópsia por Agulha/métodos , Neoplasias da Mama/patologia , Mama/patologia , Biópsia Guiada por Imagem/métodos , Imagem Tridimensional , Imagem por Ressonância Magnética/métodos , Técnicas Estereotáxicas , Adulto , Idoso , Neoplasias da Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Ultrassonografia , Vácuo
Pediatr Blood Cancer ; 56(5): 859-62, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20848640


Juvenile xanthogranuloma (JXG) is a disorder of disputed origin thought to be related to the dermal/interstitial macrophage. A 5-year-old female presented with an aggressive systemic JXG that developed 5 months after the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL). Examination of the T-cell receptor gamma (TCR-γ) rearrangement in T-ALL blasts, JXG infiltrated lymph node biopsies and micro-dissected JXG histiocytes revealed an identical bi-allelic TCR-γ rearrangement in all samples, thus providing evidence for a clonal relationship between T-ALL and JXG in this case.

Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T gama-delta/genética , Xantogranuloma Juvenil/induzido quimicamente , Xantogranuloma Juvenil/genética , Sequência de Bases , Pré-Escolar , Feminino , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Histiócitos/patologia , Humanos , Sistema Imunitário , Tecido Linfoide/patologia , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações , Xantogranuloma Juvenil/patologia