11p15 Epimutations in Pediatric Embryonic Tumors: Insights from a Methylome Analysis.

Embryonic tumors share few recurrent mutations, suggesting that other mechanisms, such as aberrant DNA methylation, play a prominent role in their development. The loss of imprinting (LOI) at the chromosome region 11p15 is the germline alteration behind Beckwith-Wiedemann syndrome that results in an increased risk of developing several embryonic tumors. This study analyzed the methylome, using EPIC Beadchip arrays from 99 sporadic embryonic tumors. Among these tumors, 46.5% and 14.6% presented alterations at imprinted control regions (ICRs) 1 and 2, respectively. Based on the methylation levels of ICR1 and ICR2, four clusters formed with distinct methylation patterns, mostly for medulloblastomas (ICR1 loss of methylation (LOM)), Wilms tumors, and hepatoblastomas (ICR1 gain of methylation (GOM), with or without ICR2 LOM). To validate the results, the methylation status of 29 cases was assessed with MS-MLPA, and a high level of agreement was found between both methodologies: 93% for ICR1 and 79% for ICR2. The MS-MLPA results indicate that 15 (51.7%) had ICR1 GOM and 11 (37.9%) had ICR2 LOM. To further validate our findings, the ICR1 methylation status was characterized via digital PCR (dPCR) in cell-free DNA (cfDNA) extracted from peripheral blood. At diagnosis, we detected alterations in the methylation levels of ICR1 in 62% of the cases, with an agreement of 76% between the tumor tissue (MS-MLPA) and cfDNA methods. Among the disagreements, the dPCR was able to detect ICR1 methylation level changes presented at heterogeneous levels in the tumor tissue, which were detected only in the methylome analysis. This study highlights the prevalence of 11p15 methylation status in sporadic embryonic tumors, with differences relating to methylation levels (gain or loss), location (ICR1 or ICR2), and tumor types (medulloblastomas, Wilms tumors, and hepatoblastomas).

Musashi-1 regulates cell cycle and confers resistance to cisplatin treatment in Group 3/4 medulloblastomas cells.

Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. In this study, we investigated the clinical significance and biological functions of Musashi-1 (MSI1) in Grp3 and Grp4-MBs. First, we assessed the expression profile of MSI1 in 59 primary MB samples (15-WNT, 18-SHH, 9-Grp3, and 17-Grp4 subgroups) by qRT-PCR. MSI1 mRNA expression levels were also validated in an additional public dataset of MBs (GSE85217). The ROC curve was used to validate the diagnostic standards of MSI1 expression. Next, the potential correlated cell-cycle genes were measured by RNA-Seq. Cell cycle, cell viability, and apoptosis were evaluated in a Grp3/Grp4 MB cell line after knockdown of MSI1 and cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non-Grp3/Grp4-MBs. We identified that MSI1 knockdown not only triggered transcriptional changes in the cell-cycle pathway, but also affected G2/M phase in vitro, supporting the role of knockdown of MSI1 in cell-cycle arrest. Finally, MSI1 knockdown decreased cell viability and sensitized D283-Med cells to cisplatin treatment by enhancing cell apoptosis. Based on these findings, we suggest that MSI1 modulates cell-cycle progression and may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.

Somatic Copy Number Alteration in Circulating Tumor DNA for Monitoring of Pediatric Patients with Cancer.

Pediatric tumors share few recurrent mutations and are instead characterized by copy number alterations (CNAs). The cell-free DNA (cfDNA) is a prominent source for the detection of cancer-specific biomarkers in plasma. We profiled CNAs in the tumor tissues for further evaluation of alterations in 1q, MYCN and 17p in the circulating tumor DNA (ctDNA) in the peripheral blood at diagnosis and follow-up using digital PCR. We report that among the different kinds of tumors (neuroblastoma, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, leiomyosarcoma, osteosarcoma and benign teratoma), neuroblastoma presented the greatest amount of cfDNA, in correlation with tumor volume. Considering all tumors, cfDNA levels correlated with tumor stage, metastasis at diagnosis and metastasis developed during therapy. In the tumor tissue, at least one CNA (at CRABP2, TP53, surrogate markers for 1q and 17p, respectively, and MYCN) was observed in 89% of patients. At diagnosis, CNAs levels were concordant between tumor and ctDNA in 56% of the cases, and for the remaining 44%, 91.4% of the CNAs were present only in cfDNA and 8.6% only in the tumor. Within the cfDNA, we observed that 46% and 23% of the patients had MYCN and 1q gain, respectively. The use of specific CNAs as targets for liquid biopsy in pediatric patients with cancer can improve diagnosis and should be considered for monitoring of the disease response.

Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas.

Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.

DNA methylation is a comprehensive marker for pediatric adrenocortical tumors.

Children diagnosed with pediatric adrenocortical tumors (pACT) have variable outcomes, and, to date, the disease lacks robust prognostic biomarkers. The prognostic potential of tumor methylation has been demonstrated in several cancers. We aimed to evaluate the pACT methylation profile and its association with disease presentation and survival. In this cross-sectional study, we accessed the DNA methylation (MethylationEPIC Array, Illumina) of 57 primary pACT from Southeastern Brazil and the respective patients' clinicopathological features. We also applied our analysis in an independent 48 pACT methylation dataset. Unsupervised learning whole-methylome analysis showed two groups with distinct methylation signatures: pACT-1 and pACT-2. Compared to pACT-2, pACT-1 tumors were enriched with higher methylation in CpG islands, mainly in gene promoter regions. The topmost hypermethylated gene in these samples was shown to be underexpressed. Patients in the pACT-1 group were older at diagnosis and were more likely to have carcinomas and nonlocalized/advanced and recurrent/metastatic disease. Univariate and bivariate regressions showed that pACT-1 methylation signature confers superior hazard ratio of disease progression and death than known prognostic features. The methylation groups had similar frequencies of germline mutations in the TP53 gene, including the regionally frequent p.R337H. Our analysis replication validated our findings and reproduced those recently described in pACT. We demonstrated the existence of different tumor methylation signatures associated with pACT presentation and clinical evolution, even in the context of germline TP53 mutations. Our data support tumor methylation profiling as a robust and independent prognostic biomarker for pACT and suggest a list of candidate genes for further validation.

Clinical manifestations of head and neck cancer in pediatric patients, an analysis of 253 cases in a single Brazilian center

Background: Pediatric head and neck cancer (PHNC) is rare and its nonspecific clinical manifestations may often lead to delayed diagnosis. We aimed to describe the signs, symptoms, and clinicopathological characteristics of PHNC. Material and Methods: Medical records were retrospectively reviewed for all PHNC cases diagnosed from 1986 to 2016 affecting patients aged 19-years and younger from a tertiary referral center in Brazil. Demographic variables, anatomical site of primary tumors, histopathological diagnoses, signs and symptoms, and patterns of misdiagnosis were collected and interpreted by statistical and descriptive analysis. Results: A total of 253 PHNC cases were included. The mean age was 9.3 years and male patients were more frequently affected (60.9%). Burkitt lymphoma (23.7%), nasopharyngeal carcinoma (15.8%), and rhabdomyosarcoma (15.4%) were the most common cancer types. The nasopharynx (28.9%), cervical/lymph node region (25.3%), and craniofacial bones (8.3%) were the predominant anatomical sites. Tumor/swelling (68.4%), was the clinical finding often presented. The univariable analysis showed association between tumor histology and clinical variables such as sex (p=0.022), age (p<0.0001), anatomical location (p<0.0001) tumor/swelling (p=0.034), pain (p=0.031), systemic/general manifestations (p=0.004), nasal/breathing alterations (p=0.012), orbital/ocular alterations (p<0.0001). Misdiagnosis such as tonsillitis, otitis, and abscess were frequent. Conclusions: Although the clinical findings of PHNC are often unspecific, this study provided signs and symptoms with significant correlations between tumor histology. The suspicion of malignancy should be considered when the main signs and symptoms reported here appear and persist, in order to conduct a timely diagnosis.(AU)

Vitamin D receptor hypermethylation as a biomarker for pediatric adrenocortical tumors.

Objective: Pediatric adrenocortical tumors (pACT) display complex genomic backgrounds, lacking robust prognostic markers and targeted therapeutic options. Vitamin D3 receptor (VDR) promoter hypermethylation and underexpression were reported in adrenocortical carcinomas from adult patients. In this study, we aimed to investigate VDR expression levels and methylation status in pACT and their clinical and prognostic significance. Design: Retrospective cross-sectional study enrolling pediatric patients with ACT from two tertiary referral institutions. Methods: We evaluated clinicopathological features, VDR mRNA (qPCR) and protein (immunohistochemistry) expression, and VDR-wide methylation of ACT samples from 108 pediatric patients. Fourteen pediatric and 32 fetal and postnatal normal adrenals were used as controls. Results: Unlike in pre- and post-natal normal adrenals, most pACT lacked nuclear VDR expression and had reduced mRNA levels, especially the carcinomas. Unsupervised analysis of VDR methylation data revealed two groups of pACT with distinct disease features and outcomes. Tumors with high VDR methylation presented lower mRNA levels, and the respective patients presented advanced disease and reduced disease-free and overall survival. Conclusions: VDR has a role in normal adrenocortical development and homeostasis, which is impaired during tumorigenesis. VDR hypermethylation and underexpression may be both predictive and prognostic biomarkers for pACT.

Anemia hemolítica autoimune na doença de Castleman multicêntrica: relato de caso / Autoimmune hemolytic anemia in multicentric Castleman's disease: case report

A doença de Castleman é um distúrbio linfoproliferativo raro, podendo se manifestar sob a forma de massas localizadas ou como doença multicêntrica. A doença de Castleman multicêntrica é caracterizada por adenopatias generalizadas, visceromegalias, manifestações autoimunes e infecções recorrentes. Este artigo apresenta o relato de caso de anemia hemolítica autoimune por anticorpos quentes em paciente com doença de Castleman multicêntrica. Resposta eficaz foi obtida com uso de corticoterapia sistêmica e tocilizumabe.

Castleman disease is a rare lymphoproliferative disorder that can manifest as localized masses or as multicentric disease. Multicentric Castleman disease is characterized by generalized adenopathies, visceromegaly, autoimmune manifestations, and recurrent infections. This article presents the case report of a patient with multicentric Castleman's disease and autoimmune hemolytic anemia by warm antibodies. Effective response was obtained with systemic corticotherapy and tocilizumab.

Silver Nimesulide Complex in Bacterial Cellulose Membranes as an Innovative Therapeutic Method for Topical Treatment of Skin Squamous Cell Carcinoma.

Oxidative stress and inflammation act on skin squamous cell carcinoma (SSCC) development and progression. Curative therapy for SSCC patients is mainly based on surgical resection, which can cause various sequelae. Silver ions have in vitro activities over tumor cells, while nimesulide has antioxidant and anti-inflammatory activities. This study aimed to evaluate the effects of a silver(I) complex with nimesulide (AgNMS) incorporated in a sustained release device based on bacterial cellulose membrane, named AgNMS@BCM, on topic SSCC treatment. The antiproliferative effect of AgNMS complex was evaluated in the SCC4, SCC15 and FaDu SCC lines. AgNMS complex activity on exposure of phosphatidylserine (PS) residues and multicaspase activation were evaluated on FaDu cells by flow cytometry. The AgNMS@BCM effects were evaluated in a SSCC model induced by 7,12-dimethylbenzanthracene/12-o-tetradecanoyl-phorbol-13-acetate (DMBA/TPA) in mice. Toxicity and tumor size were evaluated throughout the study. AgNMS complex showed antiproliferative activity in SCC15 and FaDu lines in low to moderate concentrations (67.3 µM and 107.3 µM, respectively), and induced multicaspase activation on FaDu cells. The AgNMS@BCM did not induce toxicity and reduced tumor size up to 100%. Thus, the application of AgNMS@BCM was effective and safe in SSCC treatment in mice, and can be seen as a potential and safe agent for topic treatment of SSCC in humans.

Burkitt lymphoma of the head and neck: An international collaborative study.

BACKGROUND: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with three variants (endemic, sporadic, and immunodeficiency-associated), presenting with specific epidemiological and clinical features. Burkitt lymphoma affects the head and neck region (BLHN) in approximately 10% of cases. The aim of this study was to undertake a comparative analysis of the clinicopathologic and immunohistochemical (IHC) features of BLHN diagnosed in patients from Africa, Guatemala, and Brazil. METHODS: Cases diagnosed as BLHN were collected from the files of six oral pathology laboratory services (Brazil, South Africa, and Guatemala) and one Brazilian pediatric oncology hospital from 1986 to 2020. Clinicopathological and IHC data, and Epstein-Barr virus (EBV) status by in situ hybridization data for each case were reviewed and described. RESULTS: Of the 52 cases, BLHN was predominant in pediatric patients [43 (82.69%)] and males [43 (82.69%)], with a mean age of 11.26 ± 9.68 years (range, 1-39 years). Neck and cervical lymph nodes [14 (26.92%)], and involvement of both maxilla and mandible [8 (15.38%)], were the most common anatomical sites. Clinically, tumor/swelling [40 (31.25%)], cervical lymphadenopathy [14 (10.94%)], pain [12 (9.38%)], and bone destruction [12 (9.38%)] were frequent findings. All cases showed typical morphological characteristics of BL. IHC profiles included positivity for CD20 [52 (100%)], CD10 [38 (79.17%)], Bcl6 [29 (87.88%)], and c-Myc protein [18 (81.82%)]. EBV was positive in 18 cases (62.07%). The Ki-67 index ranged from 90 to 100%. CONCLUSION: The clinicopathological and EBV profile of BLHN in South African, Guatemalan, and Brazilian patients is similar.

Tongue carcinoma as a secondary malignancy in a 17-year-old leukemia survivor: A case report.

Pediatric hematologic malignancies present an elevated survival rate, and these survivors may experience long-term complications, including secondary malignancies. This case describes a 17-year-old female patient previously treated for acute lymphoblastic leukemia (ALL) who developed a squamous cell carcinoma (SCC, T2N0M0) of the lateral border of the tongue diagnosed during dental follow-up 2 years and 9 months after the conclusion of ALL therapy (GBTLILLA99 protocol). The patient underwent exclusive surgical resection for the tongue SCC and is free of disease 11 years after the surgery. The current case report highlights the importance of monitoring the oral health of childhood cancer survivors. As part of a multidisciplinary team, our directives include counseling to avoid carcinogenic exposures.

Clinical, demographic, anatomopathological, and molecular findings in patients with medulloblastoma treated in a single health facility / Achados clínicos, demográficos, anatomopatológicos e moleculares de portadores de meduloblastoma tratados em uma única instituição

ABSTRACT Objective: To describe the clinical, demographic, anatomopathological, molecular, and survival characteristics of patients with medulloblastoma. Methods: Retrospective study based on patient information obtained from the review of medical records. Overall and event-free survival were analyzed using the Kaplan-Meier estimator, and the curves were compared by the log-rank test. Results: Among the patients investigated, 70 were male (66%), and age at diagnosis ranged from 2 months to 22 years. The most frequent signs and symptoms were headache (80.8%) and vomiting (75.8%). Regarding treatment, most patients (63.2%) underwent complete surgical resection, with a predominance of classic histology (63.2%). The 5-year overall survival rate was 67.9%, and the 10-year rate was 64.2%. Patients with molecular profile characteristic of the wingless (WNT) subgroup had a better prognosis, with 5-year overall survival of 75%. Conclusions: The clinical, demographic, anatomopathological, and molecular characteristics of patients with medulloblastoma described in the present study were mostly similar to those reported in the literature. Patients submitted to complete tumor resection had better clinical outcomes than those who underwent incomplete resection/biopsy. Patients classified as high-risk showed worse overall and event-free survival than those in the standard-risk group, and the presence of metastasis at diagnosis was associated with recurrence.

RESUMO Objetivo: Descrever as características clínicas, demográficas, anatomopatológicas, moleculares e de sobrevida de pacientes portadores de meduloblastoma. Métodos: Estudo retrospectivo, no qual as informações dos pacientes foram obtidas pela revisão dos prontuários médicos. Análises de sobrevida global e de sobrevida livre de eventos foram realizadas por meio da construção de curvas de Kaplan-Meier e a comparação entre as curvas foi feita pelo teste log-rank. Resultados: Entre os pacientes analisados, 70 pertenciam ao sexo masculino (66%) e a idade ao diagnóstico variou de dois meses a 22 anos. Os sinais e sintomas de maior frequência foram cefaleia (80,8%) e vômitos (75,8%). Em relação ao tratamento, a maioria (63,2%) dos pacientes foi submetida à ressecção cirúrgica total e apresentava como histologia predominante a forma clássica (63,2%). A taxa de sobrevida global em cinco anos foi de 67,9% e, em 10 anos, de 64,2%. Os pacientes com perfil molecular característico do subgrupo wingless (WNT) apresentaram melhor prognóstico, com sobrevida global em cinco anos de 75%. Conclusões: As características clínicas, demográficas, anatomopatológicas e moleculares dos pacientes com meduloblastoma descritas no presente estudo foram majoritariamente semelhantes às descritas na literatura. Pacientes submetidos à ressecção completa do tumor tiveram melhor evolução clínica do que aqueles com ressecção incompleta/biópsia. Pacientes estratificados como de alto risco apresentaram pior sobrevida global e livre de eventos do que o grupo standard e a presença de metástases ao diagnóstico se mostrou associada à ocorrência de recidiva da doença.

CLINICAL, DEMOGRAPHIC, ANATOMOPATHOLOGICAL, AND MOLECULAR FINDINGS IN PATIENTS WITH MEDULLOBLASTOMA TREATED IN A SINGLE HEALTH FACILITY.

OBJECTIVE: To describe the clinical, demographic, anatomopathological, molecular, and survival characteristics of patients with medulloblastoma. METHODS: Retrospective study based on patient information obtained from the review of medical records. Overall and event-free survival were analyzed using the Kaplan-Meier estimator, and the curves were compared by the log-rank test. RESULTS: Among the patients investigated, 70 were male (66%), and age at diagnosis ranged from 2 months to 22 years. The most frequent signs and symptoms were headache (80.8%) and vomiting (75.8%). Regarding treatment, most patients (63.2%) underwent complete surgical resection, with a predominance of classic histology (63.2%). The 5-year overall survival rate was 67.9%, and the 10-year rate was 64.2%. Patients with molecular profile characteristic of the wingless (WNT) subgroup had a better prognosis, with 5-year overall survival of 75%. CONCLUSIONS: The clinical, demographic, anatomopathological, and molecular characteristics of patients with medulloblastoma described in the present study were mostly similar to those reported in the literature. Patients submitted to complete tumor resection had better clinical outcomes than those who underwent incomplete resection/biopsy. Patients classified as high-risk showed worse overall and event-free survival than those in the standard-risk group, and the presence of metastasis at diagnosis was associated with recurrence.

Global frequency and distribution of head and neck cancer in pediatrics, a systematic review.

BACKGROUND: Incidence and mortality rates of childhood cancer represent a global public health issue, however, the worldwide prevalence of head and neck cancer in pediatric patients (HNCPP) is still unknown. Therefore, this study aimed to describe the frequency and distribution of HNCPP worldwide. METHODS: A specific search strategy was performed using MEDLINE, Scopus, and EMBASE to include studies based on hospital records, national cancer registries, and pathology files. Studies quality was assessed using the risk of bias checklist of the Joanna Briggs Institute Critical Appraisal. RESULTS: Nineteen publications (15,970 cases) were included. Global frequency ranged from 0.25 % to 15 %. Male patients older than 10 years of age were most affected by lymphomas, followed by carcinomas and sarcomas. Non-Hodgkin lymphoma, Hodgkin lymphoma, rhabdomyosarcoma, thyroid carcinoma, and nasopharyngeal carcinoma were the main histopathological subtypes. Neck/lymph nodes were anatomical hotspots. CONCLUSIONS: This HNCPP global overview may guide secondary prevention strategies and future etiological studies.

Oral and maxillofacial cancer in pediatric patients: 30 years experience from a Brazilian reference center.

OBJECTIVE: The aim of this study is to determine the relative frequency, demographic distribution and clinicopathological features of pediatric oral and maxillofacial cancer (POMC). METHODS: Medical records were retrospectively reviewed for all cancer cases diagnosed from 1986 to 2016 affecting patients aged 19 years and younger. Demographic variables, anatomical site, and histopathological diagnoses were collected and analyzed by descriptive statistics. RESULTS: Fifty-five (0.77%) POMCs were found among 7181 pediatric malignancies. Mean age at diagnosis was 8 years and patients aged 5-9 years presented the higher prevalence of malignant tumors (40%). White male patients were more frequently affected (78.18% and 65.45%, respectively). The most common cancer type was lymphomas (52.73%) followed by sarcomas (27.27%) and carcinomas (20%). Burkitt lymphoma (32.73%), rhabdomyosarcoma (14.55%), diffuse large B-cell lymphoma (9.09%), and mucoepidermoid carcinoma (9.09%) were the most common histopathological diagnoses. The main affected anatomical site was the oropharynx (38.18%), followed by salivary glands (30.91%), maxillofacial bone (20%), and oral cavity (10.91%). CONCLUSION: POMC has a low incidence; however, highly aggressive tumors, such as lymphomas and sarcomas, are common in this scenario. A better knowledge about the clinicopathological distribution of POMC may contribute to early diagnosis and improve survival rates.

Adrenocortical tumors associated with the TP53 p. R337H germline mutation can be identified during child-care consultations / Tumores adrenocorticais associados à mutação germinativa TP53 p. R337H podem ser identificados durante as consultas de puericultura

Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.

Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.

Demographic and clinicopathologic distribution of head and neck malignant tumors in pediatric patients from a Brazilian population: A retrospective study.

BACKGROUND: The incidence of pediatric head and neck cancer (PHNC) is increasing worldwide, especially when compared with childhood cancer in general. However, there is still a lack of knowledge about the demographic profile of such patients across the globe. Therefore, the aim of this study was to describe demographic, topographic, and histopathological features of PHNC patients from a single Brazilian institution. METHODS: Medical records were retrospectively reviewed for all cancer cases diagnosed from 1986 to 2016 affecting patients aged 19 years and younger. The demographic variables (age, gender, race), topographic aspects of primary tumors, and histopathological diagnoses were collected and analyzed by descriptive statistics. RESULTS: Three hundred and sixty-seven (5.11%) head and neck malignant tumors were found among 7181 pediatric cancers diagnosed in this period. Mean age at diagnosis was 9.35 years with male (65.67%) predominance. Patients between the age group of 10-14 years presented the higher prevalence of malignant tumors. In terms of race, 73.02% of the patients were white and 9.54% were black. The main affected anatomic site was the neck and lymph nodes (41.42%), followed by nasopharynx (22.89%) and thyroid gland (6.54%). The most common cancer type was lymphoma (52.86%), followed by carcinoma (22.89%), and sarcoma (19.07%). Burkitt lymphoma, nodular sclerosis Hodgkin lymphoma, nasopharyngeal carcinoma, and rhabdomyosarcoma were the most common histopathological diagnoses (16.62%, 13.08%, 12.81%, and 12.81%, respectively). CONCLUSION: This study originally demonstrated that lymphomas may be more frequent than carcinomas and sarcomas in Brazilian PHNC patients.

Reduced hydroxymethylation characterizes medulloblastoma while TET and IDH genes are differentially expressed within molecular subgroups.

INTRODUCTION: Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples. METHODS: The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations. RESULTS: Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2. CONCLUSION: These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup.

Adrenocortical tumors associated with the TP53 p.R337H germline mutation can be identified during child-care consultations.

OBJECTIVE: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. METHODS: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. RESULTS: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n=75) or associated with cortisol (n=18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p=0.92) and weight (p=0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92±1.4) than children with hypercortisolism alone or combined (-0.32±1,8; p=0.03). The five-year overall survival was 76.7% (SD±4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p<0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. CONCLUSIONS: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.

Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors.

BACKGROUND: The tumor protein p53 (TP53) arginine-to-histidine mutation at codon 337 (R337H) predisposes children to adrenocortical tumors (ACTs) and, rarely, to other childhood tumors, but its impact on adult cancer remains undetermined. The objective of this study was to investigate the frequency and types of cancer in relatives of children with ACT who carry the TP53 R337H mutation. METHODS: TP53 R337H testing was offered to relatives of probands with ACT. The parental lineage segregating the R337H mutation was identified in all families. The frequency and distribution of cancer types were compared according to R337H status. The authors' data also were compared with those publicly available for children with TP53 mutations other than R337H. RESULTS: The mean and median follow-up times for the probands with ACT were 11.2 years and 9.7 years (range, 3-32 years), respectively. During this time, cancer was diagnosed in 12 of 81 first-degree relatives (14.8%) carrying the R337H mutation but in only 1 of 94 noncarriers (1.1%; P = .0022). At age 45 years, the cumulative risk of cancer was 21% (95% confidence interval, 5%-33%) in carriers and 2% (95% confidence interval, 0%-4%) in noncarriers (P = .008). The frequency of cancer was higher in the R337H segregating lineages than in the nonsegregating lineages (249 of 1410 vs 66 of 984 individuals; P < .001). Breast and gastric cancer were the most common types. CONCLUSIONS: TP53 R337H carriers have a lifelong predisposition to cancer with a bimodal age distribution: 1 peak, represented by ACT, occurs in the first decade of life, and another peak of diverse cancer types occurs in the fifth decade. The current findings have implications for genetic counseling and surveillance of R337H carriers. Cancer 2017;123:3150-58. © 2017 American Cancer Society.