Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1.

BACKGROUND: Large cooperative group studies have shown the efficacy of risk-adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk-adapted intensive regimen was developed by the Brazilian cooperative group. PROCEDURE: Patients <30 years old with Ewing sarcoma were eligible. Induction chemotherapy consisted of two cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by two cycles of VDC (vincristine, doxorubicin, and cyclophosphamide), followed by local control. Patients with low risk (LR) disease (localized resectable with normal LDH) received 10 additional alternating courses of IE with VDC. For patients with high-risk (HR) disease (unresectable, pelvic, metastatic, or high LDH), two additional cycles of ICE were given. RESULTS: One-hundred seventy five patients (39% metastatic) were enrolled. Fifty-two patients (29.7%) were LR and 123 (70.3%) were HR. Overall response rate at end of induction was 27.4%. Five-year event-free survival (EFS) and overall survival (OS) estimates were 51.4% and 54.4%, respectively. Patients with localized disease had better outcomes than patients with metastases (5-year EFS 67.9% vs. 25.5%, and 5-year OS 70.3% vs. 29.1%, respectively). On multivariate analysis, the presence of metastatic disease was the only prognostic factor (P < 0.01). CONCLUSION: The VDC/ICE protocol was feasible, and considering the high tumor burden in our population, resulted in comparable results to those reported by cooperative groups in high-income countries. Further adaptation to maximize efficacy and minimize toxicity will be required.

Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward.

The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012-2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.

Targeted Inhibition of the Epidermal Growth Factor Receptor and Mammalian Target of Rapamycin Signaling Pathways in Olmsted Syndrome.

Importance: Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available. Objective: To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome. Design, Setting, and Participants: This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil. Exposures: Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d. Main Outcomes and Measures: Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment. Results: Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported. Conclusions and Relevance: This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

Lowered Cisplatin Dose and No Bleomycin in the Treatment of Pediatric Germ Cell Tumors: Results of the GCT-99 Protocol From the Brazilian Germ Cell Pediatric Oncology Cooperative Group.

PURPOSE: We describe the results of a risk-adapted, response-based therapeutic approach from the Brazilian GCT-99 study on germ cell tumors. PATIENTS AND METHODS: From May 1999 to October 2009, 579 participants were enrolled in the Brazilian GCT-99 study. Treatment, defined as specific chemotherapy regimen and number of cycles, was allocated by means of risk-group assignment at diagnosis with consideration for stage and primary tumor site. Patients at low risk received no chemotherapy. Patients at intermediate risk (IR) with a good response (GR) received four cycles of platinum and etoposide (PE), for total doses of platinum 420 mg/m(2) and etoposide 2,040 mg/m(2). Patients at IR with a partial response (PR) received three cycles of PE plus three cycles of ifosfamide, vinblastine, and bleomycin. Patients at high risk (HR) with a GR received four cycles of PE and ifosfamide (PEI) at total doses of platinum 420 mg/m(2), etoposide 1,200 mg/m(2), and ifosfamide 30 g/m(2). Patients at HR with a PR received six cycles of PEI. RESULTS: The risk-group distribution was 213 LR, 138 IR, and 129 HR for 480 evaluable patients. Overall survival (OS) and event-free survival (EFS) rates at 10 years were, respectively, 90% and 88.6% in the IR-GR group (n = 126) and 74.1% and 74.1% in the IR-PR group (n = 12). Ten-year rates for the HR-GR group (n = 86) were an OS of 66.8% and an EFS of 62.5%. The HR-PR group (n = 43) had an OS of 74.8% and an EFS of 73.4%. In univariable and multivariable analysis, increased serum lactate dehydrogenase level and histology for a metastatic immature teratoma were prognostic of a worsened outcome. CONCLUSION: Reduction of therapy to two drugs did not compromise survival outcomes for patients in the IR-GR group, and escalation of therapy with PEI did not significantly improve OS and EFS in patients at HR.

Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil.

BACKGROUND: Choroid plexus carcinomas (CPC) are rare tumors predominantly found in children. Given the high frequency of the germline R337H mutation in the TP53 gene in southern Brazil, we have evaluated the frequency of the R337H mutation in families with CPC in children. METHODOLOGY/PRINCIPAL FINDINGS: The present series included 29 patients that were admitted to the same institution from 1992 to 2010, including 22 children with CPC (0.08-13.6 years of age at diagnosis) and 7 children with papilloma of the choroid plexus (Pp; 0.5-9.8 years of age). Surgical resection was possible in 28 children. Blood and/or tumor DNA was extracted and analyzed using PCR-RFLP and results were confirmed by sequencing 240 bp of the TP53 exon 10. The patients, all parents, and some relatives submitted samples for blood DNA analysis. In addition, we have also examined the presence of the mutation in DNA from paraffin-embedded tumor samples to evaluate loss of heterozygosity. We found 63.3% (14/22) of the CPC patients positive for the germline R337H mutation; CPC samples were either heterozygous (n = 7), lost only the wild-type (n = 4), or only the R337H copy (n = 2). One CPC sample was not available. All Pp cases (7/7, 100%) were negative for R337H. Cure (>5 years survival free of disease) was observed in 18.1% of the CPC cases with the R337H mutation (2/11), 71.4% of the Pp (5/7), and 25% of CPC cases negative for the R337H mutation (2/8). Family history of cancer (with 2 or more cancer cases) was exclusively identified on the parental side segregating the R337H mutation, and 50% (7/14) of them were compatible with Li-Fraumeni-like syndrome. SIGNIFICANCE: Our results show for the first time that the R337H TP53 mutation is responsible for 63% of the CPC cases in children, suggesting a higher incidence of CPC in southern Brazil.

Immunoexpression of cell cycle biomarkers in neuroblastoma samples and its correlation with prognostic factors / Imunoexpressão de biomarcadores do ciclo celular em amostras de neuroblastomas e sua relação com fatores prognósticos

INTRODUCTION: It is widely known that the expression levels of molecules involved in apoptosis regulation and cell proliferation have prognostic value in patients with neuroblastomas. OBJECTIVE: To determine the expression of Ki67, B-cell lymphoma 2 (BCL-2), phosphatase and tensin homolog (PTEN), BCL-2 associated protein X (BAX) and caspase-8 proteins in neuroblastomas and to propose new prognostic biomarkers that could enable a better classification of risk groups. MATERIAL AND METHODS: Formalin fixed paraffin embedded neuroblastoma samples (n = 23) were arranged into tissue microarray blocks and analyzed by immunohistochemistry. The patients were classified according to clinical and pathological prognostic factors (age, site, presence or absence of bone-marrow infiltration, poorly or well differentiated ganglioneuroblastoma, Schwannian stroma rich or poor, favorable or unfavorable Shimada histology, and presence or absence of MYCN oncogene amplification) and clinical course (with or without fatal outcome, with or without relapses/residual lesion). RESULTS: Twelve patients were female; nine children were over 18 months old; nine had extra-abdominal tumors; nine had tumors with unfavorable histology. Fifteen patients underwent bone-marrow biopsy and four were positive for metastasis. Nine patients progressed to fatal outcome. CONCLUSION: Ki67 immunoexpression was lower in cases of Schwannian-stroma rich neuroblastomas (p = 0.018) and higher in poorly differentiated cases (p = 0.013). PTEN was less positive in stroma rich neuroblastomas (p = 0.024). Caspase-8 was more immunopositive in cases of negative bone marrow infiltration (p = 0.035). Therefore, these biomarkers could be applied to discriminate groups with poor prognosis.

INTRODUÇÃO: Sabe-se que os níveis de expressão de moléculas envolvidas na regulação da apoptose e da proliferação celular apresentam valor prognóstico em pacientes com neuroblastomas. OBJETIVO: Avaliar a imunoexpressão das proteínas Ki67, B-cell lymphoma 2 (BCL-2), phosphatase and tensin homolog (PTEN), caspase-8 e BCL-2 associated protein X (BAX) em neuroblastomas na tentativa de propor novos biomarcadores prognósticos que poderiam auxiliar na melhor discriminação dos grupos de risco. MATERIAL E MÉTODOS: Amostras de neuroblastoma (n = 23) foram submetidas à técnica tissue microarray e analisadas com imuno-histoquímica. Os pacientes foram classificados de acordo com os fatores prognósticos clínico-patológicos (idade, localização, medula óssea infiltrada ou não, pouco diferenciado ou em diferenciação/ganglioneuroblastoma, rico ou pobre em estroma com células de Schwann, histologia favorável ou desfavorável segundo Shimada, presença ou não da amplificação do MYCN) e com o curso clínico (se em óbito ou vivo, com ou sem lesão residual/recidiva). RESULTADOS: Doze casos eram do sexo feminino; nove tinham idade acima de 18 meses; nove apresentavam tumores extra-abdominais; e nove cursavam com histologia desfavorável. Quinze pacientes foram submetidos à biópsia de medula óssea, sendo quatro com apresentação de metástase. Nove pacientes evoluíram ao óbito. CONCLUSÃO: A imunoexpressão do Ki67 foi mais baixa nos casos ricos em estroma (p = 0,018) e elevada nos casos pouco diferenciados (p = 0,013). O PTEN apresentou-se menos positivo em neuroblastomas ricos em estroma (p = 0,024). A caspase-8 foi mais imunopositiva em casos com medula óssea negativa (p = 0,035). Esses biomarcadores poderiam ser utilizados para auxiliar a discriminar grupos de pacientes de pior prognóstico.

Neuroblastoma in southern Brazil: an 11-year study.

The authors report on the incidence and clinical characteristics of neuroblastoma in southern Brazil. The aims of the study were to evaluate the age at diagnosis, tumor stage, MYCN status, and tumor histopathology, and to relate these factors to survival. All patients with neuroblastoma, 15 years old or younger (n = 125), admitted to the three major pediatric oncology hospitals in the state of Parana over a period of 11 years (between January 1990 and December 2000), were included in the analysis. All patients were followed for at least 5 years. In addition, a FISH evaluation for MYCN status was conducted in a subset of 34 tumors. Overall survival for tumor stages 1, 2, 3, and 4 was 100%, 72%, 59%, and 17%, respectively. Sixty-two percent (77/125) of all patients were older than 2 years; these represented 71% (57/80) of the patients with stage 4 disease. Children who presented with an unfavorable histopathology had a significantly worse prognosis (20% survival) than children with a favorable histopathology (67% survival). MYCN amplification was detected most commonly in stages 3 and 4 tumors (13/16). These data showed a delayed diagnosis of neuroblastoma in children in southern Brazil, and consequently survival was considerably lower in these patients.

Linfoma T subcutâneo do tipo paniculite: relato de um caso acometendo paciente pediátrico / Subcutaneous panniculitic T cell lymphoma: a case report affecting a child

Os autores relatam um caso de linfoma T subcutâneo do tipo paniculite em uma paciente feminina de 3 anos, apresentando havia um mês múltiplos nódulos subcutâneos, indolores, disseminados no abdome, região peitoral e cervical. Ao exame histopatológico, evidenciou-se um linfoma T infiltrando tecido adiposo subcutâneo. Os linfomas T subcutâneos representam uma entidade clinicopatológica distinta, sendo raro o acometimento pediátrico

Meduloepitelioma teratóide maligno do globo ocular: relato de caso e revisão da literatura / Intraocular malignant teratoid medulloepithelioma: case report and review of the literature

Os autores relatam um caso de meduloepitelioma teratóide maligno intra-ocular acometendo uma menina de 7 anos com história de glaucoma congênito. O padrão histológico demonstrou ilhas de epitélio primitivo, com freqüentes estruturas tubulares e focos de cartilagem. Após procedimento cirúrgico, a paciente encontra-se bem, sem evidência de recorrência tumoral

Efeito da clorexidina com carbonato de cálcio no tratamento da mucosite em crianças com neoplasias malignas / The effect of chlorhexidine plus calcium carbonate for treatment of mucositis in children with malignant disease

Objetivo: Determinar a eficácia da pasta clorexidina com carbonato de cálcio no tratamento da mucosite de crianças com neoplasias malignas. Métodos: foram selecionados dois grupos de pacientes com neoplasias malignas que apresentaram mucosite oral durante a internação, em dois hospitais de referência, entre outubro de 2002 e janeirode 2004. O grupo A, com 9 casos foi tratado com pasta de carbonato de cálcio / Objective: to determine the efficacy of chloorhexidine plus calcium carbonate in children with malignant disease that developed oral mucositis. Methods: twenty-three inpatients with malignant disease and oral mucositis from two reference hospitals were analyzed from October 2002 to January 2004...

Situaçäo do Retinoblastoma nos últimos 17 anos em Curitiba - Paraná / Retinoblastoma incidence revision in the last 17 years in Curitiba - Paraná

Realizou-se uma revisäo de casos de retinoblastoma em quatro hospitais de Curitiba. Encontraram-se 92 casos nos últimos 17 anos, onde analisou-se: idade em que se estabeleceu o diagnóstico, sexo, tempo decorrido entre o início dos sintomas e o seu diagnóstico, sintomas mais comuns, lateralidade e extensäo do tumor, tempo de acompanhamento e óbito destes pacientes. Conclui-se que o tempo decorrido entre o diagnótico e o início dos sintomas é elevado, pela falta de esclarecimento da populaçäo e falta de trabalho direcionado a classe médica. Isto deverá ser melhorado com a formaçäo de equipes multidisciplinares envolvendo oftalmologistas, pediatras, oncologistas, radioterapeutas, geneticistas, psicólogos, sanitaristas e membros da comunidade

Situaçäo do retinoblastoma nos últimos 17 anos em Curitiba / Situation of retiblastoma on last 17 years in Curitiba

Realisou-se uma revisäo de retinoblastoma em 4 hospitais de Curitiba. Encontrou-se 92 casos nos últimos 17 anos, onde analisou-se: idade em se estabeleceu o diagnóstico, sexo, tempo decorrido entre o início dos sintomas e o seu diagnósticos, sintomas mais comuns, lateralidade e extensäo e óbito destes pacientes. Conclui-se que o tempo decorrido entre o diagnóstico e o início dos sintomas é elevado, pela falta de esclarecimento da populaçäo e falta de trabalho direcionado à classe médica. Isto deverá ser melhorado com a formaçäo de equipes multidisciplinares envolvendo oftalmologistas, pediatras, oncologistas, radioterapeutas, geneticistas, psicólogos, sanitaristas e membros da comunidade

Linfoma de Burkitt: estudo de oito casos e revisão de literatura / Burkitt's lymphoma: report of eight cases and review of literature

O linfoma de Burkitt envolve principalmente sítios extra-nodais. Pode ser classificado como endêmico, relacionado ao HIV e esporádico, estando a última forma relacionada à crianças e adultos jovens. No relato em questão, estudou-se oito casos de linfoma de Burkitt da variante esporádica durante os anos de 1998 e 2001. Os dados clínicos foram obtidos mediante revisão das lâminas histológicas . A relação masculino:feminino foi de 5:3, e a idade média, no momento dodiagnóstico, foi de 5 anos e 5 meses. Em cico pacientes, o tumor primário encontrava-se no abdômen, enquanto que nos tres restantes, na região cervical. Três pacientes apresentaram metástases para sistema nervoso central. A mortalidade de 62,5 por cento registrada em 9 meses foi devido ao diagnóstico tardio da doença e a agressividade biológica deste tipo de linfoma