Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10−9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10−8 and 2.9 × 10−7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

LINK: https://www.nature.com/articles/ng.2645

Vários fatores influenciam na demora para que o paciente com diagnóstico de osteossarcoma seja encaminhado para tratamento a um serviço especializado. Objetivo:conhecer o itinerário terapêutico de pacientes com osteossarcoma desde os primeiros sinais e sintomas até serem atendidos em um serviço de saúde especializado. o referencial teórico utilizado foi o modelo de cuidado à saúde proposto por Kleinman, que compreende os subsistemas: profissional, familiar e popular. Método: trata-se de um estudo descritivo, de abordagem mista, realizado no instituto de oncologia Pediátrica (ioP), são Paulo. Resultados: Participaram do estudo 16 pacientes, sendo sete do sexo feminino (43,75%) e nove do masculino (56,25%), com idade entre 12 e 23 anos. os sinais e sintomas: dor, edema e dificuldade de locomoção, apresentados por 43,75% dos pacientes, foram os principais motivadores da procura por atendimento de saúde. o sistema familiar foi o primeiro acionado na busca de solução do problema. Posteriormente, metade dos pacientes (oito), juntamente com a família, procurou um serviço de saúde e os outros 50% realizaram autotratamento. o tempo médio desde o aparecimento dos sinais e sintomas iniciais até a chegada a um serviço especializado foi de seis meses. Conclusão: Foi observada uma forte influência do subsistema familiar na tomada de decisão sobre a escolha do itinerário terapêutico dos pacientes deste estudo. entretanto, falhas nos diferentes níveis de atenção à saúde contribuíram para o atraso significativo no estabelecimento do diagnóstico.

Objetivo: Avaliar os resultados obtidos com o uso de protocolo fisioterapêutico especialmente
desenvolvido para pacientes submetidos à cirurgia de ressecção tumoral ao redor do joelho e
reconstrução com endoprótese não convencional. Métodos: Foram analisados,
prospectivamente, 23 pacientes submetidos à ressecção do tumor ósseo ao redor do joelho e
substituição por endoprótese total não convencional. A média de idade dos pacientes foi de 18
anos. Todos os pacientes apresentavam osteossarcoma no resultado anatomopatológico, sendo
13 (56,5%) com localização na extremidade distal do fêmur (grupo I) e 10 (43,5%) na proximal de
tíbia (grupo II). O tratamento fisioterapêutico iniciou­se logo após a definição do diagnóstico,
com duração mínima de seis meses de pós­operatório. Resultados: No grupo I o arco de movimento apresentou média de 112°; no grupo II, de 87°. O grau de força muscular do
quadríceps variou de 4 a 5 no grupo I e de 2 a 5 no grupo II. Todos os demais músculos
apresentaram grau 5 de força muscular. A análise observacional da marcha foi normal em 100%
dos pacientes do grupo I e 4 dos 10 pacientes do grupo II apresentaram claudicação. Conclusão: Os pacientes com tumor ósseo em extremidade distal do fêmur apresentaram resultado melhor
do que os acometidos em extremida.

Results of the Brazilian Osteosarcoma Treatment
Group Studies III and IV: Prognostic Factors and
Impact on Survival.
From the Instituto de Oncologia Pedia´ trica, Grupo de Apoio ao Adolescente e a criança com Câncer/UniversidadeFederal de São Paulo; Pediatrics Department, Hospital do Câncer; Hospital das Clínicas de São Paulo-Faculdade de Medicina da Universidade de SãoPaulo; Santa Casa de Misericórdia de São Paulo; Departments of Orthopedics and Pathology, Universidade Federal de
São Paulo-Escola Paulista de Medicina, São Paulo; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; and the Children’s Hospital of Los Angeles, Los Angeles, CA.
Submitted July 22, 2005; accepted December 16, 2005.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Address reprint requests to Antonio Sérgio Petrilli MD, PhD, Instituto de Oncologia Pediátrica, Grupo de Apoio ao Adolescente e a Criança com Câncer/Universidade Federal de São Paulo, Rua Botucatu 743, Vila Clementino, 04023-062 São Paulo, Brazil; e-mail: iopepm@dialdata.com.br.
© 2006 by American Society of Clinical Oncology

Activity of Intraarterial Carboplatin as a Single Agent in the Treatment of
Newly Diagnosed Extremity Osteosarcoma

Purpose
Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.

Methods
We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient’s clinicopathological characteristics.

Results
Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118).

Conclusions
Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.

LINK: https://link.springer.com/article/10.1007%2Fs00381-014-2403-x

Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.

Medulloblastomas are the most common malignant tumors of the central nervous system in childhood. The incidence is about 19–20% between children younger than 16 years old with peak incidence between 4 and 7 years. Despite its sensibility to no specific therapeutic means like chemotherapy and radiotherapy, the treatment is very aggressive and frequently results in regression, growth deficit, and endocrine dysfunction. From this point of view, new treatment approaches are needed such as molecular targeted therapies. Studies in glioblastoma demonstrated that ASPM gene was overexpressed when compared to normal brain and ASPM inhibition by siRNA-mediated inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM gene as a potential molecular target in glioblastoma. The aim of this work was to evaluate ASPM expression in medulloblastoma fragment samples, and to compare the results with the patient clinical features.

LINK: https://link.springer.com/article/10.1007%2Fs00381-010-1252-5

Aberrant expression of stem cell-related genes in tumors may confer more primitive and aggressive traits affecting clinical outcome. Here, we investigated expression and prognostic value of the neural stem cell marker CD133, as well as of the pluripotency genes LIN28 and OCT4 in 37 samples of pediatric medulloblastoma, the most common and challenging type of embryonal tumor. While most medulloblastoma samples expressed CD133 and LIN28, OCT4 expression was found to be more sporadic, with detectable levels occurring in 48% of tumors. Expression levels of OCT4, but not CD133 or LIN28, were significantly correlated with shorter survival (P ≤ 0.0001). Median survival time of patients with tumors hyperexpressing OCT4 and tumors displaying low/undetectable OCT4 expression were 6 and 153 months, respectively. More importantly, when patients were clinically stratified according to their risk of tumor recurrence, positive OCT4 expression in primary tumor specimens could discriminate patients classified as average risk but which further deceased within 5 years of diagnosis (median survival time of 28 months), a poor clinical outcome typical of high risk patients. Our findings reveal a previously unknown prognostic value for OCT4 expression status in medulloblastoma, which might be used as a further indicator of poor survival and aid postoperative treatment selection, with a particular potential benefit for clinically average risk patients.

LINK: https://link.springer.com/article/10.1007%2Fs11060-011-0647-9

Single agent vinorelbine in pediatric patients with progressive optic pathway glioma

The management of progressive unresectable low-grade glioma remains controversial. Treatment options have included radiotherapy, and more recently chemotherapy, usually following an initial period of observation. Within this context, we evaluated vinorelbine, a semi-synthetic vinca alkaloid that has shown evidence of activity against glioma. From July 2007 an institutional protocol with vinorelbine (30 mg/m2 days 0, 8, 22) for a total of 18 cycles, has been conducted at IOP/GRAACC/UNIFESP for children with optic pathway glioma (OPG). The main objectives were clinical and radiological response, as well as toxicity profile. Twenty-three patients with progressive OPG with a mean age of 69 months (4–179) were enrolled. Three patients had a diagnosis of neurofibromatosis type 1. Twenty-two patients were assessable for response with an overall objective response rate of 63 %, with eight patients showing stable disease. The most important toxicity was hematologic (grade III/IV neutropenia) observed in four patients. Gastrointestinal toxicity (grade I/II vomiting) was observed in seven patients and only 1 patient showed grade I peripheral neuropathy. The median progression-free survival (PFS) was 33 months (6.9–69) with a 3 and 5 year PFS of 64 ± 19 and 37 ± 20 %, respectively, for an overall 3 and 5 year-survival of 95 ± 10 %. This study suggests that vinorelbine may be an interesting option for pediatric low-grade gliomas, showing low toxicity profile and providing a good quality of life for patients with such chronic disease.

LINK: https://link.springer.com/article/10.1007/s11060-014-1652-6

Diffuse Intrinsic Brainstem Tumor in an Infant

Brainstem gliomas constitute 10% to 20% of all pediatric tumors of the central nervous system, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors is benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill defined, especially in the neonates. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Thus, we report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem fibrillary astrocytoma, treated with vinorelbine (30 mg/m2/d on days 0, 8, and 22), a vinca alkaloid that has shown activity against glioma. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas as this patient showed significant clinical improvement over a short period of time.

LINK: https://journals.lww.com/jpho-online/Abstract/2011/03000/Diffuse_Intrinsic_Brainstem_Tumor_in_an_Infant___A.9.aspx

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. Pediatr Blood Cancer 2015;62:1747–1753. © 2015 Wiley Periodicals, Inc.

LINK: https://onlinelibrary.wiley.com/doi/abs/10.1002/pbc.25562

Low-grade astrocytomas comprise about 30 % of the central nervous system tumors in children. Several investigations have searched a correlation between the BRAF gene fusions alterations and mutations at IDH1 and IDH2 genes in low grade pediatric astrocytomas. This study identified the expression of KIAA1549–BRAF fusion gene and BRAF V600E mutation, mutations at exon 4 of the IDH1 and IDH2 genes in samples of pilocytic astrocytomas (PA) and grade-II astrocytomas (A-II) pediatric patients. The correlation between these alterations and the clinical profile of the patients was also evaluated. Eighty-two samples of low-grade astrocytomas (65 PA and 17 A-II) were analyzed by PCR and sequencing for each of the targets identified. We identified the KIAA1549–BRAF fusion transcript in 45 % of the samples. BRAF V600E and BRAFins598T mutations were detected in 7 and 1 % of the samples, respectively. Mutations in the R132/R172 residues of the IDH1/IDH2 genes were detected in only two samples, and the G105G polymorphism (rs11554137:C>T) was identified in ten patients. Additionally, we observed two mutations out of the usual hotspots at IDH1 and IDH2 genes. We observed a smaller frequency of mutations in IDHs genes than previously described, but since the prior studies were composed of adult or mixed (adults and children) samples, we believe that our results represent a relevant contribution to the growing knowledge in low grade childhood astrocytomas.

LINK: https://link.springer.com/article/10.1007%2Fs11060-014-1398-1

Objectives
The aim of this study was to verify whether intracystic injections of alpha-Interferon (IFN-α) in cystic craniopharyngiomas were able to reduce the tumor by activating the Fas apoptotic pathway.

Materials and methods
Twenty-one patients with cystic craniopharyngiomas treated at the Pediatric Oncology Institute (IOP/GRAACC) of Federal University of São Paulo were submitted to intracystic chemotherapy with IFN-α. The tumor sizes of all patients were monitored and the apoptotic factor soluble FasL (sFasL) concentration was determined by ELISA (enzyme-linked immunosorbent assay) in tumor fluid samples from eight patients.

Results
There was a complete reduction in 11 patients, a partial response in seven, and a minor response in three patients. The concentration of sFasL was increased in all the eight patients examined concomitantly with the tumor size reduction.

Conclusions
Our data demonstrated that the IFN-α was able to induce Fas-mediated apoptosis together with a reduction in the tumor size; such an observation may suggest the importance to investigate still unexplored mechanisms to be exploited in craniopharyngioma therapy.

LINK: https://link.springer.com/article/10.1007/s00381-007-0409-3

To assess whether the cystic craniopharyngiomas can be controlled with the
use of intratumoral applications of interferon alpha. Method: Nineteen patients with the
diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with
interferon alpha from January 2002 to April 2006. All patients underwent placement of
an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were
made applications during chemotherapy cycles. Each cycle corresponded to application
of 3,000,000 units of interferon alpha three times per week on alternate days totalizing
36,000,000 units. Response to treatment was evaluated by calculating the tumor volume
on MRI control after one, three and six months after the end of each cycle. Patients who
developed worsening of symptoms or who had insignificant reduction in tumor volume
during follow-up underwent repeat cycle chemotherapy. Results: Four patients received
four cycles of chemotherapy, three patients received three cycles, six patients received
two cycles and six patients received one. The lower percentage of reduction in tumor
volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction
greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three
patients the tumors were reduced by less than 75%. No deaths occurred during treatment
and side effects of interferon alpha were well tolerated. No treatment was discontinued.
Follow-up after the last application ranged from one year and five months to three years
and nine months. Conclusion: The intratumoral chemotherapy with interferon alpha
decreases the volume of cystic craniopharyngiomas and so far can be considered a new
therapeutic alternative.

Pediatric Central Nervous System Tumors

The objective of this study was to determine the epidemiology of primary tumors of the central nervous system (CNS) in pediatric patients from a Brazilian oncology institute. We retrospectively analyzed 741 charts (415 males and 326 females) of patients under 21 years of age who were diagnosed with a CNS tumor. The analysis included patients from 1989 to 2009 and was performed using the World Health Organization criteria. We evaluated the distribution of age, sex, topography, clinical symptoms, symptom intervals, and classification of the tumors. Patients with clinical/radiologic diagnoses were included. Seven hundred forty-one patients with tumors in the CNS were reviewed, and 83% of the patients presented a histologic diagnosis. Males (56%) were more prevalent than females. In children under the age of 1 year, the supratentorial compartment was the predominant region involved (62.0%). Astrocytoma was the most frequent tumor type (37.0%), followed by medulloblastoma (13.6%), craniopharyngioma (10.5%), and ependymoma (6.8%). Headaches were the most common symptom, and the symptom intervals varied from 1 to 5010 days. Approximately 4% of the patients had associated genetic syndromes. Although it was not a population study and selection bias may have occurred, this study supplies important epidemiologic data from an emerging country in which population studies are rare.

LINK: https://journals.lww.com/jpho-online/Abstract/2011/12000/Pediatric_Central_Nervous_System_Tumors___A.7.aspx

Primary chemotherapy for intracranial germ cell tumors: Results of the third international CNS germ cell tumor study

Background
The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation.

Methods
Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4–6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4–6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGβ) and/or CSF HCGβ <50 mIU/ml and high-risk (HR) biopsy-proven non-germinomatous malignant elements (MMGCT) or elevated serum/CSF alpha-fetoprotein and/or HCGβ serum/CSF >50 mIU/ml.

Results
Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively.

Conclusion
These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT. Pediatr Blood Cancer 2010;54:377–383. © 2009 Wiley-Liss, Inc.

LINK: https://www.nature.com/articles/ng.2645

O objetivo do estudo foi avaliar a prevalência e a disseminação de amostras de Pseudomonas aeruginosa resistente aos carbapenêmicos e produtoras de metalo-β-lactamases isoladas de hemoculturas (2000-2005) de pacientes do Instituto de Oncologia Pediátrica da UNIFESP (IOP-GRAACC). MÉTODOS E RESULTADOS: Cinquenta e seis amostras de Pseudomonas aeruginosa foram isoladas de 49 pacientes. Trinta e duas dessas amostras foram classificadas como resistentes aos carbapenêmicos pela técnica de disco difusão e submetidas a reação de PCR para detecção de genes de MBL. Dezoitos dessas 32 amostras evidenciaram o gene blaSPM-1. Oito amostras selecionadas em diferentes anos no período de estudo apresentaram o mesmo perfil genético por pulsed-field gel electrophoresis. A terapêutica antimicrobiana foi considerada adequada em apenas 23,5% dos pacientes com bacteremia por P. aeruginosa carreando blaSPM-1 e letalidade de 70,6% no período de até 30 dias após a bacteremia e uma inadequação inicial dos esquemas antibióticos utilizados CONCLUSÕES: Evidenciamos a presença de um clone de P. aeruginosa resistente aos carbapenêmicos carreando blaSPM-1 que persistiu em amostras de hemocultura pelo período de 6 anos na instituição, com alta letalidade, justificando uma vigilância epidemiológica rigorosa e uma readequação dos esquemas de terapia antimicrobianos na instituição.

O presente estudo tem como objetivo apresentar subsídios e idéias para a elaboração de propostas pedagógicas para outros contextos hospitalares, bem como contribuir para a formação de professores em ambientes diversos dos de salas de aula tradicionais. Foi utilizado como cenário de investigação o Projeto Escola Móvel/Aluno Específico no IOP/GRAACC/UNIFESP. Os eixos teóricos que fundamentam este estudo estão voltados para os aspectos do conhecimento e da formação de professores, mais diretamente a prático-reflexiva. Trabalhamos com diferentes abordagens qualitativas da qual participam os alunos/pacientes atendidos pelo Projeto, no período de março de 2000 até junho de 2002. Os procedimentos de coleta de dados foram a entrevista individual e a observação participante. As fontes de coleta de dados foram a entrevista, os relatos de aula, a escuta da comunidade, listas de pacientes diários fornecidas pelo hospital e a etnografia de textos. Os principais resultados sinalizam para a formação de professores em ambientes diversos dos de salas de aula tradicionais, para a necessidade de se investigar o meio de forma sistemática e organizada e então organizar as ações. Ressignifica-se dessa forma, com a prática alterada pela pesquisa, o conceito de cultura escolar. Sugere ainda fórum de discussão em pequenas comunidades de professores e pesquisa com classes-hospitalares que procurem ir além do resgate da auto-estima e possibilitem, ao longo do tempo, avaliar o desempenho dos alunos em suas escolas de origem. Aponta também as questões do professor consigo mesmo no que se refere a crenças pessoais, a preocupações de trabalho em equipes multidisciplinares, à aceitação de desafios impostos pelo meio, à crença na sua capacidade de ensinar e na de seu aluno aprender e à busca constante de formação.

LINK: https://leto.pucsp.br/handle/handle/10029#preview-link0