Outcome of Children and Adolescents With Primary Intracranial Germinoma Treated With Chemotherapy and Reduced Dose-Field Irradiation: A Prospective Brazilian Experience.

PURPOSE: This prospective Brazilian single-arm trial was conducted to determine response to chemotherapy and survival after response-based radiotherapy in children with intracranial germinomas, in the setting of a multi-institutional study in a middle-income country (MIC) with significant disparity of subspecialty care. PATIENTS AND METHODS: Since 2013, 58 patients with histologic and/or serum and CSF tumor marker evaluations of primary intracranial germ cell tumors were diagnosed; 43 were germinoma with HCGß levels ≤200 mIU/mL and five between 100 and 200 mIU/mL. The treatment plan consisted of four cycles of carboplatin and etoposide followed by 18 Gy whole-ventricular field irradiation (WVFI) and primary site(s) boost up to 30 Gy; 24 Gy craniospinal was prescribed for disseminated disease. RESULTS: Mean age 13.2 years (range, 4.7-25.5 years); 29 were males. Diagnosis was made by tumor markers (n = 6), surgery (n = 25), or both (n = 10). Two bifocal cases with negative tumor markers were treated as germinoma. Primary tumor location was pineal (n = 18), suprasellar (n = 14), bifocal (n = 10), and basal ganglia/thalamus (n = 1). Fourteen had ventricular/spinal spread documented by imaging studies. Second-look surgery occurred in three patients after chemotherapy. Thirty-five patients achieved complete responses after chemotherapy, and eight showed residual teratoma/scar. Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 44.5 months, overall and event-free survivals were 100%. CONCLUSION: The treatment is tolerable, and WVFI dose reduction to 18 Gy preserves efficacy; we have demonstrated the feasibility of successfully conducting a prospective multicenter trial in a large MIC despite resource disparity.

Novel large deletions in the human alpha-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment.

Globin genes, which encode the protein subunits of hemoglobin (Hb), are organized in two different gene clusters and present a coordinated and differential pattern of expression during development. Concerning the human alpha-globin gene cluster (located at chromosome region 16p13.3), four upstream highly conserved elements known as multispecies conserved sequences (MCS-R1-4) or DNase I hypersensitive sites (HSs) are implicated in the long-range regulation of downstream gene expression. However, only the absence of the MCS-R2 site (HS-40) has proven to drastically downregulate the expression of those genes, and consequently, it has been regarded as the major and crucial distal regulatory element. In this study, Multiplex Ligation-dependent Probe Amplification was used to screen for deletions in the telomeric region of the short arm of chromosome 16, in an attempt to explain the alpha-thalassemia or the HbH disease present in a group of Portuguese patients. We report four novel and five uncommon deletions that remove the alpha-globin distal regulatory elements and/or the complete alpha-globin gene cluster. Interestingly, one of them occurred de novo and removes all HSs except HS-10, while other eliminates only the HS-40 site, the latter being replaced by the insertion of a 39 nucleotide orphan sequence. Our results demonstrate that HS-10 alone does not significantly enhance the alpha-globin gene expression. The absence of HS-40 in homozygosity, found in a patient with Hb H disease, strongly downregulates the expression of alpha-globin genes but it is not associated with a complete absence of alpha-globin chain production. The study of naturally occurring deletions in this region is of great interest to understand the role of each upstream regulatory element in the native human erythroid environment.

Hb Evora [alpha2-35 (B16), Ser-->Pro], a novel hemoglobin variant associated with an alpha-thalassemia phenotype.

We report a novel mutation in the alpha2-globin gene, codon 35 (T-->C), detected in two unrelated Portuguese families. This mutation gives rise to a previously undescribed hemoglobin (Hb) variant, which we named Hb Evora. This variant seems to be responsible for the alpha-thalassemia phenotype present in its carriers. It cannot be detected by conventional laboratory techniques, probably because of its highly unstable nature.

[Orbital granulocytic sarcoma: case report]. / Sarcoma granulocítico em órbita: relato de caso.

Orbital granulocytic sarcoma is a localized tumor consisting of malignant cells of myeloid origin. This tumor may present in association with acute myelogenous leukemia. Granulocytic sarcoma may be found in a variety of locations throughout the body including the orbit and typically affects children and young adults. There is a slight male predominance in these cases. This is an uncommon case report of a 33-year-old Latin-American woman who was admitted to the Hospital for rapidly progressive orbital proptosis. There was no systemic manifestation of leukemia. The occurrence of orbital granulocytic sarcoma before the development of systemic leukemia in children and young adults is not uncommon and these cases frequently develop hematological evidence within 2 months after initial orbital disease. In this case report, there was no systemic manifestation of leukemia in the last 30 months, even in the presence of orbital tumors. Granulocytic sarcoma is most frequently confused with malignant lymphoma, rhabdomyosarcoma and neuroblastoma. The differential diagnosis of these cases can be challenging, particularly when there is no evidence of systemic leukemia, when imaging features are not sufficiently specific to distinguish granulocytic neoplasms from other tumors. To establish the diagnosis often a biopsy is required. The treatment in such cases (orbital granulocytic sarcoma) is not standardized. Orbital granulocytic sarcoma may be suspected in cases of orbital tumors even in the absence of systemic manifestations of leukemia at any age.

Mutational spectrum of delta-globin gene in the Portuguese population.

The phenotype of increased Hb A2 typical of beta-thalassaemia (beta-thal) carriers can be reduced to normal or borderline values because of the co-inheritance of a delta-globin gene (HBD, MIM #142000) mutation, which may lead to misinterpretation of diagnostic results. To know the spectrum of delta-globin mutations in the Portuguese population we performed a mutational analysis of the delta-globin gene in a group of 51 Portuguese beta-thal carriers presenting microcytosis, hypochromia and a normal/borderline Hb A2 level and in another group of 15 individuals suspected to have delta-globin structural abnormalities. The heterozygosity for the beta(+)IVS-I-6T-->C (HBB:c. 92+6T>C) mutation was the main cause for the mentioned atypical beta-thal carrier phenotype. Furthermore, eight individuals were double heterozygous for one common beta-thal mutation and the delta(+)Cd27G-->T mutation (Hb A2-Yialousa; HBD:c.82G>T). One of them also presented a novel delta-globin gene promoter mutation,-80G-->A (HBD:c.-130G>A), responsible for about 25% decrease of the promoter activity in transient expression assays. One the other hand, in the other group of 15 individuals suspected to have delta-globin structural abnormalities observed by biochemical methods, some known Hb A2 variants were identified - Hb A2' (HBD:c.49G>C), Hb A2-Babinga (HBD:c.410G>A), and Hb A2-Wrens (HBD:c.295G>A), and the novel Hb A2-Fogo [delta64(E8)(Gly-->Ser); (HBD:c.193G>A)]. This novel Hb A2 variant was observed segregating in linkage with Hb E (HBB:c.79G>A) in a three generation family. In conclusion, six different delta-globin mutations were found, being two of them new molecular defects. All delta-alleles identified were found linked to the expected beta-globin cluster haplotype. All mutations caused a low Hb A2 level and through this could lead to misdiagnosis when inherited together with a beta-thal allele.

Hemoglobin Loves Park [beta68 (E12) Leu-->Phe]: report of five cases including one originating from a de novo mutation.

Hemoglobin (Hb) Loves Park [beta68 (E12) Leu-->Phe] was identified in a 2-year-old Portuguese boy with anemia, microcytosis, and hypochromia. This Hb variant was detected by isoelectric focusing and quantified by reverse-phase high-performance liquid chromatography (HPLC) (48.4%), and the DNA mutation was identified by HBB (beta-globin gene) sequencing. Hematological and biochemical analyses performed on his parents revealed normal hematological parameters and normal hemoglobin and globin chain profiles. DNA sequence analysis of the HBB gene of both parents showed the absence of the Hb Loves Park mutation. Study of the haplotypes in the beta-globin gene cluster confirmed parenthood. Moreover, paternity was confirmed by the study of nine short tandem repeats (STRs) and four variable-number tandem repeat (VNTRs) loci. The most likely explanation for these results is that the Hb Loves Park mutation has occurred de novo in this family. The original American cases of Hb Loves Park, from a family of Italian origin, which were never published, as well as two additional cases, are also included in this report. Functional studies revealed that Hb Loves Park is stable and has a decreased oxygen affinity.

Hb Yaoundé [beta134(H12)Val-->Ala] in association with Hb C [beta6(A3)Glu-->Lys] in a Caucasian Portuguese family.

Hb Yaoundé [beta134(H12)Val-->Ala] is a rare, silent and asymptomatic hemoglobin (Hb) variant. It was previously reported in a Black man from Cameroon, in association with Hb Kenitra [beta69(E13)Gly-->Arg], and was subsequently found and described as Hb Mataro in a sub-Saharan child. To date, Hb Yaoundé has not been described in Caucasian people and molecular studies have never been performed. Here we describe a three-generation Caucasian Portuguese family in whom Hb Yaoundé was found in association with Hb C [beta6(A3)Glu-->Lys] (in the proband) and in a heterozygous state (in the proband's mother). The Hb studies of the proband's hemolysate, performed by isoelectric focusing (IEF) and low-pressure cation exchange chromatography, only revealed an Hb variant identified as Hb C by comparison with a control. However, analysis performed by reversed-phase high-performance liquid chromatography (HPLC) showed two different beta chain variants and a complete absence of the normal beta chain. This uncommon Hb variant was identified as Hb Yaoundé by DNA sequencing analysis of the beta-globin gene (codon 134, GTG-->GCG). The beta-globin gene haplotypes were determined in all family members using polymerase chain reaction (PCR)-based methodology; Hb Yaoundé was found to be associated with the Mediterranean haplotype II. This study is the first description of Hb Yaoundé in Caucasian individuals, and its association with a Mediterranean haplotype supports the hypothesis of an independent genetic origin other than African.

Sarcoma granulocítico em órbita: relato de caso / Orbital granulocytic sarcoma: case report

O sarcoma granulocítico é tumor que freqüentemente aparece em pacientes portadores de leucemia mielóide aguda, podendo aparecer em diferentes regiões do corpo, incluindo a órbita. Nesta última localização, é mais freqüente em crianças e adultos jovens, com discreta predominância em pacientes do sexo masculino. Este é um caso de sarcoma granulocítico orbitário de evolução rápida, sem manifestação sistêmica associada em uma paciente de 33 anos de idade, o que o torna incomum. O surgimento do sarcoma granulocítico orbitário sem acometimento leucêmico pode ocorrer em cerca de 88 por cento dos pacientes com acometimento orbitário. A maioria dos pacientes apresenta evidências hematológicas de comprometimento sistêmico em 2 meses após a manifestação orbitária. Neste relato de caso, a paciente não apresenta acometimento sistêmico, apesar da manifestação orbitária estar presente há 30 meses. Os principais diagnósticos diferenciais do sarcoma granulocítico orbitário são o linfoma, o rabdomiossarcoma e o neuroblastoma. O diagnóstico pode ser dificultado, principalmente nos casos sem acometimento sistêmico, nos quais os exames de imagem e as manifestações clínicas pouco diferem de outras doenças. Para o diagnóstico deve-se realizar uma biópsia da lesão orbitária para análise anatomopatológica e imuno-histoquímica. O tratamento nos casos de sarcoma granulocítico orbitário sem acometimento sistêmico não é padronizado. A hipótese diagnóstica de sarcoma granulocítico orbitário deve ser aventada em casos de pacientes com tumoração orbitária mesmo que não apresentem sinais ou sintomas sistêmicos e independentes da faixa etária.

Avaliação da atividade proliferativa no epitélio mamário adjacente a fibroadenoma em mulheres tratadas com tamoxifeno / Evaluation of proliferative activity in the mammary epithelium adjacent to fibroadenoma in women treated with tamoxifen

Objetivo: estudar a atividade proliferativa do epitélio mamário normal adjacente a fibroadenoma em mulheres na fase lútea do ciclo menstrual, tratadas com tamoxifeno. Pacientes e Métodos: estudou-se por técnica imuno-histoquímica, com o uso do anticorpo monoclonal MIB-1, a atividade proliferativa no epitélio mamário adjacente a fibroadenoma. O estudo foi randomizado e duplo-cego. As 44 mulheres com fibroadenoma foram divididas em 3 grupos: A (n=16; placebo), B (n=15; tamoxifeno, 10 mg) e C (n=13; tamoxifeno, 20 mg). O tamoxifeno foi utilizado por 22 dias, a partir do 2º dia do ciclo menstrual, e a biópsia realizada no 23º dia. Resultados: a porcentagem média de núcleos corados por 1000 células no grupo A foi 9,2, no grupo B, 4,5, e no grupo C, 3,2. O teste de Fisher revelou que o tamoxifeno reduziu de forma significante a imunoexpressão do MIB-1 nas doses de 10 e 20 mg em comparação com o grupo placebo (p<0,0001) e não houve variação significante da atividade proliferativa nas doses de 10 e 20 mg de tamoxifeno (p=0,21). Conclusão: conclui-se que o tamoxifeno reduziu de forma significante a atividade proliferativa do epitélio mamário, nas doses de 10 e 20 mg/dia.

Teratoma de hipofaringe: relato de caso e revisäo de literatura / Hipopharynx teratoma: report of a case and review of the literature

Teratomas säo neoplasias que se originam de células pluripotenciais e säo compostos de uma larga diversidade de tecidos estranhos ao órgäo ou sítio anatômico no qual eles aparecem. Ocorrem mais freqüentemente em crianças com menos de um ano de idade, principalmente neona, sendo normalmente notados ao nascimento. Os teratomas localizados na cabeça e pescoço säo raramente observados quando presentes, säo observados na nasofaringe e na regiäo cervical. Relatamos o caso de um recém-nascido portador de desconforto respiratório devido a tumor em regiäo de hipofaringe, que ocasionava uma obstruçäo das vias aéreas superiores. O paciente foi submetido à exérese do tumor por via transoral, tendo o resultado do estudo anatomopatológico demonstrado tratar-se de um teratoma maduro

Atitudes dos pais diante de uma crianca febril: avaliacao de uma populacao frequentadora do Pronto-Socorro Infantil de um Hospital Universitario / Attitudes of parents when children have fever: Assesment of a population attending the Emergency Department of a teaching hospital

Com o objetivo de conhecer o comportamento dos pais perante uma crianca febril, bem como verificar as formas de aquisicao de tal comportamento, os autores aplicaram um questionario a 100 pais que aguardavam atendimento medico no pronto-socorro de um hospital-escola. Observou-se que a febre era motivo de preocupacao para todos os pais entrevistados e que a maioria a associava a doenca e complicacoes, dentre as quais se incluia a morte. Apena 41 por cento dos entrevistados tinha o habito de verificar a temperatura e, dentre estes, 97,6 por cento costumava intervir em temperatura abaixo de 38 graus C. Doze por cento dos pais considerava como altas temperatura que, do ponto de vista medico, sao tidas como normais ou febre baixa, recorrendo por isso ao uso de algum recurso terapeutico. Alta percentagem de pais desconhecia a evolucao natural da febre. Medicos e/ou paramedicos foram citados por 45,9 por cento das respostas como fonte de informacao dos entrevistados sobre febre

Invasäo da placa epifisária pelo osteossarcoma: é a placa uma barreira ao crescimento do tumor? / Osteosarcoma invasion of the epiphyseal plate: Is the plaque a barrier to tumor growth?

Os autores estudam 25 pacientes portadores de osteosarcoma com as placas de crescimento abertas e analisam a correlaçäo entre os achados radiográficos e o exame anatomopatológico no que se refere à destruiçäo da placa e invasäo da epífise pelo tumor. Entre os pacientes, 14 (56 por cento) eram do sexo masculino e 11 (44 por cento) do feminino. A idade variou de 4 a 17 anos, com média de 12,2 anos. A invasäo da placa foi diagnosticada pelo exame radiográfico em apenas 11 (44,0 por cento) pacientes, enquanto o exame anatomopatológico mostrou comprometimento da epífise através da placa de crescimento aberta em 21 (84,0 por cento) pacientes. Os autores concluem que a placa epifisária näo foi uma barreira ao crescimento do tumor para a epífise e que as cirurgias de preservaçäo do membro que mantenham a epífise devem ser cuidadosamente planejadas.

Schwannoma de duodeno: relato de caso / Schwannoma of duodenum: a case report

Relata-se um caso de schwannoma maligno de duodeno, tumor neural de raiz sensitiva, que raramente acomete o tubo gastrointestinal. O diagnóstico foi realizado após um episódio de hemorragia digestiva alta e a ressecçÒo foi local. Após dois anos o paciente permanecia assintomßtico mas apresentava, Ó endoscopia de controle, um novo tumor na segunda porçÒo de duodeno, sendo realizada uma gastroduodenopancreatectomia. É feita revisÒo da literatura sobre os schwannomas de intestino.

Metástases de origem primária desconhecida: primeira manifestaçäo no tecido ósseo: orientaçäo para o diagnóstico do tumor primário / Skeletal metastasis of unknown origin: first manifestation on the bone tissue: orientation for the diagnosis of the primary tumor

Trinta e sete pacientes que apresentaram metástases ósseas como primeira manifestaçao de carcinoma foram revisados. Uma seqüência simples de diagnóstico consistindo de anamnese cuidadosa, exame físico, testes laboratoriais de rotina, radiografia de tórax, mapeamento do esqueleto com tecnécio e biópsia óssea, identificou o local primário em 17 (45,9 por cento) pacientes. O local primário foi pulmao em oito (21,6 por cento), rim em quatro (10,8 por cento), próstata em dois (5,4 por cento), hepatocarcinoma, tumor de sigmóide e leiomiossarcoma em um (2,7 por cento) paciente. Com base nessa estratégia, propusemos um algoritmo que, associado aos testes imuno-histoquímicos e à utilizaçao de marcadores tumorais, deverá aumentar o índice de diagnóstico da origem primária dessas metástases.

Leiomiossarcoma de mama / Breast leiomyosarcoma

O leiomiossarcoma é um dos tumores mamários mais raros. Apresenta o melhor prognóstico entre os sarcomas de mama. A imuno-histoquímica pode ser útil para a confirmaçäo diagnóstica por meio da documentaçäo da diferenciaçäo muscular dessa neoplasia. O tratamento mais reconhecido consiste na realizaçäo da mastectomia simples sem linfadenectomia