A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.

BACKGROUND: Childhood myelodysplastic neoplasm (cMDS) often raises concerns about an underlying germline predisposition, and its verification is necessary to guide therapeutic choice and allow family counseling. Here, we report a novel constitutional t(3;8)(p26;q21) in a child with MDS, inherited from the father, the ANKRD26 and SRP72 variants from the maternal origin, and the acquisition of molecular alterations during MDS evolution. CASE PRESENTATION: A 4-year-old girl showed repeated infections and severe neutropenia. Bone marrow presented hypocellularity with dysplastic features. The patient had a t(3;8)(p26;q21)c identified by G-banding and FISH analysis. The family nucleus investigation identified the paternal origin of the chromosomal translocation. The NGS study identified ANKRD26 and SRP72 variants of maternal origin. CGH-array analysis detected alterations in PRSS3P2 and KANSL genes. Immunohistochemistry showed abnormal p53 expression during the MDS evolution. CONCLUSION: This study shows for the first time, cytogenetic and genomic abnormalities inherited from the father and mother, respectively, and their clinical implications. It also shows the importance of investigating patients with constitutional cytogenetic alterations and/or germline variants to provide information to their family nucleus for genetic counseling and understanding of the pathogenesis of childhood MDS.

Acute promyelocytic leukemia in a long-standing HIV-positive patient: Case report and literature review.

The use of antiretroviral therapy has drastically improved the life quality and prognosis of people living with the human immunodeficiency virus (HIV). The risk of acute myeloid leukemia (AML) currently does not appear to be significantly increased compared to the general population. Acute promyelocytic leukemia (APL), infrequent in people with HIV, is a distinct subtype of AML with unique molecular pathogenesis, clinical manifestations, and treatment. Herein we describe a fatal case of APL hypogranular variant in an HIV-positive patient presenting with hyperleukocytosis. Also, we conducted a literature review of the ten cases reported so far.

Therapy-related acute myeloid leukemia with KMT2A-SNX9 gene fusion associated with a hyperdiploid karyotype after hemophagocytic lymphohistiocytosis.

Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g. etoposide) promote DNA damage and are associated with KMT2A rearrangements. They are widely used as first-line treatment in hemophagocytic lymphohistiocytosis (HLH). Here we describe a newborn who developed t-AML after HLH treatment. We provide detailed clinical, cytogenetic, and molecular characteristics of this patient, including the identification of a novel gene fusion - KMT2A-SNX9 - in t-AML. Considering the dismal outcome of this case, we discuss the side-effects of etoposide administration during HLH treatment in infants.

Alterações Citogenético-Moleculares no Gene FOXO1 em uma Criança com Rabdomiossarcoma Alveolar: Relato de Caso / Citogenetic-Molecular Alterations in FOXO1 Gene in a Child with Alveolar Rhabdomyosarcoma: Case Report / Cambios Citogenetico-moleculares en el gene fOxO1 en un Niño con Rabdomiossarcoma Alveolar: Relato de Caso

Introdução: o rabdomiossarcoma (rMs) é o tumor de tecidos moles mais comum da infância. Pode ser classificado em dois subtipos principais: o rabdomiossarcoma alveolar (rMsa) e o embrionário (rMse). no rMsa, o prognóstico é desfavorável quando comparado ao rMse, necessitando de tratamento intensificado; dessa forma, a distinção entre ambos os subtipos é fundamental. citogeneticamente, o rMsa apresenta translocações cromossômicas envolvendo o gene FOXO1 em 80% dos casos. a metodologia de hibridização in situ por fluorescência (FisH) tem sido muito utilizada para caracterizar o rMsa. Relato do caso: Paciente do sexo feminino, com 7 anos de idade, apresentou ao diagnóstico rMsa parameníngeo, sem metástase ao diagnóstico. a análise por meio de FisH mostrou a translocação envolvendo o gene FOXO1 e uma cópia extra desse gene. a paciente foi incluída no protocolo de tratamento do epssG, classificada como grupo de alto risco e recebeu quimioterapia e radioterapia. no final do tratamento, foi observada resposta parcial e iniciada quimioterapia de segunda linha. não houve resposta clinicorradiológica e a paciente evoluiu com progressão de doença local refratária ao tratamento e óbito após um ano do diagnóstico. Conclusão: de acordo com o nosso conhecimento, é a primeira descrição de um caso de rMsa apresentando a translocação do gene FOXO1 e uma cópia extra desse gene em clones separados. são necessários ainda novos estudos, a fim de compreender melhor o significado prognóstico da presença dessas alterações.

Introduction:rhabdomyosarcoma (rMs) is the most common soft tissue tumor of childhood. it can be classified into two main subtypes: alveolar rhabdomyosarcoma (arMs) and embryonal (erMs). in arMs the prognosis is unfavorable when compared to erMs, requiring intensified treatment, thus the distinction between both subtypes is fundamental. cytogenetically, arMs present chromosomal translocations involving the FOXO1 gene in 80% of the cases. The fluorescence in situ hybridization methodology (FisH) has been widely used to characterize arMs subtype. Case Report: a 7-year-old female patient presented with parameningeal arMs, non-metastatic at diagnosis. FisH analysis showed translocation involving the FOXO1 gene and an extra copy of this gene. The patient was enrolled in the epssG treatment protocol, classified as a high-risk group and received chemotherapy and radiotherapy. at the end of treatment a partial response was observed, and second line chemotherapy was started. There was no clinical-radiological response and the patient progressed with local disease, refractory to rescue treatment and died of disease one year after diagnosis. Conclusion:to our knowledge, this is the first case of arMs presenting FOXO1 gene translocation and an extra copy of this gene in separate clones. More studies are necessary to understand the prognostic significance of these alterations

Introducción: el rabdomiosarcoma (rMs) es el tumor de tejidos blandos más común de la infancia. el rMs puede clasificarse en dos subtipos principales, el rabdomiosarcoma alveolar (rMsa) y el embrionario (rMse). el rMsa presenta un pronóstico desfavorable si se compara al rMse, habiendo así necesidad de intensificación del tratamiento. de esta forma, la distinción entre rMsa y rMse es fundamental. citogéticamente, el rMsa presenta en cerca del 80% de los casos de translocación cromosómica que involucra el gen FOXO1. la metodología de Hibridación fluorescente in situ (FisH) ha sido muy utilizada para caracterizar el rMsa. Caso de estudio: Paciente del sexo femenino, de 7 años de edad presentada con un diagnóstico de rMsa parameningeo, sin metástasis. el análisis a través del FisH mostró la translocación envolviendo el gen FOXO1 y una copia extra de este gen. la paciente fue incluida en el protocolo de tratamiento del epssG, clasificado como grupo de alto riesgo y recibió quimioterapia y radioterapia. al final del tratamiento fue observada una respuesta parcial y se inició la quimioterapia de segunda línea. no hubo respuesta clínico-radiológica y la paciente evolucionó con progresión de enfermedad local, refractaria y óbito después de 1 año del diagnóstico. Conclusión: de acuerdo con nuestro conocimiento, este es el primer caso de un niño con rMsa presentando la translocación del gen FOXO1 y una copia extra de este gen en clones separados. se necesitan nuevos estudios para comprender mejor el significado pronóstico de la presencia de estos cambios.

Cytogenetic as an important tool for diagnosis and prognosis for patients with hypocellular primary myelodysplastic syndrome.

We analyzed cytogenetically 105 patients with hypocellular primary MDS and their clinical implications. The main chromosomal abnormalities found were del(5q)/-5, del(6q)/+6, del(7q)/-7, del(11q), and del(17p). Pediatric patients had a higher frequency of abnormal karyotypes compared with adult patients (P < 0,05). From our patients, 18% showed evolution of the disease. The chromosomal abnormalities presented in the diagnosis of patients who evolved to AML included numerical (-7, +8) and structural del(6q), del(7q), i(7q), t(7;9), i(9q), and del(11q) abnormalities and complex karyotypes. Although the frequency of evolution from hypocellular MDS to AML is low, our results suggest that some chromosomal alterations may play a critical role during this process. We applied the IPSS in our patients because this score system has been proved to be useful for predicting evolution of disease. When we considered the patients according to group 1 (intermediate-1) and group 2 (intermediate-2 and high risk), we showed that group 2 had a high association with respect to the frequency of abnormal karyotypes (P < 0,0001), evolution of disease (P < 0,0001), and mortality (P < 0,001). In fact, the cytogenetic analysis for patients with hypocellular primary MDS is an important tool for diagnosis, prognosis, in clinical decision-making and in follow-up.

Human induced pluripotent stem cells from basic research to potential clinical applications in cancer.

The human induced pluripotent stem cells (hiPSCs) are derived from a direct reprogramming of human somatic cells to a pluripotent stage through ectopic expression of specific transcription factors. These cells have two important properties, which are the self-renewal capacity and the ability to differentiate into any cell type of the human body. So, the discovery of hiPSCs opens new opportunities in biomedical sciences, since these cells may be useful for understanding the mechanisms of diseases in the production of new diseases models, in drug development/drug toxicity tests, gene therapies, and cell replacement therapies. However, the hiPSCs technology has limitations including the potential for the development of genetic and epigenetic abnormalities leading to tumorigenicity. Nowadays, basic research in the hiPSCs field has made progress in the application of new strategies with the aim to enable an efficient production of high-quality of hiPSCs for safety and efficacy, necessary to the future application for clinical practice. In this review, we show the recent advances in hiPSCs' basic research and some potential clinical applications focusing on cancer. We also present the importance of the use of statistical methods to evaluate the possible validation for the hiPSCs for future therapeutic use toward personalized cell therapies.

Trisomy 11 as an additional chromosome alteration in a child with acute promyelocytic leukemia with poor prognosis.

The prognostic significance of the additional abnormalities to the t(15; 17) remains controversial. We report a case of promyelocytic leukemia (APL) in a ten-year-old boy. Classical and molecular cytogenetic (FISH) studies of a bone marrow sample obtained at diagnosis revealed the presence of trisomy of chromosome 11 as an additional chromosomal abnormality to the t(15; 17). The presence of the translocation t(15; 17), the cytogenetic marker of APL, is usually associated with good response to treatment with ATRA. In this case, although the patient had risk factors associated with good prognosis, he evolved and died quickly. So it seems that the presence of the trisomy 11 may be associated with disease progression and the poor outcome. To our knowledge, this is the first reported case of t(15; 17) associated with trisomy of chromosome 11 in a child with APL.

The impact of addictional chromosomal abnormalities in response to imatinib mesylate therapy for chronic myeloid leukemia

Imatinib induces a complete cytogenetic response in more than 80% of newly diagnosed patients with chronicmyeloid leukemia (CML) in the chronic phase (CP) and in 41% of patients in the first chronic phase after failureof interferon- treatment. However, some patients do not respond completely. Therefore, according to moststudies, drug resistance in CML patients treated with imatinib is correlated with cytogenetic abnormalities acquiredduring treatment. In this study we analyzed 48 CML patients treated with imatinib mesylate after interferon- resistance in order to elucidate the impact of additional chromosomal abnormalities prior to imatinib in response to therapy. Cytogenetic abnormalities in addition to the Philadelphia chromosome (Ph) were detected in 33.3% of patients. Patients with Ph as the sole cytogenetic abnormality prior to imatinib therapy presented a major cytogeneticresponse and significantly longer median overall survival (p=0.006) than patients with additional chromosomalabnormalities. Therefore, in this group of patients, another choice of treatment should be considered, such as stemcell transplantation or combination regimens as appropriate. The present study indicates the importance of detecting a double Ph chromosome prior to imatinib therapy. Patients showing this abnormality did not respond to imatinib, thus indicating the abnormality's association with resistance. Our study suggests that classical cytogenetic analysisis still an important tool prior to and during follow-up of CML patients treated with imatinib.

Imatinibe induz à resposta citogenética completa em cerca de 80 por cento dos pacientes diagnosticados com leucemia mielóide crônica (LMC) em fase crônica (FC), e em 41 por cento dos pacientes em primeira FC após falha do tratamento com interferon-alfa. Alguns pacientes, entretanto, não respondem completamente. Em muitos estudos, a resistência à droga em pacientes tratados com imatinibe é correlacionada a alterações cromossômicas adquiridas durante o tratamento. No presente estudo, foram analisados 48 pacientes tratados com imatinibe após resistência ao interferon-alfa, com o objetivo de verificar o impacto das alterações cromossômicas adicionais ao Philadelphia (Ph), prévias à terapia com imatinibe. Alterações adicionais foram detectadas em 33,3 por cento dos pacientes. Pacientes com somente o cromossomo Ph apresentaram melhor taxa de resposta citogenética e sobrevida global significativa maior quando comparados com os pacientes que apresentavam alterações cromossômicas adicionais antes do início da terapia com imatinibe. Assim, nesse grupo de pacientes, a escolha de outra conduta terapêutica, como o transplante de células tronco-hematopoéticas ou regime de combinação de drogas, pode ser indicada. O presente estudo indica a importância do duplo Ph antesdo início da terapia com imatinibe. Todos os pacientes com esta alteração não responderam ao tratamento, sendo a mesma associada à resistência à droga. Este estudo sugere que a citogenética clássica permanece como uma ferramenta importante no monitoramento de pacientes portadores de LMC tratados com imatinibe.

Karyotype abnormalities and their clinical significance in a group of chronic myeloid leukemia patients treated with hematopoietic stem cell transplantation.

CONTEXT AND OBJECTIVE: Following hematopoietic stem cell transplantation (HSCT), karyotyping is a valuable tool for monitoring engraftment and disease status. Few studies have examined the prognostic significance of karyotypes in patients who underwent HSCT for chronic myeloid leukemia (CML). The objective of this study was to evaluate the significance of pretransplantation cytogenetic status in relation to outcomes following HSCT in CML patients. DESIGN AND SETTING: Case series study at Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil. METHODS: Cytogenetic analysis was performed by G banding on 39 patients treated with HSCT. RESULTS: Thirty-one patients were in the chronic phase and eight were in the accelerated phase. Prior to HSCT, additional chromosomal abnormalities on the Philadelphia (Ph) chromosome were found in 11 patients. The most frequent additional abnormality was a double Ph, which was observed in four cases. Following HSCT, full chimeras were observed in 31 patients (79.5%). Among these, 23 (82.3%) had presented Ph as the sole abnormality. Mixed chimeras were observed in seven patients, of which three had additional abnormalities. Only one case did not present any cytogenetic response. Five patients presented cytogenetic relapse associated with clinical relapse following HSCT. Twenty-seven patients are still alive and present complete hematological and cytogenetic remission. CONCLUSION: In our study, the presence of additional abnormalities was not associated with worse outcome and relapse risk. Also, no differences in survival rates were observed. Our study supports the view that classical cytogenetic analysis remains an important tool regarding HSCT outcome.

Cytogenetic biclonality in a child with hypocellular primary myelodysplastic syndrome.

A 13-year-old boy with hypocellular primary myelodysplastic syndrome, classified as refractory cytopenia, underwent umbilical cord blood transplantation. Cytogenetic analysis revealed two rare biclonal chromosomal aberrations, del(17)(p12) and del(11)(q23). Cytogenetic analysis was a valuable tool in diagnosis, in clinical decision-making, and in treatment and follow-up. To our knowledge, this is the first reported case of cytogenetic biclonality involving chromosomes 17 and 11.

Karyotype abnormalities and their clinical significance in a group of chronic myeloid leukemia patients treated with hematopoietic stem cell transplantation

CONTEXT AND OBJECTIVE: Following hematopoietic stem cell transplantation (HSCT), karyotyping is a valuable tool for monitoring engraftment and disease status. Few studies have examined the prognostic significance of karyotypes in patients who underwent HSCT for chronic myeloid leukemia (CML). The objective of this study was to evaluate the significance of pretransplantation cytogenetic status in relation to outcomes following HSCT in CML patients. DESIGN AND SETTING: Case series study at Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brazil. METHODS: Cytogenetic analysis was performed by G banding on 39 patients treated with HSCT. RESULTS: Thirty-one patients were in the chronic phase and eight were in the accelerated phase. Prior to HSCT, additional chromosomal abnormalities on the Philadelphia (Ph) chromosome were found in 11 patients. The most frequent additional abnormality was a double Ph, which was observed in four cases. Following HSCT, full chimeras were observed in 31 patients (79.5 percent). Among these, 23 (82.3 percent) had presented Ph as the sole abnormality. Mixed chimeras were observed in seven patients, of which three had additional abnormalities. Only one case did not present any cytogenetic response. Five patients presented cytogenetic relapse associated with clinical relapse following HSCT. Twenty-seven patients are still alive and present complete hematological and cytogenetic remission. CONCLUSION: In our study, the presence of additional abnormalities was not associated with worse outcome and relapse risk. Also, no differences in survival rates were observed. Our study supports the view that classical cytogenetic analysis remains an important tool regarding HSCT outcome.

RESUMO CONTEXTO E OBJETIVO: Após o transplante de células tronco-hematopoéticas (TCTH), o cariótipo é uma ferramenta valiosa para monitorar o status do enxerto e da doença. Poucos estudos investigaram o significado prognóstico do cariótipo nos pacientes que se submeteram ao TCTH para leucemia mielóide crônica (LMC). O objetivo desse estudo foi verificar o significado dos achados citogenéticos pré-TCTH em pacientes portadores de LMC. TIPO DE ESTUDO E LOCAL: Série de casos. Instituto Nacional do Câncer (INCA), Rio de Janeiro, Brasil. METODOLOGIA: Foram realizados estudos citogenéticos por bandeamento G em 39 pacientes submetidos ao TCTH. RESULTADOS: Trinta e um pacientes estavam em fase crônica e oito em fase acelerada. Pré-TCTH, alterações cromossômicas adicionais ao cromossomo Philadelphia (Ph) foram observadas em 11 pacientes. A mais freqüente foi o duplo Ph observado em quatro casos. Após o TCTH, quimerismo total foi observado em 31 pacientes (79,5 por cento). Desses, 23 (82,3 por cento) apresentavam somente o cromossomo Ph. Quimerismo misto foi observado em sete pacientes, sendo três com alterações adicionais ao Ph. Um caso não apresentou resposta ao TCTH. Recaída citogenética associada com recaída clínica foi observada em cinco pacientes. Após o TCTH, 27 pacientes permanecem vivos e com remissão clínica e citogenética. CONCLUSÃO: Em nosso estudo a presença de alterações cromossômicas adicionais ao Ph, prévias ao TCTH, não foi associada com pior evolução, com risco de recaída, bem como não foi observada diferença entre as taxas de sobrevida. Nosso estudo sugere que a citogenética clássica permanece uma grande ferramenta no monitoramento do TCTH.