RESUMO
Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3 years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (±0.10) and 45% (±0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials.
Assuntos
Neoplasias Encefálicas/terapia , Tumor Rabdoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Terapia Combinada , Europa (Continente)/epidemiologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Sistema de Registros , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Falha de Tratamento , Resultado do TratamentoRESUMO
We report on how MLPA and Sequencing of SMARCB1/INI1/SNF5 might be applied for initial diagnosis of rhabdoid tumor patients. These techniques were successfully used to detect loss of SMARCB1 in tumor cells of the ascites in a 3-month-old patient in which tumor biopsy could not initially be made due to life threatening intraabdominal bleedings.
Assuntos
Neoplasias Abdominais/diagnóstico , Ascite/patologia , Biomarcadores Tumorais/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Tumor Rabdoide/diagnóstico , Fatores de Transcrição/metabolismo , Neoplasias Abdominais/genética , Neoplasias Abdominais/metabolismo , Ascite/genética , Ascite/metabolismo , Biomarcadores Tumorais/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Lactente , Técnicas de Amplificação de Ácido Nucleico , Reação em Cadeia da Polimerase , Prognóstico , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Proteína SMARCB1 , Fatores de Transcrição/genéticaRESUMO
Among infant malignancies, congenital tumors, especially those of the central nervous system (CNS), constitute a rather unique subgroup. Poor survival rates (28% in CNS tumors) may be attributed to the aggressive biology as well as specific therapeutic limitations innate to the young age of affected patients. Our patient developed synchronous congenital tumors: an atypical teratoid/rhabdoid tumor (AT/RT) localized in the right lateral ventricle of the brain and a malignant rhabdoid tumor (MRT) in the soft tissue of the right orbit. A de novo germline chromosomal deletion in 22q encompassing the SMARCB1 gene was detected, prompting the diagnosis of a de novo rhabdoid tumor predisposition syndrome 1 (RTPS1). The patient was reported to the European Rhabdoid Registry (EU-RHAB) and treated according to the Rhabdoid 2007 recommendation. Despite the very young age of the patient, the initially desperate situation of RTPS1, and the synchronous localization of congenital rhabdoid tumors, intensive chemotherapy was well tolerated; the child is still in complete remission 5 years following diagnosis. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with a detrimental outcome. Intensive multidrug chemotherapy, including high dose chemotherapy, may be feasible and justified.
Assuntos
Neoplasias Encefálicas/congênito , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias Orbitárias/congênito , Tumor Rabdoide/congênito , Teratoma/congênito , Fatores de Transcrição/genética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Terapia Combinada , Feminino , Humanos , Neoplasias Renais/congênito , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Primárias Múltiplas/congênito , Neoplasias Primárias Múltiplas/patologia , Neoplasias Orbitárias/patologia , Neoplasias Orbitárias/terapia , Tumor Rabdoide/patologia , Tumor Rabdoide/terapia , Proteína SMARCB1 , Sobreviventes , Teratoma/patologia , Teratoma/terapiaAssuntos
DNA Helicases/genética , DNA Helicases/metabolismo , Predisposição Genética para Doença/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tumor Rabdoide/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Tumor Rabdoide/mortalidade , Análise de SobrevidaRESUMO
Rhabdoid tumors are rare but highly aggressive malignancies of infancy and early childhood with a generally unfavorable prognosis. Despite a wide variety of anatomic locations rhabdoid tumors share mutational inactivation of the SWI/SNF (SWItch/Sucrose NonFermentable) core component gene SMARCB1 (also known as INI1, hSNF5 or BAF47) in chromosome 22. As this inactivation usually results in loss of SMARCB1 expression, detectable by an antibody against the SMARCB1 protein, the accurate diagnosis of a rhabdoid tumor may be more distinctly and frequently made. Several reports on rhabdoid tumors presenting in various anatomic sites outside the kidneys and CNS are on record. We report two cases of rhabdoid tumors originating in the heart (cardiac tissue), which were entered into the European Rhabdoid Registry (EU-RHAB). The first case presented with intracardial and -cranial lesions as well as malignant ascites, while the second patient demonstrated an isolated cardiac tumor. This induced a different therapeutic approach and subsequently different clinical course (death 7 weeks after diagnosis in patient 1). Patient 2 presented with a bifocal intracardial tumor without metastases and remains in complete remission for 46 months since diagnosis following multimodal therapy. The second case demonstrates that even in a potentially futile clinical situation early and accurate diagnosis followed by prompt and intensive multimodal therapy may offer prolonged survival, potential cure and improved quality of life.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patologia , Transplante de Células-Tronco de Sangue Periférico , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteínas Cromossômicas não Histona/biossíntese , Proteínas Cromossômicas não Histona/genética , Terapia Combinada , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Neoplasias Cardíacas/terapia , Humanos , Lactente , Masculino , Mutação , Metástase Neoplásica , Sistema de Registros , Tumor Rabdoide/terapia , Proteína SMARCB1 , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Atypical teratoid/rhabdoid tumours (AT/RT) are malignant brain tumours. Unlike most other human brain tumours, AT/RT are characterized by inactivation of one single gene, SMARCB1. SMARCB1 is a member of the evolutionarily conserved SWI/SNF chromatin remodelling complex, which has an important role in the control of cell differentiation and proliferation. Little is known, however, about the pathways involved in the oncogenic effects of SMARCB1 inactivation, which might also represent targets for treatment. Here we report a comprehensive genetic screen in the fruit fly that revealed several genes not yet associated with loss of snr1, the Drosophila homologue of SMARCB1. We confirm the functional role of identified genes (including merlin, kibra and expanded, known to regulate hippo signalling pathway activity) in human rhabdoid tumour cell lines and AT/RT tumour samples. These results demonstrate that fly models can be employed for the identification of clinically relevant pathways in human cancer.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Drosophila/genética , Tumor Rabdoide/genética , Teratoma/genética , Fatores de Transcrição/genética , Animais , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Drosophila melanogaster , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Proteína SMARCB1 , Transdução de Sinais , Proteínas Supressoras de Tumor/genéticaRESUMO
Rhabdoid tumors are highly aggressive tumors occurring in infants and very young children. Despite multimodal and intensive therapy prognosis remains poor. Molecular analyses have uncovered several deregulated pathways, among them the CDK4/6-Rb-, the WNT- and the Sonic hedgehog (SHH) pathways. The SHH pathway is activated in rhabdoid tumors by GLI1 overexpression. Here, we demonstrate that arsenic trioxide (ATO) inhibits tumor cell growth of malignant rhabdoid tumors in vitro and in a mouse xenograft model by suppressing Gli1. Our data uncover ATO as a promising therapeutic approach to improve prognosis for rhabdoid tumor patients.
Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Óxidos/farmacologia , Tumor Rabdoide/tratamento farmacológico , Fatores de Transcrição/metabolismo , Animais , Apoptose , Trióxido de Arsênio , Ciclo Celular , Proliferação de Células , Biologia Computacional , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos SCID , Transplante de Neoplasias , Prognóstico , Transdução de Sinais , Proteína GLI1 em Dedos de ZincoRESUMO
Rhabdoid tumor predisposition syndrome is usually associated with shorter survival in patients with malignant rhabdoid tumors regardless of anatomical origin. Here we present four children harboring truncating heterozygous SMARCB1/INI1 germline mutations with favorable outcome. All four patients received multi-modality treatment, three according to therapeutic recommendations by the EU-RHAB registry, two without radiotherapy, and mean event-free survival accounts for 7 years. In conclusion, intensive treatment with curative intent is justified for children with rhabdoid tumors even if an underlying rhabdoid predisposition syndrome is demonstrated.
Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Tumor Rabdoide/genética , Tumor Rabdoide/terapia , Fatores de Transcrição/genética , Criança , Pré-Escolar , Terapia Combinada , Feminino , Heterozigoto , Humanos , Recém-Nascido , Masculino , Tumor Rabdoide/diagnóstico , Proteína SMARCB1 , Síndrome , Resultado do TratamentoRESUMO
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignant pediatric brain tumor characterized by genetic alterations affecting the SMARCB1 (hSNF5/INI1) locus in chromosome band 22q11.2. To identify potential additional genetic alterations, high-resolution genome-wide analysis was performed using a molecular inversion probe single-nucleotide polymorphism (MIP SNP) assay (Affymetrix OncoScan formalin-fixed paraffin-embedded express) on DNA isolated from 18 formalin-fixed paraffin-embedded archival samples. Alterations affecting the SMARCB1 locus could be demonstrated by MIP SNP in 15 out of 16 evaluable cases (94%). These comprised five tumors with homozygous deletions, six tumors with heterozygous deletions, and four tumors with copy number neutral loss of heterozygosity (LOH) involving chromosome band 22q11.2. Remarkably, MIB SNP analysis did not yield any further recurrent chromosomal gains, losses, or copy neutral LOH. On MIP SNP screening for somatic mutations, the presence of a SMARCB1 mutation (c.472C>T p.R158X) was confirmed, but no recurrent mutations of other cancer relevant genes could be identified. Results of fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and SMARCB1 sequencing were highly congruent with that of the MIP SNP assay. In conclusion, these data further suggest the absence of recurrent genomic alterations other than SMARCB1 in AT/RT.
Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Mutação , Tumor Rabdoide/genética , Fatores de Transcrição/genética , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Feminino , Deleção de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Perda de Heterozigosidade , Masculino , Reação em Cadeia da Polimerase Multiplex , Polimorfismo de Nucleotídeo Único , Proteína SMARCB1RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths. Difficulties to diagnose HCC at early stages remain the major obstacle to curative (surgical) therapy. Therapy in advanced stages has to be considered palliative. In this situation, a considerable amount of attention should be paid to innovative treatment strategies, e.g. including antiangiogenetic drugs. RESULTS: We report on the successful treatment of a patient suffering from progressive HCC with a novel drug (EndoTAG-1, formerly named LipoPac) currently investigated in phase II studies. This drug consists of liposomally encapsulated paclitaxel. Its liposomal formulation favors the drug's adherence to the tumor neovasculature, in effect starving the tumor. CONCLUSIONS: EndoTAG-1 stopped tumor progression for 9 months in our patient. This, along with successes observed testing this drug against other indications, makes it a suitable candidate for future clinical trials.