RESUMO
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Ataxia Telangiectasia/genética , Proteínas de Neoplasias/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Ataxia Telangiectasia/complicações , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Pré-Escolar , Cromossomos Humanos/ultraestrutura , Cromotripsia , Reparo do DNA/genética , DNA de Neoplasias/genética , Feminino , Genoma Humano , Instabilidade Genômica , Humanos , Hibridização in Situ Fluorescente , Masculino , Mutação , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , RNA Neoplásico/genética , Análise de Sequência de DNA , Análise de Sequência de RNA , Encurtamento do Telômero/genética , TranscriptomaRESUMO
BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Terapia Neoadjuvante , Tumor de Wilms/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Estadiamento de Neoplasias , Nefrectomia , Nefroma Mesoblástico/tratamento farmacológico , Nefroma Mesoblástico/mortalidade , Nefroma Mesoblástico/patologia , Nefroma Mesoblástico/cirurgia , Prognóstico , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/mortalidade , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/mortalidade , Sarcoma de Células Claras/patologia , Sarcoma de Células Claras/cirurgia , Tumor de Wilms/mortalidade , Tumor de Wilms/patologia , Tumor de Wilms/cirurgiaRESUMO
We describe a patient initially diagnosed with a chronic myeloproliferative disorder in the accelerated phase. Cytogenetic analysis showed the presence of two independent clones. One clone contained a typical Philadelphia (Ph) chromosome due to t(9;22)(q34;q11), as the sole abnormality which was proven molecularly to result in the b2a2-BCR/ABL fusion. The other clone displayed a complex karyotype with several structural and numerical aberrations including trisomy 11 and 22 but lacking a t(9;22) or any other structural abnormalities involving chromosomes 9 and 22. Fluorescence in situ hybridization demonstrated that the t(9;22) was present only in cells with two copies of chromosomes 11 and 22. In contrast, cells with trisomies 11 and 22 lacked evidence for a BCR/ABL fusion. Based on the genetic findings, simultaneous chronic and acute myelocytic leukemias were diagnosed rather than a blastic phase of a chronic myelocytic leukemia.
Assuntos
Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Idoso , Medula Óssea/fisiologia , Cromossomos Humanos , Análise Citogenética , Diagnóstico Diferencial , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Cromossomo Filadélfia , Translocação GenéticaRESUMO
Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol, 10 000 U/m2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on d 8, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on d 4 and d 11 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100 U/l for at least 14 d was determined in 43 of the 45 patients who were analysed for enzyme activity.
Assuntos
Asparaginase/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Escherichia coli/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Adolescente , Anafilaxia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Asparaginase/sangue , Asparaginase/farmacocinética , Criança , Pré-Escolar , Monitoramento de Medicamentos , Ativação Enzimática , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Estudos ProspectivosRESUMO
BACKGROUND: Preradiation chemotherapy could be beneficial in malignant brain tumors, because the blood-brain tumor-barrier is disrupted after surgery, bone marrow recovery--essential for intense chemotherapy--is still intact, and CNS toxicity and ototoxicity of active drugs are lower before irradiation of a child's brain. PATIENTS AND METHODS: A neoadjuvant phase 2 and a single arm pilot trial were initiated to investigate the efficacy and toxicity of an intense multidrug regimen before radiotherapy in 147 patients aged between 3 and 29; 9 years with medulloblastoma (94), malignant glioma (22), ependymoma (21), and stPNET (10). They were treated with one or two cycles consisting of procarbazine, ifosfamide/mesna with etoposide, high dose methotrexate/CF, and cisplatin with cytarabine. RESULTS: Radiation therapy was delayed for 17-30 weeks (median 23 weeks) in 112 patients who received two cycles. Chemotherapy was well tolerated. Serious infections were observed in 20 patients, with one fatal fungal septicemia. In 69 high risk patients with a residual tumor and/or solid CNS metastases an objective response (CR plus PR) was achieved in 67% medulloblastoma, 57% stPNET, 55% anaplastic ependymoma and 25% malignant glioma. Progression-free survival (PFS) at 5 years was 57% in 14 high risk patients with medulloblastoma, who achieved a complete response (CR). After a less than CR the PFS was 20% (p = 0.01). Overall survival at 5 years was 57% in medulloblastoma, 62% in ependymoma, 36% in malignant glioma and 30% in stPNET. CONCLUSION: The HIT'88/'89 regimen was well tolerated and efficacious in regard to response rates and early PSF particularly in medulloblastoma and anaplastic ependymoma. Based on these results the prospectively randomized trial HIT'91 was designed to investigate the optimal timing of chemotherapy. Preradiation chemotherapy according to the HIT'88/'89 regimen was compared with the standard regimen using CCNU, cisplatin, and vincristine after radiation therapy. Additionally, strict quality control of the three treatment modalities was instituted to help improve the survival rates in both trial arms.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Terapia Neoadjuvante , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Projetos Piloto , Taxa de SobrevidaRESUMO
This notebook which is of postcard size contains important information in case of emergency and details about the current illness and treatment. It contains follow-up information about the pattern of growth, endocrinological development and assessment of renal tubular function. The necessary follow-up investigations and their frequency are summarized in a table as a guide for patients, parents and paediatricians.
Assuntos
Documentação/métodos , Neoplasias/terapia , Folhetos , Educação de Pacientes como Assunto/métodos , Assistência ao Convalescente/métodos , Criança , Seguimentos , Humanos , Registros Médicos Orientados a ProblemasRESUMO
The clinical features of polymorphous light eruption (PLE) are reviewed from the literature with special emphasis on the experimental reproduction of skin lesions. Our clinical experience with 180 patients is reported. In forty-three patients a newly developed UVA provocation test was performed. UVA, free of sunburn radiation (50-100 J/cm2), was administered, sometimes repeatedly up to four times, to large sites of previously involved skin. With this technic the reproduction of PLE lesions under laboratory conditions was possible in 90% of this group of forty-three patients. The diagnosis was substantiated by microscopic examination of genuine and experimentally induced lesions. Characteristic histologic features of PLE are described. Phototesting with large doses of UVA aids in confirming the diagnosis of PLE. Hitherto, this diagnosis depended often on exclusion of other dermatoses. Eusolex 8021, a UVA-effective sunscreen, blocked eruptions of PLE lesions under laboratory conditions. An effective means of treatment is offered by PUVA therapy.
Assuntos
Transtornos de Fotossensibilidade/diagnóstico , Testes Cutâneos , Raios Ultravioleta , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Luz , Masculino , Pessoa de Meia-Idade , Terapia PUVA , Transtornos de Fotossensibilidade/classificação , Transtornos de Fotossensibilidade/tratamento farmacológico , Pele/patologia , Luz Solar , Protetores Solares/uso terapêuticoRESUMO
Suntan is known to be protective against sunburn resulting from medium-wavelength ultraviolet radiation. Protection against UV-B by UV-A-induced pigmentation was studied by the evaluation of the erythema produced and by histologic alterations in the epidermis, including sunburn cell counts. Six subjects were deeply tanned with UV-A (mean cumulative dose, 700 joules/sq cm). The minimal erythemal dose to UV-B (300 +/- 5 nm) was established for each subject in normal skin and in UV-A-tanned areas. The UV-A tan provided measurable protection against UV-B-induced erythema. Following UV-B irradiation, 36 to 93 sunburn cells were counted per 10 mm of epidermal surface length in histologic sections of untanned skin as compared with four to seven sunburn cells in UV-A-tanned skin.
Assuntos
Queimadura Solar/prevenção & controle , Raios Ultravioleta , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Pele/patologia , Pele/fisiopatologia , Pigmentação da Pele/efeitos da radiação , Queimadura Solar/patologia , Queimadura Solar/fisiopatologiaRESUMO
By treatment of the mouse leukemia L 1210 with cytosinarabinoside (120 mg/kg per week) a tumour cell line was developed which was resistant to this cytostatic agent. It is possible, using the short-term test, to follow the development of resistance to cytosinarabinoside.
Assuntos
Leucemia L1210/tratamento farmacológico , Animais , Citarabina/uso terapêutico , Resistência a Medicamentos , CamundongosRESUMO
Results of exfoliative gastric cytology from two periods were compared (779 examinations in the first period, 598 in the second). In 85% of cytological examinations, a histologic diagnosis was available. 64% of histologically verified carcinoma were diagnosed by cytology, too. In the second period the percentage of false positive findings decreased from 4,7% to 1,1% and the rate of suspicious findings from 3,7% to 1,5%. The proportion of carcinomas not detected by cytology increased from 32% to 35%. The rate of correct diagnosis of two contributors remained constant (53% resp. 71%). Improvement of diagnostic accuracy depends upon better technique of yield of material by endoscopists.
Assuntos
Neoplasias Gástricas/diagnóstico , Humanos , Métodos , Controle de Qualidade , Manejo de Espécimes , Neoplasias Gástricas/patologiaRESUMO
Cytological smears from 779 cases were examined over a three-year period, cell collection and cytological diagnosis being in separate hands (material sent in from outside). Three quarters of the cytological findings could be compared with the histological diagnosis: 68% of 194 histologically proven malignant tumours were diagnosed cytologically. The diagnostic accuracy varied between 53 and 74.4%, depending on experience and precision of the endoscopist. In 18 cytologically positive cases results were different from the histological diagnosis. Initial diagnosis of malignant tumour by cytology was made in 3.6% of cases. Subsequently repeated biopsies or histological examination of surgical specimens confirmed the diagnosis.