Assuntos
Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Promielocítica Aguda/genética , Mutação , Reação em Cadeia da Polimerase/métodos , Proteína da Leucemia Promielocítica/genética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Acute myeloid leukemia (AML) is a heterogeneous disease increasing in frequency owing to an aging population. Decisions on intensive induction treatments, intensification and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task; here we examine those variables useful in assessing prognosis for a patient with non-acute promyelocitic AML focusing on core binding factor leukemia. In clinical practice, when counseling an individual patient with AML, a range of well-known clinical variables (age, performance status and tumor burden) and genetic variables (cytogenetic and gene mutation) must be considered to better define the prognostic risk.
RESUMO
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are represented by rare but life-threatening cutaneous adverse reactions to different drugs. Previous studies have found that in a Han Chinese population from Taiwan and other Asian Countries, a strong genetic association between HLA-class I alleles (B*15:02, B*58:01) and SJS and TEN was induced by carbamazepine and allopurinol, respectively. To identify genetic markers that covered the MHC region, we carried out a case-control association enrolling 20 Caucasian patients with SJS/TEN. Our patient series included 10 cases related to paracetamol, 7 to allopurinol and 3 to different drugs (plaquenil, itraconazol, nabumetone). Healthy controls were represented by 115 Caucasian bone marrow or stem cell donors. The HLA-A*, B*, C*, DRB1*, DQB1*, DQA1* and DPB1* genotyping were determined. The frequencies of HLA-A*33:03 as well as C*03:02 and C*08:01 were significantly higher in SJS/TEN patient subgroup showing allopurinol drug-induced severe cutaneous adverse reactions (SCAR) as compared to controls (28.6% vs 0%, P=0.00002, Pc=0.0011; 28.6% vs 0%, P=0.00002, Pc=0.001; 28.6% vs 0%, P=0.00002, Pc=0.001, respectively). In the same subgroup the frequencies of B*58:01, DRB1*15:02 and DRB1*13:02 alleles, although considerably higher than in control group (42.8% vs 5.2%, P=0.003; 28.6% vs 1.7%, P=0.005; 28.6% vs 3.5%, P=0.037, respectively), appeared no more statistically different after P correction (Pc=0.248; Pc=0.29; Pc=1.00, respectively). In addition, in 10 of the 20 SJS/TEN patient subgroup with paracetamol-induced SCAR no statistically significant association with HLA alleles could be found. However, in the same SJS/TEN patient subgroup showing allopurinol drug-induced SCAR, haplotype analysis indicated that B*58:01, DRB1*13:02 and DRB1*15:02 alleles, that in a single allele analysis lost statistical significance after P correction, may still confer susceptibility, because the B*58:01-DRB1*13:02 and DRB1*15:02-DQB1*05:02 are positively associated with the disease (14.2% vs 0.43%, P= 0.00001, Pc=0.00028; 14.2% vs 0.43%, P=0.00001, Pc=0.00028, respectively). Our results show that in contrast to SCAR-related to paracetamol, where HLA alleles do not appear to be involved, HLA molecules behave as a strong risk factor for SCAR-related to allopurinol even when a limited number of patients are considered.
Assuntos
Alelos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Síndrome de Stevens-Johnson/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Haplótipos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Síndrome de Stevens-Johnson/imunologia , Adulto JovemRESUMO
AIM: To verify whether, with thorough practical and theoretical training, well-controlled, non-complicated diabetic patients can safely go diving underwater with no additional medical or metabolic risks. METHODS: Twelve diabetic patients participated in the study after undergoing training focused on their diabetic status. Two dives per day were scheduled during two five-day stays on the island of Ventotene (Italy). Capillary blood glucose (BG) was checked at 60, 30 and 10 minutes before diving, and corrective measures adopted if necessary, based on BG absolute levels and dynamics. A device for continuous subcutaneous glucose monitoring (CGM), expressly modified for the purpose, was worn during dives. RESULTS: Data were gathered from 90 dives; mean BG at 60, 30 and 10 minutes before diving was 205.8+/-69.6 mg/dL, 200.0+/-66.4 mg/dL and 200.5+/-61.0mg/dL, respectively. In 56 of the 90 dives, supplementary carbohydrates or insulin were necessary, but only one dive was interrupted on account of hypoglycaemic symptoms. Mean post-dive BG was 158.9+/-80.8 mg/dL. CGM recordings showed that glucose levels gradually decreased during the dives (nadir: -19.9%). CONCLUSION: Experienced, well-controlled, complication-free young diabetic patients can safely go scuba diving, provided that they apply a rigorous protocol based on serial pre-dive BG measurements. The specific variables of underwater diving do not appear to involve significant additional risks of hypoglycaemia.
Assuntos
Automonitorização da Glicemia , Glicemia/análise , Diabetes Mellitus Tipo 1/fisiopatologia , Mergulho , Adulto , Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/métodos , Distribuição de Qui-Quadrado , Feminino , Humanos , Hipoglicemia/prevenção & controle , Masculino , Atividade Motora , SegurançaRESUMO
BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Purging da Medula Óssea/métodos , Linfoma Folicular/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Antraciclinas/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Antígenos CD20/metabolismo , Antígenos CD34/análise , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Genes bcl-2 , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Humanos , Fatores Imunológicos/administração & dosagem , Imunossupressores/administração & dosagem , Estimativa de Kaplan-Meier , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Indução de Remissão , Rituximab , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Antifungal therapy may be unable to eradicate invasive mycosis in leukemia patients. The presence of persisting pulmonary nodules owing to mycosis seems to increase the risk of fungal relapse after chemotherapy and transplant procedures. Between 1997 and 2004, 10 acute leukemia patients underwent pulmonary surgery for invasive mycosis. The median time from diagnosis of mycosis to surgery was 135 days (range 21-147). Three patients underwent emergency surgery, owing to hemoptysis. In the other seven patients with nodule/cavitation remaining after antifungal treatment, surgery (three wedge resections, four lobectomies) was scheduled before transplant. Pathologic examination confirmed two aspergillosis and three zygomycosis. The only side effect was pneumothorax in one case. Nine patients were considered cured. Six patients underwent bone marrow transplantation (three allogeneic, three autologous) with antifungal prophylaxis without relapse during the transplant procedure. In selected patients scheduled for bone marrow transplantation, surgical resection of localized pulmonary fungus nodules combined with antifungal prophylaxis seem to be an effective treatment for preventing mycotic relapse.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Pneumopatias Fúngicas/etiologia , Pneumopatias Fúngicas/cirurgia , Adulto , Idoso , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/etiologia , Aspergilose/prevenção & controle , Aspergilose/cirurgia , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mucormicose/tratamento farmacológico , Mucormicose/etiologia , Mucormicose/prevenção & controle , Mucormicose/cirurgia , RecidivaRESUMO
Systematic data on the ability of pegfilgrastim to mobilize stem cells after chemotherapy are scarce. We evaluated the efficacy of a single 6 mg dose of pegfilgrastim for mobilizing peripheral blood stem cells (PBSC) in aggressive lymphoma patients. Between July 2004 and October 2005, 17 aggressive non-Hodgkin's lymphoma and 11 poor-risk Hodgkin's lymphoma were treated with cycles containing cisplatin-aracytin. At the end of chemotherapy, the patients received 6 mg of pegfilgrastim. Duration of grade 4 neutropenia, adverse events, time to neutrophil recovery, peak and harvest of CD34+ cells were recorded. Twenty-seven out of 28 patients harvested a median of 17.3 x 10(6)/CD34+ cells (range 2.5-28.9) after a median of 9 days (range 8-12 days), with a single apheresis procedure in 25 cases. All patients had grade 3-4 neutropenia, median duration 3 days. The only adverse event was mild bone pain. To date, 13 patients have been autografted with a median of 15.4 x 10(6) CD34+ pegfilgrastim-mobilized cells per kg (range 2.5-28.9) with rapid and sustained engraftment. Mobilization, harvesting and autografting of pegfilgrastim-mobilized PBC can be successfully achieved in pretreated patients with aggressive lymphoma.
Assuntos
Antígenos CD34 , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Linfoma não Hodgkin/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Filgrastim , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/complicações , Humanos , Linfoma não Hodgkin/complicações , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Dor , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Polietilenoglicóis , Proteínas Recombinantes , Transplante AutólogoRESUMO
Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5-10 microg/kg/die. Patients failing mobilization or not achieving the target of 2.5 x 10(6) CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800 mg/m(2) every 12 h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.
Assuntos
Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Leucemia Linfocítica Crônica de Células B/terapia , Vidarabina/análogos & derivados , Adulto , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Transplante Autólogo , Vidarabina/administração & dosagemAssuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Transplante de Medula Óssea , Leucemia Promielocítica Aguda/terapia , Óxidos/administração & dosagem , Trióxido de Arsênio , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , RNA Neoplásico/análise , Recidiva , Indução de Remissão/métodos , Terapia de Salvação , Quimeras de Transplante , Transplante HomólogoRESUMO
Mucormycosis infections, caused by fungi of the families Rhizopus, Mucor or Absidia, are typically rapidly progressive and often fatal. We report a 27-year-old male with acute myeloid leukemia (AML) developing an invasive pulmonary-CNS mucormycosis during the neutropenic period after salvage induction chemotherapy; the infection was successfully controlled with surgery and antifungal therapy. The patient received two courses of consolidation chemotherapy and underwent autologous stem cells transplantation (ASCT) while receiving secondary antifungal systemic prophylaxis with liposomal Amphotericin B (L-AMB, Ambisome). There was no clinical, radiological or microbiological evidence of mycotic reactivation during the bone marrow transplantation (BMT) procedure.
Assuntos
Leucemia Mieloide/complicações , Mucormicose/terapia , Transplante de Células-Tronco , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cerebelares/induzido quimicamente , Doenças Cerebelares/microbiologia , Doenças Cerebelares/terapia , Contraindicações , Humanos , Leucemia Mieloide/microbiologia , Leucemia Mieloide/terapia , Pneumopatias Fúngicas/induzido quimicamente , Pneumopatias Fúngicas/terapia , Masculino , Mucormicose/induzido quimicamente , Mucormicose/patologia , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/terapia , Transplante AutólogoRESUMO
The aim of our study was to evaluate the impact of an early intensification programme including chemotherapy (CHT), autologous stem cell transplantation (ASCT) and radiation therapy (RT) in patients with primary mediastinal large B cell lymphoma (MLCL) with sclerosis presenting with adverse prognostic factors. Between 1993 and 1999, 19 patients with MLCL were referred to our institution. Four patients were classified as low risk according to the age-adjusted International Prognostic Index (AA-IPI). Fifteen (79%) were categorised in the high-intermediate or high risk group and were considered eligible for ASCT. Induction therapy consisted of VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin) for 12 weeks. After induction therapy the four low risk patients achieved a complete remission (CR) and did not undergo ASCT. Of the 15 poor risk patients, five achieved CR, seven partial remission (PR), and three showed refractory disease (RD). All these patients received mobilising therapy consisting of high-dose cyclophosphamide. After peripheral stem cell (PSC) collection, to obtain a greater tumor mass reduction before transplantation, the seven patients in PR underwent further treatment with high-dose etoposide and those with RD received two cycles of DHAP (dexamethasone, cytarabine and cisplatin). At the time of ASCT, seven patients were in CR, six in PR and two had RD. After transplantation using BEAM as preparative regimen, all patients but one achieved a CR. Seven patients with minimal (<25%) residual mass at computed tomography scan received further mediastinal RT even if they had a negative Ga(67) scan. At a median follow-up of 35 months from transplantation the disease free survival is 93%. The outcome following this programme of early intensification in poor prognosis MLCL results in a high incidence of durable remissions even in patients with refractory disease.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/radioterapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/radioterapia , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/radioterapia , Tórax/patologia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Terapia Combinada/métodos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma de Células B/cirurgia , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Neoplasias do Mediastino/cirurgia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prognóstico , Fatores de Risco , Esclerose , Tórax/efeitos dos fármacos , Tórax/efeitos da radiação , Transplante Autólogo , Vincristina/administração & dosagem , Vincristina/uso terapêuticoRESUMO
Options for relapsed/refractory indolent lymphoma include chemotherapy, immunotherapy and high-dose therapy with autologous support. The best combination of these approaches, however, is not defined. We treated 10 patients with relapsed/refractory follicular (n = 7) or mantle cell lymphoma (n = 3) using chemotherapy, immunotherapy, high-dose therapy and autotransplant in a sequence of four phases, each designed to play a specific role in tumour eradication. After the debulking with VACOP-B (doxorubicin, cyclophosphamide, etoposide, vincristine, prednisone, bleomycin) (phase 1), 9/10 patients responded but none achieved a molecular response. After the immuno-chemotherapy phase, which combined Rituximab with vincristine and cyclophosphamide, seven patients were in complete response (CR) and three in good partial response (PR), and all those with a molecular marker of disease showed a disappearance of the signal from marrow and blood. Phase 3, which coupled high-dose cytarabine with Rituximab, was effective in mobilizing an adequate number of progenitor cells that were polymerase chain reaction negative in all informative cases. Phase 4 consisted of high-dose therapy with autologous support followed by two doses of Rituximab. Autograft was performed in nine patients. The haematopoietic recovery was as expected. This sequence of chemotherapy, immuno-chemotherapy, stem cell mobilization with in vivo purging and autotransplant, organized in four blocks of treatment, was simple to administer and devoid of toxic effects. It permits rapid attainment of clinical and molecular response and enables the harvest of lymphoma-free peripheral blood progenitor cells even in heavily pretreated patients with relapsed or refractory disease.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Purging da Medula Óssea , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Linfoma/terapia , Adulto , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Murinos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bleomicina/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Rearranjo Gênico , Genes bcl-2 , Meia-Vida , Humanos , Linfoma Folicular/terapia , Linfoma de Célula do Manto/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prednisona/administração & dosagem , Recidiva , Rituximab , Transplante Autólogo , Vincristina/administração & dosagemRESUMO
DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) has proved to be an effective salvage therapy for refractory-relapsed MM patients. Little is known, however, about its potential as mobilizing therapy. The aim of this study was to evaluate the efficacy of DCEP in mobilizing PBSC and to define its toxicity. Fifty-five MM patients received DCEP followed by G-CSF as part of high-dose programs including autologous transplantation. At the time of mobilization, 40 patients had previously received VAD only, and 15 alkylating agents. Mobilization was successful (minimum number of CD34(+) cells 2 x 10(6)/kg) in 48/55 patients (87%), and 41/55 patients (75%) collected >4 x 10(6)/kg CD34(+) cells. Of the seven patients who did not mobilize stem cells, five (71%) had been previously exposed to alkylating agents. The median number of CD34(+) cells harvested was 5.8 x 10(6)/kg (range 2.1-22.4). There was no treatment-related mortality. The side-effects of DCEP were always tolerable. No neutropenia <1000/microl nor thrombocytopenia <50,000/microl were observed. No patient required transfusion as a consequence of therapy, or hospitalization for septic complications. In conclusion, DCEP, in addition to its demonstrated anti-tumor activity, is an effective regimen for mobilizing peripheral blood progenitor cells in myeloma patients, with little or no side-effects. These properties render DCEP a useful regimen for the debulking and mobilization phase of high-dose programs for multiple myeloma.
Assuntos
Cisplatino , Ciclofosfamida , Dexametasona , Etoposídeo , Mobilização de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Adulto , Idoso , Antígenos CD34/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Contagem de Células Sanguíneas , Purging da Medula Óssea , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Resultado do TratamentoRESUMO
Sixty-one cases of Aspergillus infection (35 acute myeloid leukemia, 15 acute lymphoid leukemia, one myelodysplastic syndrome, two aplastic anemia, eight non-Hodgkin's lymphoma) seen in our department between January 1989 and July 1999 were studied retrospectively to evaluate the clinical characteristics, to ascertain the factors that influenced the outcome from mycotic infections, and whether early diagnosis and prolonged therapy permitted completion of scheduled intensive chemotherapy and bone marrow transplantation (BMT) without fungal recurrence. The patients were divided into three diagnostic categories: proven aspergillosis (autoptic or histologic diagnosis) n = 39, probable aspergillosis (radiological diagnosis with positive microbiology) n = 9, and possible aspergillosis (radiological diagnosis alone) n = 13. In the same period among 675 acute leukemia patients the incidence of proven or probable aspergillosis was 7.1%. At onset of infection 92% of patients were neutropenic (< 0.5 x 10(9)/L). The most frequent site of infection was the lung (90%); disseminated disease was present in 20 patients. Among 44 assessable patients, 12 (27%) failed to respond to early antifungal therapy and died. Thirty-two patients were cured with antifungal treatment, three of five nonneutropenic with only itraconazole, the others with amphotericin B 1 mg/Kg/day with or without itraconazole subsequently or with liposomal amphotericin, Ambisome, if renal toxicity occurred. Twenty-four of 29 neutropenic responders, all affected by acute leukemia, continued scheduled intensive chemotherapies. Pulmonary lobectomy was successfully combined with medical treatment in two cases before scheduled BMT. After infection nine patients were submitted to BMT (six allo, one marrow unrelated donor (MUD), two auto) with Ambisome or itraconazole as secondary prophylaxis without fungal relapse (follow-up: 25-99 months). The median time from fungal infection to transplant was five months, range 3-10. Thirteen of 29 surviving patients had leukemia relapse, but only three (23%) of these showed also fungal infection recurrence. In conclusion, a high index of suspicion and careful clinical and radiological examinations are the key to identifying infected patients early and to programming the following therapeutic steps. Above all in leukemia patients, prompt and aggressive administration of antifungal agents seems to improve the outcome of invasive fungal disease and to permit intensive chemotherapy completion and transplant.
Assuntos
Aspergilose/etiologia , Neoplasias Hematológicas/virologia , Adulto , Idoso , Antifúngicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Transplante de Medula Óssea , Gerenciamento Clínico , Feminino , Neoplasias Hematológicas/complicações , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The SH2 domain-containing tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCP) is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development, proliferation and receptor-mediated mitogenic signaling pathways. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including the Kit tyrosine kinase, activated to elicit a prominent cascade of intracellular events by stem cell factor binding. The pivotal contribution of PTPN6 in modulating myeloid cell signaling has been revealed by the finding that shp-1 mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten (me/me) and motheaten viable (me(v)/me(v)) mice. Association of PTPN6 with c-Kit and negative modulation of the myeloid leukocyte signal transduction pathways prompted us to examine the expression of the protein tyrosine phosphatase PTPN6 gene in CD34(+)/CD117(+) blasts from acute myeloid leukemia patients. We identified and cloned cDNAs representing novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis of cDNA clones revealed multiple A-->G editing conversions. The editing of PTPN6 mRNA mainly occurred as an A-->G conversion of A(7866), which represents the putative branch site in IVS3 of PTPN6 mRNA. Evidence that editing of A(7866) abrogates splicing has been obtained in vitro by using an edited clone and its backward clone generated by site-directed mutagenesis. The level of the aberrant intron-retaining splice variant, evaluated by semi-quantitative RT-PCR, was lower in CD117(+)-AML bone marrow mononuclear cells at remission than at diagnosis, suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis.
Assuntos
Processamento Alternativo , Leucemia Mieloide/genética , Proteínas Tirosina Fosfatases/genética , Edição de RNA , Doença Aguda , Sequência de Bases , Células HL-60 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Íntrons , Dados de Sequência Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Proteínas Tirosina Fosfatases/metabolismo , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Tirosina Fosfatases Contendo o Domínio SH2 , Análise de Sequência de RNA , Células Tumorais CultivadasRESUMO
A G-->T transversion at nucleotide 2467 of the c-KIT gene leading to Asp816-->Tyr (D816Y) substitution in the phosphotransferase domain has been previously identified in a patient with rapidly progressing AML-M2 and mast cell involvement; the patient's blasts had a 47,XY, +4,t(8;21)(q22;q22) karyotype. Herein we confirm the simultaneous presence of both major chromosomal changes by multicolor fluorescence in situ hybridization (FISH) on interphase CD34+ mononuclear cells. By setting up culture leukemic blasts, spontaneous differentiation of adherent cells with mast-cell like features was proved by histochemical and immunoenzymatic analyses. Fluorescence in situ hybridization evidence of trisomy 4 confirmed the origin of differentiated cells from the leukemic blasts. Semiquantitative polymerase chain reaction (PCR) and phosphoimage densitometry of wild-type and mutated KIT alleles on bone marrow blasts made it possible to demonstrate that chromosome 4 trisomy led to a double dosage of the mutated KIT allele. This finding, and that of trisomy 7 and MET mutation in hereditary renal carcinoma represent the only cases of human tumors in which an increased number of chromosomes carrying an oncogene activated by point mutation have been detected.