RESUMO
Thalidomide and lenalidomide are immunomodulatory drugs that show promise in mantle cell lymphoma (MCL). In this study, their potential mechanisms of action against MCL cells were investigated, both alone and in combination with rituximab. Thalidomide, lenalidomide and rituximab have no direct effect on MCL cell viability. However, both immunomodulatory drugs indirectly affect viability by enhancing peripheral blood mononuclear cell-mediated cytotoxicity, with lenalidomide inducing significantly higher levels of toxicity than thalidomide. Rituximab induces both complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) against MCL cells. Rituximab-induced ADCC is enhanced by lenalidomide and, to a lesser extent, thalidomide. Preliminary in vivo findings in MCL patients treated with thalidomide support a role for natural killer cells in the efficacy of these drugs. In conclusion, our data support a role for immunomodulatory drugs in the treatment of MCL.
Assuntos
Fatores Imunológicos/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas do Sistema Complemento/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Fatores Imunológicos/administração & dosagem , Técnicas In Vitro , Lenalidomida , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Rituximab , Talidomida/administração & dosagemRESUMO
The aim of this study was to compare the outcomes of chemotherapy delivered at a cancer centre with chemotherapy given at a community hospital. The services were compared in terms of safety, preference for location, satisfaction and resource use. Patients were randomly allocated to two groups. One group received their first two cycles of chemotherapy at a community hospital; the other group received theirs at the cancer centre. The patients then crossed over to receive their next two cycles of chemotherapy at outreach or the cancer centre and then chose where they wanted to receive the remaining two cycles of their chemotherapy. Data were collected about patient preference, anxiety and depression, satisfaction and chemotherapy-related toxicity. Forty-two patients were randomized to the study: 38, 31 and 28 patients completed cycles two, four and final chemotherapies respectively. Thirty-one patients reached the end of the crossover period, of which 30 chose the outreach location for the remainder of their chemotherapy treatments. There was strong evidence that patients were more satisfied with outreach location for ease of access and also the environment. Recommendation from this study was that a permanent outreach chemotherapy service to community hospitals be established.
Assuntos
Antineoplásicos/uso terapêutico , Institutos de Câncer , Hospitais Comunitários , Neoplasias/tratamento farmacológico , Satisfação do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/economia , Estudos Cross-Over , Atenção à Saúde , Feminino , Acessibilidade aos Serviços de Saúde/economia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/economia , Resultado do TratamentoRESUMO
Crystals of C-reactive protein from Limulus polyphemus have been grown both with and without calcium. The space group for the calcium-free crystals is I422 or I4(1)22, and the cell parameters are a = b = 173.33 (4) A, c = 98.81 (3) A. The crystals diffract to at least 2.8 A resolution and are suitable for detailed structural studies.
Assuntos
Proteína C-Reativa , Animais , Cristalização , Caranguejos Ferradura , Oscilometria , Difração de Raios XRESUMO
Two different crystal forms of human C-reactive protein have been grown from solutions of 2-methyl-2,4-pentanediol. Both crystal forms are tetragonal, the space group for form I is P4(1)22 (or P4(3)22), and that for form II is P4(2)22. The unit cell parameters for form I are a = b = 103.0(5) A, c = 308.5(7) A and for form II are a = b = 103.1(2) A, c = 312.7(6) A. The crystals of form II diffract to at least 3.0 A resolution, and are suitable for detailed structural studies.
Assuntos
Proteína C-Reativa , Cristalografia , HumanosRESUMO
Rotation function studies of two tetragonal crystal forms of human C-reactive protein have confirmed the pentameric structure of the molecule. The two crystal forms have space groups P4122 (I) and P4222 (II) with closely similar unit cells and are often twinned together. Investigation of the crystallization conditions indicates that dissociation heterogeneity has been a major limiting factor in the reproducible growth of good single crystals. The orientation of the pentameric molecule is shown to be almost identical in both forms, about the axial direction omega = 57 degrees, phi = 45 degrees, i.e. 57 degrees away from c in the (110) plane.
Assuntos
Proteína C-Reativa/química , Humanos , Conformação Proteica , Difração de Raios XRESUMO
Allogeneic bone marrow transplantation (BMT) with marrow ablative conditioning is the treatment of choice for haematopoietic malignancies. The use of nonmyeloablative stem cell transplants has allowed the treatment of patients previously ineligible for BMT because of age or other disease. These reduced conditioning regimes allow the persistence initially of some recipient cells in the blood and bone marrow (haematopoietic chimaerism). Monitoring of the relative proportion of donor and recipient cells is required to assess the success of the procedure, to predict subsequent rejection or impending relapse and to guide the use of donor lymphocyte infusions. We present a quantitative real-time PCR approach for the measurement of haematopoietic chimaerism using the TaqMan. This approach exploits the presence of single-nucleotide polymorphisms (SNPs) to distinguish cells of patient or donor origin. We have designed and validated a panel of seven allele-specific probes to quantify the contribution of patient and donor cells in the haematopoietic population from 12 patient and donor pairs. We have compared the performance of this approach with an existing method and proved it to be superior in both accuracy and sensitivity. The use of more sensitive and accurate techniques permits earlier intervention for improved clinical outcome.
Assuntos
Reação em Cadeia da Polimerase/métodos , Quimeras de Transplante/genética , Adulto , Células Sanguíneas , Células da Medula Óssea , Sondas de DNA , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transplante HomólogoRESUMO
Samples from 51 chronic lymphocytic leukaemia (CLL) patients (42 typical, nine atypical) were assessed for in vitro response to fludarabine and cladribine (2-CdA) using the flow cytometric terminal deoxynucleotidyl transferase (TdT) assay. No difference was demonstrated between the in vitro response of typical and atypical CLL and previous treatment did not result in a more apoptosis resistant phenotype. The assay could not distinguish those patients who required subsequent treatment from those whose disease remained stable, and universal cross-resistance/sensitivity to the two purine analogues was demonstrated. The assay's potential for use in the rapid assessment of in vivo response to purine analogue therapy in CLL was limited; correctly predicting the clinical outcome of 10/12 patients to treatment but failing to predict progression in two p53 deficient patients. The level of bcl-2 in the clonal lymphocytes did not influence the in vitro, spontaneous or drug-induced, apoptosis.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vidarabina/análogos & derivados , Apoptose/efeitos dos fármacos , DNA Nucleotidilexotransferase/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Citometria de Fluxo , Humanos , Técnicas In Vitro , Leucemia Linfocítica Crônica de Células B/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Vidarabina/uso terapêuticoRESUMO
In attempt to identify major clinical features of paranasal sinusitis following allogeneic BMT, we reviewed 44 consecutive cases diagnosed at the Hammersmith Hospital between August 1993 and December 1995. All patients had symptoms and signs characteristic of sinusitis. Plain radiographs and/or CT scans revealed fluid levels in 86.4% of patients, opacification in 9.1%, and marked mucosal thickening in 4.5%. Two-thirds of patients were diagnosed within 120 days of BMT. The WBC was less than 1 x 10(9)/1 in 16.3% of patients, the neutrophil count was less than 0.5 x 10(9)/1 in 18.6%, and serum immunoglobulins were depressed (< 6.7 g/l) in 40.6%. Grade III-IV acute GVHD was present in 25.6% of patients and grade I-II in 66.7%; 68.6% developed chronic GVHD. There were 70.5% of patients receiving corticosteroids. Specific pathogens could not be identified in most cases. Pneumonia was present in 10 patients, seven of whom had Aspergillus species identified by bronchoalveolar lavage. Parainfluenza virus was isolated in three patients and Pseudomonas aeruginosa in two. Although all patients received antimicrobial therapy, 70.5% developed chronic sinusitis. Fatal complications did not occur. In 94 consecutive patients receiving allografts for CML during the period of study, WBC and neutrophil counts were lower 3 months post-BMT in patients who developed sinusitis (P < 0.02). Patients receiving higher doses of total body irradiation (13.2 and 14.4 Gy) had a greater probability of developing sinusitis (P = 0.023). Sinusitis occurred in only one of 37 patients receiving autologous transplants in the same period. Sinusitis is common following allogeneic BMT. Leukopenia is often present, but microbiological diagnosis is difficult, and progression to chronic sinusitis common.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Sinusite/etiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sinusite/microbiologia , Transplante HomólogoRESUMO
We report a 33-year-old man with Ph chromosome-positive CML who underwent an allogeneic BMT from an unrelated donor. DNA microsatellite studies showed complete donor chimaerism immediately after BMT followed by mixed chimaerism; by day + 45 haematopoiesis was exclusively of recipient origin. Throughout the first year post-transplant all marrow metaphases were Ph negative but with non-clonal rearrangements consistent with autologous recovery. Cytogenetic relapse of leukaemia was first detected 15 months post-transplant. This case is unusual in that non-malignant stem cells of recipient origin survived the transplant and reconstituted haematopoiesis very early after BMT. Later the leukaemic cells reasserted their 'proliferative' advantage.
Assuntos
Transplante de Medula Óssea , Hematopoese/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Adulto , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Masculino , Recidiva , Transplante HomólogoRESUMO
PURPOSE: To determine the frequency and nature of changes to the brain resulting from chemotherapy, radiation therapy, and bone marrow transplantation for chronic myeloid leukemia and to compare the sensitivity of conventional and registered MR scans for detecting these changes. METHODS: In 15 patients, conventional T1-weighted, T2-weighted, and fluid-attenuated inversion recovery MR sequences, as well as T1-weighted radio frequency spoiled 3-D volume MR scans were performed before, 4 to 6 days after, and up to 339 days after transplantation (13 allografts, two autografts). A subvoxel registration program was used to match the volume images precisely so that small changes could be detected after subtraction of scans. Five healthy adult control subjects were also studied on two occasions 1 month apart. RESULTS: Studies performed 4 to 339 days after transplantation showed ventricular enlargement and cortical atrophy in all 13 patients who had allografts. The changes were evident at 4 to 6 days after transplantation and became more obvious during later follow-up examinations. Similar changes were seen in one patient with an autograft but no significant change was seen in the other patient with an autograft or in the five control subjects. Accurately registered volume scans were more sensitive than unregistered conventional scans in detecting early (9/10 versus 0/10), intermediate (12/13 versus 3/12), and late (10/10 versus 4/9) ventricular enlargement on follow-up examinations. The same applied to cortical atrophy (9/10 versus 0/10, 12/13 versus 0/12, and 10/10 versus 0/9). CONCLUSION: The specific cause and clinical significance of these changes are uncertain. Subvoxel registration of serial MR images may reveal changes that are poorly seen or not apparent on conventional scans.
Assuntos
Transplante de Medula Óssea , Encéfalo/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Imageamento por Ressonância Magnética , Adolescente , Adulto , Atrofia , Córtex Cerebral/patologia , Ventrículos Cerebrais/patologia , Feminino , Humanos , Masculino , Meninges/patologia , Pessoa de Meia-Idade , Período Pós-Operatório , Técnica de SubtraçãoRESUMO
Antibodies to HLA-antigens remain a problem in multiply-transfused patients. Over a 2 yr period 44 bone marrow transplant recipients were screened at weekly intervals for the presence of HLA-antibodies using a solid phase red cell adherence technique. An adaptation of this method was used to provide cross-matched random donor platelets (XMRDP) when screening proved positive. Twelve of the 44 patients were antibody positive, 6 prior to transplantation and 6 following the transplant. Those 4 patients who developed an antibody following the transplant had a significant increase in platelet increments following the change from random donor platelets (RDP) to XMRDP even though only one patient was refractory to platelets at the time the antibody was first detected. No significant bleeding occurred during the study period. The use of routine platelet antibody screening followed by platelet cross-matching allows excellent support of thrombocytopenic patients without requiring HLA-typed blood donors and avoiding clinical platelet refractoriness.
Assuntos
Plaquetas/imunologia , Transplante de Medula Óssea/imunologia , Adolescente , Adulto , Tipagem e Reações Cruzadas Sanguíneas/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A case of multiple relapses of Candida albicans infection of deep tissues is described. Treatment was complicated by renal impairment, but therapy with a liposomal amphotericin product failed to eradicate the third recurrence which subsequently resolved after protracted exposure to oral fluconazole.
Assuntos
Anfotericina B/uso terapêutico , Candidíase/tratamento farmacológico , Fluconazol/uso terapêutico , Osteomielite/tratamento farmacológico , Adulto , Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candidíase/complicações , Feminino , Humanos , Lipossomos/uso terapêutico , Osteomielite/etiologia , RecidivaAssuntos
Análise Mutacional de DNA/instrumentação , Fator V/genética , Resistência à Proteína C Ativada/genética , Alelos , Substituição de Aminoácidos , Sequência de Bases , DNA/genética , Análise Mutacional de DNA/métodos , Frequência do Gene , Genótipo , Heterozigoto , Homozigoto , Humanos , Marrocos , Mutação Puntual , Reação em Cadeia da Polimerase/instrumentação , Reação em Cadeia da Polimerase/métodosAssuntos
Institutos de Câncer/normas , Neoplasias Hematológicas/terapia , Institutos de Câncer/organização & administração , Coleta de Dados , Gerenciamento Clínico , Tratamento Farmacológico/enfermagem , Tratamento Farmacológico/normas , Educação de Pós-Graduação em Enfermagem/normas , Serviços Médicos de Emergência/organização & administração , Serviços Médicos de Emergência/normas , Hematologia , Humanos , Oncologia , Corpo Clínico Hospitalar , Enfermagem Oncológica/educação , Equipe de Assistência ao Paciente , Inquéritos e Questionários , Reino UnidoRESUMO
Twenty-one cases of acute promyelocytic leukaemia (FAB M3) demonstrating t(15,17) chromosomal translocation were studied in detail by immunocytochemical techniques using a panel of monoclonal antibodies. A characteristic myeloid phenotype of the leukaemic cells, co-expression of CD9 and CD68 antigens and absence of HLA-DR, was noted in all cases. Although the cellular morphology of acute promyelocytic leukaemia provides the most rapid means for diagnosis, this unique leukaemic cell phenotype provides confirmatory diagnostic evidence. In view of the new therapeutic options and prognosis in acute promyelocytic leukaemia, the detection of cases with atypical morphology based on this unique phenotype would be of value. In addition, the phenotype of acute promyelocytic leukaemia is similar to that of basophils and mast cells and raises the possibility that the leukaemic cells may have undergone a degree of basophilic differentiation.
Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Leucemia Promielocítica Aguda/imunologia , Glicoproteínas de Membrana , Basófilos/imunologia , Humanos , Imunofenotipagem , Leucemia Promielocítica Aguda/genética , Tetraspanina 29 , Translocação GenéticaRESUMO
A cohort of asymptomatic human immunodeficiency virus (HIV) seropositive patients was followed over a 2 1/2-year period, to establish changes in serum vitamin B12 (B12) concentrations. Serum B12, CD4 count, and clinical progression to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) were measured. The unsaturated B12 binding capacities of the transcobalamins were also determined at the start of the study and compared to those from a homosexual HIV seronegative control group. The geometric mean of serum B12 in 218 asymptomatic HIV seropositive patients was significantly lower than of a homosexual HIV seronegative control group (P = 0.02) and the unsaturated B12 binding capacities of transcobalamins I and II were significantly higher in the asymptomatic patients compared with the same control group (P < 0.03, P < 0.0001, respectively). Fifty-nine of the asymptomatic HIV seropositive patients were followed over a 2 1/2-year period during which most had falling serum B12 levels (64%). Twelve patients progressed clinically to ARC or AIDS, of which nine had repeat serum B12 estimation prior to progression. All nine patients had or developed falling serum B12 levels without any evidence of an HIV-related bowel disorder. All patients progressing had falling CD4 counts. Subnormal serum B12 levels are common in HIV disease and occur at an early stage. B12 levels fall in most patients with time and may help predict those patients whose disease will progress the most rapidly.
Assuntos
Síndrome da Imunodeficiência Adquirida/sangue , Transcobalaminas/análise , Vitamina B 12/sangue , Síndrome da Imunodeficiência Adquirida/epidemiologia , Antígenos CD4/análise , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Fatores de Tempo , Vitamina B 12/metabolismoRESUMO
The existence of subpopulations of clonal lymphocytes in patients with low grade lymphoproliferative disorders, with regard to both cell size and bcl-2 protein concentration is reported. Flow cytometric analysis showed that the lymphocytes with higher levels of bcl-2 corresponded to a subset of larger lymphocytes. Statistical analysis suggested that the increased concentration of bcl-2 was not accounted for by the increase in cell size and it is possible that these cells form a functionally distinct component of the clonal proliferation. One patient, analysed in greater detail during treatment with a purine analogue, showed the subpopulations to exhibit a differential sensitivity to chemotherapy.