RESUMO
BACKGROUND: Insulin/insulin-like growth factor-1 signalling may underlie the promoting effect of type 2 diabetes on cancer. This study examined the association of diabetes, including steroid-induced diabetes (SID), and the impact of anti-diabetic medication on clinical outcomes of multiple myeloma (MM). METHODS: A retrospective review was conducted of 1240 MM patients. Overall survival (OS) and MM disease status prior to death were analysed. RESULTS: Diabetic patients had a significantly shorter OS than non-diabetic patients (median: 65.4 vs 98.7 months). In multivariate analysis, SID was a significant predictor of decreased OS, along with age, comorbidity, MM stage, and cytogenetic abnormalities. Analyzing only the diabetic MM patients, Cox regression showed that metformin predicted an increased OS, whereas use of insulin/analogues predicted a decreased OS. Competing risk analysis showed that DM was associated with increased cumulative incidence of death with progressive MM. Among the diabetics, multivariate regression showed that insulin/analogues were associated with increased, but metformin with decreased death with progressive MM. Potential immortal time bias was evaluated by landmark analyses. CONCLUSIONS: DM, SID in particular, is associated with poor clinical outcomes in MM. Insulin/analogues are associated with poor outcomes, whereas metformin is associated with improved outcomes. No conclusion about causal relationships can be made at this time. Managing hyperglycaemia with non-insulin regimens should be investigated in randomised trials.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Metformina/uso terapêutico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Diabetes Mellitus Tipo 2/mortalidade , Progressão da Doença , Feminino , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Estimativa de Kaplan-Meier , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
We analyzed the clinical factors associated with late cytomegalovirus (CMV) reactivation in a group of 269 consecutive recipients of allogeneic stem cell transplant (SCT) for hematological malignancies. Eighty-four subjects (31%) experienced late CMV reactivation, including 64 with prior early reactivation and 20 with isolated late reactivation. Multivariate analyses were conducted in patients with early CMV reactivation to identify factors associated with late recurrence. Important risk factors included lymphoid diagnosis, occurrence of graft-versus-host disease (GVHD), greater number of episodes of early reactivation, persistent day 100 lymphopenia and the use of a CMV-seronegative donor graft. We combined these risk factors in a predictive model to identify those at relatively low, intermediate and high risk. The low-risk group (15% cumulative incidence, CI) encompassed patients without early CMV reactivation, and subjects transplanted for a myeloid malignancy from a matched-related (MR) donor without subsequent acute GVHD. The high-risk patients (73% CI) met all of the following criteria: (1) received an MR graft but developed GVHD, or received a non-MR graft irrespective of GVHD; (2) had more than two episodes of early reactivation; and (3) received a CMV-seronegative graft and/or remained persistently lymphopenic at day 100 after SCT. The remaining patients had an intermediate incidence of 32%.
Assuntos
Infecções por Citomegalovirus/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Fatores de Risco , Linfócitos T/imunologia , Fatores de Tempo , Transplante HomólogoRESUMO
Several clinical trials have shown the superiority of autologous stem cell transplantation over conventional dose therapy for patients with multiple myeloma. This treatment, however, is limited to younger patients (<65 years) owing to concerns about toxicity and treatment-related mortality (TRM) in older patients. We treated 26 elderly myeloma patients (>70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two of the 26 patients were alive after a median follow-up of 25 months (range=8-74). Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median PFS was 24 months, whereas median OS has not been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS were 39% (range=16-61) and 65% (range=35-83), respectively. A low serum albumin (<3.5 g/dl) was associated with a shorter PFS (P=0.02). Patients with relapsed disease at transplant, and an interval of >12 months between diagnosis and autotransplant, had a shorter OS (P=0.0004 and 0.04). HDT and autologous transplant is safe and feasible in elderly myeloma patients.
Assuntos
Melfalan/administração & dosagem , Mieloma Múltiplo/terapia , Agonistas Mieloablativos/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante AutólogoRESUMO
PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.
Assuntos
Vacinas Anticâncer/imunologia , Antígeno HLA-A2/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , Peptídeos/imunologia , Biomarcadores , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Epitopos de Linfócito T/imunologia , Feminino , Antígeno HLA-A2/química , Humanos , Memória Imunológica , Imunofenotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Análise de Sobrevida , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento , VacinaçãoRESUMO
We explored the safety and efficacy of rituximab administered in combination with the standard transplant conditioning regimen of cyclophosphamide (Cy) 120 mg/kg and total body irradiation (TBI) 12 Gy for adult patients with acute lymphoblastic leukemia (ALL). Patients were eligible if their disease expressed CD20. Rituximab was administered at 375 mg/m2 weekly for four doses beginning on day -7 of the conditioning regimen. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. Thirty-five patients undergoing matched sibling (n = 23) or unrelated donor (n = 12) transplantation were studied, with a median age of 30 years (range 15-55 years). At 2 years, progression-free survival, treatment-related mortality, and overall survival were 30, 24, and 47%, respectively. There was no delay in engraftment or increased incidence of infection. The cumulative incidence of grade II-IV acute GVHD was 17%, and limited and extensive chronic GVHD was 43% at 2 years. The addition of rituximab to the standard Cy/TBI transplant conditioning regimen in ALL was safe and well tolerated, and there was a suggestion of decreased incidence of acute GVHD when compared to historically reported GVHD rates for this group of patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfoma de Burkitt/terapia , Doença Enxerto-Hospedeiro/prevenção & controle , Fatores Imunológicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Anticorpos Monoclonais Murinos , Distribuição de Qui-Quadrado , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Pessoa de Meia-Idade , Rituximab , Estatísticas não Paramétricas , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
The safety and efficacy of siltuximab (CNTO 328) was tested in combination with lenalidomide, bortezomib and dexamethasone (RVD) in patients with newly-diagnosed, previously untreated symptomatic multiple myeloma. Fourteen patients were enrolled in the study, eleven of whom qualified to receive therapy. A majority of patients (81.8%) completed the minimal number or more of the four required cycles, while two patients completed only three cycles. The maximum tolerated dose (MTD) of siltuximab with RVD was dose level -1 (siltuximab: 8.3 mg/kg; bortezomib: 1.3 mg/m(2); lenalidomide: 25 mg; dexamethasone: 20 mg). Serious adverse events were grade 3 pneumonia and grade 4 thrombocytopenia, and no deaths occurred during the study or with follow-up (median follow-up 28.1 months). An overall response rate, after 3-4 cycles of therapy, of 90.9% (95% confidence interval (CI): 58.7%, 99.8%) (9.1% complete response (95% CI: 0.2%, 41.3%), 45.5% very good partial response (95% CI: 16.7%, 76.6%) and 36.4% partial response (95% CI: 10.9%, 69.2%)) was seen. Two patients withdrew consent, and nine patients (81.8%) opted for autologous stem cell transplantation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Aberrações Cromossômicas , Dexametasona/administração & dosagem , Progressão da Doença , Feminino , Humanos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Estadiamento de Neoplasias , Qualidade de Vida , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
Cardiac involvement in light-chain amyloidosis (AL) predicts poor prognosis and is associated with higher TRM and morbidity during high-dose therapy and auto-SCT (HDT-ASCT). We studied the outcomes of 30 patients with cardiac amyloidosis undergoing HDT-ASCT at our center between January 1998 and March 2012. The median age of the patients was 53 years (range, 36-74) with a median follow-up of 35 months (range, 0.4-97 months). Twenty-seven patients (90%) had more than one organ involved besides the heart with 37% with cardiac stage ⩾3. Melphalan-based conditioning regimen (140-200 mg/m(2)) was used for HDT-ASCT. One-year TRM is 10%. Three-year OS and EFS from HDT-ASCT was 83% and 56.8%, respectively. Cumulative incidence of relapse at 3 years was 38.5%. Negative factors affecting survival included age >60 years, lack of novel induction therapy and BM plasmacytosis >10%. We conclude that HDT-ASCT is well tolerated in patients with high-risk cardiac amyloidosis and can lead to improved overall outcomes.
Assuntos
Amiloidose , Cardiopatias , Melfalan/administração & dosagem , Agonistas Mieloablativos/administração & dosagem , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adulto , Idoso , Amiloidose/mortalidade , Amiloidose/terapia , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Cardiopatias/mortalidade , Cardiopatias/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de SobrevidaRESUMO
IL-12 is a heterodimeric cytokine that is known to induce tumor regression and long-term antitumor immunity. Recombinant adeno-associated virus (rAAV) vectors are advantageous for gene therapy in that they lack pathogenicity in humans, infect dividing as well as nondividing cells, and show a broad range of infectivity. We constructed an rAAV vector expressing interleukin-12 (IL-12) for cancer immunotherapy studies in a mouse model by inserting murine IL-12 (mIL-12) p35 and p40 cDNAs into the plasmid pRep4 and inserting the encephalomyocarditis virus internal ribosomal entry site between the p35 and p40 cDNAs. The mIL-12 expression cassette containing the Rous sarcoma virus promoter and a simian virus 40 polyadenylation signal was subcloned into the AAV plasmid p008Sub/NeoR, which contains two AAV inverted terminal repeat sequences and the NeoR gene driven by the thymidine kinase promoter. rAAV virions (10(4) infectious particles/ml) were generated by cotransfection of rAAV-mIL-12 and a helper plasmid (pAAV/Ad) into 293 cells previously infected with adenovirus 5. After infection of D6 fibroblasts with rAAV-mIL-12, G418-resistant clones were isolated. Each of the 1D D6 clones isolated produced up to 5.2 ng/10(6) cells/48 hours of mIL-12 as determined by enzyme-linked immunosorbent assay. Induction of interferon-gamma, enhanced lymphocyte proliferation, and cytotoxicity assays confirmed biologically functional IL-12 production by the vector. This is the first report indicating that an rAAV vector expresses mIL-12, which can be used to model the effects of mIL-12 alone and/or in combination with other antitumor agents.
Assuntos
Dependovirus/genética , Vetores Genéticos/síntese química , Vetores Genéticos/imunologia , Interleucina-12/biossíntese , Animais , DNA Recombinante/genética , DNA Viral/genética , Vetores Genéticos/genética , Humanos , Interferon gama/biossíntese , Células K562 , Células Matadoras Naturais/imunologia , Ativação Linfocitária/genética , Camundongos , Fito-Hemaglutininas/farmacologia , Células Tumorais CultivadasRESUMO
Relapse of hematologic malignancies after allogeneic stem cell transplantation remains a common problem, in particular for patients who have advanced disease at the time of transplantation. Thiotepa has excellent antileukemic and immunosuppressive activity, and could therefore be a useful drug in the conditioning regimen for patients with advanced hematologic neoplasms. We retrospectively analyzed toxicity, engraftment and survival data of 41 patients who received a conditioning regimen of thiotepa (600 mg/m2) and hyperfractionated TBI (10 Gy) prior to matched related (n = 25) or matched unrelated (n = 16) allogeneic stem cell transplantation. The mean age at transplantation was 37.8 years (range 20-59), all but five patients had advanced hematologic malignancies at the time of transplantation. GVHD prophylaxis was with standard cyclosporine and methotrexate. Engraftment was excellent, but the regimen was associated with a high incidence of grade III renal (41%) and hepatic (15%) toxicity, and high transplant-related mortality (44% at day +90). The 3-year event-free survival was 13% and overall survival 14%. We conclude that this regimen requires modification to reduce toxicity.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante , Irradiação Corporal Total , Doença Aguda , Adulto , Antineoplásicos Alquilantes/efeitos adversos , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/mortalidade , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Tiotepa/efeitos adversos , Transplante HomólogoRESUMO
Optimal treatment approach continues to remain a challenge for systemic light chain amyloidosis (AL). So far, Auto-SCT is the only modality associated with long-term survival. However, failure to show survival benefit in randomized study raises questions regarding its efficacy. We present a comparative outcome analysis of Auto-SCT to conventional therapies (CTR) in AL patients treated over a 14-year period at our institution. Out of the 145 AL amyloidosis patients, Auto-SCT was performed in 80 patients with 1-year non-relapse mortality rate of 12.5%. Novel agents were used as part of induction therapy in 56% of transplant recipients vs 46% of CTR patients. Hematological and organ responses were seen in 74.6% and 39% in the Auto-SCT arm vs 53% and 12% in the CTR arm, respectively. The projected 5-year survival for Auto-SCT vs CTR was 63% vs 38%, respectively. Landmark analysis of patients alive at 1-year after diagnosis showed improved 5-year OS of 72% with Auto-SCT vs 65% in the CTR arm. In the multivariate analysis, age <60 years, induction therapy with novel agents, kidney only involvement and Auto-SCT were associated with improved survival. In conclusion, Auto-SCT is associated with long-term survival for patients with AL amyloidosis.
Assuntos
Amiloidose/mortalidade , Amiloidose/terapia , Transplante de Células-Tronco , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cadeias Leves de Imunoglobulina , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic SCT (allo-HSCT). A better understanding of AI in allo-HSCT recipients can serve as a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HSCT at MD Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HSCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that when the joint effects of all covariates were accounted for, cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm(3) and male gender were associated with a higher probability of disseminated AI. The OS was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months vs median of 28 months, P<0.001) and for patients with ALC ≤ 200/mm(3) (P<0.001). Disseminated AI, in patients who received allo-HSCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients.
Assuntos
Infecções por Adenoviridae/etiologia , Adenoviridae/isolamento & purificação , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Antígenos HLA/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
To enhance the therapeutic index of allogeneic hematopoietic SCT (HSCT), we immunized 10 HLA-matched sibling donors before stem cell collection with recipient-derived clonal myeloma Ig, idiotype (Id), as a tumor antigen, conjugated with keyhole limpet hemocyanin (KLH). Vaccinations were safe in donors and recipients. Donor-derived KLH- and Id-specific humoral and central and effector memory T-cell responses were detectable by day 30 after HSCT and were boosted by post-transplant vaccinations at 3 months in most recipients. One patient died before booster vaccinations. Specifically, after completing treatment, 8/9 myeloma recipients had persistent Id-specific immune responses and 5/9 had improvement in disease status. Although regulatory T cells increased after vaccination, they did not impact immune responses. At a median potential follow-up period of 74 months, 6 patients are alive, the 10 patients have a median PFS of 28.5 months and median OS has not been reached. Our results provide proof of principle that neoantigen and tumor antigen-specific humoral and cellular immunity could be safely induced in HSCT donors and passively transferred to recipients. This general strategy may be used to reduce relapse of malignancies and augment protection against infections after allogeneic HSCT.
Assuntos
Antígenos de Neoplasias/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunização/métodos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Doadores de Tecidos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Epitopos , Feminino , Antígenos HLA/imunologia , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Humanos , Imunidade Celular/imunologia , Idiótipos de Imunoglobulinas/administração & dosagem , Idiótipos de Imunoglobulinas/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Imunologia de Transplantes , Transplante HomólogoAssuntos
Transplante de Células-Tronco/efeitos adversos , Estrongiloidíase/complicações , Anti-Helmínticos/uso terapêutico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/etiologia , Síndrome Hipereosinofílica/terapia , Ivermectina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estrongiloidíase/diagnóstico , Estrongiloidíase/tratamento farmacológico , Tiabendazol/uso terapêutico , Transplante HomólogoAssuntos
Amiloidose , Transplante de Células-Tronco Hematopoéticas , Cadeias lambda de Imunoglobulina/sangue , Nefropatias , Adulto , Idoso , Amiloidose/sangue , Amiloidose/complicações , Amiloidose/mortalidade , Amiloidose/terapia , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/mortalidade , Nefropatias/terapia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 10(9)/L) and plt engraftment (>20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Recidiva , Indução de Remissão , Topotecan/administração & dosagem , Transplante Autólogo , Resultado do TratamentoAssuntos
Hepatite C/terapia , Linfoma/terapia , Linfoma/virologia , Mieloma Múltiplo/terapia , Mieloma Múltiplo/virologia , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepacivirus , Hepatite C/sangue , Humanos , Linfoma/sangue , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Transplante de Células-Tronco , Taxa de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Carga ViralAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Humanos , Lenalidomida , Melfalan/administração & dosagem , Mieloma Múltiplo/mortalidade , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Transplante Autólogo , Resultado do TratamentoAssuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome POEMS/terapia , Adulto , Antígenos CD34/metabolismo , Intervalo Livre de Doença , Feminino , Mobilização de Células-Tronco Hematopoéticas , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Síndrome POEMS/imunologia , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
Previous studies have indicated that transfer of wild-type (wt) p53 cDNA into cancer cells can suppress the tumor phenotype in vitro and in vivo. In this study we examined the effects of wt p53 transduction in the human cancer cell line H-358 (that bears a homozygous deletion of p53) using a novel recombinant adeno-associated viral vector engineered to express wt p53 (rAAVp53). Western blot analysis demonstrated the expression of wt p53 in H-358 cells following infection with rAAVp53. Furthermore, rAAVp53 inhibited the growth of the neoplastic cells and also mediated cytotoxicity. Cell cycle analysis of rAAVp53-infected cells showed a significant increase in the percentage of cells arrested at the G1-S checkpoint. H-358 cells infected with rAAVp53 underwent apoptosis as demonstrated by the morphological appearance of DAPI-stained nuclei. Direct injection of rAAVp53 into H-358 tumors implanted subcutaneously in immunodeficient nu/nu mice inhibited tumor growth completely in three of the five animals tested. Mock-infected and rAAV control treated tumors showed no growth inhibition. In situ staining in nu/nu mice detected the presence of wild-type p53 protein in residual tumor cells following rAAVp53 administration. The impressive in vivo efficacy of the rAAVp53 suggests a bystander effect. We conclude that rAAV may be effective as a gene transfer vector in the delivery of p53 to cancer cells.
Assuntos
Dependovirus , Genes p53 , Vetores Genéticos , Neoplasias/terapia , Transfecção , Animais , Apoptose/genética , Western Blotting , Humanos , Camundongos , Camundongos Mutantes , Neoplasias/química , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/análiseRESUMO
X-linked severe combined immunodeficiency syndrome (X-SCID) is a genetic disorder characterized by profound impairment of cell-mediated and humoral immunity. Affected children die of recurrent infections within 2 years of birth unless rescued by allogeneic transplantation from a suitable donor. Recently, the genetic defect responsible for X-linked SCID has been identified as a mutation in the gamma chain of the IL-2 receptor, a protein also shared by the IL-4 and IL-7 receptors and therefore now denoted the common gamma chain (gamma c). We report here the development of a high-titer amphotropic retroviral vector for transfer of gamma c. This vector was used to transfer a copy of the gamma c cDNA to murine 3T3 fibroblasts, CD34-enriched hematopoietic progenitor cells obtained from bone marrow and umbilical cord blood of normal donors, and to transplanted murine bone marrow progenitors. Murine 3T3 cells transduced by the retroviral vector were analyzed by Southern blot hybridization and Western transfer. Southern analysis confirmed the integration of unrearranged proviral DNA, and Western blot analysis demonstrated the expression of gamma c protein. CD34-enriched cells were infected with viral vectors bearing gamma c and grown in methylcellulose media. Individual colonies and pools of cells were analyzed 2 weeks later by polymerase chain reaction assay, which confirmed the proviral marking. The vector was also used to transfer a copy of the gamma c cDNA to murine bone marrow cells in a transplantation model. Infected marrow was transplanted into syngeneic Balb/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)