Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina.

BACKGROUND: Intramyocardial injection of autologous bone marrow (ABM) may induce angiogenesis. We tested the safety and feasibility of catheter-based direct percutaneous intramyocardial delivery of ABM in patients with refractory angina pectoris. METHODS: Ten patients (9 men, 67 +/- 8 years) with refractory angina (Canadian Cardiovascular Society class III-IV) and documented myocardial ischemia were enrolled. After left ventricular electromechanical mapping, freshly aspirated and filtered ABM was percutaneously injected into target myocardial ischemic areas. Clinical symptoms (as assessed according to the Canadian Cardiovascular Society class), quality of life, and myocardial perfusion were evaluated before the procedure and through the follow-up. RESULTS: In all patients, ABM was successfully injected into the target regions. No periprocedural complications occurred. At 12 months, no major cardiac events (death, acute myocardial infarction, stroke, and malignant ventricular arrhythmias) occurred. Severity of angina improved of > or = 2 classes in 3 patients. Quality of life showed a significant improvement in all patients. Myocardial perfusion in the target regions improved in 4 of 8 patients. CONCLUSIONS: Direct percutaneous intramyocardial delivery of ABM appears feasible and safe. Further evaluation is warranted to test its clinical efficacy.

High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial.

PURPOSE: To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin's lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. PATIENTS AND METHODS: Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). RESULTS: Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were.0037 and.079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively. CONCLUSION: HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.

Fludarabine, cyclophosphamide and mitoxantrone for untreated follicular lymphoma: a report from the non-Hodgkin's lymphoma co-operative study group.

The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL), Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36-70), received FLU/CY/MITO regimen (FLU 25 mg/m2 days 1-3, CY 300 mg/m2 days 1-3, Mito 10 mg/m2 day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.

Regenerative medicine: a review / Medicina regenerativa: uma revisão

Regenerative medicine is a technique to replace or repair defective or diseased tissue or organs by in vitro design with in vivo usage. It can be considered a relatively new branch of medicine born in 1997 when Whithman DH et al. proposed to integrate platelet enriched plasma (PRP) in fibrin glue. In 1998 Marx et al. demonstrated that PRP was able to induce bone regeneration of the jaw. In the same period it was discovered that a fraction of stem cells of bone marrow origin was able to repair several mesenchymal tissues or organs.

Medicina regenerativa é uma técnica de substituir ou reparar defeitos ou tecidos ou órgãos doentes por outros desenhados in vitro para uso in vivo. Estas técnicas podem ser consideradas relativamente novas já que nasceu em bancada em 1997 quando Whithman DH et al propuseram a utilização da cola de fibrina obtida em plasma rico em plaquetas (PRP) para uso terapêutico. Em 1998, Marx et al demonstraram que a PRP foi capaz de induzir regeneração óssea da mandíbula. No mesmo período, foi descoberto que frações de células-tronco de origem na medula óssea foram capazes de reparar tecidos e órgãos a partir de células mesenquimais. O autor faz aqui uma breve revisão do assunto altamente contemporâneo.

The impact of progenitor enrichment, serum, and cytokines on the ex vivo expansion of mobilized peripheral blood stem cells: a controlled trial.

The aim of this study was to verify, and possibly improve, culture conditions to expand human mobilized peripheral blood stem cells (PBSCs). We investigated the role of three parameters: A) the culture medium (serum-free versus serum-dependent); B) the initial cell population (Ficoll-separated mononucleated cells versus CD34(+)-selected cells), and C) the low concentration of recombinant cytokines, flt3 ligand, and thrombopoietin in association with a basic cocktail of stem cell factor, interleukin (IL)-6, IL-3, GM-CSF, and erythropoietin. Eighteen leukapheresis samples were monitored in static culture for 15 days. The expansion potential was assessed at day 10 and 15 by total nuclear cells, colony-forming-units (CFUs) (burst-forming units-erythroid [BFU-E], colony-forming units-granulocyte-macrophage [CFU-GM], and colony-forming units-granulocyte-erythroid-macrophage-megakaryocyte [CFU-GEMM]), and flow cytometry immunophenotyping (CD34(+)/CD38(-), CD38(+), CD33(+), CD41(+), GlyA(+) progenitor cells). The results, evaluated by multivariate analysis of variance, emphasize that some variables affected the outcome of stem and progenitor cell expansion. CD34(+) enrichment increased expansion of total nuclear cells, number of CD38(+) and CD33(+) late precursors, and number of the CFU-GM compartment. Interestingly, however, quantitative expansion of GlyA(+) and the early progenitor cells (CD34(+)/CD38(-), CFU-GEMM, BFU-E) are favored by the use of unselected mononucleated cells. Regarding the role of serum, no significant difference was observed except for expansion of total nuclear cells, CFU-GM, and BFU-E. Cytokine combinations, in particular the use of flt3 ligand, stimulated expansion of almost all the cellular subsets, reaching a statistical significance for total nuclear cells and CFU-GM. Our study indicates that progenitor and late precursor multilineage cell compartments of mobilized PBSCs may be significantly expanded in short-term cultures by well-defined experimental conditions. Furthermore, these data might be useful when evaluating ex vivo expansion of hematopoietic cells for clinical purposes.

T- Lymphoblastic lymphoma in adults / Linfoma linfoblástico T dos adultos

Adult T-lymphoblastic lymphoma is rare and has a poor prognosis. In the 80s, following the introduction of sequential, intensified chemotherapy, complete remissions in the order of 75 percent-95 percent of treated patients, were achieved. However, several patients, namely those with advanced disease, continued to relapse either in remission or during maintenance therapy. Moreover, all these early studies were not able to detect any valuable prognostic index to predict the outcome. In an attempt to reduce the relapse rate, upfront autologous stem cell transplantation in patients in complete remission was introduced. The results obtained with this approach were quite homogeneous, indicating a probability of disease-free survival of about 65 percent-75 percent and an overall survival rate of 60 percent. Successive therapies designed since 2000 were able to obtain complete remissions of above 90 percent, with a relapse rate in the order of 30 percent and an overall survival comparable to that obtained with the transplant procedure. Yet, these studies were also unable to detect valuable prognostic factors predictive of the outcome. Moreover, no study on the biologic profile of the disease has been developed. To improve the prognosis of T-lymphoblastic lymphoma it seems necessary to create national registries to collect both clinical and biological data of all lymphoblastic lymphoma patients. In this way it will be possible to reach critical numbers of data with which valid statistical analysis may be performed that is able to detect factors influencing the outcome. Moreover, subsets of patients needing intensified procedures such as stem cell transplant may be detected at diagnosis.

O linfoma linfoblástico de célula T é raro e com prognóstico ruim. Após introdução de terapêutica quimioterápica seqüencial e intensificada, remissões completas passaram a ser obtidas em 75 por cento-95 por cento dos pacientes. Entretanto, muitos pacientes, particularmente aqueles com a chamada doença avançada, continuaram a recair tanto durante a terapia de indução como na manutenção. Além disso, todos estes estudos iniciais não foram capazes de detectar qualquer índice prognóstico capaz de prever a evolução dos pacientes. No sentido de reduzir as taxas de recidiva, o transplante autólogo de célula progenitora hematopoética em pacientes em remissão completa foi introduzido. Os resultados obtidos com esta abordagem foram bastante homogêneos, indicando uma probabilidade de sobrevida livre de doença de 65 por cento-75 por cento e uma sobrevida global de 60 por cento. Sucessivos tratamentos desenhados já nos anos 2000, foram capazes de obter remissões completas acima de 90 por cento, com taxas de recidivas da ordem de 30 por cento e uma sobrevida global comparável à obtida com o transplante. Ainda, estes estudos também não foram capazes de detectar fatores prognósticos relacionados à evolução válidos. Mais ainda, qualquer estudo com perfil biológico foi desenvolvido. Para melhorar o prognóstico do LLB-T parece ser necessário esforço multicêntrico, de caráter nacional ou internacional, para coletar dados clínicos e biológicos. Nesta linha, é possível alcançar número crítico de dados com valor estatístico que poderiam ser capazes de detectar fatores com influência prognóstica. Finalmente, grupos de pacientes necessitam ser identificados para selecionar aqueles que poderiam se beneficiar do transplante de célula progenitora hematopoética detectados ao diagnóstico.

Célula mesenquimal e reparação tecidual: revisão / The evolving role of mesenchymal stem cells: a review

O autor apresenta uma revisão sobre a utilização de células-tronco mesenquimais (CTM) e os mecanismos envolvidos na reparação tecidual e na imunomodulação com ênfase ainda no controle da doença do enxerto versus o hospedeiro resistente à imunossupressão. O autor enfatiza a importância de novos marcadores celulares e de estudos clínicos associados à utilização da CTM.

The author reports a review concerning the mesenchimal stem cells (MSC) utilization and its mechanisms involved in tissue repair and modulation of immune system emphasizing the GCHD control in immunosuppression resistance. The author emphasizes the importance of new markers development and control clinical trial using MSC.