RESUMO
Rationale The utility of patent foramen ovale (PFO) closure for secondary prevention in patients with prior cryptogenic stroke is uncertain despite multiple randomized trials completed to date. Aims The Gore REDUCE Clinical Study (REDUCE) aims to establish superiority of patent foramen ovale closure in conjunction with antiplatelet therapy over antiplatelet therapy alone in reducing the risk of recurrent clinical ischemic stroke or new silent brain infarct in patients who have had a cryptogenic stroke. Methods and design This controlled, open-label trial randomized 664 subjects with cryptogenic stroke at 63 multinational sites in a 2:1 ratio to either antiplatelet therapy plus patent foramen ovale closure (with GORE® HELEX® Septal Occluder or GORE® CARDIOFORM Septal Occluder) or antiplatelet therapy alone. Subjects will be prospectively followed for up to five years. Neuroimaging is required for all subjects at baseline and at two years or study exit. Study outcomes The two co-primary endpoints for the study are freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization and incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct) through 24 months. The primary analyses are an unadjusted log-rank test and a binomial test of subject-based proportions, respectively, both on the intent-to-treat population, with adjustment for testing multiplicity. Discussion The REDUCE trial aims to target a patient population with truly cryptogenic strokes. Medical therapy is limited to antiplatelet agents in both arms thereby reducing confounding. The trial should determine whether patent foramen ovale closure with the Gore septal occluders is safe and more effective than medical therapy alone for the prevention of recurrent clinical ischemic stroke or new silent brain infarct; the neuroimaging data will provide an opportunity to further support the proof of concept. The main results are anticipated in 2017. Registration Clinical trial registration-URL: http://clinicaltrials.gov/show/NCT00738894.
Assuntos
Isquemia Encefálica/prevenção & controle , Forame Oval Patente/terapia , Inibidores da Agregação Plaquetária/uso terapêutico , Dispositivo para Oclusão Septal , Acidente Vascular Cerebral/prevenção & controle , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/cirurgia , Isquemia Encefálica/diagnóstico por imagem , Terapia Combinada , Seguimentos , Forame Oval Patente/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Recidiva , Prevenção Secundária , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: This study examines factors associated with, and clinical effects of, wire frame fractures (WFF) of the GORE HELEX Septal Occluder (HELEX). METHODS: Investigator-reported data from every HELEX implanted in the United States between 4/2000 and 4/2005 were reviewed. Clinical and procedural data from patients who experienced WFF were compared with data from patients who did not. The echocardiographic and fluoroscopic images for HELEX with WFF were reviewed for predictors of WFF and alterations in HELEX function. RESULTS: With 90% of subjects followed for >12 months, 19/298 (6.4%) HELEX implanted were found to have WFF. Thirty WFFs were observed, with multiple WFFs occurring in 8/19 HELEX. Univariate predictors of WFF were large device size (P = 0.0003) and balloon defect size (P = 0.001); however, large device size (P = 0.0003) was the only significant predictor of WFF by multivariate analysis. WFF of the 30-mm and 35-mm HELEX accounted for 84% (16/19) of all WFFs. Review of HELEX images with WFF revealed all WFF occurred along the circumferential wire, except one (straight portion of locking loop). Seventeen of 29 (59%) circumferential WFFs were on the right disk. Residual defect status remained clinically insignificant (6/19) or became completely occluded (13/19) during follow-up. There were no clinical sequelae due to WFF; however, secondary to right atrial disk mobility, the HELEX with locking loop WFF was percutaneously removed 6 weeks after implantation. CONCLUSIONS: WFF occurred in 6.4% of HELEX and were most common in large devices. With the exception of one device removed for theoretical risks, no clinical sequelae were related to WFF. WFF did not alter the function of the HELEX.
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Cateterismo Cardíaco/instrumentação , Comunicação Interatrial/terapia , Ligas , Cateterismo Cardíaco/efeitos adversos , Ecocardiografia Transesofagiana , Desenho de Equipamento , Falha de Equipamento , Análise de Falha de Equipamento , Fluoroscopia , Comunicação Interatrial/diagnóstico , Humanos , Modelos Logísticos , Razão de Chances , Politetrafluoretileno , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVES: This study sought to compare the safety and efficacy of the HELEX septal occluder (HSO) with surgical repair of atrial septal defect (ASD). BACKGROUND: The HSO is a low-profile, double-disk occluder device for percutaneous closure of secundum ASD. METHODS: Patients were enrolled (HSO arm prospectively, surgery arm prospectively/retrospectively) from 14 U.S. sites and followed up for 12 months postprocedure. Investigator-reported outcomes were evaluated, including closure success (no or clinically insignificant residual shunt) and the incidence of adverse events. The first 3 HSO patients at each site were considered training cases and were excluded from analysis. RESULTS: Between March 2001 and April 2003, 119 nontraining cases received an HSO and 128 had surgical repair. The groups were similar with statistical but clinically unimportant differences in median age, weight, and preprocedural echocardiographic defect size. Anesthesia time and hospital stay were significantly shorter in the HSO group. Closure success, defined as complete closure or a clinically insignificant residual shunt, was similar in both groups. Major and minor adverse events rates were not statistically different. The most common major adverse events for the HSO group was device embolization requiring catheter retreival (1.7%), and in the surgery group was postpericardiotomy syndrome (6.3%), including one death because of tamponade. The primary end point, clinical success, a composite of closure success and no major adverse events at 12 months, satisfied the noninferiority hypothesis comparing device closure with surgery. CONCLUSIONS: Closure of ASD with the HELEX septal occluder is safe and effective when compared with surgical repair, with reduced anesthesia time and hospital stay. (U.S. Multicenter Pivotal Study of the HELEX Septal Occluder for Percutaneous Closure of Secundum Atrial Septal Defects; this study was approved by the Food and Drug Administration before the National Institutes of Health website was active, so there is not a URL or registration number.).
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Procedimentos Cirúrgicos Cardíacos/instrumentação , Procedimentos Cirúrgicos Cardíacos/métodos , Comunicação Interatrial/cirurgia , Estudos Multicêntricos como Assunto/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Comunicação Interatrial/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Estados UnidosRESUMO
BACKGROUND: The HELEX septal occluder is a new transcatheter atrial septal defect occlusion device. This study analyzes the data collected from the first US clinical trials with this device to determine the most significant factors in successful use of the device. METHODS: Tables of subsets of data were constructed in categories of possibly significant patient and device variables compared with important outcomes. Chi2 analysis was used to determine which variables had significant impact on outcomes. RESULTS: The device was successfully implanted in 87% of patients (298/342). A major adverse event occurred in 5.8% (mostly device removal for various reasons). A significant residual leak persisted at 1 year in 2.6%. A fracture of the wire frame occurred in 8%--all were asymptomatic and only 1 required treatment. Overall composite success (no significant leak and no major adverse event) was seen in 91.5%. Patient age, body surface area, and device size had no significant influence on outcomes, except that wire frame fractures were more likely with the 35-mm device. Defect stretch diameter had the largest influence on outcomes, and implantation was possible in only 67% if the stretched diameter of the defect was >20 mm. Device-defect ratio also had a significant effect on delivery success and composite success. CONCLUSIONS: The HELEX septal occluder is best suited for small to moderate atrial septal defects with a stretch diameter <20 mm. Although composite success was achieved in 80% of patients when a device-defect ratio <1.6 was necessitated or elected, use of a device that provided a ratio >2 resulted in 95% composite success, and is recommended when possible.
Assuntos
Cateterismo Cardíaco , Embolização Terapêutica/instrumentação , Comunicação Interatrial/terapia , Próteses e Implantes , Ensaios Clínicos como Assunto , Embolização Terapêutica/efeitos adversos , Estudos de Viabilidade , Humanos , Estudos Multicêntricos como Assunto , Próteses e Implantes/efeitos adversosRESUMO
A group of 256 newly diagnosed myeloma patients were enrolled in a phase III study that included 4 monthly cycles of induction chemotherapy and tandem transplant. All patients were randomized to either receive or not receive thalidomide. A total of 221 patients (86%) received no prophylactic anticoagulation (cohort I); 35 patients received low dose coumadin (cohort II). The incidence of deep vein thrombosis (DVT) was significantly higher in the thalidomide arm hazard ratio: 4.5; P < 0.0001). As low dose coumadin (1 mg/d) failed to decrease thrombotic complications in 35 patients (cohort II), low molecular weight heparin (LMWH, enoxaparin 40 mg s.c. q.d.) was instituted as DVT prophylaxis in the thalidomide-treated patients (n = 68) of the subsequent cohort (n = 130, cohort III). This intervention eliminated the difference in DVT incidence between the two arms (thalidomide and no thalidomide). Within cohorts I and II, 36 patients, in whom thalidomide was discontinued after experiencing a thrombotic episode during chemotherapy, subsequently resumed the drug on full anticoagulation; with a median follow-up of 22 months, DVT recurred in four patients (11%). After completing induction and tandem transplantation, 55 patients were re-exposed to thalidomide and chemotherapy during consolidation treatment. Thrombotic complications were observed in 4%. Our experience, although not based on a randomized study, suggests that the excess frequency of thrombosis in patients treated with chemotherapy and thalidomide can be safely reduced by the prophylactic use of LMWH. The rate of DVT recurrence observed in our study upon thalidomide resumption was sufficiently low to allow its continuation in patients who may benefit from this therapeutic intervention.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/efeitos adversos , Trombose Venosa/induzido quimicamente , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Four Southwest Oncology Group (SWOG) standard-dose chemotherapy protocols for multiple myeloma (MM) initiated between 1982 and 1992 were evaluated. The purpose was to clarify the predictive value of specific levels of myeloma-associated monoclonal protein reduction and time to first progression using mature data sets. PATIENTS AND METHODS: Study data on 1,555 eligible previously untreated patients with MM enrolled onto SWOG phase III trials 8229, 8624, 9028, and 9210 were used in these analyses. Six-month and 12-month landmark analyses were performed to evaluate the outcome for patients in each response category. RESULTS: The overall and event-free survivals for the four protocols combined were 33 months and 18 months, respectively. Using 6- and 12-month landmarks, the median survivals of 30 to 35 months were not different for responders (> or = 50% and > or = 75% regression) versus nonresponders in patients without disease progression before the landmarks. Conversely, at the 6- and 12-month landmarks, the median survivals for patients who had experienced disease progression were 13 and 15 months, respectively, versus a 34-month median for patients who did not experience progression. Using the Cox survival model, with response and progression considered as time-dependent covariates, survival duration was influenced more by the occurrence of progression than by the occurrence of response. CONCLUSION: The magnitude of response, as a single variable, does not predict survival duration. Patients with response and stable disease have equivalent outcome. Only patients with progressive disease have a poorer outcome. The best indicator of survival is time to first progression.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas do Mieloma/metabolismo , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sudoeste dos Estados Unidos , Análise de SobrevidaRESUMO
Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.
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Mieloma Múltiplo/terapia , Amiloidose/complicações , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/história , Antineoplásicos Alquilantes/uso terapêutico , Perfilação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos , Imunoterapia , Melfalan/administração & dosagem , Melfalan/história , Melfalan/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Mieloma Múltiplo/história , Transplante de Células-Tronco de Sangue Periférico , Prognóstico , Insuficiência Renal/complicações , Terapia de Salvação/história , Talidomida/uso terapêutico , Transplante Autólogo , Transplante HomólogoRESUMO
Even during this past year, further advances have been made in understanding the molecular genetics of the disease, the mechanisms involved in the generation of myeloma-associated bone disease and elucidation of critical signaling pathways as therapeutic targets. New agents (thalidomide, Revimid, Velcade) providing effective salvage therapy for end-stage myeloma, have broadened the therapeutic armamentarium markedly. As evidenced in Section I by Drs. Kuehl and Bergsagel, five recurrent primary translocations resulting from errors in IgH switch recombination during B-cell development in germinal centers involve 11q13 (cyclin D1), 4p16.3 (FGFR3 and MMSET), 6p21 (cyclin D3), 16q23 (c-maf), and 20q11 (mafB), which account for about 40% of all myeloma tumors. Based on gene expression profiling data from two laboratories, the authors propose 5 multiple myeloma (MM) subtypes defined by the expression of translocation oncogenes and cyclins (TC molecular classification of MM) with different prognostic implications. In Section II, Drs. Barillé-Nion and Bataille review new insights into osteoclast activation through the RANK Ligand/OPG and MIP-1 chemokine axes and osteoblast inactivation in the context of recent data on DKK1. The observation that myeloma cells enhance the formation of osteoclasts whose activity or products, in turn, are essential for the survival and growth of myeloma cells forms the basis for a new treatment paradigm aimed at reducing the RANKL/OPG ratio by treatment with RANKL inhibitors and/or MIP inhibitors. In Section III, Dr. Fenton reviews apoptotic pathways as they relate to MM therapy. Defects in the mitochrondrial intrinsic pathway result from imbalances in expression levels of Bcl-2, Bcl-XL and Mcl-1. Mcl-1 is a candidate target gene for rapid induction of apoptosis by flavoperidol. Antisense oglionucleotides (ASO) lead to the rapid induction of caspace activity and apoptosis, which was potentiated by dexamethasone. Similar clinical trials with Bcl-2 ASO molecules alone and in combination with doxorubicin and dexamethasone or thalidomide showed promising results. The extrinsic pathway can be activated upon binding of the ligand TRAIL. OPG, released by osteoblasts and other stromal cells, can act as a decoy receptor for TRAIL, thereby blocking its apoptosis-inducing activity. MM cells inhibit OPG release by stromal cells, thereby promoting osteoclast activation and lytic bone disease (by enhancing RANKL availability) while at the same time exposing themselves to higher levels of ambient TRAIL. Thus, as a recurring theme, the relative levels of pro- versus anti-apoptotic molecules that act in a cell autonomous manner or in the milieu of the bone marrow microenvironment determine the outcome of potentially lethal signals. In Section IV, Dr. Barlogie and colleagues review data on single and tandem autotransplants for newly diagnosed myeloma. CR rates of 60%-70% can be reached with tandem transplants extending median survival to approximately 7 years. Dose adjustments of melphalan in the setting of renal failure and age > 70 may be required to reduce mucositis and other toxicities in such patients, especially in the context of amyloidosis with cardiac involvement. In Total Therapy II the Arkansas group is evaluating the role of added thalidomide in a randomized trial design. While data are still blinded as to the contribution of thalidomide, the overriding adverse importance of cytogenetic abnormalities, previously reported for Total Therapy I, also pertain to this successor trial. In these two-thirds of patients without cytogenetic abnormalities, Total Therapy II effected a doubling of the 4-year EFS estimate from 37% to 75% (P <.0001) and increased the 4-year OS estimate from 63% to 84% (P =.0009). The well-documented graft-vs-MM effect of allotransplants can be more safely examined in the context of non-myeloablative regimens, applied as consolidation after a single autologous transplant with melphalan 200 mg/m(2), have been found to be much better tolerated than standard myeloablative conditioning rege conditioning regimens and yielding promising results even in the high-risk entity of MM with cytogenetic abnormalities. For previously treated patients, the thalidomide congener Revimid and the proteasome inhibitor Velcade both are active in advanced and refractory MM (approximately 30% PR). Gene expression profiling (GEP) has unraveled distinct MM subtypes with different response and survival expectations, can distinguish the presence of or future development of bone disease, and, through serial investigations, can elucidate mechanisms of actions of new agents also in the context of the bone marrow microenvironment. By providing prognostically relevant distinction of MM subgroups, GEP should aid in the development of individualized treatment for MM.
Assuntos
Mieloma Múltiplo/terapia , Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/etiologia , Sistemas de Liberação de Medicamentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/genética , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Thalidomide has antiangiogenic properties and was found to be effective in patients with multiple myeloma (MM) when used in the setting of posttransplantation relapse. We have now analyzed risk factors associated with development of deep vein thrombosis (DVT) in a cohort of 535 patients treated with thalidomide with cytotoxic chemotherapy (VAD [vincristine/doxorubicin/dexamethasone], CAD [cyclophosphamide/doxorubicin/dexamethasone], DCEP [dexamethasone/cyclophosphamide/etoposide/cisplatin], or DT-PACE [dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide] or without cytotoxic chemotherapy (thalidomide and dexamethasone only). A total of 82 patients developed DVT, and the frequency was affected by a number of baseline characteristics. On multivariate analysis, the combination of thalidomide with chemotherapy including doxorubicin was associated with the highest odds ratio (OR) for DVT (4.3; P < or = 0.001); in addition, newly diagnosed disease (OR, 2.5; P = 0.001) and chromosome 11 abnormality (OR, 1.8; P = 0.048) were also independent predictors for DVT. With a median follow-up of 2.9 years, survival was inferior in patients with chromosome 13 abnormalities (P = 0.001), age > 60 years (P = 0.001), lactate dehydrogenase level > or = 190 IU/L (P = 0.002), and creatinine level > or = 2 mg/dL (P < 0.001). However, the development of DVT did not adversely affect survival when examined as a time-dependent variable and adjusted for standard risk features (hazard ratio, 0.8; P = 0.162).
Assuntos
Inibidores da Angiogênese/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Talidomida/efeitos adversos , Trombose Venosa/induzido quimicamente , Idoso , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Vincristina/administração & dosagemRESUMO
PURPOSE: To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy. PATIENTS AND METHODS: The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities. RESULTS: The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis-positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P =.01); CR + nCR, 25% v 11% (P =.01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P =.84); CR + nCR, 17% v 15% (P =.73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P <.0001); CR + nCR, 27% v 6% (P <.0001). CONCLUSION: Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalos de Confiança , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Probabilidade , Estudos Prospectivos , Terapia de Salvação , Análise de Sobrevida , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
Cytogenetic abnormalities (CA), especially of chromosome 13, have been used to identify a subgroup of previously untreated multiple myeloma (MM) patients with very poor prognosis despite high-dose therapy (HDT). We examined the prognostic implications of CA in 1000 MM patients receiving melphalan-based tandem autotransplants (median follow-up, 5 years). Negative consequences for both overall survival (OS) and event-free survival (EFS) in the presence of any CA were confirmed, especially when detected within 3 months of HDT. In the context of standard prognostic factors (SPF), 'MM-MDS' (MM karyotype that contains, in addition, CA typical of MDS) imparted a poor OS and EFS, after adjusting for any CA and all individual CA. One-year mortality was also high, especially for the MM-MDS subgroup with trisomy 8 within a MM signature karyotype (87%vs 34% in its absence, P < 0.001). No patient remained event free 5 years post transplant in the presence of these baseline high-risk CA. However, certain trisomies (e.g. chromosomes 7 and 9) and del 20 had favourable clinical consequences. The higher risk that is associated with CA compared with SPF justifies routine cytogenetic studies in all patients with MM at diagnosis and whenever additional treatment decisions are considered, such as in planning HDT either for initial response consolidation, at the time of primary unresponsiveness to induction therapy, or at relapse.
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Aberrações Cromossômicas , Mieloma Múltiplo/genética , Síndromes Mielodisplásicas/genética , Antineoplásicos Alquilantes/uso terapêutico , Análise por Conglomerados , Análise Citogenética/métodos , Intervalo Livre de Doença , Seguimentos , Deleção de Genes , Humanos , Melfalan/uso terapêutico , Monossomia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Medição de Risco , Taxa de Sobrevida , Translocação Genética , Transplante Autólogo , TrissomiaRESUMO
We aimed to develop and evaluate a staging system for multiple myeloma (MM) based on easily obtained laboratory measures. The Durie-Salmon stage is most commonly used and is an effective system of patient stratification for clinical trial research. However, the criteria are complex and many laboratory parameters are required to properly stage patients. In this analysis, we focused on two common measures with prognostic importance in MM: serum beta2 microglobulin (beta2m) and serum albumin. Pre-study data on 1555 previously untreated MM patients enrolled on four recent South-west Oncology Group (SWOG) phase III trials were used in the analysis. Staging models were developed and validated using regression tree methods for survival outcomes. SWOG stages were defined as: stage 1, beta2m < 2.5 mg/l (14% of patients, median overall survival of 55 months); stage 2, 2.5 = beta2m < 5.5 (43% of patients, median overall survival of 40 months); stage 3, beta2m >/= 5.5 and albumin >/= 30 g/l (32% of patients, median overall survival of 24 months); and stage 4, beta2m >/= 5.5 and albumin < 30 g/l (11% of patients and median overall survival of 16 months). This staging scheme was also predictive of event-free survival, first-year mortality and long-term (>/= 5 years) event-free survival. We conclude that although the SWOG stage does not represent a new prognostic marker for MM (cytogenetics, FISH), it could provide a simple alternative to the Durie-Salmon stage for patients with previously untreated MM. Additional evaluation in other MM patient populations is needed to confirm results.
Assuntos
Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cálcio/sangue , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/mortalidade , Análise Multivariada , Estadiamento de Neoplasias , Contagem de Plaquetas , Albumina Sérica/análise , Taxa de Sobrevida , Microglobulina beta-2/análiseRESUMO
We report an update on a prospective observational trial for Waldenstrom's macroglobulinemia (WM) that called for re-registration to treatment with fludarabine (30 mg/m(2)) upon the development of symptomatic or progressive disease. Patients who did not require therapy for more than 1 year (n = 54) could be distinguished from the 118 untreated patients requiring immediate therapy on the basis of hemoglobin, serum beta(2)-microglobulin (beta2m), C-reactive protein (CRP), albumin, and IgM levels, and lower incidence of extramedullary infiltration. Overall response rate (>or= partial response [PR]) to fludarabine was 38%, with 2% complete remissions (CRs). Event-free and overall survivals were significantly longer in the presence of lower levels of serum beta2m in all cohorts. Using time-dependent covariates, neither the occurrence of response (>or= PR) nor the time to response was associated with superior overall or event-free survival. These data support serum beta2m as the dominant prognostic indicator in WM, and show that this factor alone can provide valuable disease risk assessment. Response to therapy using current criteria is not a reliable predictor for survival in this disease.
Assuntos
Antineoplásicos/uso terapêutico , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Seguimentos , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Análise de Sobrevida , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/mortalidadeRESUMO
We have investigated the significance of telomerase activity (TA) and telomere length (TL) in multiple myeloma (MM). The analyses were undertaken on CD138+ MM cells isolated from the marrow of 183 patients either at diagnosis or in relapse. There was heterogeneity in telomerase expression; 36% of the patients had TA levels comparable to those detected in normal plasma cells, and 13% of patients had levels 1- to 4-fold greater than in a neuroblastoma cell line control. The TL of MM cells was significantly shorter than that of the patients' own leukocytes; in 25% of patients, the TL measured less than 4.0 kbp. Analysis of TL distribution indicated selective TA-mediated stabilization of shorter telomeres when mean TL fell below 5.5 kbp. Unusually long (10.8-15.0 kbp) telomeres were observed in 7 patients, and low TA was observed in 5 of 7 patients, suggesting the operation of a TA-independent pathway of telomere stabilization. A strong negative correlation existed between TA and TL or platelet count. TL negatively correlated with age and with interleukin-6 (IL-6) and beta2-microglobulin levels. Various cytogenetic abnormalities, including those associated with poor prognosis, strongly correlated with TA and, to a lesser extent, with short TL. High TA and short TL defined a subgroup of patients with poor prognosis. At 1 year the survival rate in patients with TA levels lower than 25% of neuroblastoma control and TL greater than 5.5 kbp was 82%, whereas in patients with higher TA and shorter TL the survival rate was 63% (P =.004). The 2-year survival rate for patients with TA levels lower than 25% was 81%, and it was 52% in those with higher TA levels (P <.0001).
Assuntos
Análise Citogenética , Mieloma Múltiplo , Telomerase/metabolismo , Telômero/ultraestrutura , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Aberrações Cromossômicas , Cromossomos Humanos Par 13 , Feminino , Granulócitos/ultraestrutura , Humanos , Interleucina-6/sangue , Linfócitos/ultraestrutura , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/ultraestrutura , Plasmócitos/imunologia , Plasmócitos/ultraestrutura , Prognóstico , Proteoglicanas/análise , Taxa de Sobrevida , Sindecana-1 , Sindecanas , Microglobulina beta-2/sangueRESUMO
Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Cromossomos Humanos Par 13 , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Diploide , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Metáfase/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fatores de TempoRESUMO
OBJECTIVES: The aim of this study was to identify prognostic factors for outcome of high-risk patients with multiple myeloma after allogeneic transplantation prepared by reduced intensity conditioning (RIC). MATERIALS AND METHODS: Data from 45 consecutive patients (median age 52 years, range 38-68), who received grafts from a sibling (n = 34) or unrelated donor (n = 11) were analyzed. Fourteen patients received an RIC allotransplant while chemosensitive (>/=partial remission [PR]), whereas 31 chemoresistant patients (Assuntos
Transplante de Células-Tronco Hematopoéticas
, Mieloma Múltiplo/terapia
, Condicionamento Pré-Transplante/métodos
, Transplante Homólogo
, Adulto
, Idoso
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Terapia Combinada
, Progressão da Doença
, Intervalo Livre de Doença
, Resistencia a Medicamentos Antineoplásicos
, Seguimentos
, Doença Enxerto-Hospedeiro/epidemiologia
, Doença Enxerto-Hospedeiro/etiologia
, Humanos
, Transfusão de Linfócitos
, Pessoa de Meia-Idade
, Mieloma Múltiplo/tratamento farmacológico
, Mieloma Múltiplo/mortalidade
, Prognóstico
, Estudos Prospectivos
, Indução de Remissão
, Fatores de Risco
, Terapia de Salvação
, Análise de Sobrevida
, Doadores de Tecidos
, Quimeras de Transplante
, Transplante Autólogo
, Resultado do Tratamento
RESUMO
Cytogenetic abnormalities of chromosome 13 (CA 13) and those detected by fluorescence in situ hybridization (FISH 13) have both been associated with poor prognosis in multiple myeloma (MM) patients. The prognostic implications of CA, FISH 13 and other standard laboratory parameters were examined in the first 231 patients enrolled in Total Therapy II, an intensive cytotoxic chemotherapy programme with tandem autotransplants. Three-year projections of event-free survival (EFS) and overall survival (OS) were 71% and 77% respectively. CA 13 was detected in 14% and significantly correlated with FISH 13 (present in 51%), tumour burden, proliferative activity and lactic dehydrogenase (LDH). Both EFS and OS were significantly shorter in patients with CA 13, FISH 13, LDH >or= 190 U/l, beta2 microglobulin >or= 4 mg/l and C reactive protein >or= 4.0 mg/l; other CA was an additional risk factor for OS. Two-thirds of CA 13 patients were identified by FISH 13 and plasma-cell-labelling index (PCLI) >or= 0.4%; however, PCLI failed to identify additional risk groups in FISH subsets. Although present in considerably fewer patients, CA 13 imparted more rapid relapse (61% at 3 years) and death (43% at 3 years) than FISH 13 (38% and 35%; P = 0.02 and 0.1 respectively) and should be part of the initial work-up of patients with MM.
Assuntos
Cromossomos Humanos Par 13 , Deleção de Genes , Mieloma Múltiplo/diagnóstico , Idoso , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Citogenética , Intervalo Livre de Doença , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Interfase , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Prognóstico , Recidiva , Indução de Remissão , Taxa de Sobrevida , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE AND DESIGN: We previously documented that there was an association between the intra-tumoral pharmacokinetics (TPK) of 5-FU and response to therapy with 5-FU and leucovorin (p < .0001). Since we have shown that other modulators of 5-FU, such as methotrexate, interferon and neutrexin alter its TPK, it was of interest to determine if the modulating effect of leucovorin would also alter the tumoral PK of 5-FU. In order to determine the effect of leucovorin on intratumoral 5-FU pharmacokinetics, 23 patients (21 evaluable) underwent 19F magnetic resonance spectroscopy (19F-MRS) twice. The first 19F-MRS was following 5-FU 600 mg/m2 alone, and the second 19F-MRS was following by leucovorin 500 mg/m2 and then 5-FU 600 mg/m2. RESULTS: A comparison of the intratumoral 5-FU pharmacokinetics indicated that there was no general effect of leucovorin on the intratumoral half-life of 5-FU. In only two of these 21 patients was the half-life of 5-FU altered, and in both cases it was decreased by more than 20%. Partial responses to 5-FU plus leucovorin therapy were seen only in patients with a long intratumoral half-life (trapping) of 5-FU (3 PR in 11 patients with T1/2 > or = 20 minutes, compared to 0 PR in 11 patients with T1/2 < 20 minutes). There was a statistically significant correlation between tumor response and the intratumoral T1/2 of 5-FU, consistent with our prior results in a larger number of patients. However, there was no statistically significant correlation of time-to-progression or survival with classification of the patients into trappers or non-trappers, probably due to the small sample size in this current study. CONCLUSION: The data reported here are compatible with the hypothesis that leucovorin enhancement of 5-fluorouracil antitumor responses is not mediated by the levels of 5-FU in tumors, but rather, is due to the modulation by leucovorin of cellular metabolic processes that follow the uptake of free 5-FU into the tumor cell. The MRS technique may be useful in selected instances for elucidating the possible metabolic interactions of drugs in vivo.
Assuntos
Fluoruracila/farmacocinética , Leucovorina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos Antineoplásicos , Distribuição de Qui-Quadrado , Interações Medicamentosas/fisiologia , Feminino , Fluoruracila/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Humanos , Leucovorina/uso terapêutico , Espectroscopia de Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Sudoeste dos Estados Unidos , Taxa de SobrevidaRESUMO
We investigate methods for identifying groups of patients with different prognosis. Our focus is on procedures that yield interpretable descriptions for groups of patients and corresponding regions of the predictor space. These strategies include tree-based methods and techniques which construct a single prognostic group through 'peeling' or refining of a larger group patients. The peeling methods are relatively new and are developed in detail. Simulations and examples for describing groups of patients with poor outcomes using data from a clinical trial for patients with multiple myeloma are presented.