RESUMO
Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.
Assuntos
Fibrinolíticos/uso terapêutico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hepatopatia Veno-Oclusiva/complicações , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/epidemiologia , Insuficiência de Múltiplos Órgãos/etiologia , Índice de Gravidade de Doença , Adulto JovemRESUMO
High-dose melphalan 200 mg/m(2) (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m(2) (MEL 140) and VEL 1.6 mg/m(2) were administered i.v. on days -2 and -1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Bortezomib/administração & dosagem , Bussulfano/administração & dosagem , Estudos de Casos e Controles , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Agonistas Mieloablativos/uso terapêutico , Agonistas Mieloablativos/toxicidade , Condicionamento Pré-Transplante/mortalidade , Condicionamento Pré-Transplante/normas , Transplante Autólogo , Resultado do TratamentoRESUMO
Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.
Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/uso terapêutico , Etoposídeo/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Bussulfano/farmacocinética , Bussulfano/uso terapêutico , Carmustina/uso terapêutico , Citarabina/uso terapêutico , Combinação de Medicamentos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Linfoma/mortalidade , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Melfalan/uso terapêutico , Pessoa de Meia-Idade , América do Norte , Análise de Sobrevida , Condicionamento Pré-Transplante/mortalidade , Transplante AutólogoRESUMO
Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase IIa study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration-time curve (AUC) of 20,000 µM × minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose .8 mg/kg pharmacokinetics (PK), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity.
Assuntos
Antineoplásicos , Ácidos Borônicos , Bussulfano , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Agonistas Mieloablativos , Pirazinas , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Autoenxertos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Bortezomib , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/farmacocinética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Agonistas Mieloablativos/farmacocinética , Estudos Prospectivos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Taxa de SobrevidaRESUMO
Uncontrolled delayed nausea and vomiting remains a problem after high-dose preparative regimens used for autologous and allogeneic hematopoietic stem cell transplants. Recently, aprepitant was approved for highly and moderately emetogenic chemotherapy, and, in particular, is effective for decreasing delayed emesis. To evaluate its safety and efficacy in the transplantation setting, we performed a randomized, placebo-controlled, phase 3 trial of aprepitant in combination with ondansetron and dexamethasone in patients treated with ablative preparative regimens. Patients were randomized to receive oral aprepitant or placebo daily with oral ondansetron and dexamethasone during and for 3 days after the completion of the preparative regimen in this prospective randomized, double-blind study. The primary objective was complete response (CR) rate, defined as no emesis with no or mild nausea. Other endpoints included number of emetic episodes, nausea severity assessed using a 100-mm visual analog scale (VAS), the need for rescue antiemetics, and transplantation outcome, including regimen-related toxicity. One hundred eighty-one patients were randomized and 179 patients were eligible for analysis. Overall, CR rates were 81.9% for the aprepitant and 65.8% for the placebo arms (P < .001). Percentages of patients with no emesis all days were 73.3% for aprepitant and 22.5% placebo (P < .001). Mean VAS scores were 16.6 mm aprepitant and 16.9 mm placebo (NS), and there were no differences in the amount of rescue antiemetics used, regimen related toxicity, engraftment, or transplantation outcome. Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, whereas not increasing RRT or affecting short-term survival but had no significant impact on the use of PRN antiemetics, or overall VAS nausea scores.
Assuntos
Antieméticos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Morfolinas/administração & dosagem , Náusea e Vômito Pós-Operatórios/prevenção & controle , Adulto , Idoso , Antieméticos/efeitos adversos , Aprepitanto , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Ondansetron/administração & dosagem , Ondansetron/efeitos adversos , Estudos Prospectivos , Índice de Gravidade de Doença , Transplante Autólogo , Transplante HomólogoRESUMO
Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) after alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previously showed that increases in day +7 TNF-receptor-1 (TNFR1) ratios (posttransplantation day +7/pretransplantation baseline) after myeloablative HCT correlate with outcomes including GVHD, NRM, and survival. Therefore, we conducted a phase II trial at 2 centers, testing whether the addition of the TNF-inhibitor etanercept (25 mg twice weekly from start of conditioning to day +56) to standard GVHD prophylaxis would lower TNFR1 levels, reduce GVHD rates, and improve NRM and survival. Patients underwent myeloablative HCT from a matched unrelated donor (URD; N = 71), 1-antigen mismatched URD (N = 26), or 1-antigen mismatched related donor (N = 3) using either total body irradiation (TBI)-based conditioning (N = 29) or non-TBI-based conditioning (N = 71). Compared to historical controls, the increase in posttransplantation day +7 TNFR1 ratios was not altered in patients who received TBI-based conditioning, but was 40% lower in patients receiving non-TBI-based conditioning. The latter group experienced relatively low rates of severe grade 3 to 4 GVHD (14%), 1-year NRM (16%), and high 1-year survival (69%). These findings suggest that (1) the effectiveness of TNF-inhibition with etanercept may depend on the conditioning regimen, and (2) attenuating the expected rise in TNFR1 levels early posttransplantation correlates with good outcomes.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunoglobulina G/farmacologia , Imunossupressores/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Etanercepte , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/uso terapêutico , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Doadores de Tecidos , Irradiação Corporal TotalRESUMO
The coronavirus disease 19 (COVID-19) pandemic has infected tens of millions across the world, but there is a significant gap in our understanding about COVID-19 in the hematopoietic stem transplant (HSCT) recipient population. Prolonged viral shedding is frequently observed with severe acute respiratory syndrome coronavirus-2 (SARSCoV-2), but studies suggest viral loads decline 10 days after symptom onset. Current CDC guidance suggests that severely ill and immunocompromised hosts are no longer infectious after 20 days from symptom onset. Cycle threshold (Ct) values are inversely proportional to the viral load and are used to detect SARS-CoV-2 RNA concentration. Specimens with reverse transcriptase PCR (RT-PCR) Ct values > 33-34 have been associated with inability to culture virus, and have been used as a surrogate for diminished infectivity. We report two cases of allogeneic peripheral blood stem cell transplant (PBSCT) recipients who had prolonged durations of infectivity with SARSCov-2, based on culture positivity and persistently low Ct values for greater than 50 days.
RESUMO
Nonrandomized trials suggest that pegfilgrastim, a pegylated granulocyte colony-stimulating factor, could be used in lieu of filgrastim after autologus peripheral blood stem cell transplantation. This phase III, randomized, double-blinded, placebo-controlled trial compared the efficacy, costs, and safety of single-dose pegfilgrastim (single 6 mg dose) versus daily filgrastim (5 microg/kg/day) for this indication. Seventy-eight patients, matched for age, sex, underlying disease, stage, and CD34/kg transplant dose were enrolled. Cytokines were started on day +1 posttransplant and continued to an absolute neutrophil count (ANC) of 5x10(9)/L for 3 days or 10x10(9)/L for 1 day. The median time to neutrophil engraftment (ANC >1.5x10(9)/L for 3 days or 5x10(9)/L for 1 day) was the same in both groups (12 days). No differences in platelet engraftment (11 versus 13 days), number of platelet transfusions (5 versus 4), percent with positive cultures for bacterial pathogens (23% versus 15%), days of fever (1 versus 2), deaths prior to engraftment (1 versus 1), or duration of hospital stay (19 versus 19 days) were seen between the pegfilgrastim and filgrastim groups, respectively. Using the average wholesale price for doses used in this trial, there was a per-patient savings of $961 for the pegfilgrastim group (P < .001). This phase III study failed to demonstrate a difference in time to neutrophil engraftment or any clinical sequelae between pegfilgrastim and filgrastim when given post-APBSCT, with pegfilgrastim achieving a cost savings over filgrastim.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/fisiologia , Custos e Análise de Custo , Método Duplo-Cego , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/economia , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/fisiologia , Transplante de Células-Tronco de Sangue Periférico/economia , Polietilenoglicóis , Proteínas Recombinantes , Regeneração , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Melphalan at a dose of 200 mg/m2 (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database (n = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32-62) in favor or the BuMelVel group (95% CI; 23-37) (p = 0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44-0.97)(p = 0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/uso terapêutico , Bussulfano/uso terapêutico , Seguimentos , Humanos , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
METHODS: Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS: Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non-BRCA1/2 genes. CONCLUSION: Testing for non-BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Variação Genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Chile/epidemiologia , Feminino , Humanos , Anamnese , Mutação , Linhagem , Vigilância da População , Medição de Risco , Fatores de RiscoRESUMO
Steroid refractory graft versus host disease (GVHD) presents a significant therapeutic challenge due to the limited efficacy and safety of second-line treatments. Three patients with extensively pretreated, refractory GVHD were treated with a targeted anti-T-cell agent, alefacept, and demonstrated rapid and clinically significant improvement in their GVHD, facilitating tapering of corticosteroids. The pathological and immunohistochemical findings of GVHD also improved, validating our clinical impression. These preliminary findings indicate that alefacept may have beneficial activity in GVHD warranting further study.
Assuntos
Corticosteroides/farmacologia , Fármacos Dermatológicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Alefacept , Transplante de Medula Óssea , Antígenos CD2/metabolismo , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Linfócitos T/efeitos dos fármacos , Resultado do TratamentoRESUMO
A 55-yr-old woman with a history of B-cell lymphoma of the nasopharynx diagnosed in March 1999 eventually underwent submyeloablative allogeneic stem cell transplantation from a sibling donor in December 2002 after conventional treatment options were exhausted. The treatment approach was somewhat altered by the fact that the patient was a practicing Jehovah's Witness and refused blood-blood product transfusion. The course of her treatment was unremarkable until around day 100 posttransplant when she developed graft failure, leading to severe anemia. Blood transfusions were refused. Donor cells were re-infused. During this treatment period, the patient's hemoglobin dropped to a low of 2.7 g/dL, with the patient experiencing severe fatigue, dyspnea on exertion, headaches, and blurred vision. Polymerized human hemoglobin (pyridoxylated) (Poly- Heme, Northfield Laboratories Inc., Evanston, IL) was given under an emergency, compassionate use protocol and successfully bridged the patient's hemoglobin and relieved symptoms during her marrow recovery period.
Assuntos
Substitutos Sanguíneos/uso terapêutico , Rejeição de Enxerto/terapia , Transplante de Células-Tronco Hematopoéticas , Hemoglobinas/uso terapêutico , Testemunhas de Jeová , Linfoma de Células B/terapia , Feminino , Hemoglobinas/análise , Humanos , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
Although bone marrow transplantation has been recognized as an effective therapy for malignant and nonmalignant blood disorders, the modality has also been associated with side-effects and complications. Among these adverse events, neurologic complications emerged as an important and frequent source of treatment-related morbidity and mortality. The survival of patients who died from complications related to central nervous system abnormalities appears to be shorter compared to those who died from non-neurological complications. The incidence of neurologic complications appears to correlate with the degree of human leukocyte antigen (HLA) disparity and the risk status of the underlying disease. Nonrelapse mortality associated with reduced intensity regimens is lower compared to myeloablative conditioning regimens. However, reduced intensity regimens are still associated with significant incidence of complications, including graft-versus-host disease, opportunistic infections, organ toxicity, and neurologic complications. Complications of sepsis-related encephalopathy in mechanically ventilated patients are frequently either overlooked or misdiagnosed. Obtaining a microbiological diagnosis through body fluid cultures or tissue identification is important in order to identify the source of infection and guide an effective antimicrobial therapy. However, pursuing a microbiological diagnosis must not delay the administration of antibiotics and resuscitation of a patient with septic shock.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Doenças do Sistema Nervoso/etiologia , Encefalopatias/etiologia , Doença Enxerto-Hospedeiro/fisiopatologia , Doença Enxerto-Hospedeiro/psicologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Infecções/epidemiologia , Infecções/etiologia , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/terapia , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/epidemiologiaRESUMO
Abstract Allogeneic transplant using reduced intensity conditioning is a therapeutic option for patients with Hodgkin lymphoma (HL) who relapse after an autograft. This was a prospective study of 31 consecutive eligible patients with HL who relapsed after an autograft and underwent an allograft using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning. At a median follow-up of 7 years the progression-free survival (PFS) was 36% (95% confidence interval [CI] 19-54%) and overall survival (OS) was 42% (95% CI 23-59%). In multivariate analysis only residual disease at the time of transplant predicted outcome, with a 4-year PFS and OS of 62% and 75% for patients with minimal residual disease versus 8% and 8% for patients with gross residual disease, respectively (p = 0.005 and p = 0.001, respectively). This benefit seemed to be irrespective of chemosensitivity, with an OS for patients with chemorefractory yet minimal disease of 71% at 4 years. BEAM allogeneic transplant is effective in producing long-term remissions after autograft failure. Regardless of chemosensitivity, minimizing tumor burden pre-transplant may improve long-term outcome.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/terapia , Neoplasia Residual/diagnóstico , Carmustina/administração & dosagem , Citarabina/administração & dosagem , Progressão da Doença , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/mortalidade , Humanos , Masculino , Melfalan/administração & dosagem , Recidiva Local de Neoplasia , Prognóstico , Transplante Autólogo , Transplante Homólogo , Falha de Tratamento , Resultado do TratamentoAssuntos
Nefropatias/diagnóstico , Nefropatias/etiologia , Paraproteinemias/diagnóstico , Paraproteinemias/etiologia , Biomarcadores , Biópsia , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Imunoglobulina A/imunologia , Nefropatias/terapia , Testes de Função Renal , Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias/terapia , Índice de Gravidade de Doença , Avaliação de SintomasRESUMO
OBJECTIVE: To describe characteristics of Clostridium difficile infection (CDI) and markers of severe CDI among patients with hematologic malignancies. DESIGN: Case-control study. SETTING: Tertiary care teaching hospital. PATIENTS AND METHODS: Inpatients with hematologic malignancies and CDI were age and time matched with 2 control inpatients without hematologic malignancies. Chart reviews were performed, and C. difficile isolates were strain typed. RESULTS: Case patients (n = 41) and control patients (n = 82) patients were different in respect to receipt of immunosuppressive agents within 2 months (92.7% vs 25.6%; P < .0001); neutropenia within 2 months (75.6% vs 3.7%; P < .0001) and mean (± standard deviation) white blood cell (WBC) count at diagnosis (vs 4.9 ± 14.1 vs 11.8 ± 6.8 x 10(3) cells/mL; P <.0001); baseline mean creatinine level (0.89 ± 0.1 vs 1.6 ± 2.4 mg/dL; P = .003), mean creatinine level at diagnosis (0.83 ± 0.4 vs 1.85 ± 1.9 mg/dL; P = .004), and creatinine increases of 1.5 times over baseline (2.4% vs 15.1%; P = .02). Immunosuppressive agents and creatinine level remained significant in multivariable analysis (P = .03 for both variables). Severity correlated with mortality when measured by alternate severity criteria but not when measured by the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America criteria, which are based solely on WBC count and creatinine elevation. The prevalence of the epidemic BI/NAP1/027 strain was similar in both groups. CONCLUSIONS: Patients with hematologic malignancies had lower creatinine levels at the time of CDI diagnosis compared with control patients. WBC counts also tended to be lower in case patients. CDI severity criteria based on WBC count and creatinine level may not be applicable to patients with hematologic malignancies.
Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/diagnóstico , Neoplasias Hematológicas/microbiologia , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Clostridioides difficile/classificação , Infecções por Clostridium/sangue , Creatinina/sangue , Feminino , Neoplasias Hematológicas/sangue , Hospitais de Ensino , Humanos , Contagem de Leucócitos , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Análise Multivariada , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. METHODS: In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645. FINDINGS: Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0.95), but not when measured by plasma cytomegalovirus DNA PCR (27.8%vs 30.4%; OR 0·88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6%vs 37.4%; OR 0.73, 0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). INTERPRETATION: Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. FUNDING: ViroPharma Incorporated.
Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Quimioprevenção/métodos , Infecções por Citomegalovirus/prevenção & controle , Placebos/administração & dosagem , Ribonucleosídeos/administração & dosagem , Transplante de Células-Tronco , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Canadá , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ribonucleosídeos/efeitos adversos , Transplante , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
Introducción: el trauma craneoencefálico por agresión constituye un motivo de consulta frecuente en los Servicios de Neurocirugía del país. Objetivo: El objetivo fue conocer la incidencia, lesiones más frecuentes, estado al ingreso, mortalidad y secuelas tempranas del paciente que ha sufrido una agresión neurotraumática con necesidad de atención especializada. Materiales y métodos: se realizó un estudio observacional, descriptivo, donde se caracterizaron 39 pacientes ingresados en el Servicio de Neurocirugía de Matanzas, en un período de dos años, que presentaron trauma craneoencefálico causado por agresión. Resultados: predominó el sexo masculino (77 %) y por debajo de los 45 años (77,4 %), en estado de embriaguez al momento del trauma (55 %). El agente vulnerante más usado en la agresión fue el machete. El 72 % de los casos ingresó con una puntuación en la escala de Glasgow entre 14 y 15; el 18 % entre, 13 y 9, y el 10 % por debajo de 8 puntos. Entre las lesiones que más se encontraron están las fracturas lineales, las fracturas deprimidas penetrantes, los focos contusivos y la presencia de hematoma epidural, 2 pacientes presentaron lesión del seno sagital superior. Requirieron cirugía el 74 % de los casos y el Glasgow al egreso fue bueno en el 77 % de los pacientes. Conclusiones: la agresión como causa de trauma craneoencefálico es relativamente frecuente en nuestro medio; la patología es casi exclusiva del sexo masculino; la riña y el alcohol están directamente relacionados con el trauma. En general, el trauma craneoencefálico por agresión presentó una baja mortalidad, pero una estimable morbilidad.
Background: Cranioencephalic trauma by aggression is a motive of frequent consultation in the Neurosurgery Services of the country. Aim: The aim was to know its incidence, its more frequent lesions, status at admission, mortality and early sequels of the patient who suffered a neurotraumatic aggression with special care necessity. Materials and methods: an observational, descriptive study was carried out characterizing 39 patients admitted in the Neurosurgery Services of Matanzas in a two-year period, who presented cranioencephalic trauma due to aggression. Outcomes: male sex predominated (77 %) and people aged less than 45 years (77.4 %), being drank at the moment of the trauma (55 %). Machete was the most used vulnerary agent in the aggression. 72 % of the cases were admitted with a 14 and 15 punctuation in the Glasgow Scale; 18 % among 13 and 9 points, and 10 % below 8 points. Among the most frequently found lesions are lineal fractures, penetrating depressed fractures, contusive focuses and the presence of epidural hematoma. 2 patients presented high sagittal sinus lesion. 74 % of the cases needed surgical treatment and Glasgow punctuation at discharge was good in 77 % of the patients. Conclusions: Aggression as a cause of cranioencephalic trauma is relatively frequent in our surroundings; the pathology is almost exclusive of the male gender; quarrelling and alcohol are directly related with the trauma. In general, cranioencephalic trauma by aggression presents low mortality, but a considerable morbidity.
RESUMO
UNLABELLED: Although autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25% to 35% of patients with primary progressive or poor-risk recurrent HL can achieve durable remission after ASCT, with disease progressive after transplant accounting for most of the treatment failures. We conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients. Between April 1998 and March 2000, 46 patients were enrolled in the study. ELIGIBILITY CRITERIA: primary progressive (n = 28) or recurrent HL (n = 18) with at least 1 of the following poor prognostic factors: first complete remission (CR) <12 months (n = 15) or extra-nodal disease (n = 4) or B symptoms at relapse (n = 4). The first cycle consisted of melphalan (150 mg/m(2)) alone. The second cycle consisted of fractionated total body irradiation (FTBI) 1200 cGy or BCNU (450 mg/m(2)) in combination with etoposide (60 mg/kg) and cyclophosphamide (100 mg/kg). Of the 46 patients, 5 (11%) did not receive the planned tandem transplants because of inadequate stem cell collection for 2 ASCT. After a median of 64 days (25-105), 41 patients received the second ASCT. With a median follow-up of 5.3 years (1.6-8.1), the 5-year estimate of overall survival, progression-free survival, and freedom from progression were 54% (95% confidence interval [CI] 40%-69%), 49% (95% CI, 34%-63%), and 55% (95%CI, 40%-70%), respectively. Our mature results from this study suggest that in patients with primary progressive or poor risk recurrent HL, this tandem ASCT program is effective and well tolerated and compares favorably with the conventional single transplant.