RESUMEN
Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Hidroxilaminas/uso terapéutico , Neoplasias/tratamiento farmacológico , Temozolomida/uso terapéutico , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Reparación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Semivida , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/efectos adversos , Hidroxilaminas/farmacocinética , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana Edad , Temozolomida/efectos adversos , Temozolomida/farmacocinéticaRESUMEN
BACKGROUND: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care. METHODS: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada. We analyzed the number and locations of network sites; access to electronic medical records (EMRs); clinical research support and participation at networks; use of patient navigators, care paths, and quality measures; and physician workforce. Responses were collected via Qualtrics software between September 2017 and December 2018. RESULTS: Of the 69 responding cancer centers, 74% were NCI-designated. Eighty-seven percent of respondents were part of a matrix health system, and 13% were freestanding. Fifty-six reported having network sites. Forty-three respondents use navigators for disease-specific populations, and 24 use them for all patients. Thirty-five respondents use ≥1 types of care path. Fifty-seven percent of networks had complete, integrated access to their main center's EMRs. Thirty-nine respondents said the main center provides funding for clinical research at networks, with 22 reporting the main center provides all funding. Thirty-five said the main center provided pharmacy support at the networks, with 15 indicating the main center provides 100% pharmacy support. Certification program participation varied extensively across networks. CONCLUSIONS: The data show academic cancer centers have extensive involvement in network cancer care, often extending into rural communities. Coordinating care through improved clinical trial access and greater use of patient navigation, care paths, coordinated EMRs, and quality measures is likely to improve patient outcomes. Although it is premature to draw firm conclusions, the survey results are appropriate for mapping next steps and data queries.
Asunto(s)
Neoplasias , Navegación de Pacientes , Médicos , Certificación , Registros Electrónicos de Salud , Humanos , Neoplasias/epidemiología , Neoplasias/terapia , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.
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Cardiomegalia/patología , Cardiomiopatías/patología , Insuficiencia Cardíaca/patología , Factores de Transcripción de Tipo Kruppel/metabolismo , Macrófagos/patología , Miocardio/patología , Animales , Cardiomegalia/inmunología , Cardiomegalia/metabolismo , Cardiomiopatías/inmunología , Cardiomiopatías/metabolismo , Células Cultivadas , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/metabolismo , Factor 4 Similar a Kruppel , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Miocardio/inmunología , Miocardio/metabolismo , PresiónRESUMEN
Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.
Asunto(s)
Anemia Aplásica , Trasplante de Células Madre Hematopoyéticas , Anemia Aplásica/tratamiento farmacológico , Animales , Trasplante de Médula Ósea , Humanos , Hidroxiprostaglandina Deshidrogenasas , RatonesRESUMEN
Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies.
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Daño del ADN/fisiología , Reparación del ADN/fisiología , Oro/química , Nanopartículas del Metal/química , Nanomedicina Teranóstica/métodos , Línea Celular Tumoral , Humanos , Estructura MolecularRESUMEN
Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe-/- background developed increased aortic lipid-rich plaques compared to control Apoe-/- mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe-/- mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe-/- marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow-derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.
Asunto(s)
Aterosclerosis/metabolismo , Células Espumosas/metabolismo , Macrófagos Peritoneales/metabolismo , Proteína Hiperexpresada del Nefroblastoma/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Aterosclerosis/etiología , Aterosclerosis/patología , Aterosclerosis/prevención & control , Médula Ósea/metabolismo , Trasplante de Médula Ósea , Antígenos CD36/metabolismo , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Progresión de la Enfermedad , Células Espumosas/patología , Metabolismo de los Lípidos/fisiología , Macrófagos Peritoneales/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Hiperexpresada del Nefroblastoma/deficienciaRESUMEN
Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Supervivencia de Injerto/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/farmacología , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Adulto , Factores de Edad , Animales , Trasplante de Médula Ósea , Femenino , Trasplante de Células Madre Hematopoyéticas , Xenoinjertos , Humanos , Masculino , RatonesRESUMEN
BACKGROUND: Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. OBJECTIVE: To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. METHODS: Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 106 MSCs/kg were thawed and administered IV. RESULTS: In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 106 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. CONCLUSION: Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Trasplante Autólogo/métodos , Adulto JovenRESUMEN
Extranodal marginal zone lymphoma (EMZL) is a B-cell lymphoma arising from mucosa-associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long-term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12-year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow-up of 44·3 months (range 2·2-214·9), median progression-free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5-111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.
Asunto(s)
Linfoma de Células B de la Zona Marginal/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , L-Lactato Deshidrogenasa/análisis , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin lymphoma that arises from mature B-cells. We delineate outcomes, prognostic factors and treatment trends among a large cohort of patients with NMZL in the rituximab era. We identified 56 such patients treated at our institutions. The majority presented with advanced stage disease (78·6%). Over a median follow-up of 38·2 months, median progression-free survival (PFS) was 42·4 months and median overall survival (OS) was not reached. Kaplan-Meier estimates of OS at 120 months after diagnosis was 71·9%. High-risk follicular lymphoma international prognostic index (FLIPI) was associated with inferior PFS. Age >60 years and elevated serum lactate dehydrogenase (LDH) were associated with inferior OS. Transformation to diffuse large B-cell lymphoma occurred in 7 patients, 6 of who presented with advanced disease. OS was comparable to our previously reported extranodal MZL cohort. FLIPI score predicted for inferior PFS and OS when both cohorts were analysed together (n = 267). In summary, outcomes in NMZL are favourable with a large majority of patients surviving at 120 months. High risk FLIPI, age >60 years, and elevated serum LDH were associated with inferior outcomes.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/mortalidad , Rituximab/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B de la Zona Marginal/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Rituximab/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
DNA repair is essential for hematopoietic stem cell (HSC) maintenance. Ku70 is a key component of the nonhomologous end-joining pathway, which is the major pathway for DNA double-strand break repair. We find that HSCs from Ku70-deficient mice are severely defective in self-renewal, competitive repopulation, and bone marrow (BM) hematopoietic niche occupancy and that loss of quiescence results in a dramatic defect in the maintenance of Ku70-deficient HSCs. Interestingly, although overexpression of Bcl2 does not rescue the severe combined immunodeficiency phenotype in Ku70-deficient mice, overexpression of Bcl2 in Ku70-deficient HSCs almost completely rescued the impaired HSC quiescence, repopulation, and BM hematopoietic niche occupancy capacities. Together, our data indicate that the HSC maintenance defect of Ku70-deficient mice is due to the loss of HSC quiescent populations, whereas overexpression of Bcl2 rescues the HSC defect in Ku70-deficient mice by restoration of quiescence. Our study uncovers a novel role of Bcl2 in HSC quiescence regulation.
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Antígenos Nucleares/genética , Puntos de Control del Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Genes bcl-2/fisiología , Células Madre Hematopoyéticas/fisiología , Animales , Antígenos Nucleares/metabolismo , Células de la Médula Ósea/fisiología , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Inmunofenotipificación , Autoantígeno Ku , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nicho de Células Madre/genética , Regulación hacia Arriba/genéticaRESUMEN
Key challenges facing the oncology community today include access to appropriate, high quality, patient-centered cancer care; defining and delivering high-value care; and rising costs. The National Comprehensive Cancer Network convened a Work Group composed of NCCN Member Institution cancer center directors and their delegates to examine the challenges of access, high costs, and defining and demonstrating value at the academic cancer centers. The group identified key challenges and possible solutions to addressing these issues. The findings and recommendations of the Work Group were then presented at the Value, Access, and Cost of Cancer Care Policy Summit in September 2015 and multi-stakeholder roundtable panel discussions explored these findings and recommendations along with additional items.
Asunto(s)
Atención a la Salud/métodos , Oncología Médica/normas , Neoplasias/economía , HumanosRESUMEN
Brentuximab vedotin (BV), an antibody-drug conjugate that targets CD30, induces high response rates in CD30(+) lymphoid malignancies. It is unknown if BV use affects procurement of autologous CD34(+) stem cells and hematopoietic engraftment after autologous stem cell transplantation (ASCT). We examined 42 patients treated with BV before mobilization. Median times from diagnosis to transplantation, from initial BV treatment to transplantation, and from last BV treatment to stem cell collection were 21 months (range, 10 to 210), 5 months (range, 1.5 to 16.8), and 30 days (range, 2 to 280), respectively. Mobilization was successful on the first attempt in 38 patients (90.4%). The median number of infused CD34(+) cells was 5.46 × 10(6)/kg (range, 1.65 to 54.78 × 10(6)/kg). The median times to neutrophil and platelet engraftment were 10 (range, 9 to 13), and 10.5 days (range, 7 to 35), respectively. BV before high-dose chemotherapy-ASCT did not adversely affect peripheral blood stem cell mobilization and subsequent engraftment in a cohort of heavily pretreated patients with CD30(+) lymphomas.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Inmunoconjugados/uso terapéutico , Antígeno Ki-1/metabolismo , Células Madre/metabolismo , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Brentuximab Vedotina , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) improves outcomes in relapsed lymphoma, but the relative efficacy of different preparative regimens is not well defined. We included patients undergoing autologous HCT using BEAM (carmustine, 300 mg/m(2), etoposide, cytarabine, and melphalan) or BEP (carmustine 600 mg/m(2), etoposide, and cisplatin) between January 2004 and December 2013; 65 patients received BEP and 64 patients BEAM. Both cohorts were similar for advanced-stage disease, extranodal and bulky disease, and prior therapies. Median neutrophil and platelet engraftment was 10 and 20 days for both regimens, respectively. Febrile neutropenia, serum creatinine concentration increase, and electrolyte abnormalities were more frequent with BEP. Incidence of carmustine pneumonitis was not higher with BEP, likely the result of corticosteroid prophylaxis, although 2 cases of fatal pneumonitis were observed after BEP. One-year nonrelapse mortality was 6.8% after BEP and 0% after BEAM (P = .379). After a median follow-up of 39.4 months (range, 1 to 128), 4-year rates of overall survival (OS) after BEP and BEAM were 80.4% and 72.3%, respectively (P = .611). Diffuse large B cell lymphoma patients transplanted after early relapse post-rituximab-based first-line therapy presented 3-year rates of OS and progression-free survival (PFS) of 73.8% and 65%, respectively. There were no statistically significant differences in the OS and PFS of follicular lymphoma, mantle cell lymphoma, or Hodgkin lymphoma. BEP is a valid alternative to BEAM in autologous HCT. Although associated with more renal and electrolytic toxicities, BEP results in similar disease control and long-term survival as BEAM. Prospective studies are needed to confirm whether intensification of conditioning regimens for autologous HCT can improve disease control in high-risk relapsed lymphoma patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Linfoma Folicular/terapia , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células del Manto/terapia , Linfoma no Hodgkin/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Carmustina/uso terapéutico , Cisplatino/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Femenino , Supervivencia de Injerto , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Linfoma Folicular/inmunología , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Riesgo , Rituximab/uso terapéutico , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
Hematopoietic stem cell (HSC) populations require DNA repair pathways to maintain their long-term survival and reconstitution capabilities, but mediators of these processes are still being elucidated. Exonuclease 1 (Exo1) participates in homologous recombination (HR) and Exo1 loss results in impaired 5' HR end resection. We use cultured Exo1(mut) fibroblasts and bone marrow to demonstrate that loss of Exo1 function results in defective HR in cycling cells. Conversely, in Exo1(mut) mice HR is not required for maintenance of quiescent HSCs at steady state, confirming the steady state HSC reliance on nonhomologous end joining (NHEJ). Exo1(mut) mice sustained serial repopulation, displayed no defect in competitive repopulation or niche occupancy, and exhibited no increased sensitivity to whole body ionizing radiation. However, when Exo1(mut) HSCs were pushed into cell cycle in vivo with 5-fluorouracil or poly IC, the hematopoietic population became hypersensitive to IR, resulting in HSC defects and animal death. We propose Exo1-mediated HR is dispensable for stem cell function in quiescent HSC, whereas it is essential to HSC response to DNA damage processing after cell cycle entry, and its loss is not compensated by intact NHEJ. In HSCs, the maintenance of stem cell function after DNA damage is dependent on the DNA repair capacity, segregated by active versus quiescent points in cell cycle.
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Daño del ADN/genética , Exodesoxirribonucleasas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Recombinación Homóloga/genética , Animales , Ciclo Celular/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/genética , Exodesoxirribonucleasas/genética , Fluorouracilo/farmacología , Células Madre Hematopoyéticas/citología , Ratones , Células Madre/citología , Células Madre/metabolismoRESUMEN
Although scid mice have been widely used for human HSC engraftment studies, the function of HSCs of scid mice has not been characterized. We hypothesized that the DNA repair defect of scid mice results in a stem cell defect that facilitates HSC engraftment. scid BM cells showed severely impaired repopulation potentials in the competitive repopulation assay. To assess the BM hematopoietic niche occupancy ability of scid HSC, WT BM cells were transplanted into scid mice without any conditioning and observed to achieve long-term engraftment. Furthermore, the defects of scid HSCs are independent of their inability to perform lymphopoiesis because a similar defect in hematopoietic niche occupancy was not observed with Rag1(-/-) recipients. These results demonstrate that scid HSCs are impaired in maintenance within the niche, which may explain the nature of the conducive marrow niche environment of scid mice for xenotransplantation.
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Movimiento Celular/genética , Supervivencia de Injerto/genética , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/fisiología , Proteínas de Homeodominio/genética , Nicho de Células Madre/genética , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Movimiento Celular/fisiología , Proliferación Celular , Células Cultivadas , Reparación del ADN por Unión de Extremidades/genética , Reparación del ADN por Unión de Extremidades/inmunología , Reparación del ADN por Unión de Extremidades/fisiología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Nicho de Células Madre/fisiologíaRESUMEN
Hematopoietic stem and progenitor cells (HPCs) are necessary for long-term survival. Genomic instability and persistent DNA damage may cause loss of adult stem cell function. The mismatch repair (MMR) pathway increases replication fidelity and defects have been implicated in malignant hematopoietic diseases. Little, however, is known about the role MMR pathway failure plays in the aging process of human HPCs. We hypothesized that loss of MMR occurs in HPCs as a process of human aging. We examined microsatellite instability and expression of the MMR genes MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in HPCs and colony-forming cell-derived clones (CFCs) from human donors aged 0 to 86 years. CFCs from donors > 45 years had a greater frequency of microsatellite instability and CD34(+) progenitors lacking MLH1 expression and protein than individuals ≤ 45 years. Loss of MSH2 did not correlate with age. Thus, a potentially early event in the normal human aging process is microsatellite instability accumulation in normal human HPCs associated with the loss of MLH1 protein expression.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Envejecimiento/patología , Células Madre Hematopoyéticas/metabolismo , Inestabilidad de Microsatélites , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/metabolismo , Células Madre/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Western Blotting , Niño , Preescolar , Ensayo de Unidades Formadoras de Colonias , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
INTRODUCTION: TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed. PURPOSE: Patients with advanced solid tumors received oral TRC102 daily for 4 days. Two weeks later, patients began standard-dose pemetrexed on day 1 in combination with oral TRC102 on days 1 to 4. The pemetrexed-TRC102 combination was repeated every 3 weeks until disease progression. METHODS: Twenty-eight patients were treated with TRC102 at 15, 30, 60 or 100 mg/m(2)/d. The MTD was exceeded at 100 mg/m(2)/d due to grade 3 anemia in 50 % of patients. TRC102 exposure increased in proportion to dose with a mean t1/2 of 28 h. A pharmacodynamic assay confirmed that TRC102 binds to pemetrexed-induced AP sites at all doses studied. Stable disease or better was achieved in 15 of 25 patients evaluable for response (60 %), including one patient with recurrent metastatic oropharyngeal carcinoma that expressed high levels of thymidylate synthase, who achieved a partial response and was progression free for 14 months. CONCLUSIONS: When administered with pemetrexed, the maximum tolerated dose of oral TRC102 is 60 mg/m(2)/d for 4 days. Randomized controlled studies are planned to evaluate the clinical benefit of adding TRC102 to pemetrexed and other agents that induce BER.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Reparación del ADN , Femenino , Glutamatos/administración & dosificación , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/análogos & derivados , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/efectos adversos , Hidroxilaminas/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pemetrexed , Adulto JovenRESUMEN
The feasibility of allogeneic transplantation, without myeloablation or post-transplant immunosuppression, was tested using in vivo chemoselection of allogeneic hematopoietic stem cells (HSCs) after transduction with a novel tricistronic lentiviral vector (MGMT(P140K)-2A-GFP-IRES-TK (MAGIT)). This vector contains P140K-O(6)-methylguanine-methyltransferase (MGMT(P140K)), HSV-thymidine kinase (TK(HSV)), and enhanced green fluorescent protein (eGFP) enabling (i) in vivo chemoselection of HSC by conferring resistance to benzylguanine (BG), an inhibitor of endogenous MGMT, and to chloroethylating agents such as 1,3-bis(2-chloroethyl)nitrosourea (BCNU) and, (ii) depletion of proliferating cells such as malignant clones or transduced donor T cells mediating graft versus host disease (GVHD), by expression of the suicide gene TK(HSV) and Ganciclovir (GCV) administration. Non-myeloablative transplantation of transduced, syngeneic, lineage-depleted (Lin(-)) BM in neonates resulted in 0.67% GFP(+) mononuclear cells in peripheral blood. BG/BCNU chemoselection, 4 and 8 weeks post-transplant, produced 50-fold donor cell enrichment. Transplantation and chemoselection of major histocompatibility complex (MHC)-mismatched MAGIT-transduced Lin(-) BM also produced similar expansion for >40 weeks. The efficacy of this allotransplant approach was validated in Hbb(th3) heterozygous mice by correction of ß-thalassemia intermedia, without toxicity or GVHD. Negative selection, by administration of GCV resulted in donor cell depletion without graft ablation, as re-expansion of donor cells was achieved with BG/BCNU treatment. These studies show promise for developing non-ablative allotransplant approaches using in vivo positive/negative selection.