RESUMEN
Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Modelos Teóricos , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Causas de Muerte , Niño , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/radioterapia , Humanos , Masculino , Neoplasias Primarias Secundarias/epidemiología , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Terapia Recuperativa , Trasplante Autólogo , Adulto JovenRESUMEN
Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Tamizaje Masivo , Neoplasias Primarias Secundarias/diagnóstico , Femenino , Humanos , Masculino , Neoplasias Primarias Secundarias/epidemiología , Especificidad de Órganos , Factores de RiesgoRESUMEN
Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1-21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16-52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0-33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Neoplasias Primarias Secundarias/epidemiología , Sobrevivientes/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Incidencia , Lactante , Masculino , Neoplasias Primarias Secundarias/etiología , Factores de Riesgo , Trasplante Autólogo , Adulto JovenRESUMEN
Optimal therapy for posttransplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low-dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein-Barr virus (EBV) (+), CD20 (+) PTLD. Fifty-five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. The complete remission (CR) rate was 69% (95% confidence interval (CI); 57%-84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, eight were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2-year event-free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%-82%) and overall survival was 83% (95% CI: 69%-91%) with median follow-up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low-dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid-organ transplantation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trastornos Linfoproliferativos/tratamiento farmacológico , Trasplante de Órganos/efectos adversos , Adolescente , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Intervalos de Confianza , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/patología , Femenino , Estudios de Seguimiento , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/patología , Masculino , Dosis Máxima Tolerada , Trasplante de Órganos/métodos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Prospectivos , Medición de Riesgo , Rituximab , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Linfohistiocitosis Hemofagocítica/cirugía , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/mortalidad , Masculino , Probabilidad , Estudios Retrospectivos , Tasa de Supervivencia , Sobrevivientes , Factores de Tiempo , Donantes de Tejidos/estadística & datos numéricos , Acondicionamiento PretrasplanteRESUMEN
The use of peripheral blood stem cells (PBSC) for allogeneic transplants in adults has greatly increased. This trend is reflected in pediatrics, where healthy children increasingly are donating PBSC or donor lymphocyte infusion (DLI) via apheresis for use by ill siblings. There is a potential concern that the risks of PBSC collection may differ for pediatric donors. However, no large studies have assessed safety issues in this population. To address this need, we reviewed 218 (213 PBSC, five DLI) collections in 201 normal pediatric donors (8 months to 17 years, median 11.8 years) at 22 institutions in the Pediatric Blood and Marrow Transplant Consortium. Donors received a median of 4 days of growth factor, and mean collection yield was 9.1 x 10(6) CD34+ cells/kg recipient weight. Younger age, days of apheresis, and male gender predicted increased yield of CD34+ cells/kg donor weight. Growth factor-induced pain was mild and reported in less than 15% of patients. Most donors <20 kg (23/25, 92%) required PRBC priming of the apheresis machine. This experience with over 200 collections demonstrates that PBSC collection is safe in normal pediatric donors and desired CD34 cell yields are easily achieved. Younger children utilize more medical resources and children <20 kg usually require a single blood product exposure.
Asunto(s)
Donantes de Sangre , Movilización de Célula Madre Hematopoyética/normas , Trasplante de Células Madre Hematopoyéticas/normas , Transfusión de Linfocitos/normas , Seguridad/normas , Adolescente , Niño , Preescolar , Movilización de Célula Madre Hematopoyética/tendencias , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Lactante , Leucaféresis/normas , Leucaféresis/tendencias , Transfusión de Linfocitos/tendencias , Masculino , Trasplante HomólogoRESUMEN
Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days -21 to -19), fludarabine (150 mg/m(2); days -8 to -4), melphalan (140/70 mg/m(2); day -3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 x 10(9)/l) and platelets (>50 x 10(9)/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.
Asunto(s)
Trasplante de Médula Ósea , Inmunosupresores/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedades Hematológicas/terapia , Humanos , Lactante , Enfermedades Linfáticas/terapia , Masculino , Errores Innatos del Metabolismo/terapia , Trasplante HomólogoRESUMEN
Acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic stem cell transplantation. Although initial treatment with corticosteroids is effective in the majority of patients, 30--60% develop steroid resistance. Anti-thymocyte globulin (ATG) is commonly used as first-line therapy for steroid resistant (SR) aGVHD. However, data on its efficacy are limited. At two institutions we reviewed the results of treatment with ATG of 58 patients with SR aGVHD. Initial manifestations of aGVHD were treated with 2 mg/kg/day of methylprednisolone (MP). Equine ATG was administered as first-line therapy for SR aGVHD, a median of 9 days (range, 3 to 39) after initiation of MP. At the time of initiation of ATG, IBMTR severity indices B, C and D were observed in 6%, 40% and 54% of patients, respectively. Improvement was observed in 30% of patients treated with ATG. Skin disease was more likely to improve with ATG (79%), while progression of gut and liver aGVHD was observed in 40% and 66% of patients, respectively. Despite initial improvement, 52 patients (90%) died a median of 40 days after ATG therapy from progressive aGVHD and/or infection (74%), ARDS (15%), or relapse (11%). Only six patients (10%), three of whom had aGVHD limited to the skin at the time ATG was administered, are long-term survivors. We conclude that initial improvement of SR aGVHD occurs with ATG in a minority of patients, and very few patients become long-term survivors. Furthermore, this treatment is associated with a high rate of major complications.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Esteroides , Análisis Actuarial , Enfermedad Aguda , Adolescente , Adulto , Niño , Preescolar , Resistencia a Medicamentos , Femenino , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Leucemia/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/mortalidadRESUMEN
OBJECTIVE: MR imaging of central nervous system (CNS) malignancies falls short of a definitive evaluation. Tissue diagnosis remains the gold standard. Diffusion-tensor MR imaging measures the apparent diffusion coefficient and diffusion anisotropy of water in tissue. The purpose of this study was to test the hypothesis that the apparent diffusion coefficient may improve the MR imaging evaluation of newly diagnosed CNS neoplasms. We examined the relationship between the apparent diffusion coefficient, anisotropy, and tumor cellularity in 12 pediatric patients. MATERIALS AND METHODS: On the basis of histopathologic evaluation, tumors in this case series were segregated into three types: low-grade gliomas, embryonal tumors, and nonembryonal high-grade tumors. Mean apparent diffusion coefficient and anisotropy values obtained from the solid components of each tumor were compared with cellularity, total cellular area, and total nuclear area derived from biopsy material. RESULTS: The apparent diffusion coefficient ratio (tumor to normal brain) correlated well with tumor classification (p = 0.001). Anisotropy was decreased similarly in all tumor classifications. The absolute apparent diffusion coefficient correlated well with cellularity (p = 0.014) and total nuclear area (p = 0.005) per high-power field. The correlation between apparent diffusion coefficient and total cellular area per high-power field was not statistically significant. CONCLUSION: The apparent diffusion coefficient may be predictive of tumor classification and may be a useful tool in characterizing tumor cellularity and total nuclear area. These parameters are not available in standard MR imaging. Therefore, diffusion-tensor imaging may enhance the diagnostic process in pediatric CNS malignancies.
Asunto(s)
Neoplasias Encefálicas/patología , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Adolescente , Anisotropía , Astrocitoma/patología , Niño , Preescolar , Femenino , Glioma/patología , Humanos , Lactante , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Estudios RetrospectivosRESUMEN
PURPOSE: To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy. PATIENTS AND METHODS: We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed. RESULTS: Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity. CONCLUSIONS: We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.
Asunto(s)
Antivirales/uso terapéutico , Inmunosupresores/efectos adversos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/terapia , Trasplante de Órganos , Complicaciones Posoperatorias , Adolescente , Antineoplásicos/uso terapéutico , Niño , Preescolar , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/uso terapéutico , Linfoma/tratamiento farmacológico , Trastornos Linfoproliferativos/epidemiología , Masculino , Grupos Raciales , Estudios RetrospectivosRESUMEN
Posttransplantation lymphoproliferative disorder (PTLD) is a condition in patients who receive transplants in which chronic immunosuppression leads to an unregulated expansion of lymphoid cells; the condition ranges from hyperplasia to malignant lymphoid proliferation. Risk factors affecting the incidence of PTLD include allograft type, Epstein-Barr virus infection, and immunosuppression. In this article, we review the clinical, histopathologic, and imaging features of PTLD in children. Because PTLD can affect nearly any organ system, a wide variety of clinical manifestations is possible. The heterogeneous nature of the disease is also reflected on imaging studies. The goals of imaging in patients with PTLD are to detect disease, guide biopsy, and direct appropriate follow-up imaging rather than to establish a specific diagnosis. Because the clinical and imaging manifestations of PTLD are nonspecific and are not reliably predictive of histopathologic subtype, tissue biopsy is necessary for final diagnosis.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Terapia de Inmunosupresión/efectos adversos , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Trasplante de Órganos/efectos adversos , Biopsia , Niño , Diagnóstico por Imagen , Humanos , Trastornos Linfoproliferativos/patología , Factores de RiesgoRESUMEN
Mice carrying a transgenic TCR with targeted disruption of the TCR alpha chain (H-Y alpha(-/-)) possess CD4(+) T cells which express the transgenic TCR beta without the alpha chain. These mice developed the murine acquired immunodeficiency syndrome (MAIDS) after infection with LP-BM5 retroviruses, a process which requires CD4(+) T cells. These cells are negative for TCR delta chain and pre-TCR alpha chain expression, and thus express a unique surface receptor with the TCR beta chain as a component. The cells respond to MAIDS virus-associated superantigen and concanavalin A, but not to protein antigens such as ovalbumin. Thus, this novel surface receptor appears to play an important role in the pathogenesis of MAIDS.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Receptores de Antígenos de Linfocitos T/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Células Cultivadas , Femenino , Genes RAG-1/genética , Hibridomas/inmunología , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , RetroviridaeRESUMEN
T cell unresponsiveness to Ag stimulation can be induced by several means. The precise mechanism by which this process occurs remains poorly understood. Preincubating T cells with either EDCI-fixed APC or ionomycin is a proven means of inducing T cell anergy with reduced IL-2 production in response to Ag stimulation. Using T cells from mice expressing the TCR transgene DO11.10, which is specific for a peptide (323-339) derived from hen egg OVA, we demonstrate that naive cells obtained directly from the host are resistant to the anergy induction by either fixed APC or ionomycin. TCR transgenic mice also deficient in the recombination-activating gene-2 (RAG-2(-/-)), preventing the formation of T cells with endogenous TCRs, were immunized with OVA, and in vivo activated T cells with low expression of CD62 were isolated. These primed cells possess the same sensitivity to ionomycin-induced anergy as in vitro activated cell lines. This unresponsive state most profoundly affects Ag-induced IL-2 production, with IFN-gamma and IL-3 affected to a lesser degree and no effect observed on IL-4 production. Thus, T cells in vivo can be distinguished phenotypically by their susceptibility to anergic stimuli. Anergy so induced affects selected T cell functions.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Anergia Clonal , Memoria Inmunológica , Activación de Linfocitos , Animales , Calcio/fisiología , Membrana Celular/inmunología , Células Cultivadas , Proteínas de Unión al ADN/fisiología , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-3/biosíntesis , Interleucina-4/biosíntesis , Ionomicina/farmacología , Ionóforos/farmacología , Ganglios Linfáticos/citología , Ratones , Ratones Noqueados , Ratones Transgénicos , Ovalbúmina/inmunología , Bazo/citologíaRESUMEN
Downregulation of major histocompatibility complex (MHC) class I expression is an important mechanism by which tumors evade classical T cell-dependent immune responses. Therefore, a system was designed to evaluate parameters for active immunization against MHC class I- tumors. Mice were capable of rejecting a MHC class I- tumor challenge after immunization with an irradiated granulocyte/macrophage colony-stimulating factor (GM-CSF) transduced MHC class I- tumor vaccine. This response was critically dependent on CD4+ T cells and natural killer (NK) cells, but minimally on CD8+ T cells. A strong protective response against MHC class I+ variants of the tumor could be elicited when mice were immunized with irradiated MHC class I+ GM-CSF-secreting tumor cells. This response required CD4+ and CD8+ T cells, and in addition, elimination of NK cells resulted in outgrowth of tumors that had lost expression of at least one MHC class I gene. Finally, class I MHC expression on the vaccinating cells inhibited the response generated against a MHC class I- tumor challenge. These results demonstrate that the host is capable of being immunized against a tumor that has lost MHC class I expression and reveal conditions under which distinct effector cells play a role in the systemic antitumor immune response.
Asunto(s)
Antígenos de Histocompatibilidad Clase I/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T/inmunología , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , ADN , Regulación hacia Abajo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Antígenos de Histocompatibilidad Clase I/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Trasplante de Neoplasias , Linfocitos T Reguladores/inmunología , Transducción Genética , Células Tumorales Cultivadas , VacunaciónRESUMEN
The effect of short-term infusion of intravenous fat on serum lipids was assessed in 23 patients who had elective cancer operations and were given 20% Intralipid for 5 days postoperatively as part of a standard total parenteral nutrition regimen. Serum lipids were measured prior to, during and after the 5-day infusion period. The percentage of cholesterol as high-density lipoproteins (HDL) fell from a mean preinfusion value of 34.7 +/- 2.8 to 27.9 +/- 2.5 (p less than 0.05), while the percentage of cholesterol as low-density lipoproteins (LDL) increased from 40.7 +/- 2.2 to 46.8 +/- 3.4 (p less than 0.05). Serum triglycerides fell significantly (p less than 0.01) from 106.2 +/- 13.7 mg/dl to 64.6 +/- 8.8 mg/dl at 3 days, being 85.3 +/- 3.7 mg/dl at 5 days. No significant change in percent cholesterol as very low-density lipoproteins (VLDL), or levels of serum total cholesterol or phospholipids occurred. Lipoprotein X was detectable in six patients after 5 days. To study triglyceride clearance 1.7 g/kg of fat emulsion was infused over 8 hr and serial blood samples obtained. Within 3 hr of stopping the fat infusion, triglyceride levels had fallen to preinfusion values.
Asunto(s)
Emulsiones Grasas Intravenosas/metabolismo , Lípidos/sangre , Colesterol/sangre , Humanos , Lipoproteína X/sangre , Lipoproteínas/sangre , Nutrición Parenteral Total , Cuidados Posoperatorios , Triglicéridos/sangreRESUMEN
Sixteen elderly postoperative patients were randomized in a crossover study comparing isocaloric volumes of 20% and 10% fat emulsions used for total parenteral nutrition (TPN). The caloric intake was maintained constant during the two 7-day periods of each infusion. The indices measured after each period were total volume of fluid administered, change in body weight, hematocrit, serum sodium, creatinine, albumin, blood urea nitrogen, glucose, inorganic phosphate, and cholesterol. The total volume of 10% isocaloric nutrient solution was significantly (p less than .05) greater than that of the 20% solution. A rise in body weight and a fall in serum indices of hydration status were observed; five patients developed clinical signs of overhydration while on the 10% solution. These changes did not occur with the 20% solution. Thus, isocaloric substitution of a 20% fat emulsion for a 10% fat emulsion with TPN prevented overhydration and hemodilution without compromising nutrient intake.
Asunto(s)
Emulsiones Grasas Intravenosas/uso terapéutico , Neoplasias/terapia , Nutrición Parenteral Total/métodos , Anciano , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/cirugía , Periodo Posoperatorio , Distribución AleatoriaRESUMEN
Hyperimmunization of BALB/c mice with concanavalin A-stimulated blasts from the Ig allotype-congenic strain, C.B20, results in the production of antibodies reactive with T cells in an allotype-restricted manner. Spleen cells from these hyperimmune BALB/c mice were used to generate a panel of hybridomas that secrete monoclonal antibodies, reactive, in an allotype-restricted manner, exclusively with T cells subpopulations, and in particular, reactive with suppressor T cell hybridomas and their secreted soluble factors. Two functional classes of antibodies were identified: those that react with single polypeptide-chain suppressor T cell factors (TsF1) and the suppressor T cell hybridomas that produce such factors, and those that react with two polypeptide-chain suppressor T cell factors (TsF2) and their corresponding suppressor T cell hybridomas. These two classes of antibody were used to isolate molecules from the membranes of the respective suppressor T cell hybrids that are functionally and structurally related to the secreted suppressor T cell factors, suggesting a receptor function for these molecules.
Asunto(s)
Epítopos/inmunología , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/aislamiento & purificación , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Mapeo Cromosómico , Epítopos/genética , Hibridomas/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Linfocinas/metabolismo , Ratones , Ratones Endogámicos/inmunología , Polímeros , Receptores de Antígenos de Linfocitos T/inmunología , Factores Supresores Inmunológicos , Linfocitos T Reguladores/análisis , Linfocitos T Reguladores/metabolismoRESUMEN
This report examines the possibility that glucocorticoids control the degradation of adrenal phenylethanolamine N-methyltransferase and pineal hydroxyindole O-methyltransferase by regulating endogenous concentrations of the cosubstrate, S-adenosylmethionine, via its metabolic enzymes, methionine adenosyltransferase and S-adenosylhomocysteine hydrolase. Assays for these latter enzymes were established and optimized in the adrenal and pineal glands. The effects of hypophysectomy and dexamethasone or ACTH treatment on these enzymes were monitored along with concomitant changes in methyltransferase activity. Hypophysectomy simultaneously decreases methionine adenosyltransferase and S-adenosylhomocysteine hydrolase activity in both tissues. Dexamethasone administration to hypophysectomized animals does not alter either methionine adenosyltransferase activity or S-adenosylhomocysteine hydrolase activity in the adrenal gland. However, it does increase S-adenosylhomocysteine hydrolase activity in the pineal gland. In contrast, ACTH administration restores both enzymes in the adrenal while being ineffective in the pineal. These results suggest that glucocorticoids may be regulating S-adenosylmethionine levels and methyltransferase activity via the metabolic enzymes, methionine adenosyltransferase and S-adenosylhomocysteine hydrolase, but that glucocorticoid control may be both tissue- and drug-specific.
Asunto(s)
Glándulas Suprarrenales/enzimología , Glucocorticoides/fisiología , Hidrolasas/metabolismo , Metionina Adenosiltransferasa/metabolismo , Glándula Pineal/enzimología , Transferasas/metabolismo , Acetilserotonina O-Metiltransferasa/metabolismo , Adenosilhomocisteinasa , Hormona Adrenocorticotrópica/farmacología , Animales , Dexametasona/farmacología , Hipofisectomía , Masculino , Feniletanolamina N-Metiltransferasa/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The most common metabolic complications of total parenteral nutrition (TPN), glucose intolerance and abnormal liver function, can be significantly reduced when 30% of the glucose calories are replaced by fat. We gave 88 patients either conventional TPN (CON-TPN, 25% dextrose and 4.25% amino acids) or modified TPN (MOD-TPN, 15% dextrose, fat, and 5% amino acids). The treatment groups were as follows: group A, no surgery with TPN only; group B, postoperative TPN; and group C, preoperative and postoperative TPN. Serial blood samples were analyzed for glucose, albumin, triglycerides, and insulin, and for liver function values. Nine patients manifested hyperglycemia and were removed from the study; seven patients had received CON-TPN and two had received MOD-TPN. In group A, the insulin level rose 50% less with MOD-TPN. There was a 50% smaller rise in the triglyceride, SGOT, and SGPT levels in patients who received MOD-TPN. Replacing one third of the TPN glucose calories with fat leads to better glucose tolerance and fewer hepatic complications.