RESUMEN
In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.
Asunto(s)
Daño del ADN , ADN Helicasas/metabolismo , Reparación del ADN , Proteínas Ribosómicas/metabolismo , Factor de Transcripción TFIIH/metabolismo , Proteína de la Xerodermia Pigmentosa del Grupo D/metabolismo , Xerodermia Pigmentosa/patología , Aductos de ADN , ADN Helicasas/genética , Células HeLa , Humanos , Proteínas Ribosómicas/genética , Factor de Transcripción TFIIH/genética , Xerodermia Pigmentosa/genética , Xerodermia Pigmentosa/metabolismo , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
This study aimed to analyze the use of the revised International Prognostic Scoring System (IPSS-R) assessed after hypomethylating treatment (HMT) for patients with myelodysplastic syndrome (MDS) undergoing an allogeneic stem cell transplantation (SCT). Among 115 patients who received pre-SCT HMT, comparison analysis of the prognostic values between the IPSS-R at the time of HMT (IPSS-R@HMT) and at the time of SCT after HMT (IPSS-R@SCT) showed a significantly higher predictive power for overall survival (OS) of the latter. Alteration in IPSS-R risk occurred in 60%, while the patients with 'down-staged' IPSS-R@SCT showed better OS compared with those with 'unchanged' or 'up-staged' risk. On multivariate analysis in all 201 patients, IPSS-R@SCT, monosomal karyotype, treatment failure to pre-SCT treatment, and high hematopoietic cell transplantation-comorbidity index were independently associated with OS. Constructed using these factors, the MDS Transplantation Prognostic Scoring System (MTPSS) identified four risk groups with 4-year OS of 76.4% in low, 61.4% in intermediate-1 and 21.9% in intermediate-2 risk groups, whereas all in the high risk group died within 2 years after SCT (P<0.001). Our study emphasizes the need for further studies aiming to evaluate a transplantation prognostic model such as the MTPSS to make appropriate decisions for transplantation in MDS.
Asunto(s)
Metilación de ADN/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , Comorbilidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Cariotipo , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Medición de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Allogeneic stem cell transplantation from HLA-matched siblings (MSD-SCT) for elderly patients with severe aplastic anemia (SAA) is not a widely accepted first-line treatment. Recently, fludarabine, lower-dose cyclophosphamide and antithymocyte globulin conditioning (Flu/lower-dose Cy/ATG) with lower toxicities has been investigated. To determine whether this regimen can overcome the negative effects of age, we analyzed 117 adult patients with SAA who received MSD-SCT using Flu/lower-dose Cy/ATG, and compared outcomes between 63 younger age group (YAG; ⩽40 years) and 54 older age group (OAG; >40 years) patients. No primary graft failure was observed. Neutrophil engraftment was significantly faster in the YAG compared with the OAG (12 vs 13 days; P=0.04). The incidences of acute grade II-IV (9.5% vs 9.3% at day 100; P=0.42) and chronic GVHD (8.1% vs 9.5% at 5 years; P=0.80), secondary graft failure (20.8% vs 7.9% at 5 years; P=0.11) and transplant-related mortality (5.4% and 11.1% at 5 years; P=0.91) were not significantly different between the YAG and OAG. In addition, failure-free (73.7% vs 81.0% at 5 years; P=0.73) and overall survival rates (93.7% vs 88.9% at 5 years; P=0.20) were comparable. Our results suggest that MSD-SCT using Flu/lower-dose Cy/ATG may be a feasible first-line treatment even in older patients with SAA.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Factores de Edad , Anemia Aplásica/complicaciones , Anemia Aplásica/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Hermanos , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
The aim of this study was to evaluate the impact of pretransplant transfusion of packed red cells (PRCs) on outcome after allogeneic stem cell transplantation (SCT) in severe aplastic anemia (SAA). A total of 221 adult SAA patients receiving allogeneic SCT were analyzed. The patients were divided into two groups according to the amount of pretransplant transfusion before SCT: the low transfusion group (⩽32 PRC units, n=164) and the high transfusion group (>32 PRC units, n=57). The incidence of engraftment failure was not different between the two groups. The incidence of acute GvHD (grades II-IV) was higher in the high transfusion group than in the low transfusion group (P=0.04), and the incidences of chronic extensive GVHD were not significantly different (P=0.136). The high transfusion group had higher 5-year transplant-related mortality (TRM) (24.8% vs 6.8%, P<0.001) and lower overall survival (OS) (72.3% vs 91.9%, P<0.001) than those in the low transfusion group. Multivariate analysis revealed that the high transfusion group and unrelated donor type were independent prognostic factors affecting OS. These results indicate that a history of higher pretransplant transfusion of PRCs was associated with increased TRM and decreased OS, suggesting that iron overload had a negative impact on outcome after SCT in SAA.
Asunto(s)
Anemia Aplásica/terapia , Transfusión de Eritrocitos/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Enfermedad Aguda , Adolescente , Adulto , Anemia Aplásica/complicaciones , Anemia Aplásica/mortalidad , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Sobrecarga de Hierro/etiología , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Donante no Emparentado , Adulto JovenAsunto(s)
Proteínas de Unión al ADN/genética , Síndromes Mielodisplásicos , Proteínas Proto-Oncogénicas/genética , Trasplante de Células Madre , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Anciano , Aloinjertos , Dioxigenasas , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Tasa de SupervivenciaRESUMEN
We investigated the prognostic relevance of IKZF1 deletions in 118 adult Ph-positive ALL patients who had minimal residual disease (MRD) data under a uniform treatment of allo-SCT following first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 patients (78.8%). IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P=0.028). After a median follow-up of 72 months, IKZF1-deleted patients had a trend for higher cumulative incidence of relapse (CIR) (38.0 vs 13.3%, P=0.052), particularly in a subgroup of early-stable molecular responders (n=40; 21.4 vs 0%, P=0.088), but comparable disease-free survival to wild-type patients. Patients with biallelic-null deletions showed higher CIR (74.6 vs 13.3%, P=0.003) and lower disease-free survival (20.0 vs 67.5%, P=0.022) than wild-type patients. In multivariate analysis, MRD kinetics were closely related to outcomes, while neither IKZF1 deletions nor their functional subtypes retained an independent statistical power. Within the limitation of sample size, however, considering both the negative impact of IKZF1 deletions on MRD kinetics and a trend for relationship between IKZF1 deletions and relapse in early-stable molecular responders, IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Factor de Transcripción Ikaros/genética , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Antineoplásicos/administración & dosificación , Femenino , Humanos , Factor de Transcripción Ikaros/deficiencia , Factor de Transcripción Ikaros/metabolismo , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Eliminación de Secuencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Emerging molecular studies have identified a subgroup of patients with unfavorable core-binding factor-positive (CBF)-AML who should be treated by intensified post-remission treatments. We analyzed 264 adults with CBF-AML from 2002 to 2011, and focused on 206 patients who achieved CR after standard '3+7' induction chemotherapy. Patients who achieved CR with an available donor were treated with allogeneic hematopoietic SCT (allo-HSCT, n=115) and the rest were treated with autologous (auto) HSCT (n=72) or chemotherapy alone (n=19). OS was not significantly different between CBFß/MYH11 (n=62) and RUNX1/RUNX1T1 (n=144), and auto-HSCT showed favorable OS compared with allo-HSCT or chemotherapy alone. Cytogenetic analysis identified that inv(16) without trisomy had a favorable OS and t(8;21) with additional chromosomes had an unfavorable OS, but multivariate analysis revealed those were NS. Patients with c-kit mutation showed inferior OS. For transplanted patients, residual post-transplant CBF-minimal residual disease quantitative PCR with higher WT1 expression at D+60 showed the worst OS with a higher incidence of relapse. Conclusively, we found that unfavorable CBF-AML can be defined with risk stratification using cytogenetic and molecular studies, and a careful risk-adapted treatment approach using frontline transplantation with novel therapies should be evaluated for this particular risk subgroup.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Inversión Cromosómica , Factores de Unión al Sitio Principal/metabolismo , Citogenética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Pronóstico , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Translocación Genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Few studies are available that compare PBSC and BM from unrelated donors, especially in adult high-risk ALL. To determine which graft source is superior in adult high-risk ALL, we analyzed the long-term outcomes of 106 consecutive transplants from 8/8-matched or 7/8-matched unrelated donors (38 PBSC vs 68 BM). All patients received a uniform strategy of pre-transplant therapy, myeloablative conditioning and GVHD prophylaxis. At 5 years, PBSC transplants showed higher incidence of chronic GVHD than did BM transplants (74.3% vs 46.7%, P=0.001). PBSC transplants showed outcomes comparable to those of BM transplants for relapse (23.7% vs 28.1%), non-relapse mortality (18.4% vs 25.0%), disease-free survival (57.9% vs 46.9%) and OS (57.9% vs 50.0%). In a separate comparison of outcomes between the two graft sources according to the presence of a Ph chromosome, no significant advantage of PBSC over BM was found in both subgroups of patients. Our data suggest that the outcomes of unrelated donor transplantation are similar between PBSC and BM in adult high-risk ALL. Whether PBSC should be the preferred graft source for a specific subgroup of adult ALL needs to be further investigated.
Asunto(s)
Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre Periférica , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Trasplante de Médula Ósea/efectos adversos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , República de Corea/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Terapéutica , Acondicionamiento Pretrasplante , Donante no Emparentado , Adulto JovenRESUMEN
Hepatic veno-occlusive disease (VOD) remains one of the most severe complications of hematopoietic SCT (HSCT). Anticoagulation and thrombolytic therapies using tissue-plasminogen activator (t-PA) have been used, but are reported to be ineffective and are associated with significant bleeding complications. We analyzed 56 moderate-to-severe post HSCT hepatic VOD cases treated with t-PA. We analyzed clinical outcomes according to the maximal daily dose of t-PA (t-PAmax) and the severity of VOD. Patients were stratified by t-PAmaxîº10 mg (n=37) vs t-PAmax>10 mg (n=19). A higher t-PAmax was associated with increased mortality. Bleeding complications were more likely at higher t-PAmax in both moderate and severe VOD (P=0.036, 0.063), especially if patients had concomitant use of anticoagulants (36.4% vs 13.3%). In moderate VOD, the response rate was 86.4% for t-PAmaxîº10 mg/day and 80% for t-PAmax>10 mg compared with 33.3% and 7.1%, respectively, for severe VOD (P=0.106). The 5-year OS in moderate and severe VOD was 49% and 7%, respectively, and it was 32% for t-PAmaxîº10 mg and 18% for t-PAmax>10 mg. Our data demonstrate that lower bleeding complications and bleeding-related deaths may result from strict limitations on the t-PAmax without concomitant use of anticoagulation therapy. However, the overall response and survival outcomes should be re-evaluated by a well-validated study in the future.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Activador de Tejido Plasminógeno/uso terapéutico , Adolescente , Adulto , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Adulto JovenRESUMEN
To investigate the risk factors for acute GVHD (aGVHD), based on NIH consensus criteria (NCC), we evaluated 775 patients who underwent allogeneic transplantation. Of them, 346 patients developed aGVHD by NCC, in whom we also analyzed factors affecting aGVHD-specific survival. The cumulative incidence of aGVHD was 44.7%, consisting of classic aGVHD (n=320) and late-onset (n=26). Multivariate analyses revealed that younger age (P=0.015), unrelated donors (P=0.004) and acute leukemia compared with other hematologic malignancies (P=0.005) were significant risk factors for aGVHD, whereas PBSCs showed no association (P=0.720). Multivariate analyses, with only aGVHD patients, revealed that late-onset aGVHD had superior aGVHD-specific survival to classic aGVHD (P=0.044), and identified the association of visceral organ involvement (P=0.002), severity of aGVHD at onset (P=0.035) and advanced disease status (P<0.001) with inferior aGVHD-specific survival. In conclusion, this study demonstrates the risk and prognostic factors for aGVHD by NCC with some differences with the previous reports that were based on old criteria. The difference in the risk factors according to different criteria will give insights about the pathophysiology of GVHD. The better prognosis of late-onset aGVHD than of classic aGVHD raises the necessity for prospective trials with a large cohort focusing on the onset time.
Asunto(s)
Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre de Sangre Periférica , Enfermedad Aguda , Adolescente , Adulto , Anciano , Consenso , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/fisiopatología , Neoplasias Hematológicas/fisiopatología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , República de Corea , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P<0.001), lower BM blast (<33%) at sAML (P=0.007), non-poor NCCN (National Cancer Comprehensive Network) cytogenetics (P=0.001) and good performance status (ECOG (Eastern Cooperative Oncology Group) îº1) (P=0.024) were significant predictors affecting favorable OS in a multivariate analysis. Of the active treatment options, allo-SCT with prior chemotherapy (CTx) showed better OS compared with CTx only or SCT without CTx (P=0.019). Our analyses suggest that active treatment, particularly SCT following CTx, should be considered in patients with sAML/MDS-HTF if the patient is medically fit.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/cirugía , Síndromes Mielodisplásicos/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Pronóstico , Tasa de Supervivencia , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto JovenAsunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Degeneración Combinada Subaguda/etiología , Degeneración Combinada Subaguda/patología , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/patología , Diagnóstico Diferencial , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Degeneración Combinada Subaguda/prevención & control , Resultado del Tratamiento , Vitamina B 12/administración & dosificación , Deficiencia de Vitamina B 12/tratamiento farmacológicoRESUMEN
We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Neoplasia Residual , Cromosoma Filadelfia , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Pirimidinas/uso terapéutico , Adolescente , Adulto , Benzamidas , Terapia Combinada , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
OBJECTIVES: The treatment guidelines for isolated superior mesenteric artery dissection (SMAD) are not well established. The purpose of this study was to report a single-centre series of SMAD and propose treatment guidelines. MATERIALS AND METHODS: Between November 2004 and December 2009, 30 patients were diagnosed with SMAD. We retrospectively reviewed their medical records. RESULTS: The subjects included 26 men and four women, with a mean age of 55.1 years. The chief complaint was abdominal pain in 17 patients, whereas 13 patients were asymptomatic. The mean follow-up was 38.3 months. The radiographic findings included intimal flap with a false lumen in 20 patients and intramural haematoma in 10 patients. The treatments included observation in 18 patients, anticoagulation in five patients, stenting in six patients and surgery in one patient. During follow-up (mean 15.6 months), there was no change in the computed tomography scans of seven patients, improvement was observed in four patients and complete resolution was observed in four patients. All patients, including the symptomatic patients, remained asymptomatic during follow-up. CONCLUSIONS: Most patients with SMAD can be successfully managed with conservative treatment. Surgical treatment or percutaneous intervention can be reserved for patients with severe mesenteric ischaemia and those for whom the initial conservative treatment fails.
Asunto(s)
Disección Aórtica/diagnóstico por imagen , Disección Aórtica/terapia , Arteria Mesentérica Superior , Adulto , Anciano , Disección Aórtica/complicaciones , Anticoagulantes/uso terapéutico , Estudios de Cohortes , Procedimientos Endovasculares , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Puntos de Rotura del Cromosoma , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Benzamidas , Proteínas de Fusión bcr-abl/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Mesilato de Imatinib , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , ARN Neoplásico , Inducción de Remisión , Trasplante Homólogo , Adulto JovenRESUMEN
Toll-like receptors (TLRs) are innate immune mediators that stimulate nuclear factor kappa B and the inflammatory cytokines. TLR1 is expressed in renal tubular epithelial cells when the kidney is injured, but the role of TLR1 gene in glomerulonephritis has not been clearly elucidated. We aimed to investigate the association of TLR1 polymorphisms with immunoglobulin A nephropathy (IgAN) in children. One hundred and ninety pediatric patients with biopsy-proven IgAN and 283 healthy control subjects were enrolled. Two single nucleotide polymorphisms of TLR1 gene [rs4833095 (missense, Asn248Ser) and rs5743557 (promoter, -414C/T)] were selected and genotyped by direct sequencing. For rs4833095, the C/T genotype in the codominant model (vs. the T/T genotype) [odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.21-3.69, P = 0.009] and the genotype containing C allele (C/T and C/C) in the dominant model (vs. the T/T genotype) (OR = 1.97, 95% CI: 1.16-3.34, P = 0.012) were associated with an increased risk of IgAN. For rs5743557, the T/T genotype in the codominant model (vs. the C/C genotype) (OR = 1.74, 95% CI: 1.02-2.96, P = 0.041) appeared to be associated with IgAN risk. In haplotype analysis, the CT haplotype revealed an association with IgAN (codominant model, OR = 1.38, 95% CI: 1.06-1.80, P = 0.017; dominant model, OR = 1.76, 95% CI: 1.16-2.67, P = 0.008). After Bonferroni correction, the association of the genotypes of rs4833095 and the CT haplotype with IgAN risk remained significant. These findings suggest that TLR1 gene polymorphisms may affect IgAN susceptibility in Korean children.
Asunto(s)
Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Glomerulonefritis por IGA/genética , Polimorfismo de Nucleótido Simple/genética , Receptor Toll-Like 1/genética , Adolescente , Estudios de Casos y Controles , Niño , Demografía , Femenino , Frecuencia de los Genes/genética , Haplotipos/genética , Humanos , Masculino , República de CoreaRESUMEN
We analyzed long-term outcomes of myeloablative stem cell transplantation (SCT) in 292 adults with Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL). Donors were related (RD; n=132), unrelated (URD; n=68; 30 well-matched (WM), 19 partially matched (PM), 19 mismatched (MM)) and autologous (AUTO; n=92). After a median follow-up of 85 months, the risk of relapse was higher for AUTO-SCT than for RD-SCT (P<0.001). MM-URD-SCT yielded higher risk of non-relapse mortality than RD-SCT (P=0.010). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; P=0.010) or MM-URD (26.3%; P=0.036), whereas DFS from other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD and 57.0% for PM-URD). Other factors associated with poorer DFS included SCT beyond first complete remission (CR), older age and adverse cytogenetics. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in first CR, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. SCT using RD, WM-URD or PM-URD may be considered the best donor sources for adult high-risk Ph-negative ALL.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Donantes de Tejidos , Adolescente , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Factores de Riesgo , Resultado del TratamientoRESUMEN
The transplantation of a large number of stem cells can overcome graft rejection but with the increased risk of GVHD. In this study, we analyzed the outcome of 32 adult patients with acquired severe aplastic anemia (SAA) who were at a high risk for graft rejection, including multiple transfusions (median 147 units, range 20-680) and long disease duration (median 67 months, range 3-347), and who had received both BM and CD34(+)-purified PBSCs from an HLA-matched sibling donor to reduce graft rejection. T cells in PBSCs were depleted using a magnetic-activated cell sorting method (CliniMACS system). Conditioning regimens consisted largely of CY and antithymocyte globulin (ATG) with fludarabine (FLU) or procarbazine (PCB). With a median follow-up of 89 months, the 8-year probability of survival was 87.5%. Neutrophils and plts promptly recovered, and none of the patients developed graft failure. The cumulative incidences of acute and chronic GVHD were 9.4 and 18.0%, respectively. Sustained engraftment and excellent survival without an apparent increase in the rate of GVHD in high-risk patients using the current approach showed that high-dose SCT with both BM and CD34(+)-purified PBSCs may yield better outcomes in heavily transfused and/or allo-immunized patients with SAA.