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Use of machine learning (ML) in the early detection of developmental delay is possible through the analysis of infant motor skills, though the large number of potential indicators limits the speed at which the system can be trained. Body joint obstructions, the inability to infer aspects of movement such as muscle tone and volition, and the complexities of the home environment - confound machine learning's ability to distinguish between some motor items. To train the system efficiently requires using an excerpted list of validated items, a salient set, which uses only those motor items that are the 'easiest' to see and identify, while being the most highly correlated to a low/qualifying score. This work describes the examination of motor items, selection of 15 items that comprise the salient set, and the ability of the set to reliably screen for motor delay in the first-year infant.
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Destreza Motora , Movimiento , Humanos , Lactante , Alberta , Tono MuscularRESUMEN
Navigating access to eye care requires that patients recognize the need for screening and care, employ limited financial and social resources, manage complex health insurance policies, and access specialty clinical care. We investigated the experience of patients through the progression of vision loss to blindness, utilizing qualitative methods. We conducted structured telephone interviews with 28 persons with blindness throughout Oregon. Utilizing closed and open-ended questions, we explored patient experience on the events preceding avoidable blindness. Coding for emergent themes was conducted independently by two researchers using a constant comparative method. Participants described important barriers to accessing eye care: at the systems level, lack of access to providers and treatment; at the community level, available social support and services; and at the individual level, readiness to act and trust in providers. These findings suggest that important barriers to accessing preventive eye care, early diagnosis and treatment, vocational rehabilitation, and social services often occur at multiple levels. Access to eye care should be prioritized in efforts to reduce preventable visual impairment.
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In the United States, there is no reliable data to describe the prevalence of eye diseases leading to visual impairment and little active surveillance to address this knowledge gap. Data that is readily available from many state blind registries may provide helpful information on trends and causes of blindness. We analyzed new registrations with the Oregon Commission for the Blind (OCB) and Oregon State Department of Administrative Services (DAS) from 1961 to 2016 for causes of and trends in blindness. Persons with blindness self-refer into the OCB registry and the Oregon State Department of Administrative Services (DAS) includes those receiving social security disability financial support and other state services. Data for 9,273 blind persons registered were analyzed. The most frequent causes of blindness were age related macular degeneration (AMD) 3,308 (38%), followed by diabetic retinopathy (DR) 729 (8%), congenital conditions 697 (8%), optic nerve atrophy 611 (7%), glaucoma 549 (6%), retinitis pigmentosa 546 (6%), retinopathy of prematurity192 (2%), cataract 180 (2%), and trauma 174 (2%). The mean age of onset of blindness was younger for Blacks (31 years) and Hispanics (33 years) than for Whites (44 years). Analysis of state-based registries can provide useful and locally relevant vision and eye health data where little information is otherwise available.
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Ceguera/epidemiología , Ceguera/etiología , Sistema de Registros , Adulto , Etnicidad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Oregon/epidemiología , Grupos RacialesRESUMEN
Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m2 IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level -1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1). GVHD responses were complete (n = 12) or partial (n = 3), with 1 progression at PO level -1. T-regulatory cells increased at day 8, CD4/CD8 and monocytes exhibited enhanced H3 acetylation, and CD4 or CD8 numbers remained unchanged with a decreased interleukin 12p40 plasma level. Panobinostat in combination with prednisone is safe and warrants further testing in GVHD.
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Glucocorticoides/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Panobinostat/uso terapéutico , Enfermedad Aguda , Femenino , Glucocorticoides/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Panobinostat/farmacologíaRESUMEN
T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400).
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Interleucina-12/antagonistas & inhibidores , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Células TH1/inmunología , Células Th17/inmunología , Ustekinumab/administración & dosificación , Adulto , Anciano , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Ustekinumab/efectos adversos , Adulto JovenRESUMEN
To determine whether coping strategies modify the risk of depression among allogeneic recipients experiencing post-transplant-related symptomatology, 105 participants (mean age = 52 years, 42% female) completed questionnaires 90 days post-transplant. A total of 28 percent reported depressive symptoms. Univariate correlations indicated that depression was associated with greater transplant-related symptomatology and avoidance, acceptance/resignation, and emotional discharge coping. Depression was negatively associated with problem-solving coping. Moderator analyses indicated that transplant-related symptomatology was significantly associated with depression among patients who frequently used maladaptive coping and rarely used adaptive coping. These data suggest that transplant-related symptomatology, combined with maladaptive coping, place patients at risk of depression.
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Adaptación Psicológica , Depresión/psicología , Trastorno Depresivo/psicología , Trasplante de Células Madre Hematopoyéticas/psicología , Neoplasias/psicología , Neoplasias/terapia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5 g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P < .0001). This was also the case for OS (hazard ratios, 6.86 [95% CI, 4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P < .0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS.
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Trasplante de Células Madre Hematopoyéticas/mortalidad , Hipoalbuminemia/diagnóstico , Valor Predictivo de las Pruebas , Adolescente , Adulto , Anciano , Femenino , Humanos , Hipoalbuminemia/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Factores de Tiempo , Receptores de Trasplantes , Trasplante Homólogo/mortalidad , Adulto JovenRESUMEN
BACKGROUND: Next-generation sequencing has identified somatic mutations that are prognostic of cancer. PATIENTS AND METHODS: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen. RESULTS: The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival. CONCLUSION: This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.
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Trasplante de Células Madre Hematopoyéticas/métodos , Isocitrato Deshidrogenasa/genética , Síndromes Mielodisplásicos/cirugía , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/patología , Adulto JovenRESUMEN
Graft-versus-host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16th April 2014 and 19th December 2015, 20 patients received IL-2 (200,000 IU/m2 thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% vs. 16.0%, P=0.0016; 0.052 k/uL vs. 0.037 k/uL, P=0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% vs. 50%, P=0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. (clinicaltrials.gov identifier: 01927120).
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Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Interleucina-2/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Sirolimus/uso terapéutico , Análisis de Supervivencia , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Fatigue is common among cancer patients and adversely impacts quality of life. As such, it is important to measure fatigue accurately in a way that is not burdensome to patients. The 7-item Patient Reported Outcome Measurement Information System (PROMIS) Cancer Fatigue Short Form scale was recently developed using item response theory (IRT). The current study evaluated the psychometric properties of this scale in two samples of cancer patients using classical test theory (CTT). METHODS: Two samples were used: 121 men with prostate cancer and 136 patients scheduled to undergo hematopoietic cell transplantation (HCT) for hematologic cancer. All participants completed the PROMIS Cancer Fatigue Short Form as well as validated measures of fatigue, vitality, and depression. HCT patients also completed measures of anxiety, perceived stress, and a clinical interview designed to identify cases of cancer-related fatigue. RESULTS: PROMIS Cancer Fatigue Short Form items loaded on a single factor (CFI=0.948) and the scale demonstrated good internal consistency reliability in both samples (Cronbach's alphas>0.86). Correlations with psychosocial measures were significant (p values<.0001) and in the expected direction, offering evidence for convergent and concurrent validity. PROMIS Fatigue scores were significantly higher in patients who met case definition criteria for cancer-related fatigue (p<.0001), demonstrating criterion validity. CONCLUSION: The current study provides evidence that the PROMIS Cancer Fatigue Short Form is a reliable and valid measure of fatigue in cancer patients.
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Fatiga/etiología , Neoplasias/complicaciones , Calidad de Vida , Encuestas y Cuestionarios/normas , Anciano , Anciano de 80 o más Años , Ansiedad/etiología , Depresión/etiología , Femenino , Humanos , Sistemas de Información , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Autoinforme/normas , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Estrés Psicológico/etiologíaRESUMEN
Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Sirolimus/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Antimetabolitos Antineoplásicos/uso terapéutico , Enfermedad Crónica , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Índice de Severidad de la Enfermedad , Hermanos , Análisis de Supervivencia , Tacrolimus/uso terapéutico , Trasplante Homólogo , Resultado del Tratamiento , Donante no EmparentadoRESUMEN
Standard primary therapy for chronic graft-versus-host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I trial examining the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy. Patients ages ≥ 18 with National Institutes of Health Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1000 mg) of i.v. ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade ≥ 3 organ toxicities, or grade 4 neutropenia lasting > 14 days. A total of 12 patients (median age 54; range, 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastrointestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well tolerated, and no DLT was observed. From the total number of adverse events (n = 29), possibly related adverse events (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy. Ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Prednisona/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Enfermedad Crónica , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Hermanos , Trasplante Homólogo , Resultado del Tratamiento , Donante no EmparentadoRESUMEN
We prospectively evaluated the allogeneic hematopoietic cell transplantation (HCT) outcomes in high-risk myelodysplastic syndrome (MDS) patients who received pretransplantation 5-azacitidine. Twenty-five patients evaluated for allogeneic HCT consult and considered medically eligible for a donor search were enrolled. Azacitidine was administered at 75 mg/m(2) for 5 to 7 days every 4 weeks until a suitable donor was found. A median of 3 (range, 0 to 6) cycles of 5-azacitidine were administered. Preallogeneic HCT responses to 5-azacitidine, based on the International Working Group criteria, were 48% partial response, 33% stable disease, and 19% progressive disease. Four patients did not proceed to allogeneic HCT. Twenty-one patients, a median age of 55 (range, 25 to 67) years, received allogeneic HCT after myeloablative pharmacokinetically targeted i.v. busulfan and fludarabine conditioning regimen. Donors were either HLA-matched related or unrelated, except for 1 mismatch unrelated donor. With a median follow-up of 30 months, 1-year relapse-free and overall survivals were 52% (95% confidence interval [CI], 30% to 71%) and 62% (95% CI, 38% to 79%), respectively. Preallogeneic HCT 5-azacitidine administration was well tolerated and provided reasonable disease control before allogeneic HCT. (Registered at ClinicalTrials.gov as NCT00660400).
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Azacitidina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Adulto , Anciano , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Proyectos Piloto , Estudios Prospectivos , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Donante no EmparentadoRESUMEN
One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/µL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) µmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.
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Antineoplásicos/uso terapéutico , Busulfano/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Pentostatina/uso terapéutico , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adulto , Anciano , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
Azacitidine's efficacy in therapy-related myeloid neoplasms (t-MN) has not been well-studied. In our retrospective review of 84 t-MN patients treated with azacitidine, median overall survival (OS) was 14.5 months and overall response rate was 43%, including 11% complete remission, 4% marrow complete remission, and 11% partial remission. In patients who underwent allogeneic transplant (25%), median OS was 19.2 versus 12.8 months (P=0.023) for those who did not. Response rates were comparable to those reported for de novo myelodysplastic syndrome. When we analyzed outcomes according to five scoring systems, only the Global MD Anderson Risk Model predicted survival with statistical significance.
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Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/mortalidad , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: There is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. DESIGN AND METHODS: We conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. RESULTS: Seventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4(+) cells in the peripheral blood, and isolated regulatory T cells were functional. CONCLUSIONS: These data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation.
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Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/diagnóstico , Sirolimus/uso terapéutico , Tacrolimus/uso terapéutico , Adulto , Anciano , Estudios de Casos y Controles , Terapia Combinada , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Estudios Prospectivos , Calidad de Vida , Tasa de Supervivencia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 µM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 µM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 µM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 µM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 µM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 µM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Busulfano/farmacocinética , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/farmacocinética , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Busulfano/sangre , Busulfano/uso terapéutico , Esquema de Medicación , Cálculo de Dosificación de Drogas , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/sangre , Agonistas Mieloablativos/uso terapéutico , Estudios Prospectivos , Recurrencia , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/sangre , Vidarabina/farmacocinética , Vidarabina/uso terapéuticoRESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies. EXPERIMENTAL DESIGN: Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured. RESULTS: The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose. CONCLUSION: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Neoplasias/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Terapia Combinada/estadística & datos numéricos , ADN-Topoisomerasas de Tipo I/sangre , Esquema de Medicación , Resistencia a Antineoplásicos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Estimación de Kaplan-Meier , Masculino , Mesna/administración & dosificación , Mesna/efectos adversos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Mucositis/inducido químicamente , Análisis Multivariante , Neoplasias/sangre , Neoplasias/metabolismo , Modelos de Riesgos Proporcionales , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinética , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Plasmablastic lymphoma (PBL) is a rare aggressive B-cell lymphoproliferative disorder. HIV-negative PBL has not been extensively reported. Nine HIV-negative PBL patients evaluated at Moffitt Cancer Center were studied. Eight patients had extranodal diseases. All patients were treated with CHOP or hyper-CVAD. Responses were observed in 8 cases (7 complete, 1 partial responses). Four patients underwent consolidation with autologous hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). At median follow-up of 23.9 months, 7 patients were alive and 5 were disease-free. Aggressive induction chemotherapy and consolidation with autologous HSCT in CR1 might be considered for patients with HIV-negative PBL.
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Linfoma de Células B/terapia , Anciano , Terapia Combinada , Femenino , Estudios de Seguimiento , Infecciones por VIH/epidemiología , Humanos , Inmunofenotipificación , Linfoma de Células B/epidemiología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The 2005 National Institutes of Health Consensus Development Conference on chronic graft-versus-host disease proposed major changes in the classification and grading of severity of chronic graft-versus-host disease. DESIGN AND METHODS: We aimed to study the association of the proposed chronic graft-versus-host disease classification and global severity with transplantation outcomes among a consecutive series of patients who received pharmacokinetically-targeted doses of intravenous busulfan and fludarabine conditioning followed by transplantation of allogeneic peripheral blood stem cells. RESULTS: From a total cohort (n = 242) of patients surviving more than 100 days after hematopoietic stem cell transplantation, 181 (75% of those at risk) had some manifestations of graft-versus-host disease after day 100. Of these, at onset 13 (7%) had late acute graft-versus-host disease, 62 (34%) had classic chronic graft-versus-host disease, and 106 (59%) had the overlap subtype of chronic graft-versus-host disease. The global severity of the chronic graft-versus-host disease was mild in 25% of cases, moderate in 46%, and severe in 29%. Multivariable modeling demonstrated the independent association of global severity of chronic graft-versus-host disease with overall survival (moderate/severe versus mild; HR 2.9, 95% CI 1.8-4.7, P < 0.0001) and non-relapse mortality (moderate versus mild; HR 3.86, 95% CI 1.17-12.73, P = 0.03, and severe versus mild (HR 10.06, 95% CI 3.07-32.97, P < 0.001). The type of onset of progressive chronic graft-versus-host disease and the platelet count at the time of diagnosis of the disease were significantly associated with overall survival. The occurrence and severity of chronic graft-versus-host disease was also significantly associated with primary disease relapse. CONCLUSIONS: Patients with moderate to severe chronic graft-versus-host disease, as determined by National Institutes of Health Consensus criteria, have an inferior overall survival and worse non-relapse mortality. Clinical and research advances are needed to improve the outcomes of affected patients.