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1.
Blood ; 135(20): 1739-1749, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32160294

RESUMEN

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.


Asunto(s)
Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pirazoles/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Resistencia a Medicamentos/efectos de los fármacos , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Pirimidinas , Inducción de Remisión , Resultado del Tratamiento , Adulto Joven
2.
Blood ; 133(16): 1742-1752, 2019 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-30803990

RESUMEN

This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.


Asunto(s)
Leucemia de Células B/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Pirrolidinas/uso terapéutico , Terapia Recuperativa/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Resultado del Tratamiento
3.
Invest New Drugs ; 36(4): 683-695, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29508247

RESUMEN

Background Ruxolitinib, a Janus kinase 1 (JAK1)/JAK2 inhibitor, plus capecitabine improved overall survival (OS) vs capecitabine in a subgroup analysis of patients with metastatic pancreatic cancer and systemic inflammation (C-reactive protein [CRP] >13 mg/dL) in the randomized phase II RECAP study. We report results from two randomized phase III studies, JANUS 1 (NCT02117479) and JANUS 2 (NCT02119663). Patients and Methods Adults with advanced/metastatic pancreatic cancer, one prior chemotherapy regimen and CRP >10 mg/L were randomized 1:1 (stratified by modified Glasgow Prognostic Score [1 vs 2] and Eastern Cooperative Oncology Group performance status [0/1 vs 2]) to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2/day (Days 1-14) or placebo plus capecitabine. The primary endpoint was OS. Results Both studies were terminated following a planned interim futility/efficacy analysis of JANUS 1. Overall, 321 and 86 patients were randomized in JANUS 1 (ruxolitinib: n = 161; placebo: n = 160) and JANUS 2 (ruxolitinib: n = 43; placebo: n = 43). There was no significant difference in OS or progression-free survival (PFS) between treatments in JANUS 1 (OS: hazard ratio [HR], 0.969, 95% confidence interval [CI], 0.747-1.256; PFS: HR, 1.056; 95% CI, 0.827-1.348) or JANUS 2 (OS: HR, 1.584; 95% CI, 0.886-2.830; PFS: HR, 1.166; 95% CI, 0.687-1.978). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib or capecitabine were identified. Conclusions Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Capecitabina/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Neoplasias Pancreáticas/metabolismo , Pirazoles/administración & dosificación , Pirimidinas
4.
Invest New Drugs ; 31(3): 760-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22907596

RESUMEN

BACKGROUND: CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. METHODS: In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. RESULTS: Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥ 3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥ 3 AEs. Common grade ≥ 3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-µg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. CONCLUSION: Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Antineoplásicos/uso terapéutico , Quimiocina CCL2/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/farmacología , Antineoplásicos/farmacología , Anticuerpos ampliamente neutralizantes , Recuento de Células , Quimiocina CCL2/sangre , Células Endoteliales/citología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Células Neoplásicas Circulantes , Orquiectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología
5.
Qual Life Res ; 22(10): 2777-86, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23589119

RESUMEN

PURPOSE: To compare pain assessment questionnaires commonly used in advanced prostate cancer trials and to determine the psychometric characteristics and longitudinal relationships by contrasting questionnaire data from two international phase 2 trials. METHODS: Scores from the Present Pain Intensity (PPI) question of the McGill Pain Questionnaire, the pain intensity scale of the Brief Pain Inventory (BPI), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) were analyzed using Pearson correlation, intraclass correlation coefficient, and Cronbach's α, respectively. Concordance was evaluated with Cohen's kappa coefficient and McNemar test at baseline (n = 224) and two subsequent observations. RESULTS: PPI and FACT-P scores were associated with the BPI score at baseline for Trials 1 and 2: PPI r = 0.66 and 0.80, respectively (P < 0.001); FACT-P (pain scale) r = -0.76 and -0.82, respectively (P < 0.001). However, concordance analysis revealed that the BPI identified pain (score > 0) at higher rates than the PPI: at baseline, BPI: 89 % (64/72) and 77 % (95/124), PPI: 68 % (49/72) and 64 % (79/124) [Trials 1 and 2, respectively; McNemar test (P < 0.001) for both studies]. The FACT-P pain scale identified pain similarly to the BPI pain intensity scale; longitudinal analysis produced comparable findings. All pain scales met standard psychometric acceptability criteria, but the BPI and FACT-P performed better than the PPI. CONCLUSIONS: Data suggest the BPI pain intensity and FACT-P pain scales are better than the PPI question at capturing the pain experience among patients with advanced prostate cancer. Additional comparative research is needed in larger population samples.


Asunto(s)
Dimensión del Dolor/instrumentación , Dolor/etiología , Neoplasias de la Próstata/complicaciones , Psicometría/estadística & datos numéricos , Calidad de Vida , Encuestas y Cuestionarios , Anciano , Ensayos Clínicos como Asunto , Estado de Salud , Humanos , Masculino , Dimensión del Dolor/métodos , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad
6.
Can J Gastroenterol ; 23(11): 769-72, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19893773

RESUMEN

BACKGROUND: The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations. METHODS: A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization. RESULTS: Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects. CONCLUSIONS: Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.


Asunto(s)
Pruebas Genéticas , Hemocromatosis/diagnóstico , Hemocromatosis/etnología , Hemocromatosis/genética , Tamizaje Masivo , Etnicidad , Femenino , Predisposición Genética a la Enfermedad/etnología , Pruebas Genéticas/ética , Genotipo , Hemocromatosis/metabolismo , Humanos , Hierro/metabolismo , Masculino , Tamizaje Masivo/ética , Tamizaje Masivo/métodos , Tamizaje Masivo/normas , Mutación , América del Norte
7.
J Natl Med Assoc ; 101(8): 808-9, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19715045

RESUMEN

We report a 22-year-old man who presented with a 2-week history of intermittent melena and worsening scrotal and leg swelling. His medical history was significant for testicular cancer for which he had undergone orchiectomy, lymphadenectomy, and platinum-based chemotherapy. Esophagogastroduodenoscopy (EGD) performed revealed polypoid mass lesions in the second and third portions of the duodenum. Biopsy revealed mixed germ cell tumor with immature teratoma, the same histology as his testicular cancer. His chemotherapy was changed to an ifosphamide-based regimen and a repeat upper endoscopic examination 5 months later revealed complete resolution of previously noted polypoid duodenal mass lesions. This also demonstrates the effectiveness of ifosphamide as second-line therapy in the setting of resistance to platinum-based therapy.


Asunto(s)
Neoplasias Duodenales/secundario , Hemorragia Gastrointestinal/etiología , Neoplasias Testiculares/complicaciones , Neoplasias Testiculares/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Neoplasias Duodenales/complicaciones , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/tratamiento farmacológico , Endoscopía del Sistema Digestivo , Humanos , Masculino , Neoplasias Testiculares/terapia
8.
N Engl J Med ; 352(17): 1769-78, 2005 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-15858186

RESUMEN

BACKGROUND: Iron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population. METHODS: Participants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload. RESULTS: Of the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 mug per liter in 78 of 89 men (88 percent) and greater than 200 microg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 microg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations. CONCLUSIONS: The C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites.


Asunto(s)
Ferritinas/sangre , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Mutación , Transferrina/análisis , Artritis/etiología , Complicaciones de la Diabetes , Femenino , Frecuencia de los Genes , Genotipo , Cardiopatías/etiología , Hemocromatosis/complicaciones , Hemocromatosis/etnología , Proteína de la Hemocromatosis , Homocigoto , Humanos , Hierro , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/etnología , Sobrecarga de Hierro/genética , Hepatopatías/etiología , Modelos Logísticos , Masculino , Fenotipo , Distribución por Sexo , Estados Unidos/epidemiología
9.
Am J Hematol ; 83(8): 618-26, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18429050

RESUMEN

How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 microg/L (men), >200 microg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 microg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 microg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 microg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 microg/L in male C282Y homozygotes is predictive of moderately increased iron stores.


Asunto(s)
Ferritinas/sangre , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/epidemiología , Hierro/metabolismo , Mediciones Epidemiológicas , Etnicidad , Femenino , Genotipo , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Sobrecarga de Hierro/etnología , Masculino , Proteínas de la Membrana/genética , Mutación Missense , Flebotomía , Valor Predictivo de las Pruebas , Prevalencia
10.
Can J Gastroenterol ; 22(11): 923-30, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19018338

RESUMEN

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.


Asunto(s)
ADN/genética , Pruebas Genéticas/métodos , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Alelos , Canadá/epidemiología , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Hemocromatosis/diagnóstico , Hemocromatosis/epidemiología , Proteína de la Hemocromatosis , Antígenos de Histocompatibilidad Clase I/sangre , Homocigoto , Humanos , Hierro/sangre , Masculino , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Distribución por Sexo , Estados Unidos/epidemiología
11.
Genet Test ; 11(3): 269-75, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17949288

RESUMEN

We characterized HFE C282Y homozygotes aged 25-29 years in the HEmochromatosis and IRon Overload Screening (HEIRS) Study using health questionnaire responses, transferrin saturation (TfSat), serum ferritin (SF), and HFE genotyping. In eight homozygotes, we used denaturing high-performance liquid chromatography and sequencing to search for HFE2 (= HJV), TFR2, HAMP, SLC40A1 (= FPN1), and FTL mutations. Sixteen of 4,008 White or Hispanic participants aged 25-29 years had C282Y homozygosity (15 White, 1 Hispanic); 15 were previously undiagnosed. Eleven had elevated TfSat; nine had elevated SF. None reported iron overload-associated abnormalities. No deleterious non-HFE mutations were detected. The prevalence of C282Y homozygosity in White or Hispanic HEIRS Study participants aged 25-29 years did not differ significantly from the prevalence of C282Y homozygosity in older White or Hispanic HEIRS Study participants. The prevalences of reports of iron overload-associated abnormalities were not significantly different in these 16 C282Y homozygotes and in HFE wt/wt control participants aged 25-29 years who did not report having hemochromatosis or iron overload. We conclude that C282Y homozygotes aged 25-29 years diagnosed by screening infrequently report having iron overload-associated abnormalities, although some have elevated SF. Screening using an elevated TfSat criterion would fail to detect some C282Y homozygotes aged 25-29 years.


Asunto(s)
Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Homocigoto , Sobrecarga de Hierro/genética , Proteínas de la Membrana/genética , Adulto , Péptidos Catiónicos Antimicrobianos/genética , Apoferritinas , Proteínas de Transporte de Catión/genética , Análisis Mutacional de ADN , Femenino , Ferritinas/genética , Pruebas Genéticas , Genotipo , Hemocromatosis/sangre , Hemocromatosis/diagnóstico , Proteína de la Hemocromatosis , Hepcidinas , Humanos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/diagnóstico , Masculino , Mutación , Receptores de Transferrina/genética
12.
Diabetes Care ; 29(9): 2084-9, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16936157

RESUMEN

OBJECTIVE: We evaluated the associations of self-reported diabetes with serum ferritin concentration, transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five field centers in the Hemochromatosis and Iron Overload Screening (HEIRS) study. RESEARCH DESIGN AND METHODS: Analyses were conducted on 97,470 participants. Participants who reported a previous diagnosis of diabetes and/or hemochromatosis or iron overload were compared with participants who did not report a previous diagnosis. RESULTS: The overall prevalence of diabetes was 13.8%; the highest prevalence was in Pacific Islanders (20.1%). Of all participants with diabetes, 2.0% reported that they also had hemochromatosis or iron overload. The mean serum ferritin concentration was significantly greater in women with diabetes in all racial/ethnic groups and in Native-American men with diabetes than in those without diabetes. The mean serum ferritin concentration was significantly lower in Asian men with diabetes than in those without diabetes. Mean TfSat was lower in participants with diabetes from all racial/ethnic groups except Native-American women than in those without diabetes. There was no significant association of diabetes with HFE genotype. The mean serum ferritin concentration was greater (P < 0.0001) in women with diabetes than in those without diabetes for HFE genotypes except C282Y/C282Y and C282Y/H63D. Log serum ferritin concentration was significantly associated with diabetes in a logistic regression analysis after adjusting for age, sex, racial/ethnic group, HFE genotype, and field center. CONCLUSIONS: Serum ferritin concentration is associated with diabetes, even at levels below those typically associated with hemochromatosis or iron overload.


Asunto(s)
Diabetes Mellitus/sangre , Ferritinas/sangre , Hemocromatosis/sangre , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/sangre , Proteínas de la Membrana/genética , Adulto , Anciano , Anciano de 80 o más Años , Asiático/estadística & datos numéricos , Diabetes Mellitus/etnología , Diabetes Mellitus/genética , Femenino , Hemocromatosis/diagnóstico , Proteína de la Hemocromatosis , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Sobrecarga de Hierro/diagnóstico , Modelos Logísticos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Mutación/genética , Encuestas y Cuestionarios , Transferrina/metabolismo
13.
J Clin Oncol ; 23(6): 1070-7, 2005 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-15718305

RESUMEN

PURPOSE: To prospectively study the pharmacokinetics and toxicity profile of docetaxel in elderly patients with cancer. PATIENTS AND METHODS: Docetaxel was administered at a dose 75 mg/m(2) once every 3 weeks to 25 elderly cancer patients aged >/= 65 years and 26 cancer patients aged younger than 65 years. Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy. RESULTS: Of 51 patients treated, 20 aged >/= 65 years (median, 71 years; range, 65 to 80 years) and 20 aged younger than 65 years (median, 53 years; range, 26 to 64 years) were assessable for pharmacokinetic studies, and 39 were assessable for toxicity. Patient characteristics were similar (P >/= .15) between the two cohorts. Mean docetaxel clearance was not altered in the elderly versus younger patients: 30.1 L/h (standard deviation [SD] 18.3 L/h) v 30.0 L/h (SD, 14.8 L/h; P = .98). The percentage of patients with grade 4 and febrile neutropenia was higher in the elderly (63% and 16%, respectively) versus younger (30% and 0%, respectively) cohort, although this observation did not reach a level of statistical significance (P = .056). From logistic regression analysis, the odds ratio for a patient aged 65 years was 1.98 for developing grade 4 neutropenia compared with a patient aged 50 years (P = .091). CONCLUSION: Docetaxel plasma pharmacokinetics are unaltered in elderly patients. Patients aged >/= 65 years appear to be more sensitive to docetaxel-induced neutropenia.


Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Neoplasias/tratamiento farmacológico , Taxoides/efectos adversos , Taxoides/farmacocinética , Adulto , Anciano , Docetaxel , Humanos , Persona de Mediana Edad , Neoplasias/metabolismo , Neutropenia/inducido químicamente
14.
J Clin Oncol ; 23(13): 3069-73, 2005 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-15860865

RESUMEN

PURPOSE: Epothilones are a new class of nontaxane tubulin polymerization agents that have activity in taxane-resistant tumors. Epothilone B (BMS-247550) is a semisynthetic analog of the natural product epothilone B. This study was performed to determine the activity of BMS-247550 in patients with soft tissue sarcomas (STSs) who had not received prior chemotherapy for metastatic disease. PATIENTS AND METHODS: Patients with measurable, advanced, or metastatic STS with no prior chemotherapy for metastatic disease were treated with BMS-2457550 50 mg/m(2) intravenously during 1 hour every 21 days. All responses were confirmed 4 weeks later. RESULTS: Thirty-one patients (median age, 54 years; range, 19 to 78 years; 48% female) were entered onto the trial and were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance score of 0% or 1%, and 39% had received prior adjuvant chemotherapy. Mean follow-up was 22 months, with a confirmed response rate of 6% (95% CI, 0% to 17%). Median time to progression was 4.5 months (95% CI, 1.9 to 8.3 months), and 1 year progression-free survival was 17% (95% CI, 8% to 38%). Median survival was 16.4 months, with a 1-year survival of 61% (95% CI, 46% to 81%). Toxicity was mainly hematologic, with eight of 31 (26%) patients experiencing grade 3 to 4 leukopenia; 15 of 31 patients (48%) experienced grade 3 to 4 neutropenia. The grade 3 to 4 nonhematologic toxicities included neuropathies (26%), myalgia (13%), and fatigue (10%). CONCLUSION: BMS-247550 has limited activity against STSs when given in this dose and schedule. The clinical toxicity is similar to that of taxanes.


Asunto(s)
Antineoplásicos/uso terapéutico , Epotilonas/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Epotilonas/administración & dosificación , Epotilonas/efectos adversos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
15.
Haematologica ; 91(6): 739-43, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16704960

RESUMEN

BACKGROUND AND OBJECTIVES: Whether degree of iron stores influences progression of human immunodeficiency virus (HIV) disease is controversial. We studied the relationship of indirect measures of iron stores with mortality in highly active antiretroviral therapy (HAART)-naive participants from the Women's Interagency HIV Study. DESIGN AND METHODS: One hundred and fifty-eight HIV-infected women who died before July 1996 were individually matched by CD4+ cell count (within +/- 50 cells/mL) and HIV RNA level (within +/- 0.50 log10 copies/mL) to 154 controls. Serum ferritin and transferrin receptor concentrations were measured in 151 pairs of women. Results. Using multivariable conditional logistic regression models that were adjusted for self-reported antiretroviral therapy use, age, smoking status, ethnicity, hemoglobin concentration, C-reactive protein and aspartate amino transferase, a log10 increase in baseline serum ferritin concentration was associated with a 1.67-fold increase in the odds of death (95% CI: 0.98, 2.86) and a one-unit decrease in transferrin receptor to log10 ferritin ratio was associated with a 1.12-fold (95% CI: 1.01, 1.23) increase in the odds of death. INTERPRETATIONS AND CONCLUSIONS: In this study, higher indirect measures of iron status were associated with reduced survival among HAART-naive HIV-infected women. Additional prospective studies with data on direct measures of iron status along with randomized trials are needed to elucidate the current equipoise over whether iron supplementation is beneficial by preventing anemia or harmful by increasing iron stores in HIV-infected women.


Asunto(s)
Ferritinas/sangre , Infecciones por VIH/sangre , Receptores de Transferrina/sangre , Recuento de Linfocito CD4 , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/inmunología , Infecciones por VIH/mortalidad , Humanos , Estudios Prospectivos , Valores de Referencia , Carga Viral
16.
Ethn Dis ; 16(4): 815-21, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17061732

RESUMEN

OBJECTIVE: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. DESIGN: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group. RESULTS: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions. CONCLUSION: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.


Asunto(s)
Etnicidad/genética , Hemocromatosis/epidemiología , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/epidemiología , Sobrecarga de Hierro/genética , Proteínas de la Membrana/genética , Mutación , Grupos Raciales/genética , Adulto , Pueblo Asiatico/genética , Pueblo Asiatico/estadística & datos numéricos , Población Negra/genética , Población Negra/estadística & datos numéricos , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genotipo , Hemocromatosis/etnología , Proteína de la Hemocromatosis , Hispánicos o Latinos/genética , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Indígenas Norteamericanos/genética , Indígenas Norteamericanos/estadística & datos numéricos , Sobrecarga de Hierro/etnología , Masculino , Nativos de Hawái y Otras Islas del Pacífico/genética , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , América del Norte/epidemiología , Población Blanca/genética , Población Blanca/estadística & datos numéricos
17.
J Natl Med Assoc ; 98(3): 352-6, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16573298

RESUMEN

About 7% of the adult population has subclinical cobalamin (B12) deficiency. Subjects with sickle cell disease (SCD) may be at higher risk of cobalamin deficiency because of increased demand, inadequate supply, coexisting folate deficiency or malabsorption. We compared the clinical and laboratory characteristics of low serum cobalamin levels in patients with SCD with those patients without this hemoglobinopathy (non-SCD). Between 1993 and 2003, 105 SCD patients and 112 non-SCD patients who had serum cobalamin measurements were identified at our institution. The mean cobalamin level in SCD patients was significantly lower (496 +/- 352 pg/ml) than that in patients without SCD (869 +/- 660 pg/ml, p<0.0001). The frequency of low cobalamin levels, defined by a serum cobalamin level of <200 pg/ml, was 18.1% (19/105) and 9.8% (11/112) in SCD and non-SCD patients, respectively (chi2=3.11, nonsignificant). The mean age of the low-cobalamin SCD and non-SCD patients was 28.1 and 62.9, respectively, and their male:female ratios were 11:8 in SCD patients and 2:9 in non-SCD patients. None of the SCD patients had neurological manifestations, but nine of the 11 non-SCD low-cobalamin level patients did. The proportion of SCD patients with unexplained low cobalamin levels (13/19) was higher than that in non-SCD patients (4/11, chi2=2.92, nonsignificant) Our data suggest that cobalamin levels are lower in SCD patients than in subjects without SCD, and low-cobalamin SCD patients are younger and more likely to be males.


Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/etnología , Negro o Afroamericano , Vitamina B 12/sangre , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad
18.
J Natl Med Assoc ; 98(8): 1356-60, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16916138

RESUMEN

Chronic eosinophilic leukemia is a rare entity, characterized by eosinophilia of >1.5 x 10(9)/L, persisting for >6 months after exclusion of other reactive and neoplastic causes of eosinophilia, and occurring in association with a clonal cytogenetic abnormality. Various chromosomal abnormalities have been associated with chronic eosinophilic leukemia. Partial deletion of the long arm of chromosome 16 is a cytogenetic abnormality first reported 20 years ago in patients with acute myeloid leukemia associated with bone marrow eosinophilia (AML-M4Eo). We report a case of a 45-year-old African-American male with hepatitis C and sustained peripheral blood eosinophilia who presented with gross hematuria, dyspnea on exertion, chills, decreased appetite and weight loss of 40 pounds associated with hepatosplenomegaly and lymphadenopathy. Bone marrow biopsy showed clonal cytogenetic abnormality consisting of deletion of the long arm of chromosome 16 (16q22). Philadelphia chromosome t (9;22) and polymerase chain reaction (PCR) analysis for C-kit and platelet-derived growth factor receptor-alpha (PDGFRA) mutations were negative. The patient was treated with imatinib at 400 mg/d with improvement of symptoms, reduction of lymphadenopathy and normalization of the eosinophil count. To our knowledge, this is the first case report of isolated del (16) (q22), a cytogenetic abnormality associated with AML-M4Eo, occurring in chronic eosinophilic leukemia. Whether this cytogenetic abnormality might represent a prodromal phase of AML-M4Eo is not known. In addition, the role of hepatitis C in inducing clonal proliferation of eosinophils is unclear.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 16 , Hepatitis C/complicaciones , Síndrome Hipereosinofílico/complicaciones , Biopsia , Médula Ósea/patología , Enfermedad Crónica , Diagnóstico Diferencial , Humanos , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/patología , Masculino , Persona de Mediana Edad
19.
J Clin Oncol ; 22(4): 730-4, 2004 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-14966098

RESUMEN

PURPOSE: African Americans have the highest cancer mortality rates and poorest survival and are more often uninsured and underinsured compared with other ethnic groups. Minority participation in clinical trials has traditionally been low, with reports ranging from 3% to 20%. The present study systematically assesses 235 consecutively diagnosed African American cancer patients regarding recruitment onto cancer treatment clinical trials at Howard University Cancer Center between January 1, 2001, and December 31, 2002. Our intent is to determine the rate-limiting factors associated with enrolling African Americans onto clinical trials at a historically black medical institution. PATIENTS AND METHODS: Two hundred thirty-five consecutively diagnosed African American cancer patients were assessed for participation in clinical trials at Howard University Hospital and Cancer Center. The study population comprised 165 women and 70 men. RESULTS: The overall eligibility rate was 8.5% (20 of 235 patients); however, among those eligible, the enrollment rate (ie, enrollment among the eligible population) was 60.0% (12 of 20 patients). Comorbidities rendered 17.1% of the patient population ineligible for the trials. Advanced disease stage, associated with poor performance status, premature death, and short life expectancy, made an additional 10% of the patient population ineligible. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in this population. Cardiovascular diseases and renal insufficiency represented 16.2% of the comorbidities. CONCLUSION: It was evident that study design exclusion and inclusion criteria rendered the majority of the study population ineligible. Among African Americans, comorbidity is a major issue that warrants considerable attention.


Asunto(s)
Negro o Afroamericano , Ensayos Clínicos como Asunto , Neoplasias/terapia , Selección de Paciente , Proyectos de Investigación , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , District of Columbia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/etnología
20.
Clin Cancer Res ; 10(24): 8341-50, 2004 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-15623611

RESUMEN

PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients. EXPERIMENTAL DESIGN: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). RESULTS: CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001). CONCLUSIONS: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Neoplasias/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Tamaño Corporal , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , ADN de Neoplasias/genética , Demografía , Femenino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Orosomucoide/metabolismo , Fenotipo
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