RESUMEN
BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Mutación Puntual , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética , Tiohidantoínas/uso terapéutico , Anciano , Anciano de 80 o más Años , ADN Tumoral Circulante/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy. METHODS: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression. RESULTS: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003). CONCLUSION: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Interleucina-6/inmunología , Mitoxantrona/administración & dosificación , Prednisona/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/patología , Carcinoma/cirugía , Humanos , Interleucina-6/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Mitoxantrona/efectos adversos , Metástasis de la Neoplasia , Orquiectomía , Prednisona/efectos adversos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response. PATIENTS AND METHODS: A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3). RESULTS: The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14). CONCLUSION: All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.
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Antieméticos/uso terapéutico , Náusea/prevención & control , Antagonistas del Receptor de Neuroquinina-1 , Piperazinas/uso terapéutico , Piperidinas/uso terapéutico , Vómitos/prevención & control , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Dexametasona/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/tratamiento farmacológico , Ondansetrón/administración & dosificación , Receptores de Neuroquinina-1/efectos de los fármacos , Vómitos/inducido químicamenteRESUMEN
INTRODUCTION: Although it is incontrovertible that Helicobacter pylori causes peptic ulcer disease, controversy persists regarding the impact of H. pylori infection on the incidence of NSAID-related complications and whether H. pylori eradication reduces the rate of adverse events. METHODS: A symptom-driven decision analytic model was developed to compare the clinical and economic impact of H. pylori screening compared to a strategy of no H. pylori testing for individuals requiring chronic NSAID therapy. In the principal analysis, it was assumed that untreated H. pylori infection increased the ulcer risk by 50% and that successful eradication reduced the risk of adverse events to that of uninfected patients. Patients' ulcer risk and the protective effect of H. pylori eradication were evaluated using sensitivity analysis. RESULTS: When compared to no H. pylori testing, H. pylori screening led to fewer symptomatic ulcers (no test, 5.4; H. pylori test, 4.6 per 100 patient years) and ulcer complications (no test, 2.6; H. pylori test, 2.3 per 100 patient years) and a higher cost per patient (no test, $435; H. pylori test, $556). The incremental cost attributable to the H. pylori screening strategy to prevent a symptomatic and complicated ulcer was $16,805 and $31,842, respectively. The clinical and cost-effectiveness advantage of H. pylori screening improved as patients' ulcer risk increased or the protective effect of H. pylori eradication was enhanced. CONCLUSIONS: Based upon the available evidence, H. pylori screening has the potential to reduce NSAID-related adverse events for average-risk patients at an incremental cost. Until controlled investigations definitively quantify the effect of H. pylori eradication on clinically significant NSAID-related adverse events, a compelling argument can be made for H. pylori testing for chronic NSAID users at increased risk of ulcer disease.
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Antiinflamatorios no Esteroideos/efectos adversos , Helicobacter pylori/aislamiento & purificación , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Costos de la Atención en Salud , Humanos , Úlcera Péptica/inducido químicamente , RiesgoRESUMEN
BACKGROUND: Elevated total homocyst(e)ine levels (>/=11 micromol/L) have been identified as a potential risk factor for coronary heart disease. However, the benefits expected from lowering homocyst(e)ine levels with folic acid and vitamin B(12) supplementation have yet to be demonstrated in clinical trials. SUBJECTS AND METHODS: We constructed a decision analytic model to estimate the clinical benefits and economic costs of 2 homocyst(e)ine-lowering strategies: (1) "treat all"-no screening, daily supplementation with folic acid (400 microg) and vitamin B(12) (cyanocobalamin; 500 microg) for all; (2) "screen and treat"-screening, followed by daily supplementation with folic acid and vitamin B(12) for individuals with elevated homocyst(e)ine levels. Simulated cohorts of 40-year-old men and 50-year-old women in the general population were evaluated. In the base-case analysis, we assumed that lowering elevated levels would reduce excess coronary heart disease risk by 40%; however, this assumption and others were evaluated across a broad range of potential values using sensitivity analysis. Primary outcomes were discounted costs per life-year saved. RESULTS: Although the treat-all strategy was slightly more effective overall, the screen and treat strategy resulted in a much lower cost per life-year saved ($13,600 in men and $27,500 in women) when compared with no intervention. Incremental cost-effectiveness ratios for the treat-all strategy compared with the screen and treat strategy were more than $500,000 per life-year saved in both cohorts. Sensitivity analysis showed that cost-effectiveness ratios for the screen and treat strategy remained less than $50,000 per life-year saved under several unfavorable scenarios, such as when effective homocyst(e)ine lowering was assumed to reduce the relative risk of coronary heart disease-related death by only 11% in men or 23% in women. CONCLUSIONS: Homocyst(e)ine lowering with folic acid and vitamin B(12) supplementation could result in substantial clinical benefits at reasonable costs. If homocyst-(e)ine lowering is considered, a screen and treat strategy is likely to be more cost-effective than universal supplementation. Arch Intern Med. 2000;160:3406-3412.
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Enfermedad Coronaria/sangre , Enfermedad Coronaria/prevención & control , Técnicas de Apoyo para la Decisión , Suplementos Dietéticos/economía , Ácido Fólico/uso terapéutico , Hematínicos/uso terapéutico , Homocisteína/sangre , Vitamina B 12/uso terapéutico , Enfermedad Coronaria/economía , Análisis Costo-Beneficio , Humanos , Estados UnidosRESUMEN
This paper presents a systematic review of the dental literature that was carried out to investigate whether the regular use of fluoride supplements in non-fluoridated communities during the period of tooth development increases the risk of dental fluorosis. A MEDLINE search was organized for all documents published, in English, between January 1966 and September 1997 using the following key words: fluorosis, dental, fluoride, fluoride supplement or supplements, drop or drops, and tablet or tablets. Twenty-four studies that assessed the development of dental fluorosis in children who had used fluoride supplements earlier in their life were included in this review. Of the 24 studies, 10 were cross-sectional/case control studies and four were follow-up studies. These studies had data that allowed a quantitative estimation of the risk of developing dental fluorosis in users of fluoride supplements. The other 10 studies were excluded because they either did not present enough data or had other methodological problems. A qualitative review of the studies found a consistent and strong association between the use of fluoride supplements and dental fluorosis. The meta-analyses of the cross-sectional/case-control studies estimated that the odds ratio of dental fluorosis in users of fluoride supplements compared with non-users ranged between 2.4 and 2.6. The meta-analyses of the follow-up studies estimated that the relative risk in long-term users was between 5.5 and 12.2. This review confirmed that in non-fluoridated communities the use of fluoride supplements during the first 6 years of life is associated with a significant increase in the risk of developing dental fluorosis.
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Cariostáticos/efectos adversos , Fluoruros/efectos adversos , Fluorosis Dental/etiología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Fluorosis Dental/epidemiología , Estudios de Seguimiento , Humanos , Lactante , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: Helicobacter pylori infection has been identified as a risk factor for certain types of gastric cancer. However, the extent to which H. pylori eradication decreases the risk of gastric cancer is unknown, raising the question of whether population-based H. pylori screening should be undertaken. OBJECTIVE: To compare clinical and economic effects of H. pylori screening, with and without confirmatory testing, with no screening to prevent gastric cancer. DESIGN: Decision analysis incorporating a Markov simulation. PATIENTS: Simulated cohorts of men and women with varying risk of gastric cancer. INTERVENTION: Three strategies were evaluated: (1) no screening; (2) H. pylori serologic testing, treat those positive for H. pylori, no follow-up testing; and (3) H. pylori serologic testing, treat those positive for H. pylori, followed by a test to confirm H. pylori eradication, retreat those who test positive. In the principal analysis, the risk of gastric cancer after H. pylori eradication was assumed to be similar to that for those without H. pylori infection. Scenarios with less optimistic assumptions regarding risk reduction of cancer were evaluated. MAIN OUTCOME MEASURES: Gastric cancer rates, discounted cost per life-year saved. RESULTS: If H. pylori eradication reduced the risk of cancer to that of people never infected, both H. pylori intervention strategies reduced gastric cancer rates so that each yielded at least 12 additional life-years per 1000 40-year-old white men screened when compared with no screening. Helicobacter pylori serologic testing without posttreatment confirmatory testing resulted in the lowest cost per additional life-year saved (S6264). The cost-effectiveness of the H. pylori screening strategies varied substantially as the level of risk reduction of cancer was varied, but remained cost-effective even at moderate rates (<30%) of excess risk reduction of cancer in all cohorts evaluated. CONCLUSIONS: Population-based H. pylori screening has the potential to produce important health benefits at a reasonable cost at moderate rates of excess risk reduction of cancer. Controlled studies are necessary to confirm and quantify the impact of H. pylori eradication on the risk of gastric cancer.
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Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/economía , Helicobacter pylori , Tamizaje Masivo , Vigilancia de la Población , Neoplasias Gástricas/economía , Neoplasias Gástricas/prevención & control , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Femenino , Infecciones por Helicobacter/diagnóstico , Humanos , Masculino , Cadenas de Markov , Tamizaje Masivo/economía , Riesgo , Sensibilidad y Especificidad , Neoplasias Gástricas/microbiología , Resultado del Tratamiento , Estados UnidosRESUMEN
We used (+)[11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter, with positron emission tomography to study striatal monoaminergic presynaptic terminals in 7 male severe chronic alcoholic subjects without Wernicke-Korsakoff disease compared with 7 male normal controls of similar ages. We found reduced specific binding in the caudate nucleus and putamen in the alcoholic group, and the difference reached significance in the putamen. Specific binding was not decreased in the thalamus, which was examined as a reference structure. We also detected deficits in blood-to-brain transfer rate, K1, in the same regions of the alcoholic group, with a significant difference in the putamen. K1 was unchanged in the thalamus. The finding of reduced striatal VMAT2 in severe chronic alcoholic patients suggests that nigrostriatal monoaminergic terminals are reduced, with or without loss of neurons from the substantia nigra. The findings suggest that the damaging effects of severe chronic alcoholism on the central nervous system are more extensive than previously considered.
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Alcoholismo/fisiopatología , Cuerpo Estriado/fisiopatología , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Terminaciones Nerviosas/fisiopatología , Neuropéptidos , Neurotransmisores/metabolismo , Tetrabenazina/análogos & derivados , Adulto , Anciano , Alcoholismo/metabolismo , Monoaminas Biogénicas/metabolismo , Estudios de Cohortes , Cuerpo Estriado/metabolismo , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Terminaciones Nerviosas/metabolismo , Fumar/efectos adversos , Tomografía Computarizada de Emisión , Proteínas de Transporte Vesicular de Aminas Biógenas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
There is a need to better understand potential bone mineral density (BMD) loss during the menopausal transition since this period may include the initiation of interventions. The study purpose was to determine if there was BMD loss at the femoral neck, lumbar spine, or total body bone sites in a population-based study of women approaching or transitioning the midlife. The 583 enrollees were 25-45 years of age at the first of four annual measurements from 1992 through 1996. Bone mineral content and bone width were measured using dual-energy X-ray absorptiometry. Considering all enrollees collectively, there was a significant 3-year decline (1%) in BMD at the femoral neck over the 3-year period (p = 0.076). There was no significant annual change in the lumbar spine (p = 0.11), and a significant annual increase in the total body BMD (p = 0.0003). Within subgroups and cross-sectionally, BMD values of the femoral neck were 5% lower in women classified as perimenopausal compared with premenopausal enrollees; BMD was 3% and 1% lower at the lumbar spine and total body site, respectively. Longitudinally, among perimenopausal women, a double oophorectomy was associated with BMD loss in the spine (p = 0.0003), even though 75-85% of these women had a hormone replacement prescription at some time during the study period. In summary, the site with evidence of loss was the femoral neck, specifically among perimenopausal women. There was little evidence of substantial total body or lumbar spine BMD loss in premenopausal women with ovaries who maintained follicle-stimulating hormone levels < 20 mIU/l in the early follicular period. Double oophorectomy, even with hormone replacement, was associated with bone loss.
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Densidad Ósea/fisiología , Premenopausia/fisiología , Población Blanca , Absorciometría de Fotón , Adulto , Estudios de Cohortes , Estudios Transversales , Terapia de Reemplazo de Estrógeno , Femenino , Cuello Femoral/diagnóstico por imagen , Humanos , Vértebras Lumbares/diagnóstico por imagen , Michigan , Persona de Mediana Edad , Ovariectomía , Análisis de Regresión , Encuestas y CuestionariosRESUMEN
OBJECTIVES: We previously demonstrated that the combination of oral estramustine (15 mg/kg/day) and oral etoposide (50 mg/m2/day) is effective first-line therapy for the treatment of hormone refractory prostate cancer. We initiated a new Phase II trial utilizing a lower dose of estramustine (10 mg/kg/day) and allowing previous chemotherapy treatment. METHODS: Estramustine (10 mg/kg/day) and etoposide (50 mg/m2/day) were administered orally for 21 of 28 days. Sixty-two patients were enrolled with a minimum of 26 weeks of follow-up. RESULTS: Of 15 patients with measurable soft tissue disease, 8 (53%) had a partial response (PR). Seven of these 8 patients also demonstrated a decrease in baseline prostate-specific antigen (PSA) of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on decrease in pretreatment PSA of more than 50%. Overall, 24 (39%) of 62 patients demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline. Twenty-two patients received previous chemotherapy. There were no differences in survival or disease response in patients treated with previous chemotherapy compared with untreated patients. Pretreatment hemoglobin, PSA, alkaline phosphatase and lactate dehydrogenase levels were not significant prognostic factors, but performance status was an important predictor of survival. CONCLUSIONS: We conclude that the combination of oral estramustine (10 mg/kg/day) and oral etoposide (50 mg/m2/day) is an active regimen for hormone refractory prostate cancer.