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Background: Patients with Fabry disease (FD, α-galactosidase A deficiency or absence) accumulate glycosphingolipids, leading to progressive dysfunction of kidneys, heart and nervous system. Generalizable real-world outcomes following agalsidase beta treatment initiation outside trials are limited. We investigated the associations of long-term agalsidase beta treatment with estimated glomerular filtration rate (eGFR) changes over time and the risk of developing a composite clinical event in a matched analysis of treated and untreated patients with FD. Methods: Agalsidase beta-treated adult patients (aged ≥16 years) from the Fabry Registry and adult untreated patients from a natural history cohort were matched 1:1 and X:X (with one occurrence and multiple occurrences of each untreated patient, respectively) by sex, phenotype, age and (for eGFR slope analysis) baseline eGFR. Outcomes included eGFR slope over 5 years and composite clinical event risk (cardiovascular, cerebrovascular or renal event, or death) over 10+ years. As a surrogate indicator of therapeutic response in paediatric patients, the percentage experiencing normalization in plasma globotriaosylceramide (GL-3) from treatment initiation was assessed in patients aged 2 to <16 years. Results: Overall, eGFR slopes for 1:1-matched untreated and treated adult patients [122 pairs (72.1% male)] were -3.19 and -1.47 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 53.9%, P = .007), and for X:X-matched [122 untreated/950 treated (59.4% male)] were -3.29 and -1.56 mL/min/1.73 m2/year, respectively (reduction in rate of decline = 52.6%, P < .001). Agalsidase beta treatment was associated with lower risk of clinical events, with hazard ratios of 0.41 (P = .003) and 0.67 (P = .008) for 1:1-matched and X:X-matched analyses, respectively. Plasma GL-3 declined markedly in paediatric patients and normalized in most within 6 months of treatment initiation. Conclusion: Agalsidase beta treatment preserves kidney function and delays progression to severe clinical events among adult patients with FD. Plasma GL-3 levels analysed in paediatric patients showed normalization of elevated pre-treatment levels in most patients.
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Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.
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Doença de Fabry , Feminino , Humanos , Doença de Fabry/tratamento farmacológico , Doença de Fabry/epidemiologia , Doença de Fabry/genética , alfa-Galactosidase/genética , alfa-Galactosidase/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Sistema de Registros , Fenótipo , Assistência Centrada no Paciente , Estudos Observacionais como AssuntoRESUMO
Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.
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Doença de Fabry , alfa-Galactosidase , Humanos , alfa-Galactosidase/uso terapêutico , Doença de Fabry/patologia , Relevância Clínica , Terapia de Reposição de Enzimas/efeitos adversos , Proteínas Recombinantes/uso terapêuticoRESUMO
There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.
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Doença de Gaucher , Neoplasias Hematológicas , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Adulto , Doença de Gaucher/complicações , Doença de Gaucher/epidemiologia , Doença de Gaucher/patologia , Humanos , Masculino , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/patologia , Sistema de Registros , RiscoRESUMO
BACKGROUND: Fractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated. METHODS: Inclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk. RESULTS: Patients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI). CONCLUSIONS: The GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed.
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Doença de Gaucher , Adolescente , Adulto , Terapia de Reposição de Enzimas , Doença de Gaucher/complicações , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Humanos , Medição de Risco , Fatores de RiscoRESUMO
Inflammation and B-cell hyperactivation have been associated with non-Hodgkin lymphoma development. This prospective analysis aimed to further elucidate pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma risk. We identified 598 incident lymphoma cases and 601 matched controls in Nurses' Health Study and Health Professionals Follow-up Study participants with archived pre-diagnosis plasma samples and measured 13 immune marker levels with multiplexed immunoassays. Using multivariable logistic regression we calculated Odds Ratios (OR) and 95% Confidence Intervals (CI) per standard deviation unit increase in biomarker concentration for risk of non-Hodgkin lymphoma and major histological subtype, stratifying additional models by years (<5, 5 to <10, ≥10) after blood draw. Soluble interleukin-2 receptor-α, CXC chemokine ligand 13, soluble CD30, and soluble tumor necrosis factor receptor-2 were individually positively associated, and B-cell activating factor of the tumor necrosis factor family inversely associated, with all non-Hodgkin lymphoma and one or more subtypes. The biomarker combinations associated independently with lymphoma varied somewhat by subtype and years after blood draw. Of note, the unexpected inverse association between B-cell activating factor and chronic lymphocytic leukemia/small lymphocytic lymphoma risk (OR: 95%CI: 0.51, 0.43-0.62) persisted more than ten years after blood draw (OR: 0.70; 95%CI: 0.52-0.93). In conclusion, immune activation precedes non-Hodgkin lymphoma diagnosis by several years. Decreased B-cell activating factor levels may denote nascent chronic lymphocytic leukemia many years pre-diagnosis.
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Biomarcadores Tumorais , Linfoma não Hodgkin , Proteínas de Neoplasias , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/imunologia , Estudos ProspectivosRESUMO
Metabolic syndrome is associated with several cancers, but evidence for aggressive prostate cancer is sparse. We prospectively investigated the influence of metabolic syndrome and its components on risk of total prostate cancer and measures of aggressive disease in a cohort of Icelandic men. Men in the Reykjavik Study (n = 9,097, enrolled 1967-1987) were followed for incident (n = 1,084 total; n = 378 advanced; n = 148 high-grade) and fatal (n = 340) prostate cancer until 2014. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for (1) measured metabolic factors at cohort entry (body mass index (BMI), blood pressure, triglycerides, fasting blood glucose) and (2) a metabolic syndrome score (range 0-4) combining the risk factors: BMI ≥30 kg/m2 ; systolic blood pressure (SBP) ≥130 or diastolic blood pressure (DBP) ≥85 mm Hg or taking antihypertensives; triglycerides ≥150 mg/dl; fasting blood glucose ≥100 mg/dl or self-reported type 2 diabetes. Hypertension and type 2 diabetes were associated with a higher risk of total, advanced, high-grade, and fatal prostate cancer, independent of BMI. Neither BMI nor triglycerides were associated with prostate cancer risk. Higher metabolic syndrome score (3-4 vs 0) was associated with a higher risk of fatal prostate cancer (HR 1.55; 95% CI: 0.89, 2.69; p trend = 0.08), although this finding was not statistically significant. Our findings suggest a positive association between midlife hypertension and diabetes and risk of total and aggressive prostate cancer. Further, metabolic syndrome as a combination of factors was associated with an increased risk of fatal prostate cancer.
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Diabetes Mellitus Tipo 2/epidemiologia , Hipertensão/epidemiologia , Síndrome Metabólica/epidemiologia , Neoplasias da Próstata/epidemiologia , Adulto , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/metabolismo , Islândia/epidemiologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fatores de Risco , Triglicerídeos/sangueRESUMO
Background: We investigated whether an immune system environment characterized by elevated serum levels of B-cell activation molecules was associated with the subsequent development of classical Hodgkin lymphoma (cHL).Methods: We measured serum levels of B-cell-stimulatory cytokines, IL6 and IL10, soluble CD30 (sCD30), and total IgE prior to cHL diagnosis in 103 cases and 206 matched controls with archived specimens in the DoD Serum Repository.Results: Prediagnosis serum sCD30 and IL6 levels had strong positive associations with risk of a cHL diagnosis 0 to 1 year prior to diagnosis [sCD30 OR = 5.5; 95% confidence interval (CI), 3.4-9.0; IL6 OR = 4.6; 95% CI, 2.9-7.5] and >1 year to 2 years pre-cHL diagnosis (sCD30 OR = 3.3; 95% CI, 1.6-6.7; IL6 OR = 2.9; 95% CI, 1.3-6.5). We observed similar, albeit not consistently significant positive associations, over 4 or more years preceding diagnosis. We did not observe a clear association with IgE levels. Of note, detectable IL10 levels were significantly associated with Epstein-Barr virus (EBV)-positive cHL cases compared with EBV-negative cases.Conclusion: In this prospective analysis, elevated sCD30 and IL6 levels and detectable IL10 preceded cHL diagnosis.Impact: The associations of these cytokines with cHL risk may reflect the production of these molecules by proliferating nascent cHL tumor cells, or by immune cells responding to their presence, prior to clinical detection. The stable elevation in cHL risk, 4 or more years prediagnosis, also suggests that a B-cell-stimulatory immune system milieu precedes, and may promote, lymphomagenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1114-23. ©2017 AACR.
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Infecções por Vírus Epstein-Barr/sangue , Doença de Hodgkin/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Antígeno Ki-1/sangue , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Carcinogênese/imunologia , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/imunologia , Doença de Hodgkin/virologia , Humanos , Imunoglobulina E/sangue , Interleucina-10/imunologia , Interleucina-6/imunologia , Antígeno Ki-1/imunologia , Masculino , Militares/estatística & dados numéricos , Estudos Prospectivos , Fatores de Risco , Estados Unidos , United States Department of Defense , Adulto JovemRESUMO
BACKGROUND: Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. OBJECTIVE: To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, ß-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. RESULTS AND LIMITATIONS: Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. CONCLUSIONS: Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. PATIENT SUMMARY: We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal.
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Anticarcinógenos/administração & dosagem , Aspirina/administração & dosagem , Médicos , Neoplasias da Próstata/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/efeitos adversos , Aspirina/efeitos adversos , Boston/epidemiologia , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/mortalidade , Fatores de Proteção , Fatores de Risco , Fatores de TempoRESUMO
Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer-specific mortality with increased high-fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989-1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer-specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer-specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high-fat milk intake was not associated with prostate cancer-specific death (95% CI: 0.78, 2.10; p-trend = 0.32; multivariate-adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high-fat milk, those who drank ≥3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p-trend = 0.004; multivariate-adjusted model). Low-fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high-fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high-fat milk intake may promote prostate cancer progression.
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Laticínios , Leite , Neoplasias da Próstata/dietoterapia , Neoplasias da Próstata/epidemiologia , Idoso , Animais , Estudos de Coortes , Gorduras na Dieta/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/patologia , Fatores de Risco , Suécia/epidemiologiaRESUMO
PURPOSE: Prostate-specific antigen (PSA) level in midlife predicted future prostate cancer (PCa) mortality in an unscreened Swedish population. Our purpose was to determine if a baseline PSA level during midlife predicts lethal PCa in a US population with opportunistic screening. MATERIALS AND METHODS: We conducted a nested case-control study among men age 40 to 59 years who gave blood before random assignment in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and ß-carotene among 22,071 US male physicians initiated in 1982 and then transitioned into a prospective cohort with 30 years of follow-up. Baseline PSA levels were available for 234 patients with PCa and 711 age-matched controls. Seventy-one participants who developed lethal PCa were rematched to 213 controls. Conditional logistic regression was used to estimate odds ratios and the area under the receiver operating characteristic curve, with 95% CIs, of the association between baseline PSA and risk of lethal PCa. RESULTS: Median PSA among controls was 0.68, 0.88, and 0.96 ng/mL for men age 40 to 49, 50 to 54, and 55 to 59 years, respectively. Risk of lethal PCa was strongly associated with baseline PSA in midlife: odds ratios (95% CIs) comparing PSA in the > 90th percentile versus less than or equal to median were 8.7 (1.0 to 78.2) at 40 to 49 years, 12.6 (1.4 to 110.4) at 50 to 54 years, and 6.9 (2.5 to 19.1) at 55 to 59 years. A total of 82%, 71%, and 86% of lethal cases occurred in men with PSA above the median at ages 40 to 49, 50 to 54, and 55 to 59 years, respectively. CONCLUSION: PSA levels in midlife strongly predict future lethal PCa in a US cohort subject to opportunistic screening. Risk-stratified screening on the basis of midlife PSA should be considered in men age 45 to 59 years.
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Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Neoplasias da Próstata/sangue , Curva ROC , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: To investigate the associations of host metabolic factors and metabolic syndrome on prostate cancer-specific death (PCSD) and overall survival (OS) in patients treated with androgen deprivation therapy (ADT) for biochemically recurrent disease. PATIENTS AND METHODS: The analysis included 273 patients with prostate cancer treated with ADT for rising prostate-specific antigen level after surgery or radiotherapy. Patients were assessed for the presence of diabetes, hypertension, dyslipidaemia and obesity before commencing ADT, and Adult Treatment Panel III criteria were used to assess the presence of the composite diagnosis of metabolic syndrome. A competing risks regression model was used to assess associations of time to PCSD with the metabolic conditions, while a multivariable Cox regression model was used to assess associations of OS with metabolic syndrome and metabolic conditions. RESULTS: During a median follow-up of 11.6 years, 157 patients (58%) died, of whom 58 (21%) died from prostate cancer. At the start of ADT the median (range) patient age was 74 (46-92) years and the median PSA level was 3.0 ng/mL. Metabolic syndrome was observed in 31% of patients; hypertension (68%) and dyslipidaemia (47%) were the most common metabolic conditions. No association of PCSD and metabolic syndrome status was observed. Patients with hypertension tended to have a higher cumulative incidence of PCSD than those without hypertension (sub-distribution hazard ratio [HR] 1.59, 95% confidence interval [CI] 0.89, 2.84; P = 0.11) although the difference was not statistically significant. Patients with metabolic syndrome had an increased risk of death from all causes (HR 1.56, 95% CI 1.07, 2.29; P = 0.02) when compared with patients without metabolic syndrome, as did patients with hypertension (HR 1.72, 95% CI 1.18, 2.49; P = 0.004). CONCLUSIONS: No association of PCSD and metabolic syndrome was observed in this cohort of men receiving ADT for biochemically recurrent prostate cancer. Metabolic syndrome was associated with an increased risk of death from all causes and a similar effect was also observed for patients with prostate cancer with hypertension alone.
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Antagonistas de Androgênios/uso terapêutico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Doenças Metabólicas/complicações , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/complicações , Medição de RiscoRESUMO
Current evidence of an association between body size and prostate cancer is conflicting, possibly due to differential effects of body size across the lifespan and the heterogeneity of the disease. We therefore examined childhood and adult body size in relation to total incident prostate cancer and prognostic subtypes in a prospective cohort of 47,491 US men in the Health Professionals Follow-up Study. We assessed adult height, body mass index (BMI) in early and middle-to-late adulthood, adult waist circumference, and body shape at age 10. With follow-up from 1986 to 2010, we estimated the relative risk (RR) of prostate cancer using Cox proportional hazards models. We identified 6,183 incident cases. Tallness was associated with increased risk of advanced-stage tumors, particularly fatal disease (RR = 1.66, 95% CI 1.23-2.23, highest vs. lowest quintile, ptrend < 0.001). High BMI at age 21 was inversely associated with total prostate cancer (RR = 0.89, 95% CI 0.80-0.98, BMI ≥ 26 vs. 20-21.9, ptrend = 0.01) and with fatal and advanced disease. The association for late adult BMI differed by age (pinteraction < 0.001); high BMI was inversely associated with total prostate cancer (RR = 0.64, 95% CI 0.51-0.78, BMI ≥ 30 vs. 21-22.9, ptrend <0.001) and with non-advanced and less aggressive tumors among men ≤ 65 years, whereas no association was seen among men >65 years. Adult waist circumference was weakly inversely associated with less aggressive disease. Childhood obesity was unclearly related to risk. Our study confirms tall men to be at increased risk of fatal and advanced prostate cancer. The influence of adiposity varies by prognostic disease subtype and by age. The relationship between body size and prostate cancer is complex. Body size changes progressively throughout life and consequent effects on prostate cancer risk may be associated with related changes in hormonal and metabolic pathways. This large prospective study examined potential associations between the risk of various prostate cancer subtypes and multiple anthropometric measures at different ages in men. Tallness was confirmed to be associated with an elevated risk of advanced prostate cancer, particularly fatal disease. The extent to which body weight influenced risk varied according to factors such as age and disease subtype.
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Tamanho Corporal/fisiologia , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Antropometria , Índice de Massa Corporal , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Several lifestyle factors have been associated with risk of lethal prostate cancer, but little is known about their combined effect. Our objective was to develop and apply a lifestyle score for prevention of lethal prostate cancer. METHODS: We developed a lifestyle score among 42 701 men in the Health Professionals Follow-up Study (HPFS) followed from 1986 to 2010 and applied it among 20 324 men in the Physicians' Health Study (PHS) followed from 1982 to 2010. One point was given for each of: not currently smoking or quit 10 or more years ago, body mass index under 30 kg/m(2), high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Diet-only scores (range = 0-3) and total scores (range = 0-6) were calculated. We used multivariable Cox proportional hazards regression to estimate the risk of lethal prostate cancer, adjusting for potential risk factors of lethal prostate cancer. All statistical tests were two-sided. RESULTS: We observed 576 lethal prostate cancer events in HPFS and 337 in PHS. Men with 5-6 vs 0-1 points had a 68% decreased risk of lethal prostate cancer (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.19 to 0.52) in HPFS and a non-statistically significant 38% decreased risk (HR = 0.62, 95% CI = 0.30 to 1.26) in PHS. For dietary factors only, men with 3 vs 0 points had a 46% decreased risk (HR = 0.54, 95% CI = 0.30 to 0.96) in the HPFS and a non-statistically significant 30% decreased risk (HR = 0.70, 95% CI = 0.40 to 1.23) in PHS. CONCLUSIONS: Adhering to a healthy lifestyle, defined by not smoking, normal body weight, high physical activity, and a healthy diet, may lower risk of lethal prostate cancer.
Assuntos
Índice de Massa Corporal , Comportamento Alimentar , Estilo de Vida , Atividade Motora , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/prevenção & controle , Comportamento de Redução do Risco , Fumar , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Peixes , Humanos , Incidência , Solanum lycopersicum , Masculino , Produtos da Carne , Pessoa de Meia-Idade , Razão de Chances , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Medição de Risco , Fatores de Risco , Autorrelato , Fumar/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Sleep deficiency is a major public health problem. There are limited human data on whether sleep duration or disruption are risk factors for prostate cancer. METHODS: We prospectively followed 32,141 men in the Health Professionals Follow-Up Study who reported their typical sleep duration in 1987, 2000, and 2008. We identified 4,261 incident prostate cancer cases, including 563 lethal cases through 2010. Sleep disruption was assessed in 2004 among 19,639 men, with 930 prostate cancer cases (50 lethal) identified from 2004 to 2010. Cox proportional hazards models were used to evaluate the association between sleep insufficiency and risk of overall and lethal prostate cancer. RESULTS: In 1987, 2% of men reported sleeping ≤5 hours per night. We found no association between habitual sleep duration or change in sleep duration with the risk of advanced or lethal prostate cancer. We also found no association between waking up during the night, difficulty falling asleep, or waking up too early, and risk of prostate cancer. In 2004, 6% of men reported never feeling rested when they woke up; these men had an increased risk of developing lethal prostate cancer compared with those who reported always feeling rested when they woke up (RR, 3.05; 95% CI, 1.15-8.10). CONCLUSIONS: We found no consistent association between self-reported sleep duration or sleep disruption and any of our prostate cancer outcomes. IMPACT: We did not find support for a consistent association between self-reported sleep and risk of advanced or lethal prostate cancer in this large cohort of men.
Assuntos
Neoplasias da Próstata/complicações , Transtornos do Sono-Vigília/etiologia , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Classic Hodgkin lymphoma (cHL) has few known modifiable risk factors, and the relationship between diet and cHL risk is unclear. We performed the first investigation of an association between dietary pattern and cHL risk in 435 cHL cases and 563 population-based controls from Massachusetts and Connecticut (1997-2000) who completed baseline diet questionnaires. We identified 4 major dietary patterns ("vegetable," "high meat," "fruit/low-fat dairy," "desserts/sweets") using principal components analysis. We computed multivariable odds ratios and 95% confidence intervals for associations of dietary pattern score (quartiles) with younger-adult (age <50 years), older-adult (age ≥50 years), and overall cHL risk. Secondary analyses examined associations by histological subtype and tumor Epstein-Barr virus (EBV) status. A diet high in desserts/sweets was associated with younger-adult (odds ratio(quartile 4 vs. quartile 1) = 1.60, 95% confidence interval: 1.05, 2.45; Ptrend = 0.008) and EBV-negative, younger-adult (odds ratio = 2.11, 95% confidence interval: 1.31, 3.41; Ptrend = 0.007) cHL risk. A high meat diet was associated with older-adult (odds ratio = 3.34, 95% confidence interval: 1.02, 10.91; Ptrend = 0.04) and EBV-negative, older-adult (odds ratio = 4.64, 95% confidence interval: 1.03, 20.86; Ptrend = 0.04) cHL risk. Other dietary patterns were not clearly associated with cHL. We report the first evidence for a role of dietary pattern in cHL etiology. Diets featuring high intake of meat or desserts and sweets may increase cHL risk.
Assuntos
Dieta , Doença de Hodgkin/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Connecticut/epidemiologia , Comportamento Alimentar , Feminino , Frutas , Comportamentos Relacionados com a Saúde , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/virologia , Humanos , Estilo de Vida , Masculino , Massachusetts/epidemiologia , Carne , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Fatores Socioeconômicos , Verduras , Adulto JovemRESUMO
Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer-specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00-6.42; Ptrend = 0.02) for prostate cancer-specific mortality and 1.67 (95% CI, 1.16-2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44-0.93; Ptrend = 0.02); the relationship with prostate cancer-specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis.
Assuntos
Dieta , Comportamento Alimentar , Longevidade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Neoplasias da Próstata/dietoterapia , Taxa de SobrevidaRESUMO
The precise role of 5'AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. Although it is well established that activation of this energy sensor inhibits the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a "conditional" tumor suppressor and "contextual" oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation, and provides an overview of the most relevant data available on AMPK activation and AMPK-activating drugs in human studies.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Hipóxia Celular , Proliferação de Células , Genes Supressores de Tumor , Humanos , Neoplasias/tratamento farmacológico , Oncogenes , Estresse FisiológicoRESUMO
Information regarding postdiagnostic dairy intake and prostate cancer survival is limited. We evaluated intake of total, high-fat and low-fat dairy after prostate cancer diagnosis in relation to disease-specific and total mortality. We included 926 men from the Physicians' Health Study diagnosed with non-metastatic prostate cancer between 1982 and 2000 who completed a diet questionnaire a median of 5 years after diagnosis and were followed thereafter for a median of 10 years to assess mortality. Cox proportional hazards regression was used to estimate associations between dairy intake and prostate cancer specific and all-cause mortality. During 8,903 person-years of follow-up, 333 men died, 56 due to prostate cancer. Men consuming ≥3 servings/day of total dairy products had a 76% higher risk of total mortality and a 141% higher risk of prostate cancer-specific mortality compared to men who consumed less than 1 dairy product/day (hazard ratio (HR) = 1.76, 95% confidence interval (CI): 1.21, 2.55, ptrend < 0.001 for total mortality; HR = 2.41, 95% CI: 0.96, 6.02, ptrend = 0.04 for prostate cancer-specific mortality). The association between high-fat dairy and mortality risk appeared to be stronger than that of low-fat dairy, but the difference between them was not statistically significant (p for difference = 0.57 for prostate cancer-specific mortality and 0.56 for total mortality). Among men without metastases when diagnosed, higher intake of dairy foods after prostate cancer diagnosis may be associated with increased prostate cancer-specific and all-cause mortality.
Assuntos
Laticínios/efeitos adversos , Gorduras na Dieta/efeitos adversos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Análise de Sobrevida , Taxa de SobrevidaRESUMO
BACKGROUND: Genetic variants in antioxidant pathways might decrease the efficacy of radiation therapy (RT) by suppressing the generation of reactive oxygen species. We studied the association between single nucleotide polymorphisms (SNPs) in the antioxidant gene superoxide dismutase-2 (SOD2) and cancer-specific outcomes after RT. PATIENTS AND METHODS: Among 816 prostate cancer patients who received radiation as primary therapy from the Physicians' Health Study and the Health Professionals Follow-up Study, we evaluated the association of 7 tagging SNPs in SOD2 with lethal prostate cancer (death from prostate cancer or distant metastasis among living patients). We sought to validate findings in a separate cohort of 612 prostate cancer patients treated with RT with a greater proportion of intermediate and high-risk Gleason scores at the Dana-Farber Cancer Institute. Genetic effects were analyzed using a codominant model, using the genotype homozygous for the major allele as baseline. RESULTS: Among patients who underwent RT in the test cohort, there was a significant association between 3 of the 7 SOD2 SNPs and lethal prostate cancer: rs6917589 (overall P = .006), rs2758331 (P = .04) and the functional valine to alanine polymorphism in rs4880 (P = .04). These SNPs were not associated with outcome among men who had undergone prostatectomy. The associations were not replicated in the validation cohort. CONCLUSION: Germline genetic variation in the SOD2 gene might be a predictive biomarker of response to RT for prostate cancer but is not consistently associated with outcome after RT across prostate cancer cohorts with different clinical characteristics.