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1.
J Am Heart Assoc ; 10(1): e016890, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33381983

RESUMO

Background Fine particulate matter <2.5 µm in diameter (PM2.5) has known effects on cardiovascular morbidity and mortality. However, no study has quantified and compared the risks of incident myocardial infarction, incident stroke, ischemic heart disease (IHD) mortality, and cerebrovascular mortality in relation to long-term PM2.5 exposure. Methods and Results We sought to quantitatively summarize studies of long-term PM2.5 exposure and risk of IHD and stroke events by conducting a review and meta-analysis of studies published by December 31, 2019. The main outcomes were myocardial infarction, stroke, IHD mortality, and cerebrovascular mortality. Random effects meta-analyses were used to estimate the combined risk of each outcome among studies. We reviewed 69 studies and included 42 studies in the meta-analyses. In meta-analyses, we found that a 10-µg/m3 increase in long-term PM2.5 exposure was associated with an increased risk of 23% for IHD mortality (95% CI, 15%-31%), 24% for cerebrovascular mortality (95% CI, 13%-36%), 13% for incident stroke (95% CI, 11%-15%), and 8% for incident myocardial infarction (95% CI, -1% to 18%). There were an insufficient number of studies of recurrent stroke and recurrent myocardial infarction to conduct meta-analyses. Conclusions Long-term PM2.5 exposure is associated with increased risks of IHD mortality, cerebrovascular mortality, and incident stroke. The relationship with incident myocardial infarction is suggestive of increased risk but not conclusive. More research is needed to understand the relationship with recurrent events.

2.
Cancer Res ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293427

RESUMO

To identify rare variants associated with prostate cancer (PrCa) susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of PrCa genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 PrCa cases, 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 PrCa cases, 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome-wide in a meta-analysis. Gene-based rare variant tests implicated a known PrCa gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. Additionally, a polygenic risk score (PRS) of 188 PrCa variants was strongly associated with risk (90th vs. 40-60th percentile OR = 2.62, P = 2.55*10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a six-fold difference in log-probability of Androgen Receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms can help clarify the full genetic architecture of PrCa and other complex traits.

3.
Nat Commun ; 11(1): 4423, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887889

RESUMO

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
4.
Cancer Med ; 9(22): 8530-8539, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32965775

RESUMO

BACKGROUND: There is limited research on the racial/ethnic differences in long-term outcomes for men with untreated, localized prostate cancer. METHODS: Men diagnosed with localized, Gleason ≤7 prostate cancer who were not treated within 1 year of diagnosis from 1997-2007 were identified. Cumulative incidence rates of the following events were calculated; treatment initiation, metastasis, death due to prostate cancer and all-cause mortality, accounting for competing risks. The Cox model of all-cause mortality and Fine-Gray sub distribution model to account for competing risks were used to test for racial/ethnic differences in outcomes adjusted for clinical factors. RESULTS: There were 3925 men in the study, 749 Hispanic, 2415 non-Hispanic white, 559 non-Hispanic African American, and 202 non-Hispanic Asian/Pacific Islander (API). Median follow-up was 9.3 years. At 19 years, overall cumulative incidence of treatment, metastasis, death due to prostate cancer, and all-cause mortality was 25.0%, 14.7%, 11.7%, and 67.8%, respectively. In adjusted models compared to non-Hispanic whites, African Americans had higher rates of treatment (HR = 1.39, 95% CI = 1.15-1.68); they had an increased risk of metastasis beyond 10 years after diagnosis (HR = 4.70, 95% CI = 2.30-9.61); API and Hispanic had lower rates of all-cause mortality (HR = 0.66, 95% CI = 0.52-0.84, and HR = 0.72, 95% CI = 0.62-0.85, respectively), and API had lower rates of prostate cancer mortality in the first 10 years after diagnosis (HR = 0.29, 95% CI = 0.09-0.90) and elevated risks beyond 10 years (HR = 5.41, 95% CI = 1.39-21.11). CONCLUSIONS: Significant risks of metastasis and prostate cancer mortality exist in untreated men beyond 10 years after diagnosis, but are not equally distributed among racial/ethnic groups.

5.
Urology ; 143: 103-111, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32525077

RESUMO

OBJECTIVES: To evaluate the association of the Genomic Prostate Score (GPS) assay result with biochemical recurrence (BCR), distant metastases (DM), and prostate-specific death (PCD) in unfavorable intermediate (UFI) risk prostate cancer patients. The GPS assay is used to help guide management decisions for newly diagnosed low and favorable intermediate (FI) risk disease. METHODS: GPS results from 2 studies (Center for Prostate Disease Research [CPDR]; Kaiser Permanente Northern California [KPNC]) in men treated with radical prostatectomy were analyzed to determine associations of the GPS result with BCR, DM, and PCD in UFI risk disease. Analyses included 299 intermediate risk prostate patients, 175 of whom had UFI risk disease (KPNC = 103; CPDR = 72). RESULTS: The GPS result as a dichotomous value (≤40 vs >40) was a significant predictor of BCR in UFI patients in multivariate analyses (hazard ratio [HR] 6.0; 95% confidence interval [CI] 2.0-22.4; P = .0035; CPDR). The GPS result was a strong predictor of all 3 endpoints in multivariate analyses (BCR HR 7.1; 95% CI 5.7-8.8; P < .0001; DM HR 5.4; 95% CI 3.8-7.8; P < .0001; PCD HR 3.4; 95% CI 1.5-8.9; P = .006; KPNC). UFI patients with GPS >40 had outcomes consistent with high-risk disease, whereas UFI patients with GPS ≤40 had outcomes similar to FI risk patients (CPDR/KPNC). CONCLUSIONS: The GPS result was a strong independent predictor of BCR, DM, and PCD in intermediate risk prostate cancer. UFI patients with GPS >40 have a poor prognosis and may benefit from additional therapeutic options.

6.
Environ Res ; 187: 109690, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32474310

RESUMO

BACKGROUND: Polychlorinated biphenyls (PCBs) were used in electrical equipment and a range of construction materials. Although banned in the United States and most of Europe in the 1970s, they are highly persistent in the environment and bioaccumulate. Whether PCBs are associated with liver cancer risk at general population levels is unknown. METHODS: This study consisted of 136 incident liver cancer cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the Norwegian Janus cohort. Sera collected in the 1960s-1980s were measured for 37 PCB congeners and markers of hepatitis B (HBV) and C (HCV) infection. Odds ratios (OR) and 95% confidence intervals (CI) for tertiles of each lipid-adjusted PCB were estimated from conditional logistic regression. We also examined the molar sum of congeners in groups: total PCBs; low, medium, and high chlorination; and Wolff functional groups. RESULTS: Concentrations of individual congeners from the 1960s/1970s sera ranged from 1.3-123.0 and 1.4-116.0 ng/g lipid among MHC cases and controls, respectively, and from 1.9-258.0 and 1.9-271.0 ng/g lipid among Janus cases and controls, respectively. Among MHC participants with sera from the 1960s, collected an average of 27 years before diagnosis among cases, the top tertile of PCBs 151, 170, 172, 177, 178, 180, and 195 was significantly associated with elevated odds of liver cancer (OR range = 2.01-2.38); most of these congeners demonstrated exposure-response trends. For example, ORtertile 3vs1 = 2.38 (95% CI: 1.22-4.64, p-trend = 0.01) for PCB 180. As a group, Wolff group 1b congeners, which are biologically persistent and weak phenobarbital inducers, were associated with increased odds. In MHC participants, ever vs. never HBV or HCV infection modified the PCB-liver cancer associations. There was little evidence of an association between PCBs and odds of liver cancer among the Janus cohort. DISCUSSION: We observed associations between a number of PCB congeners and increased odds of liver cancer among MHC, but not Janus, participants with sera from the 1960s/1970s.


Assuntos
Poluentes Ambientais , Neoplasias Hepáticas , Bifenilos Policlorados , Estudos de Casos e Controles , Europa (Continente) , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/epidemiologia , Noruega , Bifenilos Policlorados/análise , Estudos Prospectivos
7.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1501-1508, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32439797

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. METHODS: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. RESULTS: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. CONCLUSIONS: We identified 38 candidates of protein biomarkers for PDAC risk. IMPACT: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.

8.
Neurology ; 94(18): e1939-e1949, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284359

RESUMO

OBJECTIVE: To determine whether women with multiple sclerosis (MS) diagnosed according to current criteria are at an increased risk of postpartum relapses and to assess whether this risk is modified by breastfeeding or MS disease-modifying therapies (DMTs), we examined the electronic health records (EHRs) of 466 pregnancies among 375 women with MS and their infants. METHODS: We used prospectively collected information from the EHR at Kaiser Permanente Southern and Northern California between 2008 and 2016 of the mother and infant to identify treatment history, breastfeeding, and relapses. Multivariable models accounting for measures of disease severity were used. RESULTS: In the postpartum year, 26.4% relapsed, 87% breastfed, 36% breastfed exclusively for at least 2 months, and 58.8% did not use DMTs. At pregnancy onset, 67.2% had suboptimally controlled disease. Annualized relapse rates (ARRs) declined from 0.37 before pregnancy to 0.14-0.07 (p < 0.0001) during pregnancy, but in the postpartum period, we did not observe any rebound disease activity. The ARR was 0.27 in the first 3 months postpartum, returning to prepregnancy rates at 4-6 months (0.37). Exclusive breastfeeding reduced the risk of early postpartum relapses (adjusted hazard ratio = 0.37, p = 0.009), measures of disease severity increased the risk, and resuming modestly effective DMTs had no effect (time-dependent covariate, p = 0.62). CONCLUSION: Most women diagnosed with MS today can have children without incurring an increased risk of relapses. Women with suboptimal disease control before pregnancy may benefit from highly effective DMTs that are compatible with pregnancy and lactation. Women with MS should be encouraged to breastfeed exclusively.


Assuntos
Aleitamento Materno , Esclerose Múltipla , Complicações na Gravidez , Adulto , Estudos de Coortes , Feminino , Humanos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Período Pós-Parto , Gravidez , Recidiva
9.
Int J Cancer ; 146(7): 1819-1826, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226226

RESUMO

Latinos represent <1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of prostate cancer (PrCa) in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture-mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with p < 0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th-75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Idoso , Alelos , Biomarcadores Tumorais , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Razão de Chances , Polimorfismo de Nucleotídeo Único
10.
Perm J ; 242020.
Artigo em Inglês | MEDLINE | ID: mdl-31852040

RESUMO

CONTEXT: The antipsychotic drug haloperidol has antiproliferative and growth-inhibiting properties on prostate cancer cell lines in vitro by binding the sigma 1 protein. Evidence is needed regarding a possible preventive association in men. OBJECTIVE: To examine whether our epidemiologic data support an inverse association of haloperidol use with risk of prostate cancer. DESIGN: These case-control analyses used conditional logistic regression to estimate relative risk by odds ratios (ORs) adjusting for race/ethnicity and aspects of medical care related to detection of prostate cancer. We tested 3 other commonly used antipsychotic drugs, risperidone, quetiapine, and olanzapine, for sigma 1 protein binding and inhibition of clonogenic growth of prostate cancer cells. Use of any of these by men was considered use of a comparator drug. MAIN OUTCOME MEASURES: 1) association of haloperidol with prostate cancer; 2) sigma 1 binding and clonogenic growth. RESULTS: Probably owing to small numbers of haloperidol recipients, evidence of a preventive association was inconsistent, depending on the definition of long-term use. If duration of use was greater than 1 year, the odds ratio (OR) was 0.38 (95% confidence interval (CI) = 0.14-1.01) for haloperidol and 0.80 (95% CI = 0.66-0.98) for the comparator drug; if the duration of use was greater than 2 years, the OR was 0.66 (95% CI = 0.24-1.76) for haloperidol and 0.84 (95% CI = 0.66-1.08) for the comparator drug. Unlike haloperidol, risperidone, quetiapine, and olanzapine did not bind sigma 1 or inhibit clonogenic growth. CONCLUSION: Given the laboratory evidence, our ambiguous epidemiologic findings should encourage more epidemiologic evaluation of haloperidol use and risk of prostate cancer. Finding a negative association could be a scientific advance in prostate cancer prevention but would not be sufficient basis for recommending the prescription of haloperidol for that purpose.

11.
Hepatology ; 72(2): 535-547, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31808181

RESUMO

BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.

12.
Mov Disord ; 35(3): 450-456, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31774238

RESUMO

BACKGROUND: Current cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized. OBJECTIVES: To determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization. METHODS: We identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration. RESULTS: CD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68). CONCLUSIONS: CD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.

13.
Obstet Gynecol ; 135(1): 106-112, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31809425

RESUMO

OBJECTIVE: To examine relationships between interpersonal trauma exposures and urinary symptoms in community-dwelling midlife and older women. METHODS: We analyzed cross-sectional data from a multiethnic cohort of women aged 40-80 years enrolled in an integrated health care system in California. Lifetime history of intimate partner violence (IPV) and sexual assault, current posttraumatic stress disorder (PTSD) symptoms, and current urinary symptoms were assessed using structured-item questionnaires. Multivariable-adjusted logistic regression models examined associations between traumatic exposures and PTSD symptoms with any weekly urinary incontinence, stress-type incontinence, urgency-type incontinence, and nocturia two or more times per night. RESULTS: Of the 1,999 participants analyzed, 21.7% women reported lifetime emotional IPV, 16.2% physical IPV, 19.7% sexual assault, and 22.6% reported clinically significant PTSD symptoms. Overall, 45% reported any weekly incontinence, 23% stress-type incontinence, 23% urgency-type incontinence, and 35% nocturia. Exposure to emotional IPV was associated with any weekly incontinence (odds ratio [OR] 1.33, 95% CI 1.04-1.70), stress-type incontinence (OR 1.30, 95% CI 1.00-1.65), urgency-type incontinence (OR 1.30, 95% CI 1.00-1.70), and nocturia (OR 1.73, 95% CI 1.36-2.19). Physical IPV exposure was associated with nocturia (OR 1.35, 95% CI 1.04-1.77), but not incontinence. Sexual assault history was not associated with weekly incontinence of any type or nocturia. Symptoms of PTSD were associated with all urinary symptoms assessed, including any weekly incontinence (OR 1.46, 95% CI 1.15-1.85), stress-type incontinence (OR 1.70, 95% CI 1.32-2.20), urgency-type incontinence (OR 1.60, 95% CI 1.24-2.06), and nocturia (OR 1.95, 95% CI 1.55-2.45). CONCLUSION: More than 20% of women in this multiethnic, community-based cohort reported a history of IPV, PTSD symptoms, or both, which were associated with symptomatic urinary tract dysfunction. Findings highlight the need to provide trauma-informed care of midlife and older women presenting with urinary symptoms.


Assuntos
Grupos Étnicos/estatística & dados numéricos , Violência por Parceiro Íntimo/psicologia , Noctúria/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Incontinência Urinária/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Relações Interpessoais , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Noctúria/etiologia , Fatores de Risco , Inquéritos e Questionários , Incontinência Urinária/etiologia
14.
Med Decis Making ; 39(8): 962-974, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31631745

RESUMO

Background. Men with a low-risk prostate cancer (PCa) should consider observation, particularly active surveillance (AS), a monitoring strategy that avoids active treatment (AT) in the absence of disease progression. Objective. To determine clinical and decision-making factors predicting treatment selection. Design. Prospective cohort study. Setting. Kaiser Permanente Northern California (KPNC). Patients. Men newly diagnosed with low-risk PCa between 2012 and 2014 who remained enrolled in KPNC for 12 months following diagnosis. Measurements. We used surveys and medical record abstractions to measure sociodemographic and clinical characteristics and psychological and decision-making factors. Men were classified as being on observation if they did not undergo AT within 12 months of diagnosis. We performed multivariable logistic regression analyses. Results. The average age of the 1171 subjects was 61.5 years (s = 7.2 years), and 81% were white. Overall, 639 (57%) were managed with observation; in adjusted analyses, significant predictors of observation included awareness of low-risk status (odds ratio 1.75; 95% confidence interval 1.04-2.94), knowing that observation was an option (3.62; 1.62-8.09), having concerns about treatment-related quality of life (1.21, 1.09-1.34), reporting a urologist recommendation for observation (8.20; 4.68-14.4), and having a lower clinical stage (T1c v. T2a, 2.11; 1.16-3.84). Conversely, valuing cancer control (1.54; 1.37-1.72) and greater decisional certainty (1.66; 1.18-2.35) were predictive of AT. Limitations. Results may be less generalizable to other types of health care systems and to more diverse populations. Conclusions. Many participants selected observation, and this was associated with tumor characteristics. However, nonclinical decisional factors also independently predicted treatment selection. Efforts to provide early decision support, particularly targeting knowledge deficits, and reassurance to men with low-risk cancers may facilitate better decision making and increase uptake of observation, particularly AS.


Assuntos
Tomada de Decisões , Neoplasias da Próstata/psicologia , Conduta Expectante , Idoso , California , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Qualidade de Vida , Risco , Inquéritos e Questionários , Conduta Expectante/métodos
15.
Nat Commun ; 10(1): 3948, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462633

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

16.
Nat Commun ; 10(1): 3107, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308362

RESUMO

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.


Assuntos
Próstata/metabolismo , Neoplasias da Próstata/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Perfilação da Expressão Gênica , Humanos , Masculino , Modelos Genéticos , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transcriptoma
17.
EGEMS (Wash DC) ; 7(1): 2, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30937324

RESUMO

Context: Electronic medical records hold promise to transform clinical practice. However, technological and other barriers may preclude using them to guide care in real time. We used the Virtual Data Warehouse (VDW) to develop a tool that enables physicians to generate real-time, personalized prognostic information about survival after cancer. Case description: Patients with cancer often ask their oncologists, "Have you ever seen a patient like me?" To help oncologists answer this question, we developed a prototype Prognostic Information System (PRISM), a web-based tool that gathers data about the index patient from Kaiser Permanente's clinical information systems, selects a historical cohort of similar patients, and displays the survival curve of the similar patients relative to key points in their treatment course. Findings and major themes: The prototype was developed by a multidisciplinary team with expertise in oncology, research, and technology. We have completed two rounds of user testing and refinement. Successful development rested on: (1) executive support and a clinical champion; (2) collaboration among experts from multiple disciplines; (3) starting with simple cases rather than ambitious ones; (4) extensive research experience with the Virtual Data Warehouse, related databases, and an existing query tool; and (5) following agile software development principles, especially iterative user testing. Conclusion: Clinical data stored in health care systems' electronic medical records can be used to personalize clinical care in real time. Development of prognostic information systems can be accelerated by collaborations among researchers, technology specialists, and clinicians and by use of existing technology like the Virtual Data Warehouse.

18.
J Thorac Oncol ; 14(7): 1223-1232, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959120

RESUMO

INTRODUCTION: Despite adoption of molecular biomarkers in the management of NSCLC, the recently adopted eighth edition of the TNM staging system utilized only clinicopathologic characteristics and validated improvement in risk stratification of early-stage disease has remained elusive. We therefore evaluated the integration of a clinically validated molecular prognostic classifier into conventional staging. METHODS: A novel staging system, the TNMB (with the B denoting biology) system, which integrates a 14-gene molecular prognostic classifier into the eighth edition of the TNM staging system, was developed by using data from 321 patients with NSCLC at the University of California, San Francisco. The TNMB staging system was subsequently validated in an independent, multicenter cohort of 1373 patients, and its implementation was compared with adoption of the seventh and eighth edition staging systems utilizing metrics of reclassification. RESULTS: Compared with staging according to the eighth edition of the TNM system, the TNMB staging system enhanced the identification of high-risk patients, with a net reclassification improvement of 0.33 (95% confidence interval [CI]: 0.24-0.41). It better predicted differences in survival, with a relative integrated discrimination improvement of 22.1% (95% CI: 8.8%-35.3%), and it improved agreement between observed and predicted survival, with a decrease in the reclassification calibration statistic of from 39 to 21. The seventh and eighth editions failed to change the net reclassification improvement (0.01 [95% CI: -0.04 to 0.03] and 0.03 [95% CI: 0.00 to 0.06], respectively) or relative integrated discrimination improvement (2.1% [95% CI: -5.8 to 9.9] and -2.5% [95% CI: -17.6 to 12.4], respectively); in addition, the eighth edition worsened calibration, with an increase in the reclassification calibration statistic from 23 to 25. CONCLUSIONS: Incorporation of a molecular prognostic classifier significantly improved identification of high-risk patients and survival predictions compared with when conventional staging is used. The TNMB staging system may lead to improved survival of early-stage disease through more effective application of adjuvant therapy.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma de Pulmão/classificação , Adenocarcinoma de Pulmão/genética , Idoso , Carcinoma de Células Grandes/classificação , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/genética , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida
19.
Int J Cancer ; 145(9): 2360-2371, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30701531

RESUMO

Although experimental evidence indicates that certain organochlorine insecticides are hepatocarcinogens, epidemiologic evidence for most of these chemicals is very limited. We estimated associations, using prospectively collected sera, between organochlorine insecticide concentrations and cancer registry-identified primary liver cancer in two cohorts, one from the United States and one from Norway. In nested case-control studies, we used sera collected in the 1960s-1980s from 136 cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the population-based Norwegian Janus cohort. We measured concentrations of nine organochlorine insecticides/metabolites and markers of hepatitis B and C in sera. Adjusted odds ratios (OR) and 95% confidence intervals (CI) for tertiles of lipid-corrected organochlorines were calculated for each cohort using conditional logistic regression. Among MHC participants with sera from the 1960s, there was a suggestive exposure-response trend for trans-nonachlor (second and third tertile of analyte ORs = 1.63 and 1.95, respectively; p-trend = 0.08) and a nonsignificantly elevated risk for the highest tertile of oxychlordane (OR = 1.87). Among Janus participants with sera from the 1970s, we observed an apparent trend for p,p'-DDT (second and third tertile ORs = 1.70 and 2.14, respectively; p-trend = 0.15). We observed little consistency in patterns of association between the cohorts. We found limited evidence that exposure to p,p'-DDT and chlordane-related oxychlordane and trans-nonachlor may be associated with increased risk of primary liver cancer. However, the modest strength of these associations and their lack of concordance between cohorts necessitate caution in their interpretation.


Assuntos
Hidrocarbonetos Clorados/sangue , Inseticidas/sangue , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Clordano/efeitos adversos , Clordano/análogos & derivados , Clordano/sangue , DDT/efeitos adversos , DDT/sangue , Feminino , Humanos , Hidrocarbonetos Clorados/efeitos adversos , Inseticidas/efeitos adversos , Neoplasias Hepáticas/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Razão de Chances , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Estados Unidos/epidemiologia
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