RESUMO
Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9+/-) with the Sox9+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some Sox9+/Y440X mice survived, all Sox9+/- mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in Sox9+/Y440X compared with Sox9+/-. Activating Sox9Y440X specifically in the chondrocyte-osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing Sox9+/Y440X limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9Y440X failed to interact with ß-catenin and was unable to suppress transactivation of Ihh in cell-based assays. We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia.
Assuntos
Ouriços , Via de Sinalização Wnt , Humanos , Camundongos , Animais , Ouriços/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Diferenciação Celular/genética , Proteínas/metabolismo , Condrócitos/metabolismoRESUMO
BACKGROUND: There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings. METHODS: This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model. RESULTS: A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients). CONCLUSIONS: The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.
Assuntos
Mieloma Múltiplo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib , Dexametasona , Progressão da Doença , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease with the potential for significant morbidity in case of suboptimal treatment (e.g. low treatment adherence). In spite of immense research in IBD, literature on association of IBD with race/ethnicity is fragmented. In this study, we aimed to evaluate the association between race/ethnicity and treatment adherence and persistence among patients with Crohn's disease (CD) or ulcerative colitis (UC) initiated with biologic therapies. METHODS: This observational, retrospective study utilized the Optum Clinformatics (Optum) Extended Data Mart Socioeconomic Status (SES) database. Adult patients with ≥ 2 medical claims for CD or UC diagnosis, ≥ 1 medical or pharmacy claim for corresponding FDA-approved biologic therapy, and a ≥ 12-month pre-index (index date: date of the first biologic medical/pharmacy claim) continuous health plan enrollment were included. Treatment adherence was measured as the proportion of days covered of ≥ 80% and treatment persistence by the number of days from the index date to the biologics discontinuation date. Switching among biologics was allowed for both treatment adherence and treatment persistence. Multivariable regression analyses were performed to evaluate the association between race/ethnicity and treatment adherence/persistence. RESULTS: Among patients with CD (N = 1430) and UC (N = 1059) included, majority were White (CD: 80.3%, UC: 78.3%), followed by African Americans (AA; CD: 10.5%, UC: 9.7%). Among patients with CD, AA were significantly less likely to adhere to biologics (adjusted OR [95%CI]: 0.61 [0.38; 0.99]) and more likely to discontinue biologics earlier (adjusted HR [95%CI]: 1.52 [1.16; 2.0]) during the follow-up period compared to Whites, after adjusting for other patient sociodemographic and clinical characteristics. Among patients with UC, no significant differences in the treatment adherence/persistence were observed between different races/ethnicities. CONCLUSIONS: Patients with CD were found to display racial differences in the treatment adherence and persistence of biologics, with significantly lower adherence and earlier discontinuation in AA compared to Whites. Such differences were not observed in patients with UC. Future studies are warranted to understand the possible reasons for racial differences, particularly in patients with CD.
Assuntos
Produtos Biológicos , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adulto , Humanos , Estudos Retrospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Terapia Biológica , Produtos Biológicos/uso terapêuticoRESUMO
Aim: To evaluate among multiple myeloma (MM) patients, the proportions with first-line bortezomib/lenalidomide/dexamethasone (VRd) dose modifications and the associated baseline patient characteristics. Patients & methods: Adult MM patients treated with first-line VRd were selected from the Optum claims database. VRd dose modifications were defined based on lenalidomide dose. Results: Among 1497 MM patients, 33% received VRd lite and 22% VRd reduced. Compared with VRd regular, VRd lite usage was more likely to be associated with patients aged ≥75 years and female sex; VRd reduced usage was more likely to be associated with female sex and frailty. Conclusion: A large proportion of MM patients received VRd dose modifications in the real-world, which could potentially result in reduced effectiveness of VRd.
Assuntos
Mieloma Múltiplo , Adulto , Humanos , Feminino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/uso terapêuticoRESUMO
BACKGROUND: Long-acting injectable (LAI) antipsychotics use is associated with improved adherence which can reduce the rate of relapse, hospitalization, and associated costs in patients with schizophrenia. Young adults could be at higher risk of poor adherence, hence use of LAI in this population may offer a benefit but the evidence is limited. This study aimed to compare clinical and economic outcomes before and after the initiation of LAI antipsychotics in commercially insured young adults (18-35 years of age) with schizophrenia. METHODS: A retrospective claims data study was conducted using the data from the IBM MarketScan® Commercial Claims and Encounters (CCAE) Database. Patients with a continuous enrollment of at least 1-year before and 1-year after the first observed schizophrenia diagnosis (index date) and with the use of ≥1 typical or atypical LAI antipsychotic during the post-index follow-up period were included. A pre-post analysis was conducted to compare relapse rates, healthcare resource utilization, and costs before (from index date to LAI initiation) and after LAI initiation (to end of follow up). RESULTS: A total of 2222 patients who initiated LAIs after an index schizophrenia diagnosis were identified. The per patient per month (PPPM) composite relapse event rate (0.109 pre-LAI to 0.073 post-LAI) and hospitalization rate (0.091 to 0.058), all-cause inpatient visits (0.231 to 0.119), and length of stay (2.694 to 1.092 days) significantly decreased from before LAI initiation to after LAI initiation with similar trends seen for mental health and schizophrenia-related measures (all significant; P < 0.0001). All-cause total costs ($4898 to $3078 PPPM) were also decreased after LAI initiation, with similar trends seen for mental health and schizophrenia-related costs (all significant; P < 0.0001). Although medication costs were higher post-LAI period ($311 to $542 PPPM), the cost increase was substantially offset by the decreased costs associated with total healthcare costs. CONCLUSIONS: Treatment with LAI antipsychotics was associated with a decrease in relapse event rate, healthcare resource utilization, and costs after LAI initiation compared to before LAI initiation in commercially insured young adults with schizophrenia. Treatment with LAIs in young adults with schizophrenia is potentially associated with significant cost savings to commercial payers.
Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Custos de Cuidados de Saúde , Humanos , Recidiva , Estudos Retrospectivos , Esquizofrenia/tratamento farmacológico , Adulto JovemRESUMO
OBJECTIVE: To examine the effect of robotic-assisted surgery implementation for treatment of endometrial cancer in the United States on 30-day clinical outcomes and costs. METHODS: We retrospectively reviewed data of adult patients who underwent total hysterectomy for endometrial cancer in the US hospitals in Premier Healthcare Database between January 1, 2008 and September 30, 2015. We conducted trend analyses comparing the proportions of surgical approaches with the associated clinical outcomes and costs over the study period using Mann-Kendall tests. Clinical outcomes and costs of robotic-assisted surgery, laparoscopic and open surgery have been compared after propensity score 1:1 matching in the most recent 3 years (January 1, 2013-September 30, 2015). RESULTS: Of a total of 35,224 patients, use of robotic-assisted surgery increased from 9.48% to 56.82% while open surgery decreased from 70.4% to 28.1% over the study period. A 2.5% decrease in major complications (P < .001), a 2.9% decrease in minor complications (P = .001), and a 2.0% decrease 30-day readmissions (P = .001) was observed across all surgical approaches. Perioperative 30-day total cost slightly decreased from US $11,048 to US $10,322 (P = .08). Among propensity-score matched patients, robotic-assisted surgery was associated with shorter hospitalization than open surgery (median [interquartile range], 2.0 [2.0-3.0] vs 4.0 [3.0-6.0] days) and laparoscopic surgery (2.0 [2.0-3.0] vs 3.0 [2.0-4.0] days), fewer 30-day complications (20.1% vs 33.7%) (all P < .001), and comparable perioperative 30-day total costs (median [interquartile range], US $12,200 [US $9,509-US $16,341] vs US $12,018 [US $8,996-US $17,162]; P = .34) with open surgery. CONCLUSION: Robotic-assisted surgery facilitated the widespread diffusion of a minimally invasive approach nationally for endometrial cancer, with reduction of perioperative morbidity and no increase in overall treatment-related 30-day costs at national level.
Assuntos
Neoplasias do Endométrio/cirurgia , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Adolescente , Adulto , Idoso , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Taxa de Sobrevida , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Purpose: We examined underlying psychosocial processes of a behavioral treatment for urinary incontinence (UI) of prostate cancer survivors.Design: Secondary analysis of data collected from a clinical trial.Sample: Two hundred forty-four prostate cancer survivors who participated in a clinical trial of behavioral intervention to UI as intervention or control subjects.Methods: The participants had a 3-month behavioral intervention or usual care and were followed up for an additional 3 months. They were assessed at baseline, 3, and 6 months. Latent growth curve models were performed to examine trajectories of each study variable and relationships among the variables.Findings: Increasing self-efficacy and social support were significantly and independently associated with more reduction of urinary leakage frequency over time.Implications for psychosocial oncology: Providing problem-solving skills and social support, including peer support, are essential for empowering patients to reduce UI.
Assuntos
Terapia Comportamental , Sobreviventes de Câncer/psicologia , Neoplasias da Próstata/terapia , Incontinência Urinária/psicologia , Incontinência Urinária/terapia , Idoso , Sobreviventes de Câncer/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Participação do Paciente , Autoeficácia , Apoio Social , Resultado do TratamentoRESUMO
PURPOSE: This study aimed to assess whether prostate cancer survivors who received a behavioral intervention to urinary incontinence had experienced a significant mood improvement. METHODS: One hundred fifty-three prostate cancer survivors with persistent incontinence were included in this secondary data analysis. They were randomly assigned to usual care or interventions that provided pelvic floor muscle exercises and self-management skills. All subjects had measures of anxiety, depression, and anger at baseline, 3 months (post-intervention), and 6 months (follow-up). Negative binomial regression analysis was performed to examine the group status, daily leakage frequency at 3 months, and their interactions at 3 months as predictors for mood outcomes at 6 months, controlling for demographic and medical variables. RESULTS: The main effect of daily leakage frequency at 3 months significantly predicted anxiety at 6 months (p < .01). The group main effect on any mood outcomes at 6 months was not statistically significant. The interaction between the group and 3-month leakage had a significant effect on anxiety; intervention subjects achieving a significant leakage reduction at 3 months exhibited significantly less anxiety at 6 months than other subjects (p = .04). Age, employment status, and receiving surgery at baseline were significantly associated with less anxiety, depression, and anger at 6 months. CONCLUSIONS: Reduced urinary incontinence significantly predicted less anxiety, especially among the intervention subjects. The findings suggest a significant association between a behavioral therapy of urinary incontinence and anxiety reduction in prostate cancer survivors.
Assuntos
Afeto , Terapia Comportamental/métodos , Sobreviventes de Câncer/psicologia , Neoplasias da Próstata/reabilitação , Incontinência Urinária/psicologia , Incontinência Urinária/terapia , Idoso , Terapia por Exercício/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/fisiopatologia , Neoplasias da Próstata/psicologia , Resultado do TratamentoRESUMO
PURPOSE: Hypertension is a major global public health problem, including rural China. However, studies examining health-related quality of life (HRQoL) for patients with hypertension have been mostly conducted in urban populations. This study aimed to use the EuroQol five-dimensional-five-level (EQ-5D-5L) and its recently developed Chinese value set to analyze HRQoL and its influencing factors among hypertensive population in rural China. METHODS: This is a cross-sectional population-based survey. Standard interview of participants was conducted from July to September 2016 in Donghai County's 334 villages of Jiangsu Province, China. Data collection included the EQ-5D-5L, along with sociodemographic characteristics and disease-related factors such as duration of hypertension, antihypertensive treatment and comorbid conditions. The Tobit regression model was employed to analyze potential influencing factors on HRQoL. RESULTS: A total of 16,596 adults (18 years and older) with hypertension participated in this study. 62.4% were women. The mean utility score was 0.85 (standard deviation [SD] = 0.23). The proportion of participants reporting pain/discomfort problems was highest, while least patients reported problems in self-care dimension. Females, elderly, illiterate patients, ex-smokers and patients with longer duration of hypertension or comorbidities scored lower on HRQoL than others. Stroke, heart failure and coronary heart disease were associated with a larger negative impact on HRQoL among all comorbidities. CONCLUSIONS: The HRQoL was lower in this rural hypertensive population than previously reported urban counterparts. To improve the HRQoL of hypertensive patients in rural areas, it is important to control hypertension and prevent its associated co-morbidities. More attention needs to be directed to elderly female patients with less education who scored much lower HRQoL than their male counterparts.
Assuntos
Hipertensão/psicologia , Qualidade de Vida/psicologia , População Rural/estatística & dados numéricos , Idoso , Povo Asiático , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Dor/psicologia , Autocuidado , População UrbanaRESUMO
BACKGROUND: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. METHODS: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. RESULTS: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41-0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48-0.60; P<0.001) with no significant heterogeneity by country. CONCLUSIONS: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Compostos Benzidrílicos/administração & dosagem , Glicemia/metabolismo , Canagliflozina/administração & dosagem , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Feminino , Seguimentos , Alemanha/epidemiologia , Glucosídeos/administração & dosagem , Insuficiência Cardíaca/sangue , Humanos , Hipoglicemiantes/administração & dosagem , Internacionalidade , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Noruega/epidemiologia , Sistema de Registros , Fatores de Risco , Transportador 2 de Glucose-Sódio/metabolismo , Suécia/epidemiologia , Resultado do Tratamento , Reino Unido/epidemiologia , Estados Unidos/epidemiologiaRESUMO
The multinational, observational CVD-REAL study recently showed that initiation of sodium-glucose co-transporter-2 inhibitors (SGLT-2i) was associated with significantly lower rates of death and heart failure vs other glucose-lowering drugs (oGLDs). This sub-analysis of the CVD-REAL study sought to determine the association between initiation of SGLT-2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT-2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non-parsimonious propensity score was developed within each country to predict initiation of SGLT-2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent-to-treat analysis, over 188 551 and 188 678 person-years of follow-up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT-2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72-1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71-0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT-2i, specifically as it relates to ischaemic events.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Infarto do Miocárdio/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Acidente Vascular Cerebral/complicações , Estudos de Coortes , Pesquisa Comparativa da Efetividade , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/terapia , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/terapia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/terapia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Seguro Saúde , Análise de Intenção de Tratamento , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/terapia , Prevalência , Pontuação de Propensão , Modelos de Riscos Proporcionais , Risco , Países Escandinavos e Nórdicos/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/terapia , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. MATERIALS AND METHODS: We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. RESULTS: A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53-0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49-0.78) and fracture (HR 0.52, 95% CI 0.38-0.70, each p <0.0001). CONCLUSIONS: Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Estudos de Coortes , Esquema de Medicação , Humanos , Masculino , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco/métodos , Fatores de RiscoRESUMO
PURPOSE: Androgen deprivation therapy is often used as salvage treatment in men with rising prostate specific antigen after initial radical prostatectomy or radiotherapy for clinically localized prostate cancer. Given the lack of evidence from general practice, we examined the association of salvage androgen deprivation therapy with mortality in an observational cohort study. MATERIALS AND METHODS: From 3 managed care organizations we assembled a retrospective cohort of all 5,804 men with newly diagnosed localized prostate cancer from 1995 to 2009 who had a prostate specific antigen increase (biochemical recurrence) after primary radical prostatectomy or radiotherapy. The main outcomes were all-cause and prostate cancer specific mortality. We used Cox proportional hazards models to estimate mortality with salvage androgen deprivation therapy as a time dependent predictor. RESULTS: Overall salvage androgen deprivation therapy was not associated with all-cause or prostate cancer specific mortality in the prostatectomy cohort (HR 0.97, 95% CI 0.70-1.35 or HR 1.18, 95% CI 0.68-2.07) or in the radiotherapy cohort (HR 0.84, 95% CI 0.70-1.01 or HR 1.06, 95% CI 0.80-1.40, respectively). Among men with prostate specific antigen doubling time less than 9 months after the prostate specific antigen rise, salvage androgen deprivation therapy was statistically significantly associated with a decreased risk of all-cause and prostate cancer specific mortality in the prostatectomy cohort (HR 0.35, 95% CI 0.20-0.63 and HR 0.43, 95% CI 0.21-0.91) and in the radiotherapy cohort (HR 0.62, 95% CI 0.48-0.80 and HR 0.65, 95% CI 0.47-0.90, respectively). CONCLUSIONS: We found no association of salvage androgen deprivation therapy with all-cause or cause specific mortality in most men with biochemical recurrence after primary radical prostatectomy or radiotherapy for clinically localized prostate cancer. Men with quickly progressed disease may derive a clinical benefit from salvage androgen deprivation therapy.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Terapia de Salvação , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/terapia , Estudos Retrospectivos , Terapia de Salvação/métodosRESUMO
BACKGROUND: Sorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. RESULTS: A total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. CONCLUSIONS: Sunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Pirróis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/epidemiologia , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Incidência , Indóis/administração & dosagem , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/epidemiologia , Masculino , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Modelos de Riscos Proporcionais , Pirróis/administração & dosagem , Fatores de Risco , Programa de SEER , Sorafenibe , Sunitinibe , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
PURPOSE: The optimal use of androgen deprivation therapy as salvage treatment (sADT) for men after initial prostatectomy or radiotherapy for clinically localized prostate cancer is undefined. We describe patterns of sADT use and investigate clinical and sociodemographic characteristics of insured men who received sADT versus surveillance in managed care settings. METHODS: Using comprehensive electronic health records and cancer registry data from three integrated health plans, we identified all men with newly diagnosed clinically localized prostate cancer between 1995 and 2009 who received either prostatectomy (n = 16,445) or radiotherapy (n = 19,531) as their primary therapy. We defined sADT based on the timing of ADT following primary therapy and stage of cancer. We fit Cox proportional hazard models to identify sociodemographic characteristics and clinical factors associated with sADT. RESULTS: With a median follow-up of 6 years (range 2-15 years), 13 % of men who underwent primary prostatectomy or radiotherapy received sADT. After adjusting for selected covariates, sADT was more likely to be used in men who were older (e.g., HR 1.70, 95 % CI 1.48-1.96 or HR 1.33, 95 % CI 1.17-1.52 for age 70+ relative to age 35-59 for primary prostatectomy or radiotherapy, respectively), were African-American, had a short PSA doubling time, had a higher pre-treatment risk of progression, had more comorbidities, and received adjuvant ADT for initial disease. CONCLUSIONS: In men with localized prostate cancer in community practice initially treated with prostatectomy or radiotherapy, sADT after primary treatment was more frequent for men at greater risk of death from prostate cancer, consistent with practice guidelines.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Previsões , Estadiamento de Neoplasias/métodos , Prostatectomia/métodos , Neoplasias da Próstata/terapia , Terapia de Salvação/métodos , Adulto , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of a behavioral intervention for urinary incontinence of prostate cancer patients. Study subjects were either participating in or eligible but declined (i.e., nonparticipating) the active intervention study. METHODS: The intervention-participating subjects were randomized into three groups, including two intervention groups (support and telephone groups) and a usual care reference group. Intervention-nonparticipating subjects were concurrently enrolled. Intervention effectiveness was assessed on the EQ-5D measure. The costs included direct healthcare cost from medical billing data, patient out-of-pocket expense, caregiver expense, patient loss-of-work cost, and intervention cost. We calculated incremental cost-effectiveness ratios (ICERs) from societal, provider, and patient perspectives. RESULTS: Two hundred and sixty-seven intervention-participating and 69 intervention-nonparticipating post-cancer treatment patients were included. The support and telephone groups, but not the usual care group, had significantly higher EQ-5D index scores (0.054, p = 0.033, and 0.057, p = 0.026, respectively) than the intervention-nonparticipating group at month 6. Within 6 months, intervention cost per subject was $252 and $484, respectively, for providers, and $564 and $203, respectively, for the support and phone group subjects. The final ICERs were $16,759 per quality-adjusted life year (QALY) and $12,561/QALY for support and telephone groups, compared with those of the intervention-nonparticipating group. These ICERs are much smaller than $50,000/QALY, the consensus threshold to determine cost-effectiveness for society. CONCLUSIONS: The study interventions are cost-effective in consideration of eligible patients who declined the interventions. The interventions can provide meaningful outcome improvement on urinary continence at a low cost. This evidence provides critical information for future health policy decision-making of healthcare providers and payers.
Assuntos
Custos de Cuidados de Saúde , Prostatectomia/efeitos adversos , Neoplasias da Próstata/psicologia , Incontinência Urinária/etiologia , Incontinência Urinária/reabilitação , Idoso , Análise Custo-Benefício , Gastos em Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/economia , Anos de Vida Ajustados por Qualidade de Vida , Perfil de Impacto da Doença , Telefone , Resultado do Tratamento , Incontinência Urinária/economiaRESUMO
PURPOSE: We examined whether an intervention combining pelvic floor muscle exercise and symptom self-management would improve urinary continence and quality of life in patients with prostate cancer. MATERIALS AND METHODS: In a randomized, controlled, longitudinal clinical trial 279 patients with prostate cancer with persistent urinary incontinence were randomized to 1 of 3 groups, including biofeedback pelvic floor muscle exercise plus a support group, the biofeedback exercise plus telephone contact and usual care without intervention. The biofeedback plus support and plus telephone groups received 1 session of biofeedback assisted exercise and 6 biweekly sessions of problem solving therapy. This delivered symptom management skills through a peer support group or telephone contacts for 3 months. All subjects were assessed in blinded fashion at baseline, and 3 and 6 months for urinary leakage frequency, leakage amount and disease specific quality of life. RESULTS: A total of 244 subjects completed the study. The biofeedback plus support and biofeedback plus telephone groups had a lower frequency of daily urinary leakage than the group with usual care without intervention at 3 months (p=0.019 and p≤0.001, respectively) but not at 6 months. The biofeedback plus support group but not the biofeedback plus telephone group had 13.3 gm lower leakage at 6 months than the usual care group (p=0.003). Overall the biofeedback plus support and plus telephone groups reported less symptom severity (p≤0.001) and fewer incontinence problems (p≤0.01) than the usual care group at 6 months. CONCLUSIONS: Study findings show that pelvic floor muscle exercise practice plus symptom self-management in a peer support setting can significantly improve urinary continence and quality of life in patients with prostate cancer.
Assuntos
Biorretroalimentação Psicológica , Terapia por Exercício , Assistência Centrada no Paciente , Distúrbios do Assoalho Pélvico/terapia , Neoplasias da Próstata/terapia , Incontinência Urinária/terapia , Idoso , Terapia Combinada , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Resolução de Problemas , Psicoterapia , Qualidade de Vida , Encaminhamento e Consulta , Autocuidado , Grupos de Autoajuda , TelefoneRESUMO
BACKGROUND: Recurrent nocturnal hypoxemia in obstructive sleep apnea enhances sympathetic function, decreases baroreceptor sensitivity, and weakens peripheral vascular responses to adrenergic signals. The authors hypothesized that the percentage of total sleep time spent at oxyhemoglobin saturation (SaO2) less than 90% and minimum nocturnal SaO2 on preoperative polysomnography are associated with decreased intraoperative mean arterial pressure. METHODS: The authors examined the records of all patients who had laparoscopic bariatric surgery at Cleveland Clinic between 2005 and 2009 and an available polysomnography study. The authors assessed the relationships between the percentage of total sleep time spent at SaO2 less than 90% and minimum nocturnal SaO2, and the time-weighted average of mean arterial pressure. The authors used multivariable regression models to adjust for prespecified clinical confounders. RESULTS: Two hundred eighty-one patients were included in the analysis. The average change in the time-weighted average of mean arterial pressure was -0.02 (97.5% CI, -0.08, 0.04) mmHg for each 1% absolute increase in the percentage of sleep time spent at SaO2 less than 90% (P = 0.50). The average change was -0.13 (97.5% CI, -0.27, 0.01) mmHg, for each 1% absolute decrease in the minimum SaO2 (P = 0.04 > significance criterion of 0.025, Bonferroni correction). An unplanned analysis estimated 1% absolute decrease in minimum SaO2 was associated with -0.22 (98.75% CI, -0.39, -0.04) mmHg, change in mean arterial pressure (P = 0.002) in the time period between endotracheal intubation and trocar insertion. CONCLUSION: Recurrent nocturnal hypoxemia in obstructive sleep apnea is not a risk marker for intraoperative hypotension.
Assuntos
Pressão Arterial/fisiologia , Cirurgia Bariátrica/métodos , Laparoscopia/métodos , Monitorização Intraoperatória/estatística & dados numéricos , Obesidade/cirurgia , Polissonografia/estatística & dados numéricos , Apneia Obstrutiva do Sono/epidemiologia , Causalidade , Doença Crônica , Comorbidade , Feminino , Humanos , Hipotensão/diagnóstico , Hipotensão/epidemiologia , Hipóxia/diagnóstico , Hipóxia/epidemiologia , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Obesidade/epidemiologia , Ohio , Polissonografia/métodos , Análise de Regressão , Estudos Retrospectivos , Apneia Obstrutiva do Sono/fisiopatologia , Fatores de TempoRESUMO
OBJECTIVE: Bevacizumab, the first FDA-approved anti-angiogenesis agent, has been used for metastatic colorectal cancer since 2004. This study evaluated the utilization of bevacizumab among elderly metastatic colorectal cancer patients in the United States. METHODS: Using Surveillance and Epidemiology and End Results (SEER)-Medicare data, this retrospective cohort study consisted of individuals aged 65 years or older with a colorectal cancer diagnosis between 2005 and 2009, who received chemotherapy any time through 2010. This included patients with newly diagnosed metastatic colorectal cancer and patients who progressed from initially diagnosed earlier-stage disease. We ascertained comorbid conditions using ICD-9 codes and conducted logistic regression to identify patients' characteristics associated with bevacizumab use. RESULTS: A total of 8645 patients were identified (mean age 74 years; 52% male); 57% of patients received bevacizumab with initially diagnosed metastatic colorectal cancer and 44% of patients with treated progressive or recurrent disease. After adjusting for other covariates, we found that patients aged ≥80 years were less likely to receive bevacizumab compared with those aged 65-69 years (odds ratio (OR), 0.64 (95% confidence interval (CI): 0.57-0.73)), or if they had evidence of comorbid cardiomyopathy/congestive heart failure (OR, 0.82 (CI: 0.70-0.95)) or arrhythmic disorder (OR, 0.85 (CI: 0.75-0.96)). Adoption of bevacizumab into practice was rapid following its approval, and the use increased from 36% to 40% from 2005 to 2010 (p = 0.013). There were significant regional variations in bevacizumab use. CONCLUSIONS: Despite rapid uptake since its original approval, there appears to be low use of bevacizumab in elderly metastatic colorectal cancer patients in the United States. Regional variations and the strong effects of age and comorbidity suggest lack of consensus among oncologists regarding benefits and risks of bevacizumab in elderly patients.