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BACKGROUND: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling. MATERIALS AND METHODS: Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials. RESULTS: A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis. CONCLUSION: Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment. IMPLICATIONS FOR PRACTICE: The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway. METHODS: Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone. RESULTS: Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment. CONCLUSIONS: The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016;122:1897-904. © 2016 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/administración & dosificación , Anilidas/administración & dosificación , Everolimus/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Nitrilos/administración & dosificación , Receptores Androgénicos/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Compuestos de Tosilo/administración & dosificaciónRESUMEN
As the Canadian population ages, healthcare systems have become increasingly interested in exploring new ways to deliver services to frail older adults, and in particular older adults with dementia. The Specialized Seniors Clinics (SSCs) are an innovative integrated network of six outpatient clinics in BC's Fraser Health Authority that utilize interprofessional teams to provide comprehensive geriatric assessments and care planning for frail older adults. The SSCs provided approximately 19,000 appointments in the past fiscal year, and clients and primary care physicians are highly satisfied with the model. This article describes the SSC model and provides reflection on the model development, implementation and standardization processes.
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Servicios de Salud para Ancianos/organización & administración , Relaciones Interprofesionales , Derivación y Consulta/organización & administración , Anciano , Colombia Británica , Prestación Integrada de Atención de Salud/organización & administración , Política de Salud , Humanos , Modelos Organizacionales , Grupo de Atención al Paciente , Atención Dirigida al Paciente/organización & administración , Desarrollo de Programa , Evaluación de Programas y Proyectos de SaludRESUMEN
Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.
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Objectives: The mechanism of many neuropsychiatric disorders remains unknown, but the ineffectiveness of the sodium channel blocker lidocaine has been suggested to be a biomarker for Attention Deficit Hyperactivity Disorder (ADHD) and a severe form of Premenstrual Syndrome (PMS) that is considered psychiatric. We conducted single-arm double-blind clinical trials to test whether lidocaine ineffectiveness can be used as a biomarker to identify people with these conditions and provide a clue as to the molecular mechanism and potential psychopharmacological intervention. Experimental Design: We developed a noninvasive taste test for lidocaine ineffectiveness, validated by comparing lidocaine injections to pain testing in 12 subjects, and assessed it in individuals with ADHD and PMS. Principal Observations: Lidocaine ineffectiveness had a strong association in women with ADHD + PMS in a sample of 53 subjects and controls (p < 0.001). Conclusions: These results suggest the possibility of the biological understanding of the combination of ADHD and PMS that is characteristic of the psychiatric disorder Premenstrual Dysphoric Disorder (PMDD). These results and comparison to family pedigrees of a neuromuscular channelopathy with overlapping symptoms suggest the possibility that the clinical phenotype in PMDD is produced by sensory overstimulation, and amenable to molecular understanding and treatment.
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Trastorno Disfórico Premenstrual , Síndrome Premenstrual , Psicofarmacología , Femenino , Humanos , Lidocaína/farmacología , Personalidad , Trastorno Disfórico Premenstrual/tratamiento farmacológico , Síndrome Premenstrual/tratamiento farmacológico , Síndrome Premenstrual/psicología , Método Doble CiegoRESUMEN
Background: The correlation between blood-based tumor mutation burden (bTMB) and tissue-based tumor mutation burden(tTMB) has not been broadly tested in a multicancer cohort. Here, we assess the correlation between bTMB with tTMB in phase I trial patients treated with immunotherapy. As an exploratory analysis, we evaluated circulating tumor DNA (ctDNA) dynamics in responders. Methods: Patients treated with immunotherapy at the Princess Margaret phase I trials unit were enrolled. Pretreatment plasma ctDNA and matched normal blood controls were collected. Available archival tissue formalin-fixed paraffin-embedded (FFPE) samples were analyzed. A 425-gene panel was used to sequence both ctDNA and FFPE samples. Samples with TMB within the highest tertile were considered as high TMB. Results: Thirty-eight patients were accrued from 25 different trials, 86.8% of which involved an anti-PD-1/PD-L1 agent. Thirty patients (78.9%) had detectable mutations in ctDNA, of which the median (range) bTMB was 5 (1-53) mutations per megabase (mut/Mb). Of the 22 patients with available FFPE samples, mutations were detected in 21 (95.4%); the median (range) tTMB was 6 (2-124) mut/Mb. Among the 16 patients with detectable mutations in both FFPE and ctDNA, a statistically significant correlation between bTMB and tTMB was observed (ρ = 0.71; P = .002). High TMB was not associated with better survival. All 3 responders had a decrease in the variant allele frequency of mutations detected in ctDNA at a second timepoint relative to baseline, indicating a potential early marker of response. Conclusions: In this small series, bTMB correlated with tTMB. An on-treatment decrease in VAF of mutations detected in ctDNA at baseline was observed in responders. Larger studies to verify our findings are warranted.
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ADN Tumoral Circulante/genética , Análisis Mutacional de ADN/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Acumulación de Mutaciones , Neoplasias/genética , Adulto , Anciano , ADN Tumoral Circulante/sangre , Ensayos Clínicos Fase I como Asunto , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/patología , Neoplasias/terapia , Adhesión en Parafina , Proyectos Piloto , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Adulto JovenRESUMEN
As the Canadian population ages, healthcare systems have become increasingly interested in exploring new ways to deliver services to frail older adults, and in particular older adults with dementia. The Specialized Seniors Clinics (SSCs) are an innovative integrated network of six outpatient clinics in BC's Fraser Health Authority that utilize interprofessional teams to provide comprehensive geriatric assessments and care planning for frail older adults. The SSCs provided approximately 19,000 appointments in the past fiscal year, and clients and primary care physicians are highly satisfied with the model. This article describes the SSC model and provides reflection on the model development, implementation and standardization processes.
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Demencia/epidemiología , Servicios de Salud para Ancianos/organización & administración , Grupo de Atención al Paciente/organización & administración , Atención Primaria de Salud/organización & administración , Anciano , Instituciones de Atención Ambulatoria/organización & administración , Canadá/epidemiología , Evaluación Geriátrica/métodos , Humanos , Relaciones Interprofesionales , Atención Dirigida al Paciente/organización & administración , Derivación y Consulta/organización & administración , Servicio Social/organización & administración , Desarrollo de Personal/organización & administración , Integración de SistemasRESUMEN
OBJECTIVES: This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. METHODS: From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). CONCLUSIONS: The 3-step model had high detection and low false-positive levels in this diverse population.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/diagnóstico , Tamizaje Neonatal/métodos , Tripsinógeno/sangre , Algoritmos , California , Preescolar , Femenino , Pruebas Genéticas/métodos , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Valor Predictivo de las Pruebas , Prevalencia , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Treatment guidelines provide recommendations but cannot account for the wide variability in patient-tumor characteristics in individual patients. We developed an on-line interactive decision tool to provide expert recommendations for specific patient scenarios in the first-line and maintenance settings for advanced non-small-cell lung cancer. We sought to determine how providing expert feedback would influence clinical decision-making. METHOD: Five lung cancer experts selected treatment for 96 different patient cases based on patient and/or tumor-specific features. These data were used to develop an on-line decision tool. Participant physicians entered variables for their patient scenario with treatment choices, and then received expert treatment recommendations for that scenario. To determine the impact on decision-making, users were asked whether the expert feedback impacted their original plan. RESULTS: A total of 442 individual physicians, of which 88% were from outside the United States, entered 653 cases, with report on impact in 389 cases. Expert feedback affected treatment choice in 73% of cases (23% changed and 50% confirmed decisions). For cases with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion, all experts selected targeted therapy whereas 51% and 58% of participants did not. Greater variability was seen between experts and participants for cases involving EGFR or ALK wild-type tumors. Participants were 2.5-fold more likely to change to expert recommended therapy for ALK fusions than for EGFR mutations (p = 0.017). CONCLUSION: This online tool for treatment decision-making resulted in a positive influence on clinician's decisions. This approach offers opportunities for improving quality of care and meets an educational need in application of new therapeutic paradigms.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Toma de Decisiones , Neoplasias Pulmonares/terapia , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Internet , Neoplasias Pulmonares/patología , TelemedicinaRESUMEN
BACKGROUND: Pravastatin when administered with cyclosporine (CsA) has been shown to ameliorate transplant vasculopathy in the clinical setting. Previously we showed that pravastatin prevents chronic rejection in rat cardiac and liver transplant models. Here we determine whether pravastatin prevents chronic rejection in a rat renal allograft model. METHODS: Orthotopic renal transplantations were performed using Fisher 344 rats as donors and Lewis rats as recipients. Recipients were treated with low-dose CsA for 10 days to prevent acute rejection. Recipients were divided into three groups: CsA, CsA + pravastatin, and syngeneic. Renal function was assessed by serum creatinine level at day 130. Allografts were evaluated by histology and immunohistochemistry. Serum levels of alloantibodies were measured by flow cytometry. Intragraft cytokine mRNA expression was determined by semiquantitative reverse transcriptase-polymerase chain reaction. Intragraft levels of the antiapoptotic Bag-1 gene were measured by Western blot. RESULTS: Unlike allografts from the pravastatin group, control allografts demonstrated glomerulosclerosis, vascular obliteration, tubular atrophy, and interstitial fibrosis. Serum creatinine levels and graft infiltration of T cells and macrophages in the pravastatin-treated animals were significantly lower. Intragraft cytokines showed a T helper 2 polarization and decreased transforming growth factor-beta in the pravastatin group. Intragraft expression of Bag-1 was increased in the pravastatin group. CONCLUSION: This study demonstrates the ability of pravastatin to inhibit chronic rejection in rat renal allografts. Pravastatin's pleiotropic effects of reducing intragraft inflammatory cytokines, inhibiting immune cell infiltration, and causing up-regulation of the antiapoptotic gene Bag-1 suggest that its ability to prevent transplant chronic rejection may be multifactorial.
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Rechazo de Injerto/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Trasplante de Riñón/inmunología , Pravastatina/uso terapéutico , Animales , Proteínas Portadoras/genética , Enfermedad Crónica , Citocinas/biosíntesis , Citocinas/genética , Proteínas de Unión al ADN , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Isoanticuerpos/sangre , Riñón/patología , Riñón/fisiología , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Factores de TranscripciónRESUMEN
Although there are numerous clinical guidelines regarding the management of dementia, there have been few studies on their implementation in practice. Clinicians in six United States Department of Veterans Affairs medical centers (n = 200, 85% response rate) were surveyed regarding their use of practices recommended in the California Workgroup Guidelines for Alzheimer's Disease Management. The majority of providers (89% to 73%) reported that they routinely conducted neurological examinations, obtained histories from caregivers, discussed the diagnosis with the patient's family, discussed durable power of attorney, and made legally-required reports of drivers with dementia. Roughly two-thirds of providers said they routinely conducted cognitive screening examinations, screened for depression, reported elder abuse, and discussed care needs and decision-making issues with patients' families. Only half of all outpatient providers implemented caregiver support practices for at least half of their patients. Clinicians' choices of medications for cognition, mood, and behavior problems were broadly consistent with current practice guidelines. These results suggest possible priorities for quality improvement efforts. Further research is needed to clarify reasons for particular gaps between guidelines and practice and to identify specific targets for intervention.
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Enfermedad de Alzheimer/diagnóstico , Cuidadores , Guías de Práctica Clínica como Asunto , Relaciones Profesional-Familia , Directivas Anticipadas , Anciano , Enfermedad de Alzheimer/terapia , Conducción de Automóvil/legislación & jurisprudencia , Terapia Conductista , California , Cuidadores/educación , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/tratamiento farmacológico , Abuso de Ancianos/legislación & jurisprudencia , Abuso de Ancianos/prevención & control , Femenino , Humanos , Masculino , Tamizaje Masivo , Garantía de la Calidad de Atención de SaludRESUMEN
Little is known about how recent ISTSS practice guidelines (E. B. Foa, T. M. Keane, & M. J. Friedman, 2000) compare with prevailing PTSD treatment practices for veterans. Prior to guideline dissemination, clinicians in 6 VA medical centers were surveyed in 1999 (n = 321) and in 2001 (n = 271) regarding their use of various assessment and treatment procedures. Practices most consistent with guideline recommendations included psychoeducation, coping skills training, attention to trust issues, depression and substance use screening, and prescribing of SSRIs, anticonvulsants, and trazodone. PTSD and trauma assessment, anger management, and sleep hygiene practices were provided less consistently. Exposure therapy was rarely used. Additional research is needed on training, clinical resources, and organizational factors that may influence VA implementation of guideline recommendations.