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1.
Clin Cancer Res ; 29(20): 4268-4277, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37566222

RESUMO

PURPOSE: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction has led to durable responses in fewer than half of patients with mismatch repair-deficient (MMR-d) advanced colorectal cancers. Immune contexture, including spatial distribution of immune cells in the tumor microenvironment (TME), may predict immunotherapy outcome. EXPERIMENTAL DESIGN: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence (mIF) in primary colorectal cancers with d-MMR (N = 33) from patients treated with anti-PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFßR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS). RESULTS: For predicting survival among patients with MMR-d advanced colorectal cancer receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1+ cells within 10 µm of a PD-L1+ cell was significantly predictive of PFS. Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (>83 months) vs. 8.5 months (95% confidence interval (95% CI), 4.7-NR)] with a median PFS of 28.4 months for all patients [adjusted HR (HRadj) = 0.14; 95% CI, 0.04-0.56; P = 0.005]. Expression of PD-1 was observed on CD8+ T cells; PD-L1 on CD3+ and CD8+ T lymphocytes, macrophages (CD68+), and tumor cells. CONCLUSIONS: In d-MMR colorectal cancers, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Reparo de Erro de Pareamento de DNA/genética , Ligantes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Biomarcadores Tumorais , Microambiente Tumoral/genética
2.
ACS Cent Sci ; 9(4): 685-695, 2023 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-37122463

RESUMO

Protein-polymer conjugates are widely used in many clinical and industrial applications, but lack of experimental data relating protein-polymer interactions to improved protein stability prevents their rational design. Advances in synthetic chemistry have expanded the palette of polymer designs, including development of nonlinear architectures, novel monomer chemical scaffolds, and control of hydrophobicity, but more experimental data are needed to transform advances in chemistry into next generation conjugates. Using an integrative biophysical approach, we investigated the molecular basis for polymer-based thermal stabilization of a human galectin protein, Gal3C, conjugated with polymers of linear and nonlinear architectures, different degrees of polymerization, and varying hydrophobicities. Independently varying the degree of polymerization and polymer architecture enabled delineation of specific polymer properties contributing to improved protein stability. Insights from NMR spectroscopy of the polymer-conjugated Gal3C backbone revealed patterns of protein-polymer interactions shared between linear and nonlinear polymer architectures for thermally stabilized conjugates. Despite large differences in polymer chemical scaffolds, protein-polymer interactions resulting in thermal stabilization appear conserved. We observed a clear relation between polymer length and protein-polymer thermal stability shared among chemically different polymers. Our data indicate a wide range of polymers may be useful for engineering conjugate properties and provide conjugate design criteria.

4.
BMJ Open ; 12(12): e066288, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36456017

RESUMO

OBJECTIVES: To quantify the effect of the COVID-19 pandemic on the timeliness of, and geographical and sociodemographic inequalities in, receipt of first measles, mumps and rubella (MMR) vaccination. DESIGN: Longitudinal study using primary care electronic health records. SETTING: 285 general practices in North East London. PARTICIPANTS: Children born between 23 August 2017 and 22 September 2018 (pre-pandemic cohort) or between 23 March 2019 and 1 May 2020 (pandemic cohort). MAIN OUTCOME MEASURE: Receipt of timely MMR vaccination between 12 and 18 months of age. METHODS: We used logistic regression to estimate the ORs (95% CIs) of receipt of a timely vaccination adjusting for sex, deprivation, ethnic background and Clinical Commissioning Group. We plotted choropleth maps of the proportion receiving timely vaccinations. RESULTS: Timely MMR receipt fell by 4.0% (95% CI: 3.4% to 4.6%) from 79.2% (78.8% to 79.6%) to 75.2% (74.7% to 75.7%) in the pre-pandemic (n=33 226; 51.3% boys) and pandemic (n=32 446; 51.4%) cohorts, respectively. After adjustment, timely vaccination was less likely in the pandemic cohort (0.79; 0.76 to 0.82), children from black (0.70; 0.65 to 0.76), mixed/other (0.77; 0.72 to 0.82) or with missing (0.77; 0.74 to 0.81) ethnic background, and more likely in girls (1.07; 1.03 to 1.11) and those from South Asian backgrounds (1.39; 1.30 to 1.48). Children living in the least deprived areas were more likely to receive a timely MMR (2.09; 1.78 to 2.46) but there was no interaction between cohorts and deprivation (Wald statistic: 3.44; p=0.49). The proportion of neighbourhoods where less than 60% of children received timely vaccination increased from 7.5% to 12.7% during the pandemic. CONCLUSIONS: The COVID-19 pandemic was associated with a significant fall in timely MMR receipt and increased geographical clustering of measles susceptibility in an area of historically low and inequitable MMR coverage. Immediate action is needed to avert measles outbreaks and support primary care to deliver timely and equitable vaccinations.


Assuntos
COVID-19 , Sarampo , Caxumba , Rubéola (Sarampo Alemão) , Masculino , Criança , Feminino , Humanos , Caxumba/epidemiologia , Caxumba/prevenção & controle , Pandemias , COVID-19/epidemiologia , COVID-19/prevenção & controle , Estudos Longitudinais , Registros Eletrônicos de Saúde , Londres/epidemiologia , Rubéola (Sarampo Alemão)/epidemiologia , Rubéola (Sarampo Alemão)/prevenção & controle , Sarampo/epidemiologia , Sarampo/prevenção & controle , Vacinação
5.
BJGP Open ; 6(4)2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36028299

RESUMO

BACKGROUND: Patients with both atrial fibrillation (AF) and cardiovascular disease (CVD) may receive dual antithrombotic therapy (DAT) with both an anticoagulant and ≥1 antiplatelet agents. Avoiding prolonged duration of DAT and use of gastroprotective therapies reduces bleeding risk. AIM: To describe the extent and duration of DAT and use of gastroprotection in a primary care cohort of patients with AF. DESIGN & SETTING: Observational study in 1.2 million people registered with GPs across four east London clinical commissioning groups (CCGs), covering prescribing from January 2020-June 2021. METHOD: In patients with AF, factors associated with DAT prescription, prolonged DAT prescription (>12 months), and gastroprotective prescription were characterised using logistic regression. RESULTS: There were 8881 patients with AF, of whom 4.7% (n = 416) were on DAT. Of these, 65.9% (n = 274) were prescribed DAT for >12 months and 84.4% (n = 351) were prescribed concomitant gastroprotection. Independent of all other factors, females with AF were less likely to receive DAT than males (odds ratio [OR] 0.61, 95% confidence interval [CI] = 0.49 to 0.77). Similarly, older (aged ≥75 years) individuals (OR 0.79, 95% CI = 0.63 to 0.98) were less likely to receive DAT than younger patients. Among those with AF on DAT, pre-existing CVD (OR 3.33, 95% CI = 1.71 to 6.47) and South Asian ethnicity (OR 2.70, 95% CI = 1.15 to 6.32) were associated with increased gastroprotection prescriptions. Gastroprotection prescription (OR 1.80, 95% CI = 1.01 to 3.22) was associated with prolonged DAT prescription. CONCLUSION: Almost two-thirds of patients with AF on DAT were prescribed prolonged durations of therapy. Prescription of gastroprotection therapies was suboptimal in one in six patients. Treatment decisions varied by sex, age, ethnic group, and comorbidity. Duration of DAT and gastroprotection in patients with AF requires improvement.

6.
Br J Gen Pract ; 72(724): e773-e779, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35995578

RESUMO

BACKGROUND: Despite well-documented clinical benefits of longitudinal doctor-patient continuity in primary care, continuity rates have declined. Assessment by practices or health commissioners is rarely undertaken. AIM: Using the Usual Provider of Care (UPC) score this study set out to measure continuity across 126 practices in the mobile, multi-ethnic population of East London, comparing these scores with the General Practice Patient Survey (GPPS) responses to questions on GP continuity. DESIGN AND SETTING: A retrospective, cross-sectional study in all 126 practices in three East London boroughs. METHOD: The study population included patients who consulted three or more times between January 2017 and December 2018. Anonymised demographic and consultation data from the electronic health record were linked to results from Question 10 ('seeing the doctor you prefer') of the 2019 GPPS. RESULTS: The mean UPC score for all 126 practices was 0.52 (range 0.32 to 0.93). There was a strong correlation between practice UPC scores measured in the 2 years to December 2018 and responses to the 2019 GPPS Question 10, Pearson's r correlation coefficient, 0.62. Smaller practices had higher scores. Multilevel analysis showed higher continuity for patients ≥65 years compared with children and younger adults (ß coefficient 0.082, 95% confidence interval = 0.080 to 0.084) and for females compared with males. CONCLUSION: It is possible to measure continuity across all practices in a local health economy. Regular review of practice continuity rates can be used to support efforts to increase continuity within practice teams. In turn this is likely to have a positive effect on clinical outcomes and on satisfaction for both patients and doctors.


Assuntos
Continuidade da Assistência ao Paciente , Medicina Geral , Adulto , Masculino , Criança , Feminino , Humanos , Estudos Transversais , Estudos Retrospectivos , Dados de Saúde Coletados Rotineiramente , Satisfação do Paciente
7.
Heart ; 107(15): 1220-1225, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34016698

RESUMO

OBJECTIVE: The Familial Hypercholesterolaemia Case Ascertainment Tool (FAMCAT) has been proposed to enhance case finding in primary care. In this study, we test application of the FAMCAT algorithm to describe risks of familial hypercholesterolaemia (FH) in a large unselected and ethnically diverse primary care cohort. METHOD: We studied patients aged 18-65 years from three contiguous areas in inner London. We retrospectively applied the FAMCAT algorithm to routine primary care data and estimated the numbers of possible cases of FH and the potential service implications of subsequent investigation and management. RESULTS: Of the 777 128 patients studied, the FAMCAT score estimated between 11 736 and 23 798 (1.5%-3.1%) individuals were likely to have FH, depending on an assumed FH prevalence of 1 in 250 or 1 in 500, respectively. There was over-representation of individuals of South Asian ethnicity among those likely to have FH, with this cohort making up 41.9%-45.1% of the total estimated cases, a proportion which significantly exceeded their 26% representation in the study population. CONCLUSIONS: We have demonstrated feasibility of application of the FAMCAT as an aid to case finding for FH using routinely recorded primary care data. Further research is needed on validity of the tool in different ethnic groups and more refined consideration of family history should be explored. While FAMCAT may aid case finding, implementation requires information on the cost-effectiveness of additional health services to investigate, diagnose and manage case ascertainment in those identified as likely to have FH.

8.
Australas J Dermatol ; 62(3): 331-335, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34004028

RESUMO

This is the largest study of Aboriginal and Torres Strait Islander dermatologic presentations to an urban specialist clinic within a community-controlled health organisation. It adds to our understanding of Aboriginal and Torres Strait Islander dermatoepidemiology. Patient files were reviewed over the five-year audit period, with age, gender, Indigenous status, diagnosis, disease category, 'new' or 'review consultation' and 'did not attend' (DNA) data recorded. Our study shows that eczema and benign, pre-malignant or malignant neoplasms are the most common presentations for urban Aboriginal and Torres Strait Islander patients. Lupus erythematosus and cutaneous infections were less prominent in comparison to data from rural and remote populations. Overall, a broad casemix of dermatologic presentations was observed. Similar to other studies, adult male patients were under-represented. Most skin malignancies were diagnosed in this cohort; this, therefore, identifies a possible target for public health intervention. A high ratio of new to review patients is consistent with the clinic offering a consultation model of care facilitated by primary health-care providers' support within Aboriginal Community-Controlled Health Service. DNA rates in this study were lower than hospital outpatient rates in a comparative study and may be attributed to specialist dermatology care being offered in a more culturally sensitive environment. The dermatology clinic at the Victorian Aboriginal Health Services (VAHS) provides a good breadth of specialist dermatology care. The community health-care model could be replicated in centres elsewhere, including interstate, to help overcome barriers to specialist dermatology care experienced by Aboriginal and Torres Strait Islander populations. Additionally, this model improves trainee exposure and understanding of Aboriginal and Torres Strait Islander health.


Assuntos
Serviços de Saúde do Indígena/organização & administração , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Conhecimento do Paciente sobre a Medicação/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Serviços Urbanos de Saúde/organização & administração , Vitória/epidemiologia
10.
J Thorac Oncol ; 16(2): 259-268, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33334571

RESUMO

INTRODUCTION: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study. METHODS: A total of 303 treatment-naive patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary end point is investigator-assessed PFS. Secondary end points of interest are objective response rate and duration. RESULTS: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (n = 203, 67%) (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.25-0.56; p < 0.0001) and ALK IHC-positive and FISH-uninformative tumors (n = 61, 20%) (HR = 0.39, 95% CI: 0.20-0.78) but not in ALK IHC-positive and FISH-negative tumors (n = 39, 13%) (HR = 1.33, 95% CI: 0.6-3.2). Objective response rates were higher with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (90.6% versus 81.4%; stratified OR = 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive and FISH-uninformative tumors (96.0% versus 75.0%; OR = 9.29, 95% CI: 1.05-81.88) but not in ALK IHC-positive and FISH-negative tumors (28.6% versus 44.4%; OR = 0.45, 95% CI: 0.12-1.74). Next-generation sequencing was performed in 35 of 39 patients with ALK IHC-positive and FISH-negative tumors; no ALK fusion was identified in 20 of 35 patients (57.1%) by next-generation sequencing, but 10 of 20 (50.0%) had partial response or stable disease. CONCLUSIONS: Outcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.


Assuntos
Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Estudos Retrospectivos
11.
Br J Gen Pract ; 71(702): e31-e38, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33257461

RESUMO

BACKGROUND: Missed appointments are common in primary care, contributing to reduced clinical capacity. NHS England has estimated that there are 7.2 million missed general practice appointments annually, at a cost of £216 million. Reducing these numbers is important for an efficient primary care sector. AIM: To evaluate the impact of a system-wide quality improvement (QI) programme on the rates of missed GP appointments, and to identify effective practice interventions. DESIGN AND SETTING: Practices within a clinical commissioning group (CCG) in East London, with an ethnically diverse and socially deprived population. METHOD: Study practices engaged in a generic QI programme, which included sharing data on appointment systems and Did Not Attend (DNA) rates. Fourteen out of 25 practices implemented DNA reduction projects, supported by practice-based coaching. Appointment data were collected from practice electronic health records. Evaluation included comparisons of DNA rates pre- and post-intervention using interrupted times series analysis. RESULTS: In total, 25 out of 32 practices engaged with the programme. The mean DNA rate at baseline was 7% (range 2-12%); 2 years later the generic intervention DNA rates were 5.2%. This equates to a reduction of 4030 missed appointments. The most effective practice intervention was to reduce the forward booking time to 1 day. The practice that made this change reduced its mean DNA rate from 7.8% to 3.9%. CONCLUSION: Forward booking time in days is the best predictor of practice DNA rates. Sharing appointment data produced a significant reduction in missed appointments, and behaviour change interventions with patients had a modest additional impact; in contrast, introducing structural change to the appointment system effectively reduced DNA rates. To reduce non-attendance, it appears that the appointment system needs to change, not the patient.


Assuntos
Medicina Geral , Melhoria de Qualidade , Agendamento de Consultas , Inglaterra , Humanos , Londres
12.
J Psychosom Res ; 139: 110267, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33069050

RESUMO

OBJECTIVE: Investigate the association of dispositional optimism with chronic kidney disease (CKD) and rapid kidney function decline (RKFD) and determine if there is modification by age, sex, and educational attainment among African Americans. METHODS: Optimism was measured using the 6-item Life Orientation Test-Revised scale (categorized into tertiles and log transformed) among participants from the Jackson Heart Study (n = 1960). CKD was defined as the presence of albuminuria or reduced glomerular filtration rate of <60 mL/min/1.73m2, or report of dialysis at baseline examination (2000-2004). RKFD was defined as a decline >3 mL/min/1.73m2/year between baseline and exam 3 (2009-2013). The cross-sectional and prospective associations between optimism and kidney outcomes were tested using multivariable logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI), adjusting for demographics, education, risk factors, behaviors, and depressive symptoms. We tested effect modification by age, sex, and education. RESULTS: 569 participants had CKD and 326 were classified as having RKFD by exam 3. After full adjustment, the OR for CKD was 0.73 for those who reported high (vs. low) optimism (95% CI 0.55-0.99) and 0.56 (95% CI 0.27-1.15) for the optimism score. After 7.21 median years of follow up, the OR for RKFD was 0.51 for those who reported high (vs. low) optimism (95% CI 0.34-0.76), and 0.26 (95% CI 0.10-0.56) for the optimism score, after full adjustment. There was no evidence of effect modification by demographics or educational attainment. CONCLUSIONS: Higher optimism was associated with a lower odds of CKD and a lower odds of RKFD.


Assuntos
Rim/patologia , Otimismo/psicologia , Insuficiência Renal Crônica/psicologia , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
13.
Br J Gen Pract ; 70(699): e696-e704, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895242

RESUMO

BACKGROUND: The first wave of the London COVID-19 epidemic peaked in April 2020. Attention initially focused on severe presentations, intensive care capacity, and the timely supply of equipment. While general practice has seen a rapid uptake of technology to allow for virtual consultations, little is known about the pattern of suspected COVID-19 presentations in primary care. AIM: To quantify the prevalence and time course of clinically suspected COVID-19 presenting to general practices, to report the risk of suspected COVID-19 by ethnic group, and to identify whether differences by ethnicity can be explained by clinical data in the GP record. DESIGN AND SETTING: Cross-sectional study using anonymised data from the primary care records of approximately 1.2 million adults registered with 157 practices in four adjacent east London clinical commissioning groups. The study population includes 55% of people from ethnic minorities and is in the top decile of social deprivation in England. METHOD: Suspected COVID-19 cases were identified clinically and recorded using SNOMED codes. Explanatory variables included age, sex, self-reported ethnicity, and measures of social deprivation. Clinical factors included data on 16 long-term conditions, body mass index, and smoking status. RESULTS: GPs recorded 8985 suspected COVID-19 cases between 10 February and 30 April 2020.Univariate analysis showed a two-fold increase in the odds of suspected COVID-19 for South Asian and black adults compared with white adults. In a fully adjusted analysis that included clinical factors, South Asian patients had nearly twice the odds of suspected infection (odds ratio [OR] = 1.93, 95% confidence interval [CI] = 1.83 to 2.04). The OR for black patients was 1.47 (95% CI = 1.38 to 1.57). CONCLUSION: Using data from GP records, black and South Asian ethnicity remain as predictors of suspected COVID-19, with levels of risk similar to hospital admission reports. Further understanding of these differences requires social and occupational data.


Assuntos
Infecções por Coronavirus , Etnicidade/estatística & dados numéricos , Medicina Geral/métodos , Pandemias , Pneumonia Viral , Atenção Primária à Saúde/estatística & dados numéricos , Betacoronavirus , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/etnologia , Diagnóstico Diferencial , Feminino , Disparidades nos Níveis de Saúde , Humanos , Londres/epidemiologia , Masculino , Registros Médicos Orientados a Problemas/estatística & dados numéricos , Pessoa de Meia-Idade , Saúde das Minorias/estatística & dados numéricos , Múltiplas Afecções Crônicas/epidemiologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/etnologia , Prevalência , Fatores de Risco , SARS-CoV-2
14.
J Thorac Oncol ; 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34756882

RESUMO

INTRODUCTION: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in-situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive non-small-cell lung cancer (NSCLC) in the ALEX study. METHODS: 303 treatment-naïve patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary endpoint: investigator-assessed PFS. Secondary endpoints of interest: objective response rate (ORR) and duration. RESULTS: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors (n = 203, 67%) (HR 0.37, 95% CI: 0.25-0.56) and ALK IHC-positive/FISH-uninformative tumors (n = 61, 20%) (HR 0.39, 95% CI: 0.20-0.78), but not ALK IHC-positive/FISH-negative tumors (n = 39, 13%) (HR 1.33, 95% CI: 0.6-3.2). ORRs were higher with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors 90.6% versus 81.4%; stratified odds ratio [OR] 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive/FISH-uninformative tumors (96.0% versus 75.0%; OR 9.29, 95% CI: 1.05-81.88), but not ALK IHC-positive/FISH-negative tumors (28.6% versus 44.4%; OR 0.45, 95% CI: 0.12-1.74). Next-generation sequencing (NGS) was performed in 35/39 patients with ALK IHC-positive/FISH-negative tumors; no ALK fusion was identified in 20/35 (57.1%) patients by NGS, but 10/20 (50.0%) had partial response/stable disease. CONCLUSION: Outcomes of patients with ALK IHC-positive/FISH-positive and ALK IHC-positive/FISH-uninformative NSCLC were similar to the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.

15.
J Thorac Oncol ; 12(5): 804-813, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28147239

RESUMO

INTRODUCTION: The availability of high-quality, rigorously validated diagnostic tests that can be broadly implemented is necessary to efficiently identify patients with anaplastic lymphoma kinase (ALK)-positive NSCLC who can potentially benefit from treatment with crizotinib. Here we present data on the recently approved Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ), the only immunohistochemistry (IHC)-based assay linked to treatment outcome. METHODS: NSCLC specimens prospectively tested for anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by flourescent in situ hybridization (FISH) in the PROFILE 1014 clinical trial of crizotinib versus chemotherapy (N = 1018, including 179 ALK-positive and 754 ALK-negative specimens) were evaluated using the ALK (D5F3) CDx assay. Hazard ratios for progression-free survival comparing crizotinib and chemotherapy for ALK IHC-positive patients and ALK FISH-positive patients, as well as for concordance with the enrollment ALK FISH assay, were determined. RESULTS: Results from both assays were obtained for 933 cases. Percent positive, negative, and overall agreement rates were 86.0% , 96.3%, and 94.3%, respectively. There were 53 discrepant cases, of which 25 were ALK FISH-positive/ALK IHC-negative and 28 were ALK FISH-negative/ALK IHC-positive. The hazard ratios using observed outcomes were 0.401 for ALK FISH-positive/ALK IHC-positive cases and 0.407 for all ALK FISH-positive cases tested with ALK IHC versus 0.454 for all ALK FISH-positive cases enrolled in the trial. Outcome data for ALK FISH-negative/ALK IHC-positive cases were not available for analysis. Between-reader agreement rates for ALK IHC involving three independent laboratories exceeded 98%. CONCLUSIONS: The ALK (D5F3) CDx assay is a stand-alone companion diagnostic test for identification of patients for treatment with crizotinib. This automated assay provides an effective option to accurately and rapidly identify patients with ALK-positive NSCLC. The simple binary scoring algorithm results in high reader-to-reader precision.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico , Crizotinibe , Intervalo Livre de Doença , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Seleção de Pacientes , Reprodutibilidade dos Testes , Resultado do Tratamento
16.
Am J Community Psychol ; 54(3-4): 316-27, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25213395

RESUMO

Families play an important role in the lives of individuals with mental illness. Coping with the strain of shifting roles and multiple challenges of caregiving can have a huge impact. Limited information exists regarding race-related differences in families' caregiving experiences, their abilities to cope with the mental illness of a loved one, or their interactions with mental health service systems. This study examined race-related differences in the experiences of adults seeking to participate in the National Alliance on Mental Illness Family-to-Family Education Program due to mental illness of a loved one. Participants were 293 White and 107 African American family members who completed measures of problem- and emotion-focused coping, knowledge about mental illness, subjective illness burden, psychological distress, and family functioning. Multiple regression analyses were used to determine race-related differences. African American caregivers reported higher levels of negative caregiving experiences, less knowledge of mental illness, and higher levels of both problem-solving coping and emotion-focused coping, than White caregivers. Mental health programs serving African American families should consider targeting specific strategies to address caregiving challenges, support their use of existing coping mechanisms and support networks, and increase their knowledge of mental illness.


Assuntos
Adaptação Psicológica , Negro ou Afro-Americano/psicologia , Cuidadores/psicologia , Família/psicologia , Transtornos Mentais/enfermagem , Estresse Psicológico/psicologia , População Branca/psicologia , Adulto , Depressão/psicologia , Relações Familiares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Child Youth Serv Rev ; 33(11): 2253-2260, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22628903

RESUMO

Mental health service underutilization among African American adolescents is well documented, yet not fully understood. Discordance between adolescents and their parents on perceived need for seeing a counselor for an emotional need or psychiatrist for psychiatric or medical services may help explain low service use among this population. This exploratory, prospective study examined the relationship between parent-adolescent concordance on perceived need for emotional counseling or psychiatric services and mental health service use. The relationships between gender and perceived service need and concordance and adolescent severity of depressive symptoms were also explored. Parent-adolescent dyads (n=108) receiving community-based adolescent outpatient mental health services responded to interview questions concerning their perception of whether an emotional counselor and a psychiatrist were needed in the past six months. Findings revealed low parent-adolescent concordance on perceived need for an emotional counselor and a psychiatrist. A greater proportion of adolescents reported a need than parents. There was no association between gender and perceived need for an emotional counselor and a psychiatrist. Lower rates of parent-adolescent concordance were found among youth reporting elevated depressive symptoms compared to youth reporting normal range symptoms. Concordant dyads kept a higher number of appointments than discordant dyads. Implications for clinical social work practice and future research are discussed.

18.
Physiother Theory Pract ; 25(7): 516-22, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19925174

RESUMO

Six-minute walk distance (6MWD) is commonly used as a measure of functional exercise capacity in clinical practice and research. Regression equations to predict 6MWD in healthy individuals are available, but the equations predict distances that vary considerably for an individual. The aims of this study were to 1) measure 6MWDs in healthy Caucasian Australians aged 45-85 years; 2) determine whether evidence exists for Australian-specific prediction equations for Caucasian individuals by comparing measured 6MWDs with predicted 6MWDs derived by using published regression equations; and 3) develop regression equations for males and females. One hundred nine subjects (48 males) completed the 6-minute walk test (6MWT). Measurements of height, leg length, weight, habitual physical activity, and peak heart rate (HR) achieved during the 6MWT were obtained. 6MWD (better of two tests) was 682 +/- 73 m (mean +/- SD) and 643 +/- 70 m in the males and females, respectively (p<0.01). Published regression equations underestimated 6MWDs in female subjects. Gender-specific regression equations using age and anthropometric data explained 40% and 43% of the variance in 6MWD in males and females, respectively. Validation of the regression equations in a prospective subject cohort is required.


Assuntos
Teste de Esforço , Caminhada/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores Sexuais , População Branca
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