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1.
Epidemiol Psychiatr Sci ; 29: e157, 2020 Aug 14.
Article in English | MEDLINE | ID: mdl-32792035

ABSTRACT

AIMS: Optimism is associated with reduced cardiovascular disease risk; however, few prospective studies have considered optimism in relation to hypertension risk specifically. We investigated whether optimism was associated with a lower risk of developing hypertension in U.S. service members, who are more likely to develop high blood pressure early in life. We also evaluated race/ethnicity, sex and age as potential effect modifiers of these associations. METHODS: Participants were 103 486 hypertension-free U.S. Army active-duty soldiers (mean age 28.96 years, 61.76% White, 20.04% Black, 11.01% Hispanic, 4.09% Asian, and 3.10% others). We assessed optimism, sociodemographic characteristics, health conditions, health behaviours and depression status at baseline (2009-2010) via self-report and administrative records, and ascertained incident hypertension over follow-up (2010-2014) from electronic health records and health assessments. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and adjusted models for a broad range of relevant covariates. RESULTS: Over a mean follow-up of 3.51 years, 15 052 incident hypertension cases occurred. The highest v. lowest optimism levels were associated with a 22% reduced risk of developing hypertension, after adjusting for all covariates including baseline blood pressure (HR = 0.78; 95% CI = 0.74-0.83). The difference in hypertension risk between the highest v. lowest optimism was also maintained when we excluded soldiers with hypertension in the first two years of follow-up and, separately, when we excluded soldiers with prehypertension at baseline. A dose-response relationship was evident with higher optimism associated with a lower relative risk (p < 0.001). Higher optimism was consistently associated with a lower risk of developing hypertension across sex, age and most race/ethnicity categories. CONCLUSIONS: In a diverse cohort of initially healthy male and female service members particularly vulnerable to developing hypertension, higher optimism levels were associated with reduced hypertension risk independently of sociodemographic and health factors, a particularly notable finding given the young and healthy population. Results suggest optimism is a health asset and a potential target for public health interventions.


Subject(s)
Health Status , Hypertension/epidemiology , Military Personnel/statistics & numerical data , Optimism , Primary Prevention , Adult , Female , Follow-Up Studies , Health Behavior , Humans , Hypertension/prevention & control , Incidence , Male , Middle Aged , Military Personnel/psychology , Outcome Assessment, Health Care , Proportional Hazards Models , Prospective Studies , Risk Factors , United States/epidemiology
2.
Lancet Oncol ; 18(1): 75-87, 2017 01.
Article in English | MEDLINE | ID: mdl-27908594

ABSTRACT

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. FINDINGS: 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. INTERPRETATION: In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. FUNDING: Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Fallopian Tube Neoplasms/drug therapy , Indoles/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Platinum/pharmacology , Aged , Antineoplastic Agents/pharmacology , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Carcinoma, Ovarian Epithelial , Fallopian Tube Neoplasms/genetics , Fallopian Tube Neoplasms/pathology , Female , Follow-Up Studies , Germ-Line Mutation/genetics , Humans , International Agencies , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/pathology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerases/chemistry , Prognosis , Prospective Studies , Salvage Therapy , Survival Rate
3.
Clin Cancer Res ; 22(10): 2386-95, 2016 05 15.
Article in English | MEDLINE | ID: mdl-26747242

ABSTRACT

PURPOSE: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. EXPERIMENTAL DESIGN: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. RESULTS: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. CONCLUSIONS: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation/genetics , Acrylamides/therapeutic use , Adult , Aged , Aged, 80 and over , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Humans , Male , Middle Aged , Mutation/drug effects , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use
5.
Cancer Discov ; 5(7): 713-22, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25934077

ABSTRACT

UNLABELLED: Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required. SIGNIFICANCE: This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms.


Subject(s)
Acrylamides/administration & dosage , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Small Cell Lung Carcinoma/drug therapy , Acrylamides/pharmacology , Cell Line, Tumor , DNA, Neoplasm/blood , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/blood , Gene Amplification , Gene Expression Regulation, Neoplastic , Genetic Heterogeneity , Humans , Lung Neoplasms/blood , Lung Neoplasms/genetics , Mutation , Prospective Studies , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Small Cell Lung Carcinoma/genetics
6.
N Engl J Med ; 372(18): 1700-9, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-25923550

ABSTRACT

BACKGROUND: Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS: In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS: A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS: Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).


Subject(s)
Acrylamides/administration & dosage , Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Acrylamides/adverse effects , Acrylamides/pharmacokinetics , Aged , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , ErbB Receptors/antagonists & inhibitors , Female , Humans , Hyperglycemia/chemically induced , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics
7.
Kidney Int ; 66(4): 1444-52, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15458437

ABSTRACT

BACKGROUND: Experimental autoimmune glomerulonephritis (EAG) was induced in Wistar-Kyoto (WKY) rats by immunization with rat glomerular basement membrane (GBM) in adjuvant. This model is characterized by anti-GBM antibody production, accompanied by focal necrotizing glomerulonephritis with crescent formation. There is also glomerular infiltration by T cells and macrophages. Our hypothesis was that blocking the interaction between CD154 (CD40L) on Th cells and CD40 on antigen-presenting cells should inhibit T-cell activation, and thus the development of EAG. METHODS: The in vivo effects of a hamster anti-rat monoclonal antibody to CD154 (AH.F5) were examined in EAG starting at day -1 prior to immunization, day +7 after immunization, or day +14 after immunization. RESULTS: When administered from day -1 at a dose of 10 mg/kg intraperitoneally three times per week for the duration of the study (4 weeks), AH.F5 resulted in a marked reduction in circulating anti-alpha3(IV)NC1 antibodies, deposits of IgG on the GBM, albuminuria, deposits of fibrin in the glomeruli, severity of glomerular abnormalities, and numbers of glomerular T cells and macrophages. When administered from day +7 at the same dose, AH.F5 resulted in a moderate reduction in the severity of disease, while administration from day +14 had no significant effect. CONCLUSION: These studies demonstrate for the first time that early blockade of the CD154-CD40 T-cell costimulatory pathway can prevent the development of crescentic nephritis, and that delayed treatment can reduce the severity of disease. This confirms the importance of T cell mediated immunity in the pathogenesis of EAG, and suggests that strategies targeting T-cell costimulation may provide a novel approach in the treatment of human glomerulonephritis.


Subject(s)
Anti-Glomerular Basement Membrane Disease/immunology , Anti-Glomerular Basement Membrane Disease/therapy , Antibodies, Monoclonal/pharmacology , CD40 Antigens/immunology , CD40 Ligand/immunology , Albuminuria/immunology , Albuminuria/therapy , Animals , Antibodies/blood , Autoantibodies , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Creatinine/metabolism , Fibrin/metabolism , Fluorescent Antibody Technique, Direct , Immunoglobulin G/blood , Kidney Glomerulus/immunology , Kidney Glomerulus/metabolism , Male , Rats , Rats, Inbred WKY , T-Lymphocytes/immunology
8.
Nephron Exp Nephrol ; 95(3): e100-10, 2003.
Article in English | MEDLINE | ID: mdl-14646362

ABSTRACT

BACKGROUND/AIMS: Integrins are adhesion molecules of fundamental importance to the recruitment of leucocytes in inflammation. The alpha4beta1 integrin (VLA-4) is a leucocyte ligand for endothelial vascular cell adhesion molecule-1 (VCAM-1), fibronectin and osteopontin. We addressed the role of VLA-4 in mediating progressive renal injury in vivo using a blocking monoclonal antibody (mAb) in a rat model of crescentic glomerulonephritis. METHODS: WKY rats with nephrotoxic nephritis were given anti-VLA-4 or control mAb at 2.5 mg/kg by i.p. injection on alternate days. In separate experiments, antibodies were given from days 5-13, from days 13-21 or from days 14-28. RESULTS: Early treatment with anti-VLA-4 mAb from days 5-13 showed a significant effect on renal function, with a reduction in albuminuria (p < 0.01) and a higher creatinine clearance (p < 0.05). Delayed treatment from days 13-21 also showed a reduction in albuminuria (p < 0.05) and serum creatinine (p < 0.05). However, there was no significant effect on glomerular or interstitial scarring in these two experiments. In the late treatment study, in which anti-VLA-4 mAb was administered from days 14-28, serum creatinine was reduced (p < 0.05), creatinine clearance was improved (p < 0.05), and renal survival was significantly prolonged (p < 0.05). Interstitial scarring was significantly less in treated rats (p < 0.05). Glomerular macrophage and CD8+ cell counts were higher in anti-VLA-4 mAb treated rats (p < 0.05), possibly reflecting greater glomerular scarring in control animals. CONCLUSION: Leucocyte VLA-4 mediates pro-inflammatory and pro-fibrotic effects within the kidney, independent of any role in recruitment of leucocytes into the kidney. Blocking VLA-4 is a promising therapeutic approach in human glomerulonephritis.


Subject(s)
Anti-Glomerular Basement Membrane Disease/prevention & control , Integrin alpha4beta1/antagonists & inhibitors , Integrin alpha4beta1/physiology , Albuminuria/metabolism , Animals , Anti-Glomerular Basement Membrane Disease/pathology , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/therapeutic use , Basement Membrane/immunology , Basement Membrane/pathology , Cicatrix/prevention & control , Creatinine/blood , Creatinine/metabolism , Creatinine/urine , Drug Administration Schedule , Immune Sera/adverse effects , Immune Sera/metabolism , Immunoglobulin G/blood , Immunoglobulin G/metabolism , Immunoglobulin G/therapeutic use , Integrin alpha4beta1/immunology , Kidney Glomerulus/immunology , Kidney Glomerulus/pathology , Rabbits , Rats , Rats, Inbred WKY
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