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Dive into the research topics where Jeffrey T. Chapman is active.

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Featured researches published by Jeffrey T. Chapman.


The New England Journal of Medicine | 2011

Efficacy and safety of sirolimus in lymphangioleiomyomatosis

Francis X. McCormack; Yoshikazu Inoue; Joel Moss; Lianne G. Singer; Charlie Strange; Koh Nakata; Alan F. Barker; Jeffrey T. Chapman; Mark L. Brantly; James M. Stocks; Kevin K. Brown; Joseph P. Lynch; Hilary J. Goldberg; Lisa R. Young; Brent W. Kinder; Gregory P. Downey; Eugene J. Sullivan; Thomas V. Colby; Roy T. McKay; Marsha M. Cohen; Leslie L. Korbee; Angelo M. Taveira-DaSilva; Hye Seung Lee; Jeffrey P. Krischer; Bruce C. Trapnell

BACKGROUND Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. METHODS We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). RESULTS During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. CONCLUSIONS In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).


Annals of Internal Medicine | 2010

Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

Scott M. Palmer; Ajit P. Limaye; Missy Banks; Dianne Gallup; Jeffrey T. Chapman; E. Clinton Lawrence; Jordan M. Dunitz; Aaron Milstone; John V. Reynolds; Gordon L. Yung; Kevin M. Chan; Robert M. Aris; Edward R. Garrity; Vincent G. Valentine; Jonathan McCall; Shein-Chung Chow; R.D. Davis; Robin K. Avery

BACKGROUND Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION Longer-term effects of extended prophylaxis were not assessed. CONCLUSION In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.


The Lancet Respiratory Medicine | 2013

Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial

Lisa R. Young; Hye Seung Lee; Yoshikazu Inoue; Joel Moss; Lianne G. Singer; Charlie Strange; Koh Nakata; Alan F. Barker; Jeffrey T. Chapman; Mark L. Brantly; James M. Stocks; Kevin K. Brown; Joseph P. Lynch; Hilary J. Goldberg; Gregory P. Downey; Jeffrey J. Swigris; Angelo M. Taveira-DaSilva; Jeffrey P. Krischer; Bruce C. Trapnell; Francis X. McCormack

BACKGROUND VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis. METHODS In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes. FINDINGS We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448). INTERPRETATION Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials. FUNDING National Institutes of Health, US Department of Defense.


European Respiratory Journal | 2011

Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis

Debasis Sahoo; Debabrata Bandyopadhyay; Meng Xu; Karla Pearson; Joseph Parambil; C. A. Lazar; Jeffrey T. Chapman; Daniel A. Culver

Leflunomide has been reported as an alternative therapy in sarcoidosis. However, the published data are limited. We performed a retrospective chart review of the tolerance and effects of leflunomide therapy in patients with sarcoidosis. 76 patients were included. The most common reasons for initiation were progression of disease or failure of other immunomodulator therapy. Side-effects attributable to leflunomide were noted in 34% of subjects, prompting discontinuation in 17%. The lungs were a target of therapy in 33 (44%) and extrapulmonary organs were a target in 45 (59%). The mean±sd change in forced vital capacity in the 6 months prior to leflunomide was −0.1±0.3 L, and it was +0.09±0.3 L in the following 6 months (p=0.01). For extrapulmonary target organ response, 51% had a good response and 32% a partial response. The median corticosteroid dose at initiation was 10 mg (interquartile range 5–20) mg at baseline, and 0 (0–10) mg at the 6-month follow-up (p<0.001). Leflunomide is a viable alternative agent for pulmonary and extrapulmonary sarcoidosis. Leflunomide appears to facilitate reduction of steroid dose and can be considered as monotherapy or as add-on therapy in cases of progressive disease.


Lung | 2007

Sleep-Related Breathing Disorders in Patients with Idiopathic Pulmonary Fibrosis

Charalampos Mermigkis; Jeffrey T. Chapman; Joseph A. Golish; Demetrios Mermigkis; Kumaraswamy Budur; Antony Kopanakis; Vlassis Polychronopoulos; Richard C. Burgess; Nancy Foldvary-Schaefer

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually fatal lung disease of unknown etiology. The aim of this study was to describe clinical and polysomnographic features of sleep-related breathing disorders (SRBD) and to identify predictors of obstructive sleep apnea (OSA) in IPF patients. Eight hundred fifty-seven patients with IPF were admitted to the Cleveland Clinic from 2001 to 2005. An all-night polysomnogram (PSG) was performed in 18 of them to investigate complaints suggestive of sleep-disordered breathing. OSA was confirmed in 11 of the 18 IPF patients with complaints suggestive of sleep apnea, while the remain 7 patients had a diagnosis of primary snoring or upper airway resistance syndrome (UARS). All patients showed a reduction in sleep efficiency, REM sleep, and slow wave sleep. The apnea-hypopnea index (AHI) was positively correlated with body mass index (p < 0.0001, r = 0.80). The REM AHI and overall AHI were negatively correlated with FEV1 (p = 0.008, r = −0.59 and p = 0.04, r = −0.49, respectively) and FVC percentages (p = 0.03, r = −0.50 and p = 0.08, r = −0.42, respectively). Our study is the first describing SRBD in IPF patients. An increased BMI and a significant impairment in pulmonary function testing may be predictors of OSA in this population. In the absence of effective treatments for IPF, the diagnosis and treatment of comorbid SRBD may lead to improvements in quality of life.


American Journal of Transplantation | 2005

Clinical utility of cytomegalovirus viral load in bronchoalveolar lavage in lung transplant recipients

Roy F. Chemaly; Belinda Yen-Lieberman; Jeffrey T. Chapman; Amy Reilly; B. Nebiyou Bekele; Steven M. Gordon; Gary W. Procop; Nabin K. Shrestha; Carlos M. Isada; Malcolm M. DeCamp; Robin K. Avery

The utility of cytomegalovirus (CMV) viral load (VL) by quantitative hybrid capture assay (Q‐HCA) was investigated in bronchoalveolar lavage (BAL) from lung transplant recipients and compared with BAL cultures and blood VL. Forty‐three consecutive BAL samples from 27 lung transplant recipients were analyzed. All samples had shell vial (SV) cultures in addition to Q‐HCA. Histopathology was done on all lung tissues, and immunohistochemistry (IHC) in those with positive CMV cultures. Fifteen (56%) lung transplant recipients had both positive BAL SV cultures and BAL VL. Five of 15 had CMV pneumonitis with a VL in BAL >500 000 copies/mL (mean: 1638 450). Ten patients without CMV pneumonitis had VL in BAL <500 000 copies/mL (mean 81 820, p = 0.002). High VL in BAL and blood invariably meant CMV pneumonitis, but 2 patients with CMV pneumonitis had high BAL VL but relatively low blood VL. Initial CMV seronegativity was associated with pneumonitis (4/5 vs. 1/10; p = 0.004) and higher BAL CMV VL (p = 0.03). High CMV BAL or blood VL did not correlate with acute rejection or development of bronchiolitis obliterans syndrome (BOS). High CMV VL in BAL in lung transplant recipients is strongly associated with CMV pneumonitis, and may be more predictive than peripheral blood viral load.


American Journal of Respiratory and Critical Care Medicine | 2016

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management

Francis X. McCormack; Nishant Gupta; Geraldine R. Finlay; Lisa R. Young; Angelo M. Taveira-Da Silva; Connie G. Glasgow; Wendy K. Steagall; Simon R. Johnson; Steven A. Sahn; Jay H. Ryu; Charlie Strange; Kuniaki Seyama; Eugene J. Sullivan; Robert M. Kotloff; Gregory P. Downey; Jeffrey T. Chapman; MeiLan K. Han; Jeanine D'Armiento; Yoshikazu Inoue; Elizabeth P. Henske; John J. Bissler; Thomas V. Colby; Brent W. Kinder; Kathryn A. Wikenheiser-Brokamp; Kevin K. Brown; J.-F. Cordier; Cristopher A. Meyer; Vincent Cottin; Jan Brozek; Karen Smith

BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS After considering the panels confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.


Clinics in Chest Medicine | 2001

EXHALED MONOXIDES AS A PULMONARY FUNCTION TEST: Use of Exhaled Nitric Oxide and Carbon Monoxide

Jeffrey T. Chapman; Augustine M. K. Choi

Although there has been tremendous improvement in the technologic ability to measure exhaled gases and monitor biologic processes in the lung, it has not yet found a clinical role outside the research laboratory. Common themes seem to be significant overlap in the amount of exhaled gases in clinically distinct populations, confounding variables such as infection, smoking, and environmental exposure, and lack of consistent change with disease management. If these tests are ever to be used by the general pulmonologist, consistent links between the measurements and the response to disease modification will need to be demonstrated at the very least and, ideally, the clinician would like to see improved outcomes when these noninvasive tests are employed regularly.


The Journal of Thoracic and Cardiovascular Surgery | 2011

Pretransplant gastroesophageal reflux compromises early outcomes after lung transplantation.

Sudish C. Murthy; Edward R. Nowicki; David P. Mason; Marie Budev; Anthony Nunez; Lucy Thuita; Jeffrey T. Chapman; Kenneth R. McCurry; Gosta Pettersson; Eugene H. Blackstone

OBJECTIVES Gastroesophageal reflux disease (GERD) is implicated as a risk factor for bronchiolitis obliterans syndrome after lung transplantation, but its effects on acute rejection, early allograft function, and survival are unclear. Therefore, we sought to systematically understand the time-related impact of pretransplant GERD on graft function (spirometry), mortality, and acute rejection early after lung transplantation. METHODS From January 2005 to July 2008, 215 patients underwent lung transplantation; 114 had preoperative pH testing, and 32 (28%) had objective evidence of GERD. Lung function was assessed by forced 1-second expiratory volume (FEV(1); percent of predicted) in 97 patients, mortality by follow-up (median, 2.2 years), and acute rejection by transbronchial biopsy. RESULTS Pretransplant GERD was associated with decreased FEV(1) early after lung transplantation (P = .01) such that by 18 months, FEV(1) was 70% of predicted in double lung transplant patients with GERD versus 83% among non-GERD patients (P = .05). A similar decrease was observed in single lung transplantation (50% vs 60%, respectively; P = .09). GERD patients had lower survival early after transplant ( P = .02)-75% versus 90%. Presence of GERD did not affect acute rejection (P = .6). CONCLUSIONS For lung transplant recipients, pretransplant GERD is associated with worse early allograft function and survival, but not increased acute rejection. The compromise in lung function is substantial, such that FEV(1) after double lung transplant in GERD patients approaches that of single lung transplant in non-GERD patients. We advocate thorough testing for GERD before lung transplantation; if identified, aggressive therapy early after transplant, including fundoplication, may prove efficacious.


Annals of the American Thoracic Society | 2017

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis

Calvin Lu; Hye Seung Lee; George P. Pappas; Daniel F. Dilling; Charles D. Burger; Adrian Shifren; Srihari Veeraraghavan; Jeffrey T. Chapman; Joseph Parambil; Stephen J. Ruoss; Lisa R. Young; Stephen R. Hammes; Elizabeth Kopras; Tammy Roads; Jeffrey P. Krischer; Francis X. McCormack

Rationale: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women and can worsen with pregnancy, estrogen treatment, and the menstrual cycle, suggesting an important role for estrogen in disease pathogenesis. Objectives: To assess the efficacy and safety of the aromatase inhibitor letrozole in the treatment of LAM. Methods: Seventeen postmenopausal women with LAM were enrolled in this phase II trial and randomized to receive letrozole 2.5 mg daily (n = 9) or placebo (n = 8) for a period of 12 months. Five patients in each group were also taking sirolimus at baseline and remained on the drug throughout the treatment period. Lung function, exercise capacity, quality of life, and serum vascular endothelial growth factor D (VEGF‐D) were measured at baseline and at 3‐month intervals. Results: Fifteen patients completed the study. Two patients withdrew. There were no differences in adverse events in the letrozole and placebo groups. The target enrollment of 25 patients per arm was not met, so the efficacy of letrozole could not be assessed as planned. After adjusting for sirolimus use, we found that the rate of change in FEV1 for all subjects was ‐3 ± 3 ml/mo (P = 0.4), and for serum VEGF‐D, the rate of change was ‐0.024 ± 0.009 pg/ml/mo (P = 0.015), showing a steeper decline in the letrozole group (‐0.029 ± 0.013; P = 0.025). All patients who were taking sirolimus had a reduction in VEGF‐D levels from baseline to the last visit, compared with only half of the patients who were not taking sirolimus. In a post hoc analysis, eight matched letrozole‐treated‐placebo‐treated pairs were constructed, six of which demonstrated better FEV1 improvement for the letrozole‐treated patients. Conclusions: Letrozole treatment appears to be safe and well tolerated in postmenopausal patients with LAM, including those taking sirolimus. Enrollment in this trial was compromised by the publication of an effective treatment (sirolimus) in the same month as the study opened, resulting in limited power to detect treatment effects. Post hoc matched pairs exploration studies provide tentative support for additional studies of letrozole in LAM. Considering the reduced rate of lung function decline in postmenopausal patients, future studies will likely require enhanced study designs, such as selective enrollment of those with prognostic biomarkers predictive of decline. Clinical trial registered with www.clinicaltrials.gov (NCT01353209).

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Kevin K. Brown

University of Colorado Denver

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Joel Moss

National Institutes of Health

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Charlie Strange

Medical University of South Carolina

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Hye Seung Lee

University of South Florida

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