89 results on '"David K. Madtes"'
Search Results
2. Clinical Impact and Generalizability of a Computer-Assisted Diagnostic Tool to Risk-Stratify Lung Nodules With CT
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Scott J, Adams, David K, Madtes, Brent, Burbridge, Josiah, Johnston, Ilya G, Goldberg, Eliot L, Siegel, Paul, Babyn, Viswam S, Nair, and Michael E, Calhoun
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Radiology, Nuclear Medicine and imaging - Abstract
To evaluate whether an imaging classifier for radiology practice can improve lung nodule classification and follow-up.A machine learning classifier was developed and trained using imaging data from the National Lung Screening Trial (NSLT) to produce a malignancy risk score (malignancy Similarity Index [mSI]) for individual lung nodules. In addition to NLST cohorts, external cohorts were developed from a tertiary referral lung cancer screening program data set and an external nonscreening data set of all nodules detected on CT. Performance of the mSI combined with Lung-RADS was compared with Lung-RADS alone and the Mayo and Brock risk calculators.We analyzed 963 subjects and 1,331 nodules across these cohorts. The mSI was comparable in accuracy (area under the curve = 0.89) to existing clinical risk models (area under the curve = 0.86-0.88) and independently predictive in the NLST cohort of 704 nodules. When compared with Lung-RADS, the mSI significantly increased sensitivity across all cohorts (25%-117%), with significant increases in specificity in the screening cohorts (17%-33%). When used in conjunction with Lung-RADS, use of mSI would result in earlier diagnoses and reduced follow-up across cohorts, including the potential for early diagnosis in 42% of malignant NLST nodules from prior-year CT scans.A computer-assisted diagnosis software improved risk classification from chest CTs of screening and incidentally detected lung nodules compared with Lung-RADS. mSI added predictive value independent of existing radiological and clinical variables. These results suggest the generalizability and potential clinical impact of a tool that is straightforward to implement in practice.
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- 2023
3. Transforming Growth Factor-α and Epidermal Growth Factor
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David K. Madtes
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- 2022
4. Multidisciplinary Team-Based Management of Incidentally Detected Lung Nodules
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Sudhakar Pipavath, Megan E. Zadworny, Francys C. Verdial, Guang-Shing Cheng, Farhood Farjah, David K. Madtes, Richard Kim, Jesse J. Hubbard, and Douglas E. Wood
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Male ,Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,Lung Neoplasms ,Critical Care and Intensive Care Medicine ,Multidisciplinary team ,Risk Assessment ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary approach ,Early Medical Intervention ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Medical diagnosis ,Lung cancer ,Early Detection of Cancer ,Original Research ,Patient Care Team ,Health Services Needs and Demand ,Incidental Findings ,Lung ,business.industry ,Solitary Pulmonary Nodule ,Nodule (medicine) ,Middle Aged ,medicine.disease ,United States ,medicine.anatomical_structure ,030228 respiratory system ,Practice Guidelines as Topic ,Female ,Guideline Adherence ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Cohort study - Abstract
Background Each year, > 1.5 million Americans are diagnosed with an incidentally detected lung nodule. Practice guidelines attempt to balance the benefit of early detection of lung cancer with the risks of diagnostic testing, but adherence to guidelines is low. The goal of this study was to determine guideline adherence rates in the setting of a multidisciplinary nodule clinic and describe reasons for nonadherence as well as associated outcomes. Methods This cohort study included 3 years of follow-up of patients aged ≥ 35 years with an incidentally detected lung nodule evaluated in a multidisciplinary clinic that used the 2005 Fleischner Society Guidelines. Results Among 113 patients, 67% (95% CI, 58-76) were recommended a guideline-concordant nodule evaluation; 7.1% (95% CI, 3.1-13) and 26% (95% CI, 18-25) were recommended less or more intense evaluation, respectively. In contrast, 58% (95% CI, 48-67), 22% (95% CI, 18-25), and 23% (95% CI, 16-32) received a guideline-concordant, less intense, or more intense evaluation. The most common reason for recommending guideline-discordant care was concern for two different diagnoses that would each benefit from early detection and treatment. A majority of lung cancer diagnoses (88%) occurred in patients who received guideline-concordant care. There were no lung cancer cases in those who received less intense nodule care. Conclusions A multidisciplinary nodule clinic may serve as a system-level intervention to promote guideline-concordant care, while also providing a multidisciplinary basis by which to deviate from guidelines to address the needs of a heterogeneous patient population.
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- 2020
5. Partnership with Interventional Pulmonologist
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Wendy M. Suhre, David K. Madtes, John D. Lang, and Basem Abdelmalak
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Sedation ,Pulmonologist ,General Medicine ,medicine.disease ,Interventional pulmonology ,03 medical and health sciences ,0302 clinical medicine ,Otorhinolaryngology ,Bronchoscopy ,030220 oncology & carcinogenesis ,Anesthesiology ,General partnership ,medicine ,Medical emergency ,medicine.symptom ,030223 otorhinolaryngology ,business ,Medicaid ,Pulmonologists - Abstract
Via the emergence of new bronchoscopic technologies and techniques, there is enormous growth in the number of procedures being performed in nonoperating room settings. This, coupled with a greater focus from the Centers for Medicare and Medicaid Services for mandated anesthesiology oversight of procedural sedation for bronchoscopy by the pulmonologists has led to a more frequent working partnership between interventional pulmonologists and anesthesiologists. This article offers the interventional pulmonologist insight into how the anesthesiologist thinks and approaches anesthetic care delivery.
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- 2019
6. Assessment of Plasma Proteomics Biomarker’s Ability to Distinguish Benign From Malignant Lung Nodules
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Z. Hammoud, J. Ma, L. Wilkins, L. DeSouza, T. Deluca, K. Voelker, A. Muterspaug, A. Chesnutt, J. Lamberti, D. Midthun, L. Murdoch, Nichole T. Tanner, W. McConnell, Peter J. Mazzone, L. Jacques, R. Murali, L. Leake, W. Krimsky, Kenneth C. Fang, E. Kuo, B. Dimitt, A. Levesque, K. Robinson, A. Lackey, B. Fortin, A. Pierre, G.A. Silvestri, A. Case, F. Allison, L. Yarmus, A. Sorenson, J. Sanchez, S. King, L. Carter, Steven C. Springmeyer, David K. Madtes, N. Tanner, J. Leach, P. Mazzone, P. McCarthy, J. Fisher, K. Oakjones-Burgess, R. Aronson, A. Overton, N. Desai, J.M. Ayers, D. Kah, F. Laberge, B. Sigal, P. Massion, A. Balekian, K. Maletteri, H. Barrentine, Paul Kearney, A. Georgeson, M. Henderson, Gerard A. Silvestri, J. Hubbard, C. Krawiecki, K. Fangmann, N. Ettinger, K. Mileham, T. Setchfield, M. Balaan, Pierre P. Massion, M. Beukemann, Anil Vachani, G. Hong, K. Rothe, Harvey I. Pass, David E. Midthun, V. Markland-Gentles, Alexander Porter, J. Landis, and William N. Rom
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Male ,Proteomics ,Lung Neoplasms ,diagnosis ,pCA, probability of cancer ,Critical Care and Intensive Care Medicine ,Mass Spectrometry ,0302 clinical medicine ,Risk Factors ,Pulmonary nodule ,Medicine ,Prospective Studies ,pulmonary nodules ,Lung Cancer ,Biopsy, Needle ,Middle Aged ,Neoplasm Proteins ,Pre- and post-test probability ,NPV, negative predictive value ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,VA, Veterans Affairs ,Multiple Pulmonary Nodules ,biomarker ,Female ,Radiology ,Plasma proteomics ,TTNA, transthoracic needle biopsy ,Cardiology and Cardiovascular Medicine ,Adult ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Sensitivity and Specificity ,Diagnosis, Differential ,03 medical and health sciences ,Text mining ,Predictive Value of Tests ,Humans ,In patient ,Lung cancer ,Aged ,Lung ,business.industry ,Solitary Pulmonary Nodule ,risk models ,medicine.disease ,030228 respiratory system ,AUC, area under the receiver-operating characteristic curve ,business ,Classifier (UML) ,Biomarkers - Abstract
Background Lung nodules are a diagnostic challenge, with an estimated yearly incidence of 1.6 million in the United States. This study evaluated the accuracy of an integrated proteomic classifier in identifying benign nodules in patients with a pretest probability of cancer (pCA) ≤ 50%. Methods A prospective, multicenter observational trial of 685 patients with 8- to 30-mm lung nodules was conducted. Multiple reaction monitoring mass spectrometry was used to measure the relative abundance of two plasma proteins, LG3BP and C163A. Results were integrated with a clinical risk prediction model to identify likely benign nodules. Sensitivity, specificity, and negative predictive value were calculated. Estimates of potential changes in invasive testing had the integrated classifier results been available and acted on were made. Results A subgroup of 178 patients with a clinician-assessed pCA ≤ 50% had a 16% prevalence of lung cancer. The integrated classifier demonstrated a sensitivity of 97% (CI, 82-100), a specificity of 44% (CI, 36-52), and a negative predictive value of 98% (CI, 92-100) in distinguishing benign from malignant nodules. The classifier performed better than PET, validated lung nodule risk models, and physician cancer probability estimates (P
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- 2018
7. Neutrophils dominate the immune cell composition in non-small cell lung cancer
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Jesse J. Hubbard, Martin W. McIntosh, Heather E. Metz, Grace H. Y. Yang, A. McGarry Houghton, Mark L. Hanke, Kyoung-Hee Kim, Sylvia Lee, David K. Madtes, Julia Kargl, and Stephanie E. Busch
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0301 basic medicine ,Cell type ,Science ,Cell ,General Physics and Astronomy ,chemical and pharmacologic phenomena ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Receptor ,Lung cancer ,Multidisciplinary ,medicine.diagnostic_test ,General Chemistry ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Immune checkpoint ,respiratory tract diseases ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,bacteria ,Adenocarcinoma - Abstract
The response rate to immune checkpoint inhibitor therapy for non-small-cell lung cancer (NSCLC) is just 20%. To improve this figure, several early phase clinical trials combining novel immunotherapeutics with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC. The results show that the immune cell composition is fundamentally different in lung adenocarcinoma as compared with lung squamous cell carcinoma, and that neutrophils are the most prevalent immune cell type. Using T-cell receptor-β sequencing and tumour reactivity assays, we predict that tumour reactive T cells are frequently present in NSCLC. These results should help to guide the design of clinical trials and the direction of future research in this area.
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- 2017
8. Decline in the Use of Surgical Biopsy for Diagnosis of Pulmonary Disease in Hematopoietic Cell Transplantation Recipients in an Era of Improved Diagnostics and Empirical Therapy
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George B. McDonald, Guang-Shing Cheng, David K. Madtes, Steven A. Pergam, Michael Boeckh, and Zach Stednick
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Adult ,Azoles ,Diagnostic Imaging ,Lung Diseases ,Male ,medicine.medical_specialty ,Adolescent ,Biopsy ,Lung biopsy ,History, 21st Century ,Article ,Surgical lung biopsy ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Post-transplant ,Bronchoscopy ,Aspergillosis ,Humans ,Medicine ,030212 general & internal medicine ,Respiratory Tract Infections ,Diagnostic Techniques and Procedures ,Retrospective Studies ,Transplantation ,Lung ,medicine.diagnostic_test ,business.industry ,Proportional hazards model ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Hematology ,History, 20th Century ,Middle Aged ,Surgery ,medicine.anatomical_structure ,Mycoses ,030228 respiratory system ,Cohort ,Late pulmonary complications ,Female ,business ,Algorithms - Abstract
Highlights • Use of biopsy for diagnosis of post-HCT lung disease has declined significantly. • Improved testing and increased azole use are associated with this decrease. • Less invasive methods have improved diagnostics for respiratory pathogens. • We outline an algorithm for appropriate use of lung biopsy in these patients., Historically, diagnosis of enigmatic pulmonary disease after hematopoietic cell transplantation (HCT) required lung biopsy, but recent advancements in diagnosis and therapy for respiratory infections have changed how clinicians approach pulmonary abnormalities. We examined temporal trends in the use of lung biopsy after HCT. We retrospectively reviewed patients who underwent their first allogeneic HCT at the Fred Hutchinson Cancer Research Center between the years 1993 to 1997, 2003 to 2007, and 2013 to 2015 and subsequently underwent surgical lung biopsy for any reason. Lung biopsy between cohorts were analyzed using a Cox proportional hazards model with death and relapse considered competing risks. Of 1418 patients, 52 (3.7%) underwent 54 post-HCT surgical lung biopsies during 1993 to 1997 compared with 24 (2.1%) and 25 biopsies in the 2003 to 2007 cohort; 2 cases of surgical lung biopsies out of 786 HCT recipients occurred during the 2013 to 2015 cohort (.25%). The median time to biopsy post-HCT was 71.5 days (IQR, 31 to 89) for the early cohort and 97 days (IQR, 42 to 124) for the late cohort, for an overall biopsy incidence of .15 and .075 per 1000 patient days in the first year after HCT, respectively. Patients in the 2003 to 2007 cohort were less likely to undergo a lung biopsy (adjusted HR, .50; 95% CI, .29 to .83; P = .008) when compared with patients in the early cohort, but more patients in the early cohort underwent lung biopsy without antecedent bronchoscopy (25/54 [46%] versus 3/25 [12%], P = .005). Although infections were a more common finding at biopsy in the early cohort (35/1418 versus 8/1148, P
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- 2016
9. Prediction of Lung Cancer Screening Eligibility Using Simplified Criteria
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Lucas M Donovan, Matthew Triplette, Kristina Crothers, David H. Au, and David K. Madtes
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Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Lung Neoplasms ,Adolescent ,Advisory Committees ,Eligibility Determination ,Computed tomography ,Medicare ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Predictive Value of Tests ,medicine ,Humans ,030212 general & internal medicine ,Early Detection of Cancer ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Medicaid ,Smoking ,Middle Aged ,Former Smoker ,Nutrition Surveys ,United States ,respiratory tract diseases ,Intensity (physics) ,Cross-Sectional Studies ,Logistic Models ,030228 respiratory system ,Female ,Radiology ,business ,Tomography, X-Ray Computed ,Lung cancer screening - Abstract
Rationale: Lung cancer screening with low-dose chest computed tomography decreases mortality for high-risk current or former smokers. Lifetime smoking intensity (cigarette pack-years), an essential...
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- 2019
10. Examinations of Adherence to Follow-Up Recommendations in Lung Cancer Screening
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K. Peterson, J.H. Thayer, Erin K. Kross, David K. Madtes, Allison M. Cole, Matthew Triplette, and Kristina Crothers
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medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,business ,Lung cancer screening - Published
- 2019
11. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer
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Sudhakar Pipavath, A. McGarry Houghton, Stephanie E. Busch, Jesse J. Hubbard, Huajia Zhang, Heather E. Metz, Grace H. Y. Yang, Nicholas M. Mark, Julia Kargl, and David K. Madtes
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Oncology ,Male ,Molecular composition ,Lung Neoplasms ,Immune checkpoint inhibitors ,medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Critical Care and Intensive Care Medicine ,Pathogenesis ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Pneumonectomy ,education.field_of_study ,COPD ,General Medicine ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Flow Cytometry ,Editorial Commentary ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Non small cell ,Immunosuppressive Agents ,Signal Transduction ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Population ,Pulmonary disease ,Sensitivity and Specificity ,03 medical and health sciences ,Immune system ,Internal medicine ,medicine ,Humans ,education ,Lung cancer ,Aged ,Tumor microenvironment ,Lung ,business.industry ,Original Articles ,medicine.disease ,respiratory tract diseases ,030228 respiratory system ,Immunology ,business - Abstract
Chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) are interrelated diseases with substantial mortality, and the pathogenesis of both involves aberrant immune functioning.To profile immune cell composition and function in patients with NSCLC and describe the effects of COPD on lung and tumor microenvironments.We profiled resected lung and tumor tissue using flow cytometry and T-cell receptor sequencing in patients with and without COPD from a prospective cohort of patients undergoing resection of NSCLC. A murine cigarette smoke exposure model was used to evaluate the effect on pulmonary immune populations. A separate retrospective cohort of patients who received immune checkpoint inhibitors (ICIs) was analyzed, and their survival was quantified.We observed an increased number of IFN-γ-producing CD8In patients with COPD, Th1 cell populations were expanded in both lung and tumor microenvironments, and the presence of COPD was associated with longer progression-free intervals in patients treated with ICIs. This has implications for understanding the immune mediators of COPD and developing novel therapies for NSCLC.
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- 2019
12. Early detection of lung cancer in a population at high risk due to occupation and smoking
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David K. Madtes, Janet Shorter, Laura S. Welch, Knut Ringen, Kim Cranford, John M. Dement, and Patricia Quinn
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Male ,medicine.medical_specialty ,Lung Neoplasms ,Population ,Early detection ,Risk management tools ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Occupational Exposure ,medicine ,Humans ,030212 general & internal medicine ,Lung cancer ,education ,Early Detection of Cancer ,Aged ,Neoplasm Staging ,education.field_of_study ,Lung ,business.industry ,Smoking ,Public Health, Environmental and Occupational Health ,Cancer ,Middle Aged ,medicine.disease ,030210 environmental & occupational health ,United States ,medicine.anatomical_structure ,Carcinogens ,Female ,Risk assessment ,business ,Lung cancer screening - Abstract
ObjectiveThe US National Comprehensive Cancer Network (NCCN) recommends two pathways for eligibility for Early Lung Cancer Detection (ELCD) programmes. Option 2 includes individuals with occupational exposures to lung carcinogens, in combination with a lesser requirement on smoking. Our objective was to determine if this algorithm resulted in a similar prevalence of lung cancer as has been found using smoking risk alone, and if so to present an approach for lung cancer screening in high-risk worker populations.MethodsWe enrolled 1260 former workers meeting NCCN criteria, with modifications to account for occupational exposures in an ELCD programme.ResultsAt baseline, 1.6% had a lung cancer diagnosed, a rate similar to the National Lung Cancer Screening Trial (NLST). Among NLST participants, 59% were current smokers at the time of baseline scan or had quit smoking fewer than 15 years prior to baseline; all had a minimum of 30 pack-years of smoking. Among our population, only 24.5% were current smokers and 40.1% of our participants had smoked fewer than 30 pack-years; only 43.5% would meet entry criteria for the NLST. The most likely explanation for the high prevalence of screen-detected lung cancers in the face of a reduced risk from smoking is the addition of occupational risk factors for lung cancer.ConclusionOccupational exposures to lung carcinogens should be incorporated into criteria used for ELCD programmes, using the algorithm developed by NCCN or with an individualised risk assessment; current risk assessment tools can be modified to incorporate occupational risk.
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- 2018
13. Prediction Model for Nodal Disease Among Patients With Non-Small Cell Lung Cancer
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Douglas E. Wood, David K. Madtes, Michael S. Mulligan, Rachel Waworuntu, Katherine Odem-Davis, Francys C. Verdial, Billanna Hwang, and Farhood Farjah
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Pulmonary and Respiratory Medicine ,Male ,medicine.medical_specialty ,Lung Neoplasms ,Disease ,030204 cardiovascular system & hematology ,Logistic regression ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Positron Emission Tomography Computed Tomography ,medicine ,Carcinoma ,Humans ,Prospective Studies ,Lung cancer ,Prospective cohort study ,Aged ,Neoplasm Staging ,medicine.diagnostic_test ,business.industry ,Mediastinum ,Models, Theoretical ,medicine.disease ,Confidence interval ,030228 respiratory system ,Positron emission tomography ,Lymphatic Metastasis ,Surgery ,Female ,Radiology ,Cardiology and Cardiovascular Medicine ,business ,Cohort study ,Forecasting - Abstract
BACKGROUND: We characterized the performance characteristics of guideline-recommended invasive mediastinal staging for lung cancer and developed a prediction model for nodal disease as a potential alternative approach to staging. METHODS: We conducted a prospective cohort study of adults with suspected/ confirmed non-small cell lung cancer without evidence of distant metastatic disease (by computed tomography/positron emission tomography) who underwent nodal evaluation by invasive mediastinal staging and/or at the time of resection. The true-positive rate (TPR) was the proportion of patients with true nodal disease selected to undergo invasive mediastinal staging based on guideline recommendations, and the false-positive rate (FPR) was the proportion of patients without true nodal disease selected to undergo invasive mediastinal staging. Logistic regression was used to predict nodal disease using radiographic predictors. RESULTS: Among 123 eligible subjects, 31 (25%) had pathologically confirmed nodal disease. A guideline-recommended invasive staging strategy had a TPR and FPR of 100% and 65%, respectively. The prediction model fit the data well (goodness-of-fit test p=0.55) and had excellent discrimination (optimism corrected c-statistic 0.78, 95% confidence interval 0.72–0.89). Exploratory analysis revealed that use of the prediction model could achieve a FPR of 44% at a TPR of 97%. CONCLUSIONS: A guideline-recommended strategy for invasive mediastinal staging selects all patients with true nodal disease and a majority of patients without nodal disease for invasive mediastinal staging. Our prediction model appears to maintain (within a margin of error) the sensitivity of a guideline-recommended invasive staging strategy and has the potential to reduce the use of invasive procedures.
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- 2018
14. The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type
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Timothy R. Watkins, Lisa K. Vande Vusse, Douglas Bolgiano, and David K. Madtes
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medicine.medical_specialty ,Proportional hazards model ,business.industry ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Retrospective cohort study ,Hematology ,Hematopoietic stem cell transplantation ,030204 cardiovascular system & hematology ,medicine.disease ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Platelet transfusion ,Interquartile range ,Idiopathic pneumonia syndrome ,Internal medicine ,medicine ,Immunology and Allergy ,business ,Idiopathic interstitial pneumonia ,030215 immunology - Abstract
BACKGROUND Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p = 0.47). CONCLUSION The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS.
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- 2015
15. Reevaluation of the Pretransplant Assessment of Mortality Score after Allogeneic Hematopoietic Transplantation
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Rainer Storb, Min Fang, H. J. Deeg, Paul J. Martin, Brandon K.C. Au, Philippe Armand, Frederick R. Appelbaum, Jason W. Chien, Ted Gooley, Christopher J. Gibson, David K. Madtes, Mohamed L. Sorror, and Michael Boeckh
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,Survival ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Comorbidity ,Models, Biological ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,parasitic diseases ,medicine ,Risk of mortality ,Humans ,Child ,Survival rate ,Retrospective Studies ,Risk assessment ,Carbon Monoxide ,Transplantation ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Alanine Transaminase ,Hematology ,Allogeneic hematopoietic cell transplantation ,Allografts ,3. Good health ,Surgery ,Survival Rate ,Alanine transaminase ,030220 oncology & carcinogenesis ,Creatinine ,Hematologic Neoplasms ,Cohort ,biology.protein ,Female ,business ,030215 immunology - Abstract
The Pretransplant Assessment of Mortality (PAM) score was developed in 2006 to predict risk of mortality after allogeneic hematopoietic cell transplantation (HCT). Transplant practices have evolved during the past decade, suggesting the need to reevaluate the performance of the PAM score. We used statistical modeling to analyze and recalibrate mortality based on overall PAM scores, its components, and conditioning regimen in a retrospective cohort of 1549 patients who had HCT from 2003 through 2009. PAM scores correlated with mortality, but the effect size was smaller in the current study than in previous studies. PAM scores also demonstrated a stronger association with mortality in patients who received myeloablative conditioning than in those who received reduced-intensity conditioning. In contrast to the original study, carbon monoxide diffusing capacity, serum alanine aminotransferase, and serum creatinine concentrations were no longer significantly associated with 2-year mortality, whereas patient and donor cytomegalovirus serology was associated with mortality in the current cohort. Based on our findings, we developed and tested a revised PAM score for clinicians to estimate survival after allogeneic HCT with myeloablative conditioning regimens for patients with hematologic malignancy. Prognostic models such as the PAM score should be updated and recalibrated periodically to accommodate changes in clinical practice.
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- 2015
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16. Validation of a Multiprotein Plasma Classifier to Identify Benign Lung Nodules
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Xiao-Jun Li, Anil Vachani, Peter J. Mazzone, Clive Hayward, David E. Midthun, William N. Rom, Harvey I. Pass, Pui Yee Fong, Michel Laviolette, Jing Shi, Pierre P. Massion, Stephen W. Hunsucker, Paul Kearney, Eric S. Edell, Kenneth C. Fang, David K. Madtes, Michael G. Walker, and York E. Miller
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Male ,Proteomics ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Multivariate statistics ,Lung Neoplasms ,Bioinformatics ,Molecular diagnostic ,Lung nodule ,Biomarkers, Tumor ,medicine ,Humans ,Lung cancer ,Aged ,Retrospective Studies ,Multiple Pulmonary Nodules ,Lung ,business.industry ,Retrospective cohort study ,Original Articles ,Biomarker ,Middle Aged ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,ROC Curve ,Oncology ,Cohort ,Biomarker (medicine) ,Female ,Translational Oncology ,Radiology ,business ,Classifier (UML) ,Algorithms - Abstract
Introduction Indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and often undergo invasive procedures unnecessarily, suggesting potential roles for diagnostic adjuncts using molecular biomarkers. The primary objective was to validate a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, yielding a range of probability estimates based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs. Methods A retrospective, multicenter, case-control study was performed using multiple reaction monitoring mass spectrometry, a classifier comprising five diagnostic and six normalization proteins, and blinded analysis of an independent validation set of plasma samples. Results The classifier achieved validation on 141 lung nodule-associated plasma samples based on predefined statistical goals to optimize sensitivity. Using a population based nonsmall-cell lung cancer prevalence estimate of 23% for 8 to 30 mm IPNs, the classifier identified likely benign lung nodules with 90% negative predictive value and 26% positive predictive value, as shown in our prior work, at 92% sensitivity and 20% specificity, with the lower bound of the classifier's performance at 70% sensitivity and 48% specificity. Classifier scores for the overall cohort were statistically independent of patient age, tobacco use, nodule size, and chronic obstructive pulmonary disease diagnosis. The classifier also demonstrated incremental diagnostic performance in combination with a four-parameter clinical model. Conclusions This proteomic classifier provides a range of probability estimates for the likelihood of a benign etiology that may serve as a noninvasive, diagnostic adjunct for clinical assessments of patients with IPNs.
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- 2015
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17. Early Onset Noninfectious Pulmonary Syndromes after Hematopoietic Cell Transplantation
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David K. Madtes and Lisa K. Vande Vusse
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Pathology ,Transplantation Conditioning ,Pulmonary toxicity ,Lung injury ,Gastroenterology ,Idiopathic pneumonia syndrome ,Article ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Lung ,Hematopoietic cell transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Diffuse alveolar hemorrhage ,Pneumonia ,Syndrome ,medicine.disease ,Transplantation ,030220 oncology & carcinogenesis ,Pulmonary venoocclusive disease ,business ,Pulmonary alveolar proteinosis ,Cryptogenic organizing pneumonia ,030215 immunology ,Cryptogenic Organizing Pneumonia - Abstract
This article reviews the noninfectious pulmonary syndromes that cause morbidity and mortality early after hematopoietic cell transplantation with an emphasis on risk factors, clinical manifestations, treatment, and outcomes. The first section covers idiopathic pneumonia syndrome and its subtypes: peri-engraftment respiratory distress syndrome, diffuse alveolar hemorrhage, delayed pulmonary toxicity syndrome, and cryptogenic organizing pneumonia. The second section covers pulmonary toxicities of chemotherapies and immunosuppressive agents used in this setting. The final section covers less common syndromes, including pulmonary alveolar proteinosis, venous thromboembolism, pulmonary cytolytic thrombi, pulmonary venoocclusive disease, and transfusion-related acute lung injury.
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- 2017
18. Randomized, Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Idiopathic Pneumonia Syndrome after Allogeneic Stem Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network Protocol
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David K. Madtes, John R. Wingard, Juan Wu, James L.M. Ferrara, Eric S. White, Rebecca J. Drexler, Vincent T. Ho, Brent R. Logan, Kenneth R. Cooke, Robert J. Soiffer, Gregory A. Yanik, Daniel J. Weisdorf, Nancy L. DiFronzo, Sergio Giralt, Mary M. Horowitz, and Shelly L. Carter
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Adult ,Male ,medicine.medical_specialty ,Bone marrow transplantation ,IPS ,TNF ,Placebo-controlled study ,Lung injury ,Placebo ,Gastroenterology ,Article ,Receptors, Tumor Necrosis Factor ,Etanercept ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Adrenal Cortex Hormones ,Idiopathic pneumonia syndrome ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Idiopathic Interstitial Pneumonias ,Idiopathic interstitial pneumonia ,Aged ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Pneumonia ,Pulmonary ,Hematology ,Middle Aged ,medicine.disease ,3. Good health ,Surgery ,Discontinuation ,Treatment Outcome ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive methylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.
- Published
- 2014
19. The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation
- Author
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Timothy R. Watkins, David K. Madtes, J. Randall Curtis, Terry Gernsheimer, Katherine A. Guthrie, and Lisa K. Vande Vusse
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Extramural ,medicine.medical_treatment ,Immunology ,Case-control study ,Retrospective cohort study ,Hematology ,Hematopoietic stem cell transplantation ,respiratory system ,Lung injury ,medicine.disease ,Red blood cell ,surgical procedures, operative ,medicine.anatomical_structure ,Platelet transfusion ,immune system diseases ,Idiopathic pneumonia syndrome ,medicine ,Immunology and Allergy ,business - Abstract
BACKGROUND Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury.
- Published
- 2013
20. Acute Pulmonary Complications of Bone Marrow and Stem Cell Transplantation
- Author
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Guang-Shing Cheng and David K. Madtes
- Subjects
medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Lung injury ,medicine.disease ,Intensive care unit ,law.invention ,Transplantation ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,Idiopathic pneumonia syndrome ,law ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,030212 general & internal medicine ,Differential diagnosis ,education ,business ,Pneumonitis ,Cryptogenic Organizing Pneumonia - Abstract
Recipients of hematopoietic cell transplantation (HCT) are at risk for a variety of acute pulmonary complications including infectious pneumonias and noninfectious acute lung injury syndromes. With advances in HCT technology, prophylaxis and supportive care, overall survival after HCT has improved and the epidemiology of respiratory complications has shifted from early onset to late onset after HCT. However, acute respiratory failure remains the most common indication for admission to an intensive care unit in this population and prognosis is generally poor. Given the broad differential diagnosis of radiographic pulmonary abnormalities in HCT recipients, prompt evaluation with noninvasive testing and invasive diagnostics such as bronchoscopy is warranted. This chapter reviews the current understanding of etiology, diagnostic considerations and treatment of significant acute pulmonary complications in HCT, including idiopathic pneumonia syndrome, cryptogenic organizing pneumonia, and cytomegalovirus pneumonia.
- Published
- 2016
21. Pulmonary Complications of Stem Cell and Solid Organ Transplantation
- Author
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David K. Madtes
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,Stem cell ,Solid organ transplantation ,business - Published
- 2016
22. Contributors
- Author
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Lewis Adams, Dan Elie Adler, Alvar Agusti, Evangelia Akoumianaki, Anthony J. Alberg, Kurt H. Albertine, Barbara D. Alexander, Paul H. Alfille, Devanand Anantham, Douglas A. Arenberg, Najib T. Ayas, Aranya Bagchi, John Randolph Balmes, Niaz Banaei, Christopher F. Barnett, Robert P. Baughman, Margaret R. Becklake, Joshua O. Benditt, Neal L. Benowitz, Nirav R. Bhakta, Anant D. Bhave, Paul D. Blanc, Eugene R. Bleecker, Alfred A. Bove, T. Douglas Bradley, Elisabeth Brambilla, V. Courtney Broaddus, Laurent Brochard, Malcolm V. Brock, Kevin K. Brown, Paul G. Brunetta, Jacques Cadranel, Bartolome Celli, Edward D. Chan, Richard N. Channick, Jean Chastre, Guang-Shing Cheng, Kelly Chin, Kian Fan Chung, Christine Clerici, Thomas V. Colby, Harold R. Collard, Carlyne D. Cool, Jean-François Cordier, Ricardo Luiz Cordioli, Tamera J. Corte, Vincent Cottin, Mark S. Courey, Robert L. Cowie, Kristina Crothers, Gerard F. Curley, Charles L. Daley, J. Lucian Davis, Teresa De Marco, Stanley C. Deresinski, Christophe Deroose, Leland G. Dobbs, Christophe Dooms, Gregory P. Downey, Roland M. du Bois, Megan M. Dulohery, Richard M. Effros, Mark D. Eisner, Brett M. Elicker, Armin Ernst, Joel D. Ernst, John V. Fahy, Peter F. Fedullo, David Feller-Kopman, Brett E. Fenster, Tasha E. Fingerlin, Andrew P. Fontenot, Stephen K. Frankel, Joe G.N. Garcia, G.F. Gebhart, Daniel Lee Gilstrap, Nicolas Girard, Mark T. Gladwin, Robb W. Glenny, Warren M. Gold, Michael B. Gotway, Giacomo Grasselli, James M. Greenberg, David E. Griffith, James F. Gruden, MeiLan King Han, William Henderson, Nicholas S. Hill, Wynton Hoover, Philip C. Hopewell, Jennifer L. Horan-Saullo, Richard L. Horner, Laurence Huang, Gérard Huchon, Yoshikazu Inoue, Michael D. Iseman, James E. Jackson, Claudia V. Jakubzick, Julius P. Janssen, James R. Jett, Kirk Jones, Marc A. Judson, Midori Kato-Maeda, Brian P. Kavanagh, Shaf Keshavjee, Kami Kim, R. John Kimoff, Talmadge E. King, Jeffrey S. Klein, Laura L. Koth, Robert M. Kotloff, Monica Kraft, Elif Küpeli, John G. Laffey, Stephen E. Lapinsky, Stephen C. Lazarus, Frances Eun-Hyung Lee, Jarone Lee, Y.C. Gary Lee, Warren L. Lee, Teofilo L. Lee-Chiong, Catherine Lemière, Richard W. Light, Andrew H. Limper, Robert Loddenkemper, Njira Lugogo, Maurizio Luisetti, Andrew M. Luks, Charles-Edouard Luyt, Roberto F. Machado, Neil R. MacIntyre, William MacNee, David K. Madtes, Lisa A. Maier, Fabien Maldonado, Atul Malhotra, Thomas R. Martin, Nick A. Maskell, Robert J. Mason, Pierre P. Massion, Michael A. Matthay, Richard A. Matthay, Annyce S. Mayer, Stuart B. Mazzone, F. Dennis McCool, Francis Xavier McCormack, Atul C. Mehta, Rosario Menéndez, Adam S. Morgenthau, Alison Morris, Timothy A. Morris, Aaron R. Muncey, John F. Murray, Jeffrey L. Myers, Jay A. Nadel, Catherine Nelson-Piercy, Tom S. Neuman, Joshua D. Nosanchuk, Thomas G. O'Riordan, Victor Enrique Ortega, Prasad M. Panse, William Pao, Peter A. Paré, David R. Park, Nicholas J. Pastis, Nicolò Patroniti, Karen C. Patterson, Antonio Pesenti, Allan Pickens, Benjamin A. Pinsky, Steven D. Pletcher, Frank L. Powell, Loretta G. Que, Elizabeth F. Redente, David W.H. Riches, Bruce W.S. Robinson, Roberto Rodriguez-Roisin, Cecile S. Rose, John M. Routes, Steven M. Rowe, Clodagh M. Ryan, Jay H. Ryu, Jonathan M. Samet, Christian E. Sandrock, Robert B. Schoene, David A. Schwartz, Richard M. Schwartzstein, Marvin I. Schwarz, Moisés Selman, Lecia V. Sequist, John M. Shannon, Claire L. Shovlin, Gerard A. Silvestri, Philip L. Simonian, Jonathan P. Singer, Arthur S. Slutsky, Gerald C. Smaldone, George M. Solomon, Eric J. Sorscher, Erik R. Swenson, Nichole T. Tanner, Herbert B. Tanowitz, Antoni Torres, Bruce C. Trapnell, William David Travis, John J. Treanor, George E. Tzelepis, Olivier Vandenplas, Johan F. Vansteenkiste, Thomas K. Varghese, Jørgen Vestbo, Peter D. Wagner, Momen M. Wahidi, W. Dean Wallace, Louis M. Weiss, Scott T. Weiss, Athol U. Wells, John B. West, Douglas B. White, Jeanine P. Wiener-Kronish, Kathryn A. Wikenheiser-Brokamp, Prescott G. Woodruff, Richard G. Wunderink, D. Dante Yeh, Rachel L. Zemans, Leslie Zimmerman, and Richard L. Zuwallack
- Published
- 2016
23. Navigational Bronchoscopy With Biopsy Versus Computed Tomography—guided Biopsy for the Diagnosis of a Solitary Pulmonary Nodule
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Christopher R. Dale, Jed A. Gorden, Vincent S. Fan, David K. Madtes, and David L. Veenstra
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Solitary pulmonary nodule ,medicine.diagnostic_test ,business.industry ,Cost effectiveness ,Radiography ,fungi ,food and beverages ,Navigational bronchoscopy ,medicine.disease ,Cardiothoracic surgery ,Biopsy ,Medicine ,Tomography ,Radiology ,business ,Lung cancer - Abstract
Background:Solitary pulmonary nodules (SPNs) are frequent and can be malignant. Both computed tomography-guided biopsy and electromagnetic navigational bronchoscopy (ENB) with biopsy can be used to diagnose a SPN. A nondiagnostic computed tomography (CT)–guided or ENB biopsy is often followed by vid
- Published
- 2012
24. The Use of Ex Vivo Generated Regulatory T-Cell Preparations in a Canine Lung Allograft Model
- Author
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Michael S. Mulligan, Wayne J. E. Lamm, David K. Madtes, Barry E. Storer, Billanna Hwang, Kraig Abrams, George E. Georges, Richard A. Nash, and Robert Glenny
- Subjects
Graft Rejection ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Time Factors ,Regulatory T cell ,030230 surgery ,T-Lymphocytes, Regulatory ,Article ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Text mining ,medicine ,Animals ,Transplantation ,Lung ,Extramural ,business.industry ,Graft Survival ,Allografts ,Adoptive Transfer ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Models, Animal ,Graft survival ,business ,Ex vivo ,Lung Transplantation - Published
- 2017
25. An Official American Thoracic Society Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: Idiopathic Pneumonia Syndrome
- Author
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Kenneth R. Cooke, John A. Belperio, David K. Madtes, Rodney J. Folz, Angela Panoskaltsis-Mortari, Matthias Griese, and Imad Y. Haddad
- Subjects
Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Lung injury ,Critical Care and Intensive Care Medicine ,Mice ,Idiopathic pneumonia syndrome ,Intensive care ,medicine ,Animals ,Humans ,Intensive care medicine ,Societies, Medical ,American Thoracic Society Documents ,business.industry ,Respiratory disease ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Pneumonia ,Syndrome ,medicine.disease ,United States ,Clinical trial ,Disease Models, Animal ,medicine.anatomical_structure ,business - Abstract
Acute lung dysfunction of noninfectious etiology, known as idiopathic pneumonia syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS.Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS.An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords "idiopathic pneumonia syndrome" or "lung injury" or "pulmonary complications" AND "bone marrow transplant" or "hematopoietic stem cell transplant." No specific inclusion or exclusion criteria were determined a priori for this review.Experimental models that reproduce the various patterns of lung injury observed after HSCT have identified that both soluble and cellular inflammatory mediators contribute to the inflammation engendered during the development of IPS. To date, 10 preclinical murine models of the IPS spectrum have been established using various donor and host strain combinations used to study graft-versus-host disease (GVHD). This, as well as the demonstrated T cell dependency of IPS development in these models, supports the concept that the lung is a target of immune-mediated attack after HSCT. The most developed therapeutic strategy for IPS involves blocking TNF signaling with etanercept, which is currently being evaluated in clinical trials.IPS remains a frequently fatal complication that limits the broader use of allogeneic HSCT as a successful treatment modality. Faced with the clinical syndrome of IPS, one can categorize the disease entity with the appropriate tools, although cases of unclassifiable IPS will remain. Significant research efforts have resulted in a paradigm shift away from identifying noninfectious lung injury after HSCT solely as an idiopathic clinical syndrome and toward understanding IPS as a process involving aspects of both the adaptive and the innate immune response. Importantly, new laboratory insights are currently being translated to the clinic and will likely prove important to the development of future strategies to prevent or treat this serious disorder.
- Published
- 2011
- Full Text
- View/download PDF
26. Expression of Human α1-Antitrypsin in Mice and Dogs Following AAV6 Vector-mediated Gene Transfer to the Lungs
- Author
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Zejing Wang, Rainer Storb, Andrew E. Vaughan, Stephen J. Tapscott, Christine L. Halbert, David K. Madtes, and A. Dusty Miller
- Subjects
DNA, Complementary ,Transgene ,Genetic enhancement ,medicine.medical_treatment ,Genetic Vectors ,Enzyme-Linked Immunosorbent Assay ,Biology ,Mice ,Immune system ,Dogs ,alpha 1-Antitrypsin Deficiency ,Gene expression ,Drug Discovery ,medicine ,Genetics ,Animals ,Humans ,Vector (molecular biology) ,Lung ,Molecular Biology ,Pharmacology ,Gene Transfer Techniques ,Immunosuppression ,Genetic Therapy ,Original Articles ,Dependovirus ,Molecular biology ,medicine.anatomical_structure ,alpha 1-Antitrypsin ,Immunology ,Molecular Medicine ,Bronchoalveolar Lavage Fluid ,Lymphoproliferative response - Abstract
We evaluated the potential of lung-directed gene therapy for alpha1-antitrypsin (AAT) deficiency using an adeno-associated virus type 6 (AAV6) vector containing a human AAT (hAAT) complementary DNA (cDNA) delivered to the lungs of mice and dogs. The results in normal and immune-deficient mice showed that hAAT concentrations were much higher in lung fluid than in plasma, and therapeutic levels were obtained even in normal mice. However, in normal mice an immune response against the vector and/or transgene limited long-term gene expression. An AAV6 vector expressing a marker protein verified that AAV6 vectors efficiently transduced lung cells in dogs. Delivery of AAV6-hAAT resulted in low levels of hAAT in dog serum but therapeutic levels in the lung that persisted for at least 58 days to 4 months in three immunosuppressed dogs. Expression in the serum was not detectable after 45 days in one nonimmune suppressed dog. A lymphoproliferative response to AAV capsid but not to hAAT was detected even after immunosuppression. These results in mice and dogs show the feasibility of expression of therapeutic levels of AAT in the lungs after AAV vector delivery, and advocate for approaches to prevent cellular immune responses to AAV capsid proteins for persistence of gene expression in humans.
- Published
- 2010
- Full Text
- View/download PDF
27. Immunomodulatory Effects of Mixed Hematopoietic Chimerism: Immune Tolerance in Canine Model of Lung Transplantation
- Author
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Kraig Abrams, Richard A. Nash, Murad Yunosov, Robert C. Hackman, Rainer Storb, David K. Madtes, Stephen F. Ziegler, Cristina Castilla-Llorente, Billanna Hwang, Julie Randolph-Habecker, Hans D. Ochs, Barry E. Storer, Alexander S. Farivar, Michael S. Mulligan, Marina Lesnikova, George E. Georges, Peter Chen, Robb W. Glenny, and Wayne J. E. Lamm
- Subjects
Graft Rejection ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Transplantation Chimera ,Article ,Immune tolerance ,Dogs ,Immune system ,T-Lymphocyte Subsets ,Animals ,Transplantation, Homologous ,Immunology and Allergy ,Medicine ,Lung transplantation ,Pharmacology (medical) ,Transplantation ,business.industry ,Graft Survival ,Hematopoietic Stem Cell Transplantation ,FOXP3 ,Immunosuppression ,Flow Cytometry ,Hematopoiesis ,Respiratory Function Tests ,Models, Animal ,Immunology ,business ,Immunosuppressive Agents ,Lung Transplantation - Abstract
Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (por = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients ator =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.
- Published
- 2009
28. Tissue Inhibitor of Metalloproteinase-1 Moderates Airway Re-Epithelialization by Regulating Matrilysin Activity
- Author
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Kurt Poindexter, Phillip Liu, David K. Madtes, John K. McGuire, Wei Yan, Kyoung Hee Kim, William C. Parks, Peter Chen, Robert C. Hackman, Ann J. Chen, and Roy A. Black
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Respiratory Mucosa ,Naphthalenes ,Matrix metalloproteinase ,Biology ,Cell Line ,Pathology and Forensic Medicine ,Epithelial Damage ,Mice ,Cell Movement ,Fibrosis ,medicine ,Animals ,Humans ,Regeneration ,Matrilysin ,Bronchiolitis Obliterans ,Lung ,Cells, Cultured ,Mice, Knockout ,Tissue Inhibitor of Metalloproteinase-1 ,Epithelial Cells ,Cell migration ,respiratory system ,Tissue inhibitor of metalloproteinase ,medicine.disease ,Epithelium ,respiratory tract diseases ,Enzyme Activation ,medicine.anatomical_structure ,Matrix Metalloproteinase 7 ,Airway ,Protein Binding ,Regular Articles - Abstract
Obliterative bronchiolitis (OB) is the histopathological finding in chronic lung allograft rejection. Mounting evidence suggests that epithelial damage drives the development of airway fibrosis in OB. Tissue inhibitor of metalloproteinase (TIMP)-1 expression increases in lung allografts and is associated with the onset of allograft rejection. Furthermore, in a mouse model of OB, airway obliteration is reduced in TIMP-1-deficient mice. Matrilysin (matrix metallproteinase-7) is essential for airway epithelial repair and is required for the re-epithelialization of airway wounds by facilitating cell migration; therefore, the goal of this study was to determine whether TIMP-1 inhibits re-epithelialization through matrilysin. We found that TIMP-1 and matrilysin co-localized in the epithelium of human lungs with OB and both co-localized and co-immunoprecipitated in wounded primary airway epithelial cultures. TIMP-1-deficient cultures migrated faster, and epithelial cells spread to a greater extent compared with wild-type cultures. TIMP-1 also inhibited matrilysin-mediated cell migration and spreading in vitro. In vivo, TIMP-1 deficiency enhanced airway re-epithelialization after naphthalene injury. Furthermore, TIMP-1 and matrilysin co-localized in airway epithelial cells adjacent to the wound edge. Our data demonstrate that TIMP-1 interacts with matrix metalloproteinases and regulates matrilysin activity during airway epithelial repair. Furthermore, we speculate that TIMP-1 overexpression restricts airway re-epithelialization by inhibiting matrilysin activity, contributing to a stereotypic injury response that promotes airway fibrosis via bronchiole airway epithelial damage and obliteration.
- Published
- 2008
29. Myeloperoxidase Inactivates TIMP-1 by Oxidizing Its N-terminal Cysteine Residue
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Yi Wang, Jay W. Heinecke, Xiaoyun Fu, Henry Rosen, David K. Madtes, Baohai Shao, and Thomas R. Martin
- Subjects
chemistry.chemical_classification ,Methionine ,medicine.diagnostic_test ,biology ,Hypochlorous acid ,Proteolysis ,Inflammation ,Peptide ,Cell Biology ,Matrix metalloproteinase ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Myeloperoxidase ,medicine ,biology.protein ,medicine.symptom ,Molecular Biology ,Cysteine - Abstract
An imbalance between the proteolytic activity of matrix metalloproteinases (MMPs) and the activity of tissue inhibitors of metalloproteinases (TIMPs) is implicated in tissue injury during inflammation. The N-terminal cysteine of TIMP-1 plays a key role in the inhibitory activity of the protein because it coordinates the essential catalytic Zn2+ of the MMP, preventing the metal ion from functioning. An important mechanism for controlling the interaction of TIMPs with MMPs might involve hypochlorous acid (HOCl), a potent oxidant produced by the myeloperoxidase (MPO) system of phagocytes. Here, we show that HOCl generated by the MPO-H2O2-chloride system inactivates TIMP-1 by oxidizing its N-terminal cysteine. The product is a novel 2-oxo acid. Liquid chromatography-mass spectrometry and tandem mass spectrometry analyses demonstrated that methionine and N-terminal cysteine residues were rapidly oxidized by MPO-derived HOCl but only oxidation of the N-terminal cysteine of TIMP-1 correlated well with loss of inhibitory activity. Importantly, we detected the signature 2-oxo-acid N-terminal peptide in tryptic digests of bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome, demonstrating that TIMP-1 oxidation occurs in vivo. Loss of the N-terminal amino group and disulfide structure are crucial for preventing TIMP-1 from inhibiting MMPs. Our findings suggest that pericellular production of HOCl by phagocytes is a pathogenic mechanism for impairing TIMP-1 activity during inflammation.
- Published
- 2007
30. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies
- Author
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David N. Fredricks, Ruth Hall Sedlak, Yae Jean Kim, Ted Gooley, Steven P. Miller, Takahiro Fukuda, Robert C. Hackman, Michael Boeckh, Jane Kuypers, Erik Samayoa, Guixia Yu, Charles Y. Chiu, Meei Li Huang, Keith R. Jerome, Sachiko Seo, David Myerson, David K. Madtes, Hu Xie, Christian Renaud, and Cynthia E. Fisher
- Subjects
Adult ,Male ,Adolescent ,Immunology ,Congenital cytomegalovirus infection ,Biology ,medicine.disease_cause ,Biochemistry ,Asymptomatic ,Cohort Studies ,Young Adult ,Idiopathic pneumonia syndrome ,medicine ,Aspergillosis ,Humans ,Child ,Pathogen ,Lung ,Transplantation ,medicine.diagnostic_test ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Bacterial Infections ,Lung Injury ,Middle Aged ,medicine.disease ,Pneumonia ,Bronchoalveolar lavage ,Aspergillus ,Virus Diseases ,Female ,Rhinovirus ,medicine.symptom ,Bronchoalveolar Lavage Fluid - Abstract
Newer diagnostic methods may link more idiopathic pneumonia syndrome (IPS) cases to an infectious agent. Bronchoalveolar lavage (BAL) samples from 69 hematopoietic cell transplant (HCT) recipients with IPS diagnosed between 1992 and 2006 were tested for 28 pathogens (3 bacteria and 25 viruses) by quantitative polymerase chain reaction and for Aspergillus by galactomannan assay. Research BALs from 21 asymptomatic HCT patients served as controls. Among 69 HCT patients with IPS, 39 (56.5%) had a pathogen detected. The most frequent pathogens were human herpesvirus-6 (HHV-6) (N = 20 [29%]) followed by human rhinovirus (HRV), cytomegalovirus (CMV), and Aspergillus (N = 8 [12%] in each). HHV-6 and HRV were rarely detected in controls, whereas CMV and Aspergillus were occasionally detected with low pathogen load. Patients with pathogens had worse day-100 survival than those without (hazard ratio, 1.88; P = .03). Mortality in patients with only pathogens of “uncertain” significance in lung was similar to that in patients with pathogens of “established” significance. Metagenomic next-generation sequencing did not reveal additional significant pathogens. Our study demonstrated that approximately half of patients with IPS had pathogens detected in BAL, and pathogen detection was associated with increased mortality. Thus, an expanded infection detection panel can significantly increase the diagnostic precision for idiopathic pneumonia.
- Published
- 2015
31. Tissue Inhibitor of Metalloproteinase-1 Deficiency Amplifies Acute Lung Injury in Bleomycin-Exposed Mice
- Author
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David K. Madtes, Kyoung Hee Kim, Paul D. Soloway, Robert C. Hackman, Charles W. Frevert, Kristin M. Burkhart, Julie Randolph-Habecker, and Peter Chen
- Subjects
Lipopolysaccharides ,Male ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Neutrophils ,Pulmonary Fibrosis ,Clinical Biochemistry ,Gene Expression ,Hemorrhage ,Vascular permeability ,Lung injury ,Biology ,Bleomycin ,Article ,Capillary Permeability ,Mice ,chemistry.chemical_compound ,Fibrosis ,Weight Loss ,Pulmonary fibrosis ,medicine ,Animals ,Molecular Biology ,Respiratory Distress Syndrome ,Antibiotics, Antineoplastic ,Tissue Inhibitor of Metalloproteinase-1 ,Lung ,Cell Biology ,respiratory system ,Tissue inhibitor of metalloproteinase ,medicine.disease ,Mice, Mutant Strains ,Neutrophilia ,Specific Pathogen-Free Organisms ,respiratory tract diseases ,Mice, Inbred C57BL ,Pulmonary Alveoli ,Chemotaxis, Leukocyte ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,chemistry ,medicine.symptom - Abstract
Bleomycin-induced lung injury triggers a profound and durable increase in tissue inhibitor of metalloproteinase (TIMP)-1 expression, suggesting a potential role for this antiproteinase in the regulation of lung inflammation and fibrosis. TIMP-1 protein induction is spatially restricted to areas of lung injury as determined by immunohistochemistry. Using TIMP-1 null mutation mice, we demonstrate that TIMP-1 deficiency amplifies acute lung injury as determined by exaggerated pulmonary neutrophilia, hemorrhage, and vascular permeability compared with wild-type littermates after bleomycin exposure. The augmented pulmonary neutrophilia observed in TIMP-1–deficient animals was not found in similarly treated TIMP-2–deficient mice. Using TIMP-1 bone marrow (BM) chimeric mice, we observed that the TIMP-1–deficient phenotype was abolished in wild-type recipients of TIMP-1–deficient BM but not in TIMP-1–deficient recipients of wild-type BM. Acute lung injury in TIMP-1–deficient mice was accompanied by exaggerated gelatinase-B activity in the alveolar compartment. TIMP-1 deficiency did not alter neutrophil chemotactic factor accumulation in the injured lung nor neutrophil migration in response to chemotactic stimuli in vivo or in vitro. Moreover, TIMP-1 deficiency did not modify collagen accumulation after bleomycin injury. Our results provide direct evidence that TIMP-1 contributes significantly to the regulation of acute lung injury, functioning to limit inflammation and lung permeability.
- Published
- 2005
32. Pretransplant Lung Function, Respiratory Failure, and Mortality after Stem Cell Transplantation
- Author
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David K. Madtes, Jason W. Chien, David H. Au, Tanyalak Parimon, and Joan G. Clark
- Subjects
Adult ,Male ,Washington ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Critical Care and Intensive Care Medicine ,Pulmonary function testing ,FEV1/FVC ratio ,DLCO ,Diffusing capacity ,Internal medicine ,Preoperative Care ,medicine ,Humans ,Transplantation, Homologous ,Lung volumes ,F. Transplantation ,Lung ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Proportional hazards model ,business.industry ,Respiratory disease ,Middle Aged ,respiratory system ,medicine.disease ,Hematologic Diseases ,respiratory tract diseases ,Surgery ,Respiratory failure ,Cardiology ,Female ,Blood Gas Analysis ,Lung Volume Measurements ,Respiratory Insufficiency ,business ,Stem Cell Transplantation - Abstract
Rationale: The role of pulmonary function before stem cell transplant as a potential risk factor for the development of early post-transplant respiratory failure and mortality is controversial. Methods: We conducted a retrospective analysis of the pretransplant pulmonary function of 2,852 patients who received their transplant between 1990 and 2001. Measurements: Pretransplant FEV1, FVC, total lung capacity (TLC), diffusing capacity of carbon monoxide (DLCO), and the alveolar–arterial oxygen tension difference P(A-a)O2 were measured and assessed for association with development of early respiratory failure and mortality in Cox proportional hazard logistic models. Main Results: In multivariate analyses, progressive decrease of all lung function parameters was associated with a stepwise increase in risk of developing early respiratory failure and mortality when assessed in independent models. On the basis of a significant correlation between FEV1 and FVC (r = 0.81), FEV1 and TLC (r = 0.61), and FVC and TLC (r = 0.80), and a lack of correlation between FEV1 and DLCO, we developed a pretransplant lung function score based on pretransplant FEV1 and DLCO to determine the extent of pulmonary compromise before transplant. Multivariate analysis indicated that higher pretransplant lung function scores are associated with a significant increased risk for developing early respiratory failure (category II hazard ratio [HR], 1.4; category III HR, 2.2; category IV HR, 3.1; p < 0.001) and death (category II HR, 1.2; category III HR, 2.2; category IV HR, 2.7; p < 0.005). Conclusions: These results suggest that not only does compromised pretransplant lung function contribute to the risk for development of early respiratory failure and mortality but this risk may be estimated before transplant by grading the extent of FEV1 and DLCO compromise.
- Published
- 2005
33. Pulmonary function testing prior to hematopoietic stem cell transplantation
- Author
-
Jason W. Chien, Joan G. Clark, and David K. Madtes
- Subjects
Lung Diseases ,Transplantation ,medicine.medical_specialty ,education.field_of_study ,Hematology ,business.industry ,medicine.medical_treatment ,Population ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,Risk Assessment ,Post transplant ,Respiratory Function Tests ,Pulmonary function testing ,surgical procedures, operative ,Internal medicine ,medicine ,Humans ,Stem cell ,Intensive care medicine ,education ,business ,Risk assessment ,Lung function - Abstract
The pretransplant pulmonary function test plays an important role in the management of noninfectious pulmonary complications after hematopoietic stem cell transplantation (HCT). Although these tests are widely used as standard preoperative assessments in the nontransplant population, common conditions associated with the HCT patient requires that particular attention be given to interpretation of pulmonary function testing (PFT) results, such as comparison of serial pulmonary function tests and evaluation of the diffusion capacity. Although their utility in helping to predict the likelihood of developing post transplant pulmonary complications and mortality is not well established, current data indicate that pretransplant PFTs are important as a reference for the interpretation of post transplant PFTs and for identifying patients at high risk for developing pulmonary complications and/or mortality after HCT. Future studies of pretransplant pulmonary function should consider the advances in HCT, so that pretransplant PFTs will become a useful tool in pretransplant risk assessment and help the transplant oncologist to determine the most appropriate conditioning regimen for a patient with compromised lung function.
- Published
- 2005
34. Trafficking of Th1 Cells to Lung
- Author
-
Joan G. Clark, David K. Madtes, John M. Harlan, Anne E. Dixon, Kristin M. Burkhart, Janis B. Mandac-Dy, and Daniel C. Bullard
- Subjects
Pulmonary and Respiratory Medicine ,Adoptive cell transfer ,Recombinant Fusion Proteins ,Lymphocyte ,Clinical Biochemistry ,Cell ,Neuraminidase ,Inflammation ,Biology ,Mice ,Cell Movement ,In vivo ,Cell Adhesion ,medicine ,Animals ,Humans ,Lung ,Molecular Biology ,Cells, Cultured ,Membrane Glycoproteins ,Antibodies, Monoclonal ,Cell Biology ,T lymphocyte ,Th1 Cells ,respiratory system ,Adoptive Transfer ,In vitro ,Cell biology ,Mice, Inbred C57BL ,P-Selectin ,medicine.anatomical_structure ,Selectins ,medicine.symptom ,Selectin ,Protein Binding - Abstract
Trafficking of lymphocytes to lung is a critical component of pulmonary immune defense and surveillance. Selectins, expressed on vascular endothelium, regulate T lymphocyte emigration into tissues, such as skin, but the role of the selectins in trafficking of T cells to lung has not been well characterized. Here, we used a model of lung inflammation induced by adoptive transfer of alloreactive Th1 cells to analyze the role of P- and E-selectin in Th1 cell trafficking to lung in vivo. We found that both P- and E-selectin play an important role in Th1 lymphocyte migration to lung. We confirmed that the Th1 cells express P-selectin glycoprotein ligand-1, which was functional in binding to P- and E-selectin in vitro. However, our studies reveal that a ligand distinct from P-selectin glycoprotein-1 also binds these selectins in vitro and appears to play a physiologic role in in vivo emigration of Th1 lymphocytes into the lung.
- Published
- 2004
35. Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants
- Author
-
Peter Cummings, Robert C. Hackman, David K. Madtes, Barry E. Storer, J. Randall Curtis, and Todd D. Freudenberger
- Subjects
Adult ,Male ,medicine.medical_specialty ,Immunology ,Population ,Graft vs Host Disease ,Bronchiolitis obliterans ,Skin Diseases ,Biochemistry ,Risk Factors ,Idiopathic pneumonia syndrome ,Internal medicine ,Odds Ratio ,medicine ,Humans ,education ,Retrospective Studies ,education.field_of_study ,business.industry ,Hematopoietic Stem Cell Transplantation ,Bronchiolitis obliterans organizing pneumonia ,Cell Biology ,Hematology ,Odds ratio ,medicine.disease ,Transplantation ,Intestinal Diseases ,Graft-versus-host disease ,Cryptogenic Organizing Pneumonia ,Case-Control Studies ,Relative risk ,Acute Disease ,Chronic Disease ,Female ,Mouth Diseases ,business - Abstract
Bronchiolitis obliterans organizing pneumonia (BOOP) has been reported following hematopoietic stem cell (HSC) transplantation, but the clinical features and risk factors for this disorder have not been well characterized. This case-control study of 49 patients with histologic BOOP and 161 control subjects matched by age and year of transplantation describes the clinical features and analyzes the risk factors for BOOP following HSC transplantation. Data on clinical features and outcome were collected by chart review. Odds ratios, estimating the relative risk of BOOP in allogeneic HSC recipients, were calculated by conditional logistic regression with adjustment for potential confounding factors. Clinical features of BOOP in this population were similar to idiopathic BOOP and BOOP occurring in other disease settings. There was an association between acute and chronic graft-versus-host disease (GVHD) and the subsequent development of BOOP (odds ratios, 3.8 [95% CI, 1.2 to 12.3] and 3.1 [95% CI, 1.1 to 9.2], respectively). Patients with BOOP were more likely to have acute GVHD involving the skin (odds ratio, 4.6; P = .005) and chronic GVHD involving the gut (odds ratio, 6.6; P = .018) and oral cavity (odds ratio, 5.9; P = .026). This study shows that histologic BOOP following HSC transplantation has clinical features that resemble idiopathic BOOP and is strongly associated with prior acute and chronic GVHD. These results have important implications for the care of patients who develop respiratory symptoms after HSC transplantation and may help elucidate the pathogenesis of idiopathic BOOP. (Blood. 2003;102:3822-3828)
- Published
- 2003
36. Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus -host disease after haematopoietic stem cell transplantation from an HLA-identical sibling
- Author
-
Toshitada Takahashi, Anthony G. Brickner, Edus H. Warren, Ming Tseh Lin, Paul J. Martin, David K. Madtes, Ted Gooley, Victor H. Engelhard, John A. Hansen, Stanley R. Riddell, and Yoshiki Akatsuka
- Subjects
Transplantation ,Haematopoiesis ,Graft-versus-host disease ,Immunopathology ,Immunology ,medicine ,Minor histocompatibility antigen ,Hematology ,Human leukocyte antigen ,Odds ratio ,Biology ,Risk factor ,medicine.disease - Abstract
Summary. We recently identified a new minor histocompatibility antigen, termed HA-8, which is presented by human leucocyte antigen (HLA)-A*0201 or HLA-A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA-A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte antigen (HLA)-identical sibling was conducted to determine whether HA-8 disparity correlated with clinical outcome. HA-8 disparity was detected in 72 recipients, and grades II–IV graft-versus-host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA-8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1·8; 95% confidence interval, 1·0–3·1; P = 0·04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA-8 disparity was not sufficient to change other clinical outcomes.
- Published
- 2003
37. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation
- Author
-
John L. Wagner, Chien-Shing Chen, M. Siadak, Emin Kansu, Joan G. Clark, Michael Boeckh, Claudio Anasetti, Mary E.D. Flowers, F R Appelbaum, R Storb, Robert P. Witherspoon, Deeg Hj, Kristy Seidel, David K. Madtes, Keith M. Sullivan, Jan Storek, Jean E. Sanders, Paul J. Martin, William I. Bensinger, and James C. Wade
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Risk Factors ,Idiopathic pneumonia syndrome ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Risk factor ,Infection Control ,Transplantation ,business.industry ,Incidence ,Incidence (epidemiology) ,Respiratory disease ,Hematopoietic Stem Cell Transplantation ,Pneumonia ,Hematology ,Middle Aged ,medicine.disease ,Hematologic Diseases ,Survival Analysis ,Surgery ,Pneumocystis Infections ,Treatment Outcome ,Histocompatibility ,Etiology ,Female ,business ,Follow-Up Studies - Abstract
The incidence, etiology, outcome, and risk factors for developing pneumonia late after hematopoietic stem cell transplantation (SCT) were investigated in 1359 patients transplanted in Seattle. A total of 341 patients (25% of the cohort) developed at least one pneumonic episode. No microbial or tissue diagnosis (ie clinical pneumonia) was established in 197 patients (58% of first pneumonia cases). Among the remaining 144 patients, established etiologies included 33 viral (10%), 31 bacterial (9%), 25 idiopathic pneumonia syndrome (IPS, 7%), 20 multiple organisms (6%), 19 fungal (6%), and 16 Pneumocystis carinii pneumonia (PCP) (5%). The overall cumulative incidence of first pneumonia at 4 years after discharge home was 31%. The cumulative incidences of pneumonia according to donor type at 1 and 4 years after discharge home were 13 and 18% (autologous/syngeneic), 22 and 34% (HLA-matched related), and 26 and 39% (mismatched related/unrelated), respectively. Multivariate analysis of factors associated with development of late pneumonia after allografting were increasing patient age (RR 0.5 for20 years, 1.2 for40 years, P=0.009), donor HLA-mismatch (RR 1.6 for unrelated/mismatched related, P=0.01), and chronic graft-versus-host disease (GVHD; RR 1.5, P=0.007). Our data suggest that extension of PCP prophylaxis may be beneficial in high-risk autograft recipients. Further study of long-term anti-infective prophylaxis based on patient risk factors after SCT appear warranted.
- Published
- 2003
38. Invasive Mediastinal Staging for Lung Cancer: Better Prediction, Better Selection
- Author
-
David K. Madtes, Farhood Farjah, Michael S. Mulligan, Billanna Hwang, Douglas E. Wood, Rachel Waworuntu, and Francys C. Verdial
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine ,Lung cancer ,medicine.disease ,business ,Selection (genetic algorithm) ,Mediastinal staging - Published
- 2017
39. P1.03-036 Adherence to Eligibility Criteria for Low-Dose CT Screening in an Academic Center
- Author
-
Bernardo H. L. Goulart, Stuart Greenlee, David K. Madtes, Scott D. Ramsey, Jacob Bloom, and Mikael Anne Greenwood-Hickman
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Oncology ,business.industry ,medicine ,Low dose ct ,Center (algebra and category theory) ,Medical physics ,business - Published
- 2017
40. Selective Induction of Tissue Inhibitor of Metalloproteinase-1 in Bleomycin-Induced Pulmonary Fibrosis
- Author
-
David K. Madtes, Lee A. Kaback, Joan G. Clark, and Andrew L. Elston
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Pulmonary Fibrosis ,Clinical Biochemistry ,In situ hybridization ,Lung injury ,Biology ,Bleomycin ,Mice ,chemistry.chemical_compound ,Matrix Metalloproteinase 13 ,Gene expression ,Pulmonary fibrosis ,medicine ,Animals ,Collagenases ,RNA, Messenger ,Lung ,Molecular Biology ,In Situ Hybridization ,Tissue Inhibitor of Metalloproteinase-3 ,Tissue Inhibitor of Metalloproteinase-2 ,Tissue Inhibitor of Metalloproteinase-1 ,medicine.diagnostic_test ,Cell Biology ,respiratory system ,Tissue inhibitor of metalloproteinase ,medicine.disease ,Immunohistochemistry ,Molecular biology ,respiratory tract diseases ,Disease Models, Animal ,Bronchoalveolar lavage ,chemistry ,Interstitial collagenase ,Bronchoalveolar Lavage Fluid ,Procollagen - Abstract
Tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that have the capacity to modify cellular activities and to modulate matrix turnover. We demonstrate that TIMP-1 messenger RNA (mRNA) and protein expression are selectively and markedly increased in a murine model of bleomycin-induced pulmonary fibrosis. Northern analysis showed that lung steady-state TIMP-1 mRNA levels increased 14-fold after bleomycin administration compared with control mice. Expression of the genes for TIMP-2, TIMP-3, and interstitial collagenase (matrix metalloproteinase-13) was unaltered in the injured lung. In situ hybridization demonstrated that TIMP-1 gene induction was spatially restricted to areas of lung injury. Metalloproteinase inhibitory activity of relative molecular mass of ~ 21 to 28 kD, corresponding to the molecular weights for TIMP-1 and TIMP-2, was identified in lung extracts of bleomycin-injured mice by reverse zymography. Western analysis demonstrated that TIMP-1 protein levels in bronchoalveolar lavage fluid (BALF) of bleomycin-treated mice increased 220- and 151-fold at Days 4 and 28, respectively, compared with control mice. TIMP-2 immunoreactive protein in the BALF increased 20- and 103-fold relative to controls at Days 4 and 28, respectively. These results demonstrate that TIMP-1 gene expression is selectively increased, and that the expression of TIMP-1 and TIMP-2 is differentially regulated in bleomycin-induced pulmonary fibrosis. The profound and durable increase in TIMP-1 and TIMP-2 proteins suggests an important regulatory role for these antiproteases in the inflammatory and fibrotic responses to bleomycin-induced lung injury.
- Published
- 2001
41. Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-γ-inducible chemokines
- Author
-
David K. Madtes, Joan G. Clark, Anne E. Dixon, Janis B. Mandac, and Paul J. Martin
- Subjects
Lung Diseases ,Pulmonary and Respiratory Medicine ,Physiology ,Mice, Inbred Strains ,Lung injury ,Biology ,CCL7 ,Chemokine CXCL9 ,CCL5 ,Interferon-gamma ,Mice ,Physiology (medical) ,Animals ,CXCL10 ,CCL17 ,CXCL11 ,Lung ,CXCL16 ,Cell Biology ,Th1 Cells ,Chemokine CXCL10 ,Mice, Inbred C57BL ,Immunology ,Cytokines ,Intercellular Signaling Peptides and Proteins ,Chemokines ,Chemokines, CXC ,CCL23 - Abstract
Proinflammatory responses generated by T helper type 1 (Th1) cells may contribute significantly to immune-mediated lung injury. We describe a murine model of Th1 cell-induced lung injury in which adoptive transfer of alloreactive Th1 cells produces pulmonary inflammation characterized by mononuclear cell vasculitis, alveolitis, and interstitial pneumonitis. To investigate the link between activation of Th1 cells in the lung and inflammatory cell recruitment, we characterized cytokine and chemokine mRNA expression in Th1 cells activated in vitro and in lung tissue after adoptive transfer of Th1 cells. Activated Th1 cells per se express mRNA for interferon (IFN)-gamma and several members of the tumor necrosis factor family as well as the C-C chemokine receptor-5 ligands regulated on activation normal T cells expressed and secreted and macrophage inflammatory protein-1alpha and -1beta. Additional chemokine genes were induced in the lung after Th1 cell administration, most notably IFN-gamma-inducible protein (IP-10) and monokine induced by IFN-gamma (MIG). Remarkable increases in IP-10- and MIG-immunoreactive proteins were present in inflammatory foci lung and identified in macrophages, endothelium, bronchial epithelium, and alveolar structures. The findings suggest that IFN-gamma-inducible chemokines are an important mechanism for amplifying inflammation initiated by Th1 cells in the lung.
- Published
- 2000
42. Collagen accumulation is decreased in SPARC-null mice with bleomycin-induced pulmonary fibrosis
- Author
-
Thomas P. Strandjord, David K. Madtes, Daniel J. Weiss, and E. Helene Sage
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Physiology ,Pulmonary Fibrosis ,Biology ,Lung injury ,Bleomycin ,Extracellular matrix ,Mice ,chemistry.chemical_compound ,Fibrosis ,Physiology (medical) ,Pulmonary fibrosis ,medicine ,Animals ,Osteonectin ,RNA, Messenger ,Fibroblast ,Lung ,Mice, Knockout ,Cell Biology ,respiratory system ,Blotting, Northern ,medicine.disease ,Immunohistochemistry ,Molecular biology ,respiratory tract diseases ,Mice, Inbred C57BL ,Hydroxyproline ,medicine.anatomical_structure ,chemistry ,biology.protein ,Female ,Collagen ,Type I collagen - Abstract
Secreted protein acidic and rich in cysteine (SPARC) has been shown to be coexpressed with type I collagen in tissues undergoing remodeling and wound repair. We speculated that SPARC is required for the accumulation of collagen in lung injury and that its absence would attenuate collagen accumulation. Accordingly, we have assessed levels of collagen in SPARC-null mice in an intratracheal bleomycin-injury model of pulmonary fibrosis. Eight- to ten-week-old SPARC-null and wild-type (WT) mice received bleomycin (0.0035 U/g) or saline intratracheally and were subsequently killed after 14 days. Relative levels of SPARC mRNA were increased 2.7-fold ( P < 0.001) in bleomycin-treated WT lungs in comparison with saline-treated lungs. Protein from bleomycin-treated WT lung contained significantly more hydroxyproline (191.9 μg/lung) than protein from either bleomycin-treated SPARC-null lungs or saline-treated WT and SPARC-null lungs (147.4 μg/lung, 125.4 μg/lung, and 113.0 μg/lung, respectively; P < 0.03). These results indicate that SPARC is increased in response to lung injury and that accumulation of collagen, as indicated by hydroxyproline content, is attenuated in the absence of SPARC. The properties of SPARC as a matricellular protein associated with cell proliferation and matrix turnover are consistent with its participation in the development of pulmonary fibrosis.
- Published
- 1999
43. Idiopathic pneumonia after bone marrow transplantation: Cytokine activation and lipopolysaccharide amplification in the bronchoalveolar compartment
- Author
-
Joan G. Clark, David K. Madtes, Thomas R. Martin, Robert C. Hackman, Stephen W. Crawford, and Allen Farrand
- Subjects
Adult ,Lipopolysaccharides ,Pathology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Lipopolysaccharide Receptors ,Bronchi ,Lung injury ,Critical Care and Intensive Care Medicine ,Idiopathic pneumonia syndrome ,Humans ,Medicine ,Bone Marrow Transplantation ,Membrane Glycoproteins ,medicine.diagnostic_test ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Respiratory disease ,Pneumonia ,Middle Aged ,Transforming Growth Factor alpha ,medicine.disease ,Pulmonary Alveoli ,Transplantation ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Cytokine ,Case-Control Studies ,Immunology ,Cytokines ,Interleukin-2 ,Bone marrow ,Carrier Proteins ,business ,Bronchoalveolar Lavage Fluid ,Acute-Phase Proteins ,Interleukin-1 - Abstract
To determine whether idiopathic pneumonia syndrome (IPS), a form of noninfectious lung injury that follows bone marrow transplantation, is associated with cytokine activation and increased susceptibility to lipopolysaccharide (LPS).Case series.Tertiary referral center for marrow transplantation.Recipients with biopsy-confirmed IPS; normal volunteers and marrow transplant recipients without IPS were analyzed as controls.Levels of lymphocyte and macrophage-derived cytokines as well as components of the LPS, LPS-binding protein (LBP), and CD14 system in bronchoalveolar lavage (BAL) fluid were determined. We found evidence of increased vascular permeability (BAL protein) and inflammatory cytokine activation (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor-alpha) in patients with IPS. Patients without IPS had BAL fluid cytokine and protein levels that were similar to levels in BAL fluid from normal volunteers. Moreover, components of the LPS amplification system (LBP and soluble CD14) were increased in patients with IPS but not in patients without IPS.These results provide direct evidence for proinflammatory cytokine activation in IPS and suggest that these patients might be at increased risk for LPS-mediated injury through the LBP amplification pathway.
- Published
- 1999
44. Mice with a targeted intronic deletion in the Col1a1 gene respond to bleomycin-induced pulmonary fibrosis with increased expression of the mutant allele
- Author
-
Sheriar G. Hormuzdi, Thomas P. Strandjord, David K. Madtes, and Paul Bornstein
- Subjects
Male ,Genetically modified mouse ,Pulmonary Fibrosis ,Transgene ,Mutant ,Intron ,Transfection ,Biology ,Molecular biology ,Introns ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Bleomycin ,Mice ,Gene Expression Regulation ,Downregulation and upregulation ,Animals ,Female ,Collagen ,Allele ,Molecular Biology ,Gene ,Alleles ,Gene Deletion - Abstract
Experiments designed to examine the role of the first intron in regulation of the Col1a1 gene by transfection and in transgenic mice have led to conflicting conclusions. Recently, Hormuzdi et al. [Hormuzdi, S.G., Penttinen, R., Jaenisch, R., Bornstein, P., 1998. A gene-targeting approach identifies a function for the first intron in expression of the alpha1(I) collagen. Mol. Cell. Biol. 18, 3368-3375.] created a targeted deletion in this intron in mice and demonstrated an age-dependent reduction in expression of the mutated allele in lung and skeletal muscle. In this study, intratracheal instillation of bleomycin in mice was used to induce pulmonary fibrosis in control and intron-deleted animals. This stimulus for collagen synthesis was associated with a marked upregulation of the intron-deleted allele in mutant mice. Our results establish that the inhibition of expression of the mutant Col1a1 gene is not fixed, since the gene can still respond to physiological signals. We propose that cis-acting elements, elsewhere in the gene, can compensate for the lack of intronic sequences in the mutated Col1a1 allele and account for the conditional nature of the inhibition. This model has the potential to resolve the conflicting results of previous transfection and transgenic experiments in which different fragments of the Col1a1 gene were used.
- Published
- 1999
45. Transforming Growth Factor- α Deficiency Reduces Pulmonary Fibrosis in Transgenic Mice
- Author
-
Robert C. Hackman, Joan G. Clark, Ashley R. Dunn, Andrew L. Elston, and David K. Madtes
- Subjects
Pulmonary and Respiratory Medicine ,Genetically modified mouse ,medicine.medical_specialty ,Pathology ,Genotype ,Pulmonary Fibrosis ,Clinical Biochemistry ,Mice, Transgenic ,Lung injury ,Bleomycin ,Pathogenesis ,Mice ,Hydroxyproline ,chemistry.chemical_compound ,Internal medicine ,Pulmonary fibrosis ,medicine ,Animals ,Lung ,Molecular Biology ,DNA Primers ,Mice, Knockout ,Base Sequence ,Epidermal Growth Factor ,business.industry ,DNA ,Cell Biology ,Transforming Growth Factor alpha ,respiratory system ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Intercellular Signaling Peptides and Proteins ,RNA ,Collagen ,business ,Cell Division ,Heparin-binding EGF-like Growth Factor ,Transforming growth factor - Abstract
Despite evidence that implicates transforming growth factor-alpha (TGF-alpha) in the pathogenesis of acute lung injury, the contribution of TGF-alpha to the fibroproliferative response is unknown. To determine whether the development of pulmonary fibrosis depends on TGF-alpha, we induced lung injury with bleomycin in TGF-alpha null-mutation transgenic mice and wild-type mice. Lung hydroxyproline content was 1.3, 1.2, and 1.6 times greater in wild-genotype mice than in TGF-alpha-deficient animals at Days 10, 21, and 28, respectively, after a single intratracheal injection of bleomycin. At Days 7 and 10 after bleomycin treatment, lung total RNA content was 1.5 times greater in wild-genotype mice than in TGF-alpha-deficient animals. There was no significant difference between mice of the two genotypes in lung total DNA content or nuclear labeling indices after bleomycin administration. Wild-genotype mice had significantly higher lung fibrosis scores at Days 7 and 14 after bleomycin treatment than did TGF-alpha-deficient animals. There was no significant difference between TGF-alpha-deficient mice and wild-genotype mice in lung inflammation scores after bleomycin administration. To determine whether expression of other members of the epidermal growth factor (EGF) family is increased after bleomycin-induced injury, we measured lung EGF and heparin-binding- epidermal growth factor (HB-EGF) mRNA levels. Steady-state HB-EGF mRNA levels were 321% and 478% of control values in bleomycin-treated lungs at Days 7 and 10, respectively, but were not significantly different in TGF-alpha-deficient and in wild-genotype mice. EGF mRNA was not detected in normal or bleomycin-treated lungs of mice of either genotype. These results show that TGF-alpha contributes significantly to the pathogenesis of pulmonary fibrosis after bleomycin-induced injury, and that compensatory increases in other EGF family members do not occur in TGF-alpha-deficient mice.
- Published
- 1999
46. Pulmonary veno-occlusive disease following reduced-intensity cord blood transplantation
- Author
-
David K. Madtes, C T Allen, J Schramm, Jonathan A. Gutman, and Colleen Delaney
- Subjects
Transplantation ,medicine.medical_specialty ,Pathology ,Intimal hyperplasia ,business.industry ,Reduced intensity ,Hematology ,Disease ,medicine.disease ,Pulmonary hypertension ,Fibrosis ,Internal medicine ,Cardiology ,Medicine ,Pulmonary Veno-Occlusive Disease ,business ,Progressive disease ,Cord blood transplantation - Abstract
Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that is characterized histopathologically by intimal proliferation and fibrosis of the pulmonary venules and small veins leading to progressive vascular obstruction. PVOD carries a poor prognosis, with most reported patients experiencing progressive disease and death within 2 years of diagnosis.1
- Published
- 2008
47. Low-Dose Computed Tomography Screening for Lung Cancer
- Author
-
Laura S. Welch, David K. Madtes, and Knut Ringen
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Low dose ,Computed tomography ,General Medicine ,medicine.disease ,Tomography x ray computed ,Cancer screening ,Internal Medicine ,medicine ,Adenocarcinoma ,Radiology ,Lung cancer ,business ,Lung cancer screening ,Mass screening - Published
- 2015
48. Lung Injury Induced by Alloreactive Th1 Cells Is Characterized by Host-Derived Mononuclear Cell Inflammation and Activation of Alveolar Macrophages
- Author
-
Joan G. Clark, David K. Madtes, Robert C. Hackman, Wei Chen, Martin A. Cheever, and Paul J. Martin
- Subjects
Immunology ,Immunology and Allergy - Abstract
We have investigated a murine model of acute lung injury caused by i.v. administration of a T cell clone (CD4+, Th1 phenotype) that recognizes Ly5, a polymorphic cell surface glycoprotein expressed on hemopoietic cells. Alloreactive cloned T cells, specific for host Ly5 Ag, cause a mononuclear cell pulmonary vasculitis and interstitial pneumonitis. In further studies of the cellular mechanisms involved in this model, we found that mature host T cells or B cells are not required, since lung injury was comparable in transgenic host mice that lack these cells (RAG-1 knockout). Cloned T cells labeled in vitro with bromodeoxyuridine were localized in inflammation foci in lung, but the majority of cells in the foci were not labeled. Using transgenic mice that constitutively express lacZ, we determined that the mononuclear cell vasculitis is of host cell origin. Alveolar macrophages (AM) from T cell-treated mice spontaneously secreted TNF-α in culture, whereas TNF-α was not detected in AM cultures from control mice. TNF-α production in response to LPS stimulation was significantly higher in AM cultures derived from T cell-treated mice than in those from control mice. Challenge with sublethal doses of LPS resulted in 50% mortality in T cell-treated mice and was associated with augmented AM TNF-α production and protein in bronchoalveolar lavage fluid. We conclude that immune activation of T cells of the Th1 phenotype can initiate lung injury characterized by a host-derived mononuclear cell inflammation and activation of AM.
- Published
- 1998
49. T Cells Specific for a Polymorphic Segment of CD45 Induce Graft-Versus-Host Disease with Predominant Pulmonary Vasculitis
- Author
-
Wei Chen, Gurkamal S. Chatta, William D. Rubin, Joan G. Clark, Robert C. Hackman, David K. Madtes, Denny H. Ligitt, Yoichiro Kusunoki, Paul J. Martin, and Martin A. Cheever
- Subjects
Immunology ,Immunology and Allergy - Abstract
To study the character of graft-vs-host disease (GVHD) induced by T cells specific for hemopoietic cells, T cells specific for a polymorphic segment of CD45 were transferred into CD45 congenic mice. C57BL/6 mice that express the CD45b allele were immunized with a 13 mer peptide representing the polymorphic segment (p257–268) of CD45a protein. Conversely, C57BL/6 mice congenic for CD45a were immunized with the CD45b peptide. CD4+ T cells specific for allelic CD45 peptides were elicited. Importantly, T cells specific for CD45 peptides proliferated specifically and vigorously in response to spleen cells expressing the appropriate polymorphic CD45 protein. T cells specific for CD45 induced a substantial graft-vs-host response (GVHR) with predominant early pulmonary vasculitis and later more widespread interstitial mononuclear cell infiltration and alveolitis. No GVHR was induced in bone marrow chimeras expressing only donor hemopoietic cells. Thus, donor T cell recognition of host hemopoietic cells is sufficient to elicit GVHR, but the classical skin, liver, and gut manifestations of GVHD were not observed. The CD45-specific T cells used secreted Th1 cytokines, but without detectable soluble IL-2. Studies using CD45-specific T cells with different effector functions might allow further dissection of donor cell requirements for GVHD syndromes.
- Published
- 1998
50. Association Between AGT SNPs, Plasma AGT Levels, and Risk for IPS After Allogeneic HCT
- Author
-
Lue Ping Zhao, Jason W. Chien, Cindy Zhang, Barry E. Storer, Makoto Onizuka, John A. Hansen, Paul J. Martin, Yao Li, Hongwei Wang, Wenhong Fan, and David K. Madtes
- Subjects
Oncology ,medicine.medical_specialty ,Transplantation ,business.industry ,Internal medicine ,medicine ,Single-nucleotide polymorphism ,Allogeneic hct ,Hematology ,business - Published
- 2013
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