Papers by Donald R VanDevanter
Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention
Pediatric pulmonology, Jan 3, 2017
The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expirato... more The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).(1,2,4,6) We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1 ) decline. Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients). Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were ...
Remarkable advances in the management of individuals born with cystic fibrosis (CF) would not hav... more Remarkable advances in the management of individuals born with cystic fibrosis (CF) would not have been realized without empiric trial and error by CF clinicians with treatments developed and available for other purposes. As the testing and registration of CF-specific treatments have increased, so too have associated health care costs, particularly those of chronic medications. The transition of CF from a lethal pediatric disease to a life-shortening one with an adult majority, concurrent with sharp increases in chronic medication costs, has placed many CF treatments under increased scrutiny by third-party payers, particularly when prescribed to individuals from CF subpopulations that may not have been included in registration trials. Despite overall health improvements in the CF cohort and the increasing availability of CF-specific therapies, many physicians remain tasked with managing the health of patients from subpopulations that may be too young, too sick, or too complicated to have been included in clinical trials. An understanding of why particular CF subpopulations may have been excluded from registration trials, as well as consideration of a treatment's described mechanism of action, can support assessment for the potential for benefit (and risk) in these populations and help physicians advocate for patient access to treatments.
Background: There are few objective data to guide management of cystic fibrosis (CF) pulmonary ex... more Background: There are few objective data to guide management of cystic fibrosis (CF) pulmonary exacerbations. We studied intravenous (IV) antibiotic treatment failure as defined by a need to retreat patients with IV antibiotics within 30 days of completion of a prior IV antibiotic treatment for pulmonary exacerbation.
Background: Single-center analyses have suggested that the number of CF pulmonary exacerbations (... more Background: Single-center analyses have suggested that the number of CF pulmonary exacerbations (PEx) treated with intravenous antibiotics an individual has experienced in the prior year is significantly associated with their future PEx hazard. Methods: We studied Prior-year PEx association with future PEx hazard by Cox proportional hazards regression among CF Foundation Patient Registry patients who experienced PEx after Jan 1, 2010. Results: Among 13,579 patients, those with 1, 2, 3, or ≥ 4 Prior-year PEx treated with intravenous antibiotics were at 1.8, 2.9, 4.8, and 8.7 higher PEx hazard vs those without (P b .0001). Adjustment with significant demographic and clinical covariates (univariate P ≤ .0001) reduced Prior-year PEx hazard ratios to 1.6, 2.4, 3.6, and 6.0 (P b .0001). No other covariates had adjusted hazard ratios of N 1.7. Conclusions: Prior-year PEx strongly associate with future PEx hazard and should be accounted for in prospective trials where treatment-associated change in PEx hazard is an efficacy outcome.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 2014
Antibiotic-Resistant <i>Pseudomonas aeruginosa</i> in Cystic Fibrosis
Respiration, 2007
Pediatric Pulmonology, 2005
Recent studies suggest that chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF... more Recent studies suggest that chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) involve anaerobic biofilms, and that these biofilms are the reason chronic infections are rarely eradicated by antibiotic therapy, regardless of the in vitro susceptibility of infecting bacteria. These observations led to the development of an in vitro method for testing antibiotic susceptibility of CF clinical isolates in biofilms (Moskowitz et al., J Clin Microbiol 2004;42:1915-1922 and unearthed an apparent paradox. Antibiotics that remain cornerstones of clinical management of CF pulmonary exacerbations (e.g., beta-lactam antibiotics) appear to have little to no activity at clinically achievable concentrations when tested in vitro against clinical P. aeruginosa isolates growing in biofilms. The proven clinical efficacy of beta-lactam antibiotics in treating exacerbations, and the selection for beta-lactam resistance in vivo, suggest that planktonic bacteria play a significant role in pulmonary exacerbations of CF. A model of infection architecture is proposed in which biofilm and planktonic compartments each play a role in infection persistence and pulmonary exacerbation, respectively. Infection architecture may partially account for the observed lack of correlation between in vitro antibiotic susceptibility testing and clinical response to antibiotic therapy.
Nucleic Acids Research, 1992
DNA fragments under 200 kilobase pairs (kbp), between 200 kbp and 2 megabase pairs (Mbp), and bet... more DNA fragments under 200 kilobase pairs (kbp), between 200 kbp and 2 megabase pairs (Mbp), and between 2 Mbp and 6 Mbp are optimally separated by pulsed field gel electrophoretic techniques using different switching frequencies, electrophoretic field strengths, angles of reorientation, and/or agarose concentrations (1). For this reason, analyses of uncharacterized DNA fragments using pulsed-field techniques often require preliminary studies to determine what size ranges DNA fragments of interest fall within and it is not uncommon to run at least two different pulsed-field gels in order to fully characterize large DNA fragments from a single cell source (e.g. 2).
The Journal of Pediatrics, 2005
Electrophoretic isolation of extrachromosomal DNA from tumor cells
Genes, Chromosomes and Cancer, 1995
Gene amplification allows transformed cells to overexpress specific genes and gain a survival adv... more Gene amplification allows transformed cells to overexpress specific genes and gain a survival advantage. For this reason, cloning and characterization of amplified genes can improve our understanding of the biology of transformed cells. The techniques of in-gel renaturation and chromosome microdissection can enrich for amplified DNA sequences, but both are labor intensive and have other drawbacks. We have developed an alternative strategy of enriching for amplified DNA sequences that involves two-directional agarose gel electrophoresis of extrachromosomal circular DNA. Extrachromosomal circles can be detected with repetitive DNA probes and can be used to produce DNA probes suitable for fluorescence in situ hybridization for location of genomic origin. The ability to enrich for amplified DNA without specialized equipment or transformed cell metaphases should prove useful in the search for new genes which are important in tumor cell progression.
Recombination between separateMYC amplification structures in COLO320 cells
Genes, Chromosomes and Cancer, 1993
Cytogenetically visible gene amplification structures can consist of arrays of amplicons presumab... more Cytogenetically visible gene amplification structures can consist of arrays of amplicons presumably formed by secondary &quot;rearrangements&quot; following amplicon formation. The structural evolution of gene amplification sites in tumor cells suggests that complex secondary structures may have some selective advantage in the tumor cell environment. Although secondary amplicon rearrangements are a hallmark of the gene amplification process, little is known about the mechanics of this process. COLO320 neuroendocrine tumor cells carry two different types of amplified MYC oncogene sequences, one type with an intact MYC gene and the other with a rearranged &quot;chimeric&quot; MYC gene. We have studied various clonal subpopulations of COLO320 cells and identified regions within and downstream of the MYC locus that are unique to each amplicon type. Using double-label fluorescence in situ hybridization with DNA probes unique to each amplicon type, we have observed that both chromosomal and extrachromosomal MYC amplicon arrays in COLO320 cells frequently consist of heterogeneous mixtures of each MYC amplicon type. Our results suggest that the two MYC amplicon types of COLO320 cells were formed simultaneously but independently, and that double minute chromosomes observed in COLO320 cells were formed by intermolecular homologous recombination secondary to amplicon formation.
Microbial diversity in the cystic fibrosis airways: where is thy sting?
Future Microbiology, 2012
Trisomy 8 in primary esthesioneuroblastoma
Cancer Genetics and Cytogenetics, 1991
Esthesioneuroblastoma is a rare malignancy believed to be derived from neuroectodermal stem cells... more Esthesioneuroblastoma is a rare malignancy believed to be derived from neuroectodermal stem cells within the olfactory epithelium. We have obtained the karyotype of a primary esthesioneuroblastoma following brief (7-day) in vitro culture, and have determined that the only observable cytogenetic anomaly is the presence of an additional chromosome 8. Previously, the karyotypes of two cell lines established from metastatic esthesioneuroblastomas have been reported to contain the equivalent of three copies of chromosome 8, in addition to other chromosomal aberrations, including the reciprocal translocation, t(11;22)(q24;q12). Examination of the cytogenetic literature suggests that an extra copy of chromosome 8 is a common occurrence in undifferentiated small round cell tumors frequently observed to carry the t(11;22), including esthesioneuroblastoma, Ewing&amp;amp;#39;s sarcoma, peripheral neuroepithelioma, Askin&amp;amp;#39;s tumor, and rhabdomyosarcoma. These data, combined with our report of a small round cell tumor with the karyotype 47,XY, +8, indicate that trisomy 8 may be a common phenomenon in these tumors, and may also provide some sort of selective advantage to these tumor types.
Background: Studies have described illness associated with cystic fibrosis (CF) early in life, bu... more Background: Studies have described illness associated with cystic fibrosis (CF) early in life, but there is no comprehensive accounting of the prevalence and ages of disease manifestation and progression described in individual studies.
Methods: We searched for peer-reviewed English-language studies of the health of children ≤6 years old with CF (published 1990–2014). Structural abnormalities and dysfunction of the digestive and respiratory systems were summarized across relevant studies by system and age
group. Results: Primary studies (125 total) from 22 countries described abnormalities, dysfunction, and disease progression in infancy and early childhood. Improved health was consistently observed in association with diagnosis via newborn screening compared with cohorts diagnosed later
by symptomatic presentation. Conclusions: The peer-reviewed literature is remarkably consistent: CF-associated growth impairment and airway abnormalities are reported at birth, and disease progression is reported in infancy and throughout childhood. Earlier access to routine CF management is associated with improved subsequent health status.
Journal of Cystic Fibrosis, 2014
Journal of Cystic Fibrosis, 2015
Text: Objective: To evaluate safety of levofloxacin inhalation solution (LIS) 240mg BID in subjec... more Text: Objective: To evaluate safety of levofloxacin inhalation solution (LIS) 240mg BID in subjects with cystic fibrosis from 3 controlled trials. Methods: Pooled disposition and treatmentemergent adverse events (AE) from subjects receiving LIS or placebo (PBO) in 2 doubleblind, 28day singletreatment cycle, controlled studies (MPEX204 and 207) and LIS or tobramycin inhalation solution [TIS] 300 mg BID in 1 openlabel, 28day 3cycle, controlled study (MPEX209) were analysed. Data from MPEX209 Ext. (28day, 3cycle, LIS only) were also analysed. Results: The numbers of subjects (mean age) receiving ≥1 dose of study drug and included in the safety analyses were: 409 LIS (29y), 146 PBO (29y) and 90 TIS (29y). Study discontinuations were: 6.8% LIS, 2.1% PBO and 7.8% TIS, primarily due to AEs (2.9% LIS; 2.1% PBO) or other (5.6% TIS). Early discontinuations of study drug (but not necessarily study participation) were: 13.9% LIS, 14.4% PBO and 15.6% TIS. Most common AEs in LIS group (LIS, PBO, TIS, respectively) were: cough (54.5%, 37.7%, 52.2%), disease progression (47.2%, 36.3%, 63.3%), sputum increase (43.5%, 29.5%, 44.4%), dysgeusia (31.3%, 0.7%, 0%), respiratory tract congestion (31.1%, 27.4%, 34.4%) and increased viscosity of bronchial secretion (23.7%, 14.4%, 31.1%). Possible/probable treatmentrelated AEs (≥1) occurred in 48.2% LIS (mainly dysgeusia), 18.5% PBO and 15.6% TIS subjects. Disease progression was the most common serious AE (10.8% LIS, 8.9% PBO, 21.1% TIS); no deaths occurred. No new safety signals were noted in the MPEX209 extension. Conclusions: LIS was safe and generally welltolerated, with dysgeusia the only distinguishing AE compared with TIS.
188 Standardized treatment of pulmonary exacerbations (STOP) study: Clinical presentations of pulmonary exacerbations
Journal of Cystic Fibrosis, 2015
WS07.1 Standardized treatment of pulmonary exacerbations (STOP) study: Treatment goals for pulmonary exacerbations
Journal of Cystic Fibrosis, 2015
Uploads
Papers by Donald R VanDevanter
Methods: We searched for peer-reviewed English-language studies of the health of children ≤6 years old with CF (published 1990–2014). Structural abnormalities and dysfunction of the digestive and respiratory systems were summarized across relevant studies by system and age
group. Results: Primary studies (125 total) from 22 countries described abnormalities, dysfunction, and disease progression in infancy and early childhood. Improved health was consistently observed in association with diagnosis via newborn screening compared with cohorts diagnosed later
by symptomatic presentation. Conclusions: The peer-reviewed literature is remarkably consistent: CF-associated growth impairment and airway abnormalities are reported at birth, and disease progression is reported in infancy and throughout childhood. Earlier access to routine CF management is associated with improved subsequent health status.
Methods: We searched for peer-reviewed English-language studies of the health of children ≤6 years old with CF (published 1990–2014). Structural abnormalities and dysfunction of the digestive and respiratory systems were summarized across relevant studies by system and age
group. Results: Primary studies (125 total) from 22 countries described abnormalities, dysfunction, and disease progression in infancy and early childhood. Improved health was consistently observed in association with diagnosis via newborn screening compared with cohorts diagnosed later
by symptomatic presentation. Conclusions: The peer-reviewed literature is remarkably consistent: CF-associated growth impairment and airway abnormalities are reported at birth, and disease progression is reported in infancy and throughout childhood. Earlier access to routine CF management is associated with improved subsequent health status.