Impact of Payor-Initiated Switching of Inhaled Corticosteroids on Lung Function.

OBJECTIVES: To evaluate the impact of a payor-initiated formulary change in inhaled corticosteroid coverage on lung function in patients with asthma and on provider prescribing practices. This formulary change, undertaken in August 2016 by a Medicaid payor in Kentucky, eliminated coverage of beclomethasone dipropionate, a metered dose inhaler (MDI), in favor of mometasone furoate, available as MDI and dry powder inhaler (DPI). STUDY DESIGN: A retrospective chart review was conducted on children with asthma ages 6-18 years covered by the relevant payor from a university-based pediatric practice who were seen before the formulary change (February to July 2016) and after (February to July 2017). Spirometry data from each visit was compared using the paired Student t test. RESULTS: Fifty-eight patients were identified who were initially on beclomethasone dipropionate and had spirometry available at both visits. Those who switched from an MDI to a DPI (n = 24) saw a decline in median predicted forced expiratory volume in 1 second from 98.5% to 91% (P = .013). A decline was also seen in forced expiratory flow at 25%-75%, from 89.5% predicted to 76% predicted (P = .041). No significant changes were observed in children remaining on an MDI. Seven patients discontinued inhaled corticosteroid therapy. CONCLUSIONS: This study suggests insurance formulary changes leading to use of a different inhaler device may have a detrimental impact on pediatric lung function, which may be a surrogate measure for overall asthma control. This could be due to a lack of adequate timely educational intervention as well as the inability of some children to use DPIs.

Effectiveness of convective water vapor energy therapy versus prostatic urethral lift for symptomatic benign prostatic hyperplasia: a systematic review and indirect comparison.

PURPOSE: To synthesize the evidence from randomized controlled trials of prostatic urethral lift (PUL) and convective water vapor thermal energy therapy (WAVE) for minimally invasive treatment of men with benign prostatic hyperplasia. METHODS: A systematic search of databases was performed to identify trials comparing WAVE or PUL to either an active or sham surgery control in subjects with symptomatic benign prostatic obstruction. A controlled indirect treatment comparison based on the approach of Bucher was performed for outcomes including International Prostate Symptom Score and maximum urinary flow rate (Qmax). The durability of treatment response was assessed by life-table analysis of freedom from retreatment through 4 years. RESULTS: Two multicenter sham-controlled trials (Rezum II Study, NCT01912339: LIFT Study, NCT01294150) were identified. The trials employed a common sham procedure and were similar with respect to their designs and subjects' baseline characteristics. Comparisons on the treatment effect in excess of sham response found non-significant differences between WAVE and PUL for symptom score [mean difference (MD): - 1.7 points; 95% confidence interval (CI): - 4.8, 1.4] but Qmax improvements favored WAVE [MD: 3.4 ml/sec; CI: 1.2, 5.6]. The proportion free of retreatment through 4 years was 89.1% for WAVE versus 75.4% for PUL [log-rank P = 0.004]. CONCLUSIONS: PUL and WAVE provide similar subjective improvements but flow-rate improvement and durability of response seem greater for WAVE. The confirmation of these findings in a randomized trial is warranted.

Anti-inflammatory dosing of theophylline in the treatment of status asthmaticus in children.

BACKGROUND: Low-dose theophylline has been recognized for its ability to restore histone deacetylase-2 activity which leads to improved steroid responsiveness and thus improved clinical outcome. We retrospectively evaluated the effect of low-dose theophylline therapy in pediatric patients hospitalized for an acute asthma exacerbation as a proof of concept study. METHODS: We compared patients who received low-dose theophylline (5-7 mg/kg/day) in addition to current standard of care to patients who were treated with current standard of care alone. The primary outcome of the study was hospital length of stay (LOS). Generalized linear mixed-effects modeling (GLMM) was used to test whether receiving theophylline independently predicted outcomes. A Cox (proportional hazards) regression model was also developed to examine whether theophylline impacted LOS. RESULTS: After adjustment for illness severity measures, theophylline significantly reduces LOS (ß=-21.17, P<0.001), time to discontinue oxygen (ß=-15.88, P=0.044), time to spirometric improvement (ß=-16.60, P=0.014), and time to space albuterol (ß=-23.2, P<0.001) as well as reduced costs (ß=-US$2,746, P<0.001). Furthermore, theophylline significantly increased the hazards of being discharged from the hospital (hazards ratio =1.75, 95% confidence interval 1.20-2.54, P=0.004). There was no difference in side effects between patients who receive low-dose theophylline and those who did not. CONCLUSION: The results of this retrospective study suggest low-dose theophylline may have a positive effect in acute status asthmaticus. This study suggests that further research with a prospective, randomized, double-blinded, placebo controlled trial may be warranted to confirm and extend our findings.

Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy.

RATIONALE: Neuroendocrine cell hyperplasia of infancy (NEHI) is a diffuse lung disease that presents in infancy and improves during childhood. Long-term outcomes have not previously been described. In one familial cohort, we have reported that NEHI is associated with a heterozygous variant of NKX2.1/TTF1. OBJECTIVES: Our objective was to determine whether pulmonary abnormalities persist in adults with NEHI, to aid in elucidating the natural history of this disease. METHODS: Four adult relatives with heterozygous NKX2.1 mutation and with clinical histories compatible with NEHI enrolled in a prospective study that included questionnaires, pulmonary function tests, and chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS: Mild radiologic abnormalities including mosaicism were seen in all four cases. Three individuals had obstruction on pulmonary function tests, two had marked air trapping, and three had symptomatic impairments with exercise intolerance. CONCLUSIONS: Although clinical improvement occurs over time, NEHI may result in lifelong pulmonary abnormalities in some cases. Further studies are required to better describe the natural history of this disease and would be facilitated by additional delineation of genetic mechanisms to enable improved case identification.

Decreasing mechanical ventilator support in medically fragile children with bronchopulmonary dysplasia: A step-by-step weaning protocol at a pediatric long term extended care facility.

PURPOSE: Prolonged mechanical ventilation (PMV) in medically fragile children is commonly used in pediatric long term extended care facilities (P-LTEC). Currently, PMV weaning is performed in an unstandardized fashion. Without an official protocol, patients are subjected to delayed weaning, infection, increased mortality, and difficulty obtaining placement at adult group homes. A step-wise approach may help these children wean from PMV effectively. METHODS: A retrospective chart review of five tracheostomized children with bronchopulmonary dysplasia was conducted. RESULTS: A 5-step weaning protocol was created using data collected retrospectively. First, pressure control ventilator settings were decreased until rate = 10, fraction of inspired oxygen = 30% and pressure support = 6-10. Second, continuous positive airway pressure (CPAP) was trialed while awake with ventilator at night. Third, CPAP was continued for 24 hours. Fourth, tracheostomy collar (TC) was trialed while awake, with CPAP at night. Lastly, TC was continued for 24 hours. Advancing to Step 2 required the most time, likely secondary to episodic illnesses, with a mean of 31.2 months. The process required 3.2 months to advance to Step 3, 1.6 months to achieve Step 4, and 2.6 months to attain Step 5. CONCLUSION: Using the data obtained in this case series an official protocol could be created to wean P-LTEC residents from PMV, with reasonable expectations of the process.

Unilateral pulmonary vein atresia: A rare case of hemoptysis.

We present a rare case of hemoptysis secondary to isolated unilateral pulmonary vein atresia. Isolated pulmonary vein atresia is a rare condition in which patients typically acquire a diagnosis in infancy and early childhood [Mataciunas et al.; Pourmoghadam et al.]. Our patient presented during puberty with several previous episodes of hemoptysis prior to her admission and diagnosis. The initial diagnosis was suspected in our patient from chest computerized tomography (CT), and confirmed with cardiac catheterization and pulmonary angiography. Treatment aim is to preserve lung function and minimize irreversible pulmonary remodeling [Pourmoghadam et al.; Harrison et al.]. Conservative monitoring can be considered with milder or asymptomatic cases, while others may require preoperative collateral artery banding, surgical anastomosis between the pulmonary vein (PV) & left atrium (LA) and even pneumonectomy [Pourmoghadam et al.].

Drug and device development for localized prostate cancer: report of a Food and Drug Administration/American Urological Association public workshop.

Summary of the discussion at a public workshop cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association reviewing potential trial designs for product and device development for the treatment of localized prostate cancer. Product development for treatment of localized prostate cancer has been stymied by the impracticality of using overall survival as an endpoint in patients with localized disease and the lack of acceptable surrogate endpoints. A workshop evaluating potential trial designs for the development of therapies for localized prostate cancer was held in San Diego, CA, in May 2013. Invited experts represented multiple stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates. The expert panel discussed development of products for all risk strata of clinically localized prostate cancer. The panel responded to specific questions from FDA, discussing trial design for patients with low-, intermediate-, and high-risk prostate cancer, focal therapy for prostate cancer, patients who have undergone definitive radiation therapy, and adjuvant therapy for patients undergoing radiation therapy or surgery. Expert commentary provided by the panel will inform a planned FDA guidance on pathways for product and device development for treatment of localized prostate cancer and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products or devices for the treatment of this disease.

Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop.

OBJECTIVE: To summarize the discussion at a public workshop, cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association, reviewing potential trial designs for the development of new therapies for non-muscle-invasive bladder cancer (NMIBC). There have been only 3 drug approvals for NMIBC in the last 30 years, and product development for this disease has been stymied by difficulties in trial design and patient accrual. METHODS: A workshop evaluating potential trial design for the development of therapies for NMIBC was held in San Diego, CA, in May 2013. Invited experts representing all stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates, discussed development of products for all risk strata of NMIBC. RESULTS: The panel responded to specific questions from the FDA, discussing eligibility criteria, efficacy endpoints, and trial design for patients with a mix of high-grade papillary disease and carcinoma in situ, Bacillus Calmette-Guerin (BCG)-refractory disease, and intermediate-risk disease. Panel members also addressed the magnitude of response that would be clinically meaningful for various disease strata and trial design options for perioperative intravesical chemotherapy instillation at the time of resection of bladder tumors. CONCLUSION: Expert commentary provided by panel members will inform a planned FDA guidance on pathways for drug and biologic development for NMIBC and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products for this disease.

Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene.

PURPOSE: Prostate cancer (PCa) prevention remains an appealing strategy for the reduction of overtreatment and secondary adverse effects. We evaluated the efficacy of toremifene citrate 20 mg in PCa prevention among men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on biopsy. PATIENTS AND METHODS: One thousand five hundred ninety men with HGPIN, or HGPIN and atypia, and no PCa on prostate biopsy were randomly assigned 1:1 to receive toremifene citrate 20 mg or placebo in a 3-year phase III, double-blind, multicenter trial. Men underwent annual biopsy until cancer detection or study end. Efficacy analysis was performed in 1,467 men who underwent at least one on-study biopsy. Baseline risk factors were evaluated to determine influence on cancer detection. RESULTS: Cancer was detected in 34.7% and 32.3% of men in the placebo and treatment groups, respectively, with no observed difference (P = .39, log-rank test) in PCa-free survival. The 3-year Kaplan-Meier PCa-free survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group. Exploration of baseline risk factors demonstrated no subset in which a risk reduction was observed. In the placebo group, 17.9%, 12.9%, and 13.6% of men at risk at the beginning of years 1, 2, and 3, respectively, were diagnosed with PCa. CONCLUSION: Although toremifene 20 mg did not lower the PCa detection rate, men with isolated HGPIN have a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion in chemoprevention trials and require surveillance by periodic prostate biopsy.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS: In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS: The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS: Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

From Childhood Asthma to Chronic Obstructive Pulmonary Disease: Evidence Supporting a Disease Continuum.

In this review, we analyze the available evidence showing a link between asthma and chronic obstructive pulmonary disease (COPD). Many features (epidemiologic, physiologic, and histologic) overlap between these two conditions. Both environmental cigarette smoke exposure and early lung development are risk factors for the development of asthma and COPD. However, recent studies suggest that up to 25% of COPD cases were nonsmokers. Asthma during early childhood, independent of smoking history, may be an independent risk factor for the later development of COPD. One explanation for this phenomenon suggests that early small airway dysfunction (including chronic airway inflammation and airway remodeling) can lead to permanent impairment in lung physiology. Several reasons why control of airway inflammation is difficult in some patients are explored. Finally, we examine the available evidence suggesting overlapping histologic features in both asthma and COPD.