Outcomes of Stable Multiple Sclerosis Patients Staying on Initial Interferon Beta Therapy Versus Switching to Another Interferon Beta Therapy: A US Claims Database Study.

INTRODUCTION: This study was designed to assess real-world outcomes of patients with multiple sclerosis (MS) who were stable on interferon (IFN) beta therapy in the year prior to switching to another IFN beta therapy versus those who continued on the initial treatment. METHODS: This study used administrative claims from MarketScan Commercial Claims and Encounters Database, from January 1, 2010, to March 31, 2015, to identify MS patients aged 18-64 years who remained relapse free for at least 1 year while continuously treated with an IFN beta therapy. Stable patients remaining on their initial IFN beta therapy (no-switch patients) were matched with stable patients who switched IFN beta therapy (switch patients) using propensity score matching (first claim = index date). Outcome measures included annualized relapse rate (ARR), the percentage of patients who relapsed, medication possession ratio, and the proportion of days covered and were measured during the year following the index date. RESULTS: This study identified 531 patients in the no-switch group and 177 patients in the switch group, with subsets of 270 patients in the no-switch group and 90 patients in the switch group stable on intramuscular (IM) IFN beta-1a therapy. All outcomes during the follow-up year were significantly better in the no-switch group than in the switch group. For all patients, ARR in the switch group was more than twice that in the no-switch group (P = 0.002). For patients stable on IM IFN beta-1a at baseline, ARR was twice as high in the switch group as in the no-switch group (P = 0.012). CONCLUSION: Among all patients stable on IFN beta therapy and the subset stable on IM IFN beta therapy in particular, those who remained on therapy had significantly better outcomes than those who switched to another IFN beta therapy. FUNDING: Biogen (Cambridge, MA, USA).

Tracheal replacement with a bioabsorbable scaffold in sheep.

BACKGROUND: A significant native tracheal approximation phenomenon was observed in our previous study [Tsukada H, Ernst A, Gangadharan S, et al. Tracheal replacement with a silicone-stented fresh aortic allograft in sheep. Ann Thorac Surg 2010;89:253-8], in which sheep trachea was replaced with an allogenic aortic graft in order to attempt transplantation. Because an appropriate tracheal replacement graft has yet to be determined, other means to repair or replace tracheal tissue have to be evaluated. The aim of this study was to test a bioabsorbable scaffold for temporary tracheal grafting. METHODS: Eight male sheep underwent cervical tracheal replacement (5 cm) using a copolymer of L-lactide and ε-caprolactone sponge tube reinforced by polyglycolic acid. A silicone stent (7 cm) was placed perioperatively to prevent graft collapse. Routine bronchoscopy and computed tomographic scans were scheduled for up to 9 months and necropsies with histologic examinations were scheduled at 9 months (n = 3), 6 months (n = 2), 4 months (n = 1), 3 months (n = 1), and 2 months (n = 1) after surgery. RESULTS: No procedural deaths and postoperative complications occurred. Planned follow-up points were reached in all animals. Computed tomographic imaging of the grafted area showed tracheal approximation up to 75% at 9 months after surgery. Silicone stents were removed at 9 months in three animals. Symptomatic airway collapse was observed at 6 hours, 1 week, and 2 weeks after stent removal. Epithelialization of the entire grafted area was confirmed in all sheep that were followed beyond 4 months. CONCLUSIONS: Tracheal axial approximation occurs consistently after tracheal resection and replacement. Our data suggest that bioabsorbable materials can be used as a reliable, temporary, tracheal replacement conduit.

A novel animal model for hyperdynamic airway collapse.

OBJECTIVE: Tracheobronchomalacia (TBM) is increasingly recognized as a condition associated with significant pulmonary morbidity. However, treatment is invasive and complex, and because there is no appropriate animal model, novel diagnostic and treatment strategies are difficult to evaluate. We endeavored to develop a reliable airway model to simulate hyperdynamic airway collapse in humans. METHODS: Seven 20-kg male sheep were enrolled in this study. Tracheomalacia was created by submucosal resection of > 50% of the circumference of 10 consecutive cervical tracheal cartilage rings through a midline cervical incision. A silicone stent was placed in the trachea to prevent airway collapse during recovery. Tracheal collapsibility was assessed at protocol-specific time points by bronchoscopy and multidetector CT imaging while temporarily removing the stent. Esophageal pressure and flow data were collected to assess flow limitation during spontaneous breathing. RESULTS: All animals tolerated the surgical procedure well and were stented without complications. One sheep died at 2 weeks because of respiratory failure related to stent migration. In all sheep, near-total forced inspiratory airway collapse was observed up to 3 months postprocedure. Esophageal manometry demonstrated flow limitation associated with large negative pleural pressure swings during rapid spontaneous inhalation. CONCLUSIONS: Hyperdynamic airway collapse can reliably be induced with this technique. It may serve as a model for evaluation of novel diagnostic and therapeutic strategies for TBM.

Tracheal replacement with a silicone-stented, fresh aortic allograft in sheep.

BACKGROUND: Tracheal tissue regeneration after allogeneic aortic transplants in sheep has been reported. We sought to confirm these findings and elucidate the mechanism of this transformation. METHODS: Ten male sheep underwent cervical tracheal replacement with fresh, descending thoracic aortic allografts, 8 cm long, from female sheep, without postoperative immunosuppressive therapy. A 10-cm silicone stent was placed to prevent airway collapse. Graft evaluations with flexible bronchoscopy and computed tomography were conducted between 2 weeks and 1 year after surgery. RESULTS: There were no procedural deaths, but 6 animals died or required euthanasia between 12 days and 3 months postoperatively owing to severe tracheitis, cervical lymphadenitis, pneumonia, graft necrosis, stent migration, or airway obstruction after stent removal. The 4 remaining sheep were euthanized as planned at 6 to 12 months after surgery. Harvested tracheas revealed no evidence of graft incorporation into the surrounding tissue, and there was no histologic evidence of any neocartilage within or around the graft at any point. Bronchoscopy revealed marked graft necrosis in the 4 animals surviving to planned euthanasia. In all sheep, computed tomography imaging revealed that the graft was replaced by connective tissue without any signs of cartilage regeneration. Image analysis also indicated profound shortening of the grafted area up to 87.5% at 1 year after implantation, secondary to axial shift of the native trachea. CONCLUSIONS: Fresh aortic allografts appear to be unsuitable for primary tracheal replacement. However, the observed graft shortening may allow for two-staged, end-to-end reconstruction of large tracheal defects with temporary grafting techniques.

Airway stenting: Applications and practice management considerations.

BACKGROUND: Airway stenting is a procedure that is performed increasingly often, and the availability of metallic stents placed by flexible bronchoscopy may have contributed to the increased usage. These procedures have an impact on the required physician skill set and practice management. We review the indications for airway stenting, and how the requirement of combined therapies and technical aspects of central airway stenting pertain to practice management. PROCEDURE: We compared several reimbursement scenarios for managing stent placement using the Centers for Medicare and Medicaid Services relative value units (RVUs) and average reimbursement amounts. We also compared the reimbursement to other commonly performed activities performed by pulmonary and critical care physicians. An analysis of Medicare facility outpatient and inpatient payment for procedures using silicone and metallic stents was also conducted. RESULTS: Professional reimbursement is identical regardless of stent type, method of insertion, and anesthesia administered. The net facility reimbursement largely depends on stent costs. The RVUs alone are a poor comparator for the reimbursement of therapeutic bronchoscopy because of Correct Coding Initiatives edits. Considering the time necessary for performing advanced therapeutic bronchoscopy, the professional fees are not attractive. The net facility reimbursement largely depends on stent costs. CONCLUSION: The placement of airway stents is not reimbursed at competitive rates and may even lead to a net loss for the facility. The practice management benefits of central airway therapy are probably best obtained by a multidisciplinary airway team with an established cost center structure.

Use of a removable endobronchial valve for the treatment of bronchopleural fistula.

We report the case of a patient with a prolonged bronchopleural fistula and empyema that were successfully treated by the placement of a removable, unidirectional endobronchial valve. This is the first report of the use of such a device for this indication.

Microdebrider bronchoscopy: a new tool for the interventional bronchoscopist.

PURPOSE: We report our experience with a new airway tool, the microdebrider, in treating central airway obstruction. DESCRIPTION: From April 2002 to April 2004, 23 patients undergoing treatment of central airway obstruction were managed with the microdebrider. All procedures were done under general anesthesia with either a rigid bronchoscope (19 patients) or a suspension laryngoscope (4 patients). The microdebrider was used in an oscillating mode with rotation speeds of 1,000 to 3,000 rpm to resect obstructing tissue. EVALUATION: Fourteen patients (61%) had tracheal granulation tissue from prior intubation or tracheostomy, 6 (26%) had idiopathic subglottic stenosis, and 3 (26%) had malignant disease. Obstructing lesions were rapidly removed in all patients with interventions lasting between 2 and 15 minutes. There were no procedure-related complications. No patients required reoperation for airway obstruction in follow-up ranging from 1 to 24 months. CONCLUSIONS: Microdebrider bronchoscopy is a new technique that allows for precise, rapid, and safe removal of lesions obstructing the central airways. Complications of thermal modalities such as airway injury, tracheoesophageal fistulas, and airway fires can be avoided.

Reducing maintenance and repair costs in an interventional pulmonology program.

BACKGROUND: In the current economic climate, hospitals and academic institutions demand that medical departments function in an efficient and cost-effective manner. Detailed business plans are necessary to build new clinical programs, and institutions have learned that new programs are associated with significant costs for purchasing and maintaining equipment. We report our experience with repairs to equipment before and after starting our interventional pulmonary (IP) program, and with the effect of an educational program on reducing these costs. METHODS: We retrospectively studied the costs of equipment repair in the 3 years preceding and in the 5 years following the development of an IP program in our institution, a university-based tertiary referral center. We also studied the effect of an educational program that was designed to enhance the skills of physicians and technical staff in handling the equipment. RESULTS: The cost of repairs to the equipment during the 3 years prior to the development of the IP program was $42 (US dollars) per procedure. In the initial 3 years following the start of the IP program, the yearly average cost rose 21% to $51 per procedure. After the introduction of the educational program, the yearly repair costs decreased by 84% to $8 per procedure. Based on our experience, we estimate that a reasonable budget for the cost of repairs is $50 per procedure. CONCLUSIONS: An educational program was effective in dramatically decreasing the costs of equipment repair after initiating an IP program. This is the first study to offer budgetary guidelines for equipment repair in an IP program and to demonstrate that an educational program can effectively reduce costs.

Effect of clopidogrel with and without aspirin on bleeding following transbronchial lung biopsy.

BACKGROUND: Clopidogrel, a potent inhibitor of platelet aggregation, is being commonly prescribed in the elderly population due to its benefits in patients with atherosclerotic diseases. It is currently unknown whether clopidogrel increases the risk of bleeding during invasive pulmonary procedures. METHODS: Pigs of the Yorkshire species were randomized to one of the following two arms: clopidogrel (75 mg/d) alone; or clopidogrel plus aspirin (75 mg/d and 325 mg/d, respectively). The animals underwent flexible bronchoscopy with transbronchial lung biopsies under fluoroscopic guidance at baseline and after 1 week of daily oral intake of their assigned drugs. The main outcome of the study was the quantity of blood collected through the bronchoscope following transbronchial lung biopsy (TBLB). RESULTS: Sixteen animals were enrolled in the study, with 8 animals randomized to each arm. No statistically significant difference was found in the average quantity of blood resulting from transbronchial lung biopsies between procedures performed at baseline and those performed after animals received either clopidogrel (mean [+/- SD] dose, 1.41 +/- 1.14 mL) or clopidogrel plus aspirin (mean dose, 1.75 +/- 1.28 mL; p = 0.42). CONCLUSIONS: Clopidogrel, with or without aspirin, does not increase bleeding complications after TBLB in healthy pigs.

Alpha-keto amides as inhibitors of histone deacetylase.

Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.

Ultrasound guidance for medical thoracoscopy: a novel approach.

BACKGROUND: Commonly, a pneumothorax is induced before medical thoracoscopy to facilitate safe entry into the pleural space. OBJECTIVE: Evaluate the use of transthoracic ultrasound to locate a safe entry site for trocar placement during medical thoracoscopy without induction of a preprocedure pneumothorax. METHOD: The study was designed as a prospective cohort study, performed in the setting of a tertiary care hospital with an active interventional pulmonology program. It included 20 consecutive patients referred for medical thoracoscopy. RESULTS: Ultrasound identified entry sites in all 20 patients. All sites were successfully used, despite the presence of adhesions in 3 patients. There were no complications. CONCLUSIONS: Ultrasound could safely and reliably identify entry sites for trocar placement during medical thoracoscopy, even in patients with pleural adhesions. The use of ultrasound may replace the practice of pneumothorax induction before medical thoracoscopy.

Trifluoromethyl ketones as inhibitors of histone deacetylase.

Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.

Succinimide hydroxamic acids as potent inhibitors of histone deacetylase (HDAC).

A series of succinimide hydroxamic acids was prepared and evaluated in vitro for HDAC inhibition and tumor cell antiproliferation. While the original macrocyclic analogue 6 was quite potent in both assays, several appropriately substituted non-macrocyclic succinimides, such as 23, were equipotent.

Repeat bedside percutaneous dilational tracheostomy is a safe procedure.

OBJECTIVE: Previous tracheostomy has been considered a relative contraindication for percutaneous dilational tracheostomy. The objective of this study was to assess the safety of percutaneous dilational tracheostomy in critically ill patients with a history of previous tracheostomy. DESIGN: Retrospective, single-center case series of all consecutive patients requiring repeat tracheostomy for continued mechanical ventilatory support. SETTING: Intensive care unit of a tertiary-care referral center. SUBJECTS: Fourteen patients (eight female, six male) with a median age of 70 yrs (range, 33-94). All patients had previously undergone tracheostomy. INTERVENTION: Bedside percutaneous dilational tracheostomy. MEASUREMENT AND MAIN RESULTS: Subjects' previous tracheostomies dated back between 10 days and 8 yrs. Present intubation time before percutaneous dilational tracheostomy varied between 4 and 30 days. Bedside percutaneous dilational tracheostomy was performed successfully in all 14 patients by trained pulmonologists and surgeons. Eleven patients received an 8-mm and three received a 7-mm tracheostomy tube. There were no significant periprocedural complications, and no patient required surgical revision. The only postprocedural complication was accidental decannulation in one patient, which was managed with repeat percutaneous dilational tracheostomy. CONCLUSIONS: Trained physicians can safely perform bedside percutaneous dilational tracheostomy after previous tracheostomy. Percutaneous dilational tracheostomy offers an alternative to surgical tracheostomy in this particular patient population and should not be considered contraindicated.

Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.