Colin T. Gillespie

A Phase I Clinical Trial of Single-Dose Intrapleural IFN-β Gene Transfer for Malignant Pleural Mesothelioma and Metastatic Pleural Effusions: High Rate of Antitumor Immune Responses

Purpose: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-β gene transfer using an adenoviral vector (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). Experimental Design: Ad.IFN-β was administered through an indwelling pleural catheter in doses ranging from 9 × 1011 to 3 × 1012 viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. Results: Intrapleural Ad.IFN-β was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 × 1011 vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 × 1012 vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-β message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. Conclusions: Intrapleural instillation of Ad.IFN-β is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

A Phase I Trial of Repeated Intrapleural Adenoviral-mediated Interferon-β Gene Transfer for Mesothelioma and Metastatic Pleural Effusions

We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-β (Ad.IFN-β) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-β vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-β through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-β were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.

Endobronchial Valve Treatment for Prolonged Air Leaks of the Lung: A Case Series

PURPOSE An endobronchial valve developed for treatment of severe emphysema has characteristics favorable for bronchoscopic treatment of air leaks. We present the results of a consecutive case series treating complex alveolopleural fistula with valves. DESCRIPTION Patients with air leaks that persisted after treatment gave consent and compassionate use approval was obtained. Bronchoscopy with balloon occlusion was used to identify the airways to be treated. IBV Valves (Spiration, Redmond, WA) were placed after airway measurement. EVALUATION During a 15-month period, 8 valve placement procedures were performed in 7 patients and all had improvement in the air leak. The median duration of air leakage was 4 weeks before and 1 day after treatment, with a mean of 4.5 days. Discharge within 2 to 3 days of the procedure occurred in 57% of the patients. A median of 3.5 valves (mode, 2.4) were used, and all valve removals were successful. There were no procedural or valve-related complications. CONCLUSIONS Removable endobronchial valves appear to be a safe and effective intervention for prolonged air leaks.

Comparison of Moderate versus Deep Sedation for Endobronchial Ultrasound Transbronchial Needle Aspiration

RATIONALE Most bronchoscopic procedures are performed using moderate sedation achieved by combining a short-acting benzodiazepine with an opioid agent. Propofol (2.6-diisopropylphenol), a short-acting hypnotic agent, has been increasingly used to provide deep sedation in the endoscopy community with an acceptable safety profile. OBJECTIVES To compare the impact of moderate versus deep sedation on the adequacy and diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS A retrospective review of prospectively collected data was performed at two academic institutions with interventional pulmonary fellowships using two methods of sedation during EBUS (deep vs. moderate sedation). Rapid on-site cytologic evaluation was used on all procedures in both groups. EBUS-TBNA nodal sampling was considered adequate if the aspirate yielded a specific diagnosis or lymphocytes. EBUS-TBNA was considered diagnostic if a lymph node aspirate yielded a specific diagnosis or if subsequent surgical sampling or prolonged radiographic surveillance revealed no nodal pathology. MEASUREMENTS AND MAIN RESULTS No difference was observed in the indication for EBUS-TBNA between the two groups. More lymph nodes were sampled per patient in the deep sedation group (314 nodes from 163 patients; 2.2 nodes per patient) than in the moderate sedation group (181 lymph nodes from 146 patients; 1.4 nodes per patient; P < 0.01). The EBUS-TBNA diagnostic yield was higher for the deep sedation group (80% of patients) than for the moderate sedation group (66% of patients; P < 0.01). CONCLUSIONS Diagnostic yield and number of lymph nodes sampled using deep sedation is superior to moderate sedation in patients undergoing EBUS-TBNA. Prospective studies accounting for other factors including patient selection and cost are needed.

Interferon β adenoviral gene therapy in a patient with ovarian cancer

Background A 47-year-old woman with a history of ovarian cancer and a 6-year disease-free remission presented with dyspnea and increased abdominal girth. The patient was found to have ascites and a large left pleural effusion, both of which contained malignant cells consistent with recurrent ovarian cancer. Her disease progressed despite treatment with chemotherapeutic and hormonal agents. She was then enrolled in a phase I clinical trial of adenoviral-mediated interferon β gene therapy.Investigations Abdominal and chest CT scans, 2-[18F]fluoro-2-deoxyglucose PET scan, viral cultures, interferon cytokine analysis, immunophenotyping, and tumor cytotoxicity analyses.Diagnosis Stage IV ovarian cancer with malignant ascites and pleural effusion.Management Tunneled pleural catheter and intrapleural adenoviral-mediated interferon β gene therapy.

Interventional Pulmonology Fellowship Accreditation Standards: Executive Summary of the Multisociety Interventional Pulmonology Fellowship Accreditation Committee

&NA; Interventional pulmonology (IP) is a rapidly evolving subspecialty of pulmonary medicine. In the last 10 years, formal IP fellowships have increased substantially in number from five to now > 30. The vast majority of IP fellowship trainees are selected through the National Resident Matching Program, and validated in‐service and certification examinations for IP exist. Practice standards and training guidelines for IP fellowship programs have been published; however, considerable variability in the environment, curriculum, and experience offered by the various fellowship programs remains, and there is currently no formal accreditation process in place to standardize IP fellowship training. Recognizing the need for more uniform training across the various fellowship programs, a multisociety accreditation committee was formed with the intent to establish common accreditation standards for all IP fellowship programs in the United States. This article provides a summary of those standards and can serve as an accreditation template for training programs and their offices of graduate medical education as they move through the accreditation process.

Donor transmission of malignant melanoma in a lung transplant recipient 32 years after curative resection

In the current era of organ shortages and long wait times for life‐saving transplants, marginal or extended donors are increasingly being considered; one such category of marginal organs is from donors with a previous history of malignancy. Melanoma in particular has been associated with increased risk of developing late recurrence. In this report, we describe a case of fatal donor melanoma transmission to a 64‐year‐old lung transplant recipient 32 years after surgical excision of the melanoma. Based on this report and review of the available literature, we conclude that a history of donor melanoma, regardless of the stage and time interval from ‘curative’ surgical resection, should remain a strong relative contraindication to transplantation.

Validation of an Interventional Pulmonary Examination

BACKGROUND Interventional pulmonology (IP) is an emerging subspecialty with a dedicated 12 months of additional training after traditional pulmonary and critical care fellowships with fellowships across the country. A multiple-choice question (MCQ) examination was developed to measure didactic knowledge acquired in IP fellowships. METHODS Interventional pulmonologists from 10 academic centers developed a MCQ-based examination on a proposed curriculum for IP fellowships. The 75 multiple-choice question examination was proctored, time limited (120 min), and computer-based. The examination was administered to IP faculty, IP fellows in their last month of fellowship, graduating pulmonary and critical care fellows in their last month of training, and incoming first-year pulmonary and critical care fellows. RESULTS The mean score for IP faculty was 87% (range, 83%-94%), 74% for IP fellows (range, 61%-81%, SD 5.09, median 76%), 62% for graduating pulmonary and critical care fellows (range 52% to 73%), and 50% for incoming pulmonary/critical care fellows (range, 35%-65%). There was a graduated increase in mean scores with level of IP training. Scores differed significantly across the four groups (P = .001). CONCLUSION A validated MCQ examination can measure IP knowledge. There is a difference in IP knowledge based on IP training exposure.

Bronchial effects of cryoballoon ablation for atrial fibrillation

BACKGROUND Damage to extracardiac structures, including the esophagus and phrenic nerve, is a known complication of cryoballoon ablation (CBA) during pulmonary vein (PV) isolation for atrial fibrillation (AF). Other adjacent structures, including the pulmonary bronchi and lung parenchyma, may be affected during CBA at the PV ostia. OBJECTIVE The purpose of this study was to prospectively study the bronchial effects of CBA in humans undergoing CBA for PV isolation. METHODS Ten patients undergoing CBA for AF under general anesthesia were enrolled in an institutional review board-approved prospective observational study. Real-time bronchoscopy was performed during cryoablation of PVs adjacent to pulmonary bronchi to monitor for thermal injury. Patients were followed for the development of respiratory complaints postprocedure. RESULTS In 7 of 10 patients (70%) and in 13 of 22 freezes (59%), ice formation was visualized in the left mainstem bronchus during CBA in the left upper PV. Ice formation was not seen in the right mainstem bronchus during right upper PV CBA. The average time to ice formation was 89 seconds. There was no significant difference (P = -.45) in average minimum balloon temperature during freezes with ice formation (-48.5°C) and freezes without ice formation (-46.3°C). No patients went on to develop respiratory complications. CONCLUSION Unrecognized ice formation occurs frequently in the left mainstem bronchus during CBA for AF. This information helps explain the source of cough and hemoptysis in some patients who undergo CBA. The long-term consequences of this novel finding and the implications for procedural safety are unknown.

Secondary Carina Y-stent Placement for Post–lung-transplant Bronchial Stenosis

Background:Post–lung-transplant bronchial stenosis (TBS) may cause significant morbidity and mortality. Although often transiently relieved by balloon bronchoplasty, stents may be required for long-term airway patency. We report a series of lung transplant patients in whom a silicone Y-stent was placed at the secondary carina for long-standing relief of post–transplant-airway stenosis. Methods:Six lung transplant patients received 10 silicone Y-stents in the secondary carina over the past 18 months for post–transplant-bronchial stenosis. All patients failed other interventional therapeutic procedures including balloon bronchoplasty and/or conventional stenting before secondary carina Y-stent placement. Patient data include 12 months’ follow-up after Y-stent insertion. The number of procedures and the interval between procedures was examined before and after secondary carina silicone Y-stent placement. Results:There was a significantly prolonged therapeutic effect accomplished in these patients after secondary carina Y-stent placement with the exception of 1 patient. When stents were tolerated by the patient, the mean number of procedures before secondary carina Y-stent insertion was 15.6, but only 4.8 after Y-stent insertion. The number of days between procedures was 24.5 days before the Y-stent insertion and 85.8 days after the Y-stent insertion. There were no complications in any patient during secondary carina Y-stent insertion. Conclusions:Secondary carina silicone Y-stent placement in TBS decreased the number of therapeutic procedures and provided longer-lasting results in most posttransplant patients who required multiple prior procedures for TBS.