Assessing a biomarker's ability to reduce invasive procedures in patients with benign lung nodules: Results from the ORACLE study.

A blood-based integrated classifier (IC) has been clinically validated to improve accuracy in assessing probability of cancer risk (pCA) for pulmonary nodules (PN). This study evaluated the clinical utility of this biomarker for its ability to reduce invasive procedures in patients with pre-test pCA ≤ 50%. This was a propensity score matching (PSM) cohort study comparing patients in the ORACLE prospective, multicenter, observational registry to control patients treated with usual care. This study enrolled patients meeting the intended use criteria for IC testing: pCA ≤ 50%, age ≥40 years, nodule diameter 8-30 mm, and no history of lung cancer and/or active cancer (except for non-melanomatous skin cancer) within 5 years. The primary aim of this study was to evaluate invasive procedure use on benign PNs of registry patients as compared to control patients. A total of 280 IC tested, and 278 control patients met eligibility and analysis criteria and 197 were in each group after PSM (IC and control groups). Patients in the IC group were 74% less likely to undergo an invasive procedure as compared to the control group (absolute difference 14%, p <0.001) indicating that for every 7 patients tested, one unnecessary invasive procedure was avoided. Invasive procedure reduction corresponded to a reduction in risk classification, with 71 patients (36%) in the IC group classified as low risk (pCA < 5%). The proportion of IC group patients with malignant PNs sent to surveillance were not statistically different than the control group, 7.5% vs 3.5% for the IC vs. control groups, respectively (absolute difference 3.91%, p 0.075). The IC for patients with a newly discovered PN has demonstrated valuable clinical utility in a real-world setting. Use of this biomarker can change physicians' practice and reduce invasive procedures in patients with benign pulmonary nodules. Trial registration: Clinical trial registration: ClinicalTrials.gov NCT03766958.

Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial.

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 < .001). If the integrated classifier results were used to direct care, 40% fewer procedures would be performed on benign nodules, and 3% of malignant nodules would be misclassified. CONCLUSIONS: When used in patients with lung nodules with a pCA ≤ 50%, the integrated classifier accurately identifies benign lung nodules with good performance characteristics. If used in clinical practice, invasive procedures could be reduced by diverting benign nodules to surveillance. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov).

An integrated risk predictor for pulmonary nodules.

It is estimated that over 1.5 million lung nodules are detected annually in the United States. Most of these are benign but frequently undergo invasive and costly procedures to rule out malignancy. A risk predictor that can accurately differentiate benign and malignant lung nodules could be used to more efficiently route benign lung nodules to non-invasive observation by CT surveillance and route malignant lung nodules to invasive procedures. The majority of risk predictors developed to date are based exclusively on clinical risk factors, imaging technology or molecular markers. Assessed here are the relative performances of previously reported clinical risk factors and proteomic molecular markers for assessing cancer risk in lung nodules. From this analysis an integrated model incorporating clinical risk factors and proteomic molecular markers is developed and its performance assessed on a subset of 222 lung nodules, between 8mm and 20mm in diameter, collected in a previously reported prospective study. In this analysis it is found that the molecular marker is most predictive. However, the integration of clinical and molecular markers is superior to both clinical and molecular markers separately. CLINICAL TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT01752101).

Clinical Utility of a Plasma Protein Classifier for Indeterminate Lung Nodules.

Evaluation of indeterminate pulmonary nodules is a complex challenge. Most are benign but frequently undergo invasive and costly procedures to rule out malignancy. A plasma protein classifier was developed that identifies likely benign nodules that can be triaged to CT surveillance to avoid unnecessary invasive procedures. The clinical utility of this classifier was assessed in a prospective-retrospective analysis of a study enrolling 475 patients with nodules 8-30 mm in diameter who had an invasive procedure to confirm diagnosis at 12 sites. Using this classifier, 32.0 % (CI 19.5-46.7) of surgeries and 31.8 % (CI 20.9-44.4) of invasive procedures (biopsy and/or surgery) on benign nodules could have been avoided. Patients with malignancy triaged to CT surveillance by the classifier would have been 24.0 % (CI 19.2-29.4). This rate is similar to that described in clinical practices (24.5 % CI 16.2-34.4). This study demonstrates the clinical utility of a non-invasive blood test for pulmonary nodules.

Endoscopic treatment of native lung hyperinflation using endobronchial valves in single-lung transplant patients: a multinational experience.

BACKGROUND: Hyperinflation of the native lung (NLH) is a known complication to single-lung transplantation for emphysema. The hyperinflation can lead to compression of the graft and cause respiratory failure. Endobronchial valves have been used to block airflow in specific parts of the native lung, reducing the native lung volume and relieving the graft. OBJECTIVE: We report short-term follow-up and safety from 14 single-lung transplant patients with NLH treated with bronchoscopic lung volume reduction using endobronchial valves. METHODS: Retrospective clinical information related to endobronchial valve treatment was obtained from four centres. All patients were treated with IBV(TM) Valve System (Spiration, Olympus Respiratory America, Redmond, WA, USA). All patients had evidence of severe NLH with mediastinal displacement. RESULTS: A total of 74 IBV valves were placed in 14 patients, with an average of 5.3 (range 2-10). Five patients had two procedures with staged treatment. Eleven patients reported symptom relief, and nine had lung function improvements. There was a significant increase in forced expiratory volume in 1 s of 9% (P = 0.013) and forced vital capacity of 15% (P = 0.034) within the first months after treatment. There were no reported device-related adverse events nor reports of migration. Two patients had pneumothorax. One patient had pneumonia in the location of the valve placement, and another had infection within days. Three other patients were hospitalised with infection 2 months after treatment. CONCLUSIONS: Treating NLH with IBV endobronchial valves leads to clinical improvement in the majority of patients, and the treatment has an acceptable safety.

The IBV Valve trial: a multicenter, randomized, double-blind trial of endobronchial therapy for severe emphysema.

BACKGROUND: Lung volume reduction surgery improves quality of life, exercise capacity, and survival in selected patients but is accompanied by significant morbidity. Bronchoscopic approaches may provide similar benefits with less morbidity. METHODS: In a randomized, sham procedure controlled, double-blind trial, 277 subjects were enrolled at 36 centers. Patients had emphysema, airflow obstruction, hyperinflation, and severe dyspnea. The primary effectiveness measure was a significant improvement in disease-related quality of life (St. George's Respiratory Questionnaire) and changes in lobar lung volumes. The primary safety measure was a comparison of serious adverse events. RESULTS: There were 6/121 (5.0%) responders in the treatment group at 6 months, significantly >1/134 (0.7%) in the control group [Bayesian credible intervals (BCI), 0.05%, 9.21%]. Lobar volume changes were significantly different with an average decrease in the treated lobes of -224 mL compared with -17 mL for the control group (BCI, -272, -143). The proportion of responders in St. George's Respiratory Questionnaire was not greater in the treatment group. There were significantly more subjects with a serious adverse event in the treatment group (n=20 or 14.1%) compared with the control group (n=5 or 3.7%) (BCI, 4.0, 17.1), but most were neither procedure nor device related. CONCLUSIONS: This trial had technical and statistical success but partial-bilateral endobronchial valve occlusion did not obtain clinically meaningful results. Safety results were acceptable and compare favorably to lung volume reduction surgery and other bronchial valve studies. Further studies need to focus on improved patient selection and a different treatment algorithm. TRIAL REGISTRY: ClinicalTrials.gov NCT00475007.

Multicentre European study for the treatment of advanced emphysema with bronchial valves.

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p<0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.

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.

Bronchoscopic management of prolonged air leak.

Prolonged pulmonary parenchymal air leaks are an important clinical problem. Standard treatment of prolonged air leaks include continued chest tube drainage, pleural sclerosis, or surgery. Approaches that are less invasive than bedside sclerosis or surgery are desirable but bronchoscopy approaches tried over the years have had limited success. In 2001, an American College of Chest Physicians (ACCP) consensus statement concluded there was no role for bronchoscopy for the treatment of prolonged air leaks. The development of bronchial valves for treatment of emphysema allowed the use of these devices for air leaks under compassionate use regulations. Multiple reports of successful bronchial valve treatments, along with the US Food and Drug Administration's (FDA) humanitarian use approval of a bronchial valve for certain postsurgical air leaks, provide new evidence that there is likely a role for endobronchial treatment of prolonged air leaks in selected patients.

Treatment of heterogeneous emphysema using the spiration IBV valves.

Ninety-eight emphysema patients were treated at 13 international sites during a 3-year series of single-arm, open-label studies with the IBV valve and a multi-lobar treatment approach. Fifty six percent of subjects had a clinically meaningful improvement in health-related quality of life, but standard pulmonary function and exercise studies were insensitive effectiveness measures. Quantitative CT analyses of regional lung changes showed lobar volume changes in over 85% of subjects. Lung volume reduction was an uncommon mechanism for a treatment response with bilateral upper lobe treatment. A redirection of inspired air, an interlobar shift to health-ier lung tissue, was the most common mechanism for a valve treatment response.

Pulmonary rehabilitation and clinical trial design in patients with severe COPD.

Pulmonary rehabilitation confers significant benefit to patients with COPD. The beneficial effects are seen in dyspnea and health-related quality of life. These measures are often considered in clinical trials as study endpoints. Pulmonary rehabilitation may affect the study population and study enrollment in clinical trials of other therapies in COPD, so it is important to anticipate the effects of pulmonary rehabilitation when designing and performing clinical trials. We review pulmonary rehabilitation and clinical trial design in patients with severe COPD. No publications were found that specifically address the impact of pulmonary rehabilitation on study design. No consensus statements, guidelines, or pharmaceutical studies in COPD were found that addressed pulmonary rehabilitation and study design. Pre-operative pulmonary rehabilitation is almost universal with lung transplantation and lung volume reduction surgery (LVRS). The National Emphysema Treatment Trial (NETT) included a mandatory pre-operative pulmonary rehabilitation program. The NETT reported that the mandatory pre-operative program reduced their study population by 32%. The NETT pre-operative program is required for Medicare reimbursement for LVRS, restricting the surgery to the subgroup of patients completing the program. Pulmonary rehabilitation can affect selection of the study population, study enrollment, outcome measures, and influence whether the results can be generalized to other patients. Clinical trials with medications, devices, or surgery for severe COPD should consider study designs that anticipate the significant effects of pulmonary rehabilitation.

A multicenter trial of an intrabronchial valve for treatment of severe emphysema.

OBJECTIVES: Minimally invasive endoscopic treatment of emphysema could provide palliation with less risk than lung volume reduction surgery and offer therapy to patients currently not considered for lung volume reduction surgery. The Intrabronchial Valve is used to block bronchial airflow in the most emphysematous areas of lung. METHODS: Patients with severe chronic obstructive pulmonary disease and heterogeneous upper lobe-predominant emphysema were eligible. Patients underwent flexible bronchoscopic placement of valves into segmental or subsegmental airways in both upper lobes. Outcomes assessed over a minimum of 6 months of follow-up included the safety, feasibility, tolerance, and success of valve placement; health-related quality of life; exercise capacity; pulmonary function; and gas exchange. RESULTS: Five centers treated 30 patients. Patient follow-up ranged from 1 to 12 months. A mean of 6.1 valves were placed per patient. Valves were positioned by means of flexible bronchoscopy in 99% of desired airways, and the procedure duration ranged from 15 to 125 minutes (mean, 65 minutes). Hospital discharge occurred within 2 days in 27 of 30 patients. There were no deaths or episodes of valve migration, tissue erosion, or significant bleeding. Eighty-three percent of patients had no adverse events judged probably or definitely related to the device. Patients experienced significant improvement in health-related quality of life, although the physiologic and exercise outcomes did not show statistically significant improvements. CONCLUSIONS: These first multicenter results with the Intrabronchial Valve demonstrate significant improvements in health-related quality of life and acceptable safety, ease of use, and procedural complication rates. The valve might be a safer and less-invasive alternative to surgical therapy for patients with severe emphysema.

Lung volume reduction surgery: a meta-analysis of randomized clinical trials.

BACKGROUND: Observational studies have suggested that lung volume reduction surgery (LVRS) is superior to optimal medical therapy for selected subsets of patients with advanced emphysema. Randomized clinical trials (RCTs) with the exception of the National Emphysema Treatment Trial (NETT), failed to enroll a sufficient number of patients to provide clinicians and patients with convincing outcome data on the usefulness of LVRS. It was postulated that a meta-analysis of these RCTs (3-12 months' follow up) may provide more compelling information on the value of LVRS in patients with emphysema. METHODS: A comprehensive search of the MEDLINE database between January 1994 and January 2004 for RCTs on LVRS was performed. RESULTS: From a total of eight RCTs on record, six studies (306 patients) with 3- to 12-month follow up were deemed suitable for meta-analysis. Key baseline features of these RCT populations included heterogeneous emphysema, comparable inclusion/exclusion criteria and, in retrospect, low walking capacity as measured by the 6-minute walk distance (6MWD). This profile closely resembles NETT's 'predominantly upper lobe--low exercise tolerance emphysema' cohort. The LVRS arm of the meta-analysis population showed better results than the medical cohort in terms of pulmonary function (FEV(1) p < 0.0001, FVC p < 0.0001, residual volume p < 0.0001, total lung capacity p = 0.004), gas exchange (arterial partial pressure of oxygen p < 0.0001) and exercise capacity (6MWD p = 0.0002). Although information on quality-of-life measures was not sufficiently uniform to qualify for meta-analysis, a survey of available data revealed better results in the surgical than in the medical arms of each RCT. Mortality 6-12 months after random assignment to treatment was similar in the two study arms, suggesting that the operative mortality from LVRS was offset, within months, by deaths in the medical arm. CONCLUSIONS: This meta-analysis showed that a selected subset of patients with advanced, heterogeneous emphysema and low exercise tolerance (6MWD) experienced better outcomes from LVRS than from medical therapy.

Novel surgical system for reducing lung tissue and preventing air leaks.

PURPOSE: This study assessed the feasibility of using the VALR surgical system (Spiration Inc, Redmond, WA), limited by federal law to investigational use, for capturing and reducing a selected portion of affected lobes in patients undergoing lobectomy. DESCRIPTION: The tested system consists of a hand-held vacuum-regulated introducer loaded with a flexible, silicone sleeve. Targeted tissue is drawn into the introducer and the silicone sleeve is deployed and sutured in place. The end of the proximal sleeve includes a compression band for applying uniform radial pressure, suture ports, and silicone lugs lining the inner lumen for reinforcing sleeve position. EVALUATION: The system was effective in capturing 25% to 30% tissue of each lobe tested. Mean intraoperative test time was 8.5 minutes. The compression sleeve did not slip or dislodge after suturing, and no tissue damage or leaks were observed. CONCLUSIONS: It was feasible using vacuum to draw and isolate a portion of pulmonary tissue within a silicone sleeve. The system was intuitive to apply, easy to use, and produced effective reduction and sealing of tissue.