Rodolfo C. Morice

Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia.

PURPOSERetinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.PATIENTS AND METHODSWe prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.RESULTSIn the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and pla...

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration in the Diagnosis of Lymphoma.

Background: The diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of lymphoma in patients with mediastinal lymphadenopathy is not well defined. Methods: A retrospective review was performed of all patients with mediastinal lymphadenopathy referred for EBUS-TBNA between August 2005 and December 2006 in whom lymphoma was suspected based on prior history or clinical presentation. Mediastinal biopsy specimens were taken using a linear array ultrasonic bronchoscope (Olympus XBF-UC 160F) and a 22-gauge cytology needle (NA-202C Olympus) with on-site cytopathological support. The EBUS-TBNA result was compared with a reference standard of pathological tissue diagnosis or a composite of ⩾6 months of clinical follow-up with radiographic imaging. Results: Of 236 patients who underwent EBUS-TBNA, 25 were eligible for inclusion. Indications for EBUS-TBNA were suspected mediastinal recurrence of lymphoma (n = 13) and mediastinal lymphadenopathy of unknown cause (n = 12). Adequate lymph node sampling was accomplished in 24/25 patients (96%); there were no complications. EBUS-TBNA identified lymphoma in 10 patients and benign disease in 14 patients. There was one false negative EBUS-TBNA for lymphoma (lymphoma prevalence 11/25 (44%)). Follow-up over a median of 10.5 months (range 1–19) confirmed stable or regressive lymphadenopathy in all 14 patients without a lymphoma diagnosis, consistent with a benign diagnosis. Overall, EBUS-TBNA had a sensitivity of 90.9%, specificity of 100%, positive predictive value of 100% and negative predictive value of 92.9% for the diagnosis of lymphoma. Conclusions: EBUS-TBNA is an accurate, safe and useful tool in the investigation of suspected lymphoma with isolated mediastinal adenopathy, and may diminish the need for more invasive procedures such as mediastinoscopy.

Complications, Consequences, and Practice Patterns of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration: Results of the AQuIRE Registry

BACKGROUND Few studies of endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA) have been large enough to identify risk factors for complications. The primary objective of this study was to quantify the incidence of and risk factors for complications in patients undergoing EBUS-TBNA. METHODS Data on prospectively enrolled patients undergoing EBUS-TBNA in the American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education (AQuIRE)database were extracted and analyzed for the incidence, consequences, and predictors of complications. RESULTS We enrolled 1,317 patients at six hospitals. Complications occurred in 19 patients (1.44%;95% CI, 0.87%-2.24%). Transbronchial lung biopsy (TBBx) was the only risk factor for complications,which occurred in 3.21% of patients who underwent the procedure and in 1.15% of those who did not (OR, 2.85; 95% CI, 1.07-7.59; P 5 .04). Pneumothorax occurred in seven patients(0.53%; 95% CI, 0.21%-1.09%). Escalations in level of care occurred in 14 patients (1.06%;95% CI, 0.58%-1.78%); its risk factors were age . 70 years (OR, 4.06; 95% CI, 1.36-12.12; P 5 .012),inpatient status (OR, 4.93; 95% CI, 1.30-18.74; P 5 .019), and undergoing deep sedation or general anesthesia (OR, 4.68; 95% CI, 1.02-21.61; P 5 .048). TBBx was performed in only 12.6% of patients when rapid on site cytologic evaluation (ROSE ) was used and in 19.1% when it was not used ( P 5 .006).Interhospital variation in TBBx use when ROSE was used was significant ( P , .001). CONCLUSIONS TBBx was the only risk factor for complications during EBUS-TBNA procedures.ROSE significantly reduced the use of TBBx.

A randomized controlled trial of supplemental oxygen versus air in cancer patients with dyspnea

Context: The symptomatic benefits of oxygen in patients with cancer who have nonhypoxic dyspnea are not well defined. Objective: To determine whether or not oxygen is more effective than air in decreasing dyspnea and fatigue and increasing distance walked during a 6-minute walk test. Patients and methods: Patients with advanced cancer who had no severe hypoxemia (i.e., had an O2 saturation level of] / 90%) at rest and had a dyspnea intensity of] / 3 on a scale of 0–10 (03/4/no shortness of breath, 103/4/worst imaginable shortness of breath) were recruited from an outpatient thoracic clinic at a comprehensive cancer center. This was a double-blind, randomized crossover trial. Supplemental oxygen or air (5 L/min) was administered via nasal cannula during a 6-minute walk test. The outcome measures were dyspnea at 3 and 6 minutes, fatigue at 6 minutes, and distance walked. We also measured oxygen saturation levels at baseline, before second treatment phase, and at the end of study. Results: In 33 evaluable patients (31 with lung cancer), no significant differences between treatment groups were observed in dyspnea, fatigue, or distance walked (dyspnea at 3 minutes: P = 0.61; dyspnea, fatigue, and distance walked at 6 minutes: P = 0.81, 0.37, and 0.23, respectively). Conclusions: Currently, the routine use of supplemental oxygen for dyspnea during exercise in this patient population cannot be recommended.

Resection of lung cancer is justified in high-risk patients selected by exercise oxygen consumption

The medical criteria for inoperability have been difficult to define in patients with lung cancer. Sixty-six patients with non-small cell lung cancer and radiographically resectable lesions were evaluated prospectively in a clinical trial. The patients were considered by cardiac or pulmonary criteria to be high risk for pulmonary resection. If exercise testing revealed a peak oxygen uptake of 15 mL.kg-1.min-1 or greater, the patient was offered surgical treatment. Of the 20 procedures performed, nine were lobectomies, two were bilobectomies, and nine were wedge or segmental resections. All patients were extubated within 24 hours and discharged within 22 days after operation (median time to discharge, 8 days). There were no deaths, and complications occurred in 8 (40%) of the 20 patients. Five patients whose peak oxygen uptake was lower than 15 mL.kg-1.min-1 also underwent surgical intervention; there was one death. Thirty-four patients whose peak oxygen uptake was less than 15 mL.kg-1.min-1 and 7 who declined operation underwent radiation therapy alone (35 patients) or radiation therapy and chemotherapy (6 patients). There were no treatment-related deaths, and the morbidity rate was 12% (5/41). The median duration of survival was 48 +/- 4.3 months for the patients treated surgically and 17 +/- 2.7 months for those treated medically (p = 0.0014). We conclude that a subgroup of patients who would be considered to have inoperable disease by traditional medical criteria can be selected for operation on the basis of oxygen consumption exercise testing. There is a striking survival benefit to an aggressive surgical approach in these patients.

Diagnostic Yield and Complications of Bronchoscopy for Peripheral Lung Lesions. Results of the AQuIRE Registry.

RATIONALE Advanced bronchoscopy techniques such as electromagnetic navigation (EMN) have been studied in clinical trials, but there are no randomized studies comparing EMN with standard bronchoscopy. OBJECTIVES To measure and identify the determinants of diagnostic yield for bronchoscopy in patients with peripheral lung lesions. Secondary outcomes included diagnostic yield of different sampling techniques, complications, and practice pattern variations. METHODS We used the AQuIRE (ACCP Quality Improvement Registry, Evaluation, and Education) registry to conduct a multicenter study of consecutive patients who underwent transbronchial biopsy (TBBx) for evaluation of peripheral lesions. MEASUREMENTS AND MAIN RESULTS Fifteen centers with 22 physicians enrolled 581 patients. Of the 581 patients, 312 (53.7%) had a diagnostic bronchoscopy. Unadjusted for other factors, the diagnostic yield was 63.7% when no radial endobronchial ultrasound (r-EBUS) and no EMN were used, 57.0% with r-EBUS alone, 38.5% with EMN alone, and 47.1% with EMN combined with r-EBUS. In multivariate analysis, peripheral transbronchial needle aspiration (TBNA), larger lesion size, nonupper lobe location, and tobacco use were associated with increased diagnostic yield, whereas EMN was associated with lower diagnostic yield. Peripheral TBNA was used in 16.4% of cases. TBNA was diagnostic, whereas TBBx was nondiagnostic in 9.5% of cases in which both were performed. Complications occurred in 13 (2.2%) patients, and pneumothorax occurred in 10 (1.7%) patients. There were significant differences between centers and physicians in terms of case selection, sampling methods, and anesthesia. Medical center diagnostic yields ranged from 33 to 73% (P = 0.16). CONCLUSIONS Peripheral TBNA improved diagnostic yield for peripheral lesions but was underused. The diagnostic yields of EMN and r-EBUS were lower than expected, even after adjustment.

Oral Epithelium as a Surrogate Tissue for Assessing Smoking-Induced Molecular Alterations in the Lungs

Abstract The lungs and oral cavity of smokers are exposed to tobacco carcinogens. We hypothesized that tobacco-induced molecular alterations in the oral epithelium are similar to those in the lungs, and thus the oral epithelium may be used as a surrogate tissue for assessing alterations in the lungs. We used methylation-specific PCR to analyze promoter methylation of the p16 and FHIT genes at baseline and 3 months after intervention in 1,774 oral and bronchial brush specimens from 127 smokers enrolled in a randomized placebo-controlled chemoprevention trial. The association between methylation patterns in oral tissues and bronchial methylation indices (methylated sites / total sites per subject) was analyzed in a blinded fashion. At baseline, promoter methylation in bronchial tissue was present in 23% of samples for p16, 17% for FHIT, and 35% for p16 and FHIT; these percentages were comparable to methylation in oral tissue: 19% (p16), 15% (FHIT), and 31% (p16 and FHIT). Data from both oral and bronchial tissues were available for 125 individuals, in whom the two sites correlated strongly with respect to alterations (P < 0.0001 for both p16 and FHIT). At baseline, the mean bronchial methylation index was far higher in patients with oral tissue methylation (in either of the two genes; 39 patients) than in patients without oral tissue methylation (86 patients): 0.53 ± 0.29 versus 0.27 + 0.26 methylation index (P < 0.0001). Similar correlations occurred at 3 months after intervention. Our results support the potential of oral epithelium as a surrogate tissue for assessing tobacco-induced molecular damage in the lungs and thus have important implications for designing future lung cancer prevention trials and for research into the risk and early detection of lung cancer.

Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers

Abstract Cigarette smoke is the major cause of lung cancer and can interact in complex ways with drugs for lung cancer prevention or therapy. Molecular genetic research promises to elucidate the biological mechanisms underlying divergent drug effects in smokers versus nonsmokers and to help in developing new approaches for controlling lung cancer. The present study compared global gene expression profiles (determined via Affymetrix microarray measurements in bronchial epithelial cells) between chronic smokers, former smokers, and never smokers. Smoking effects on global gene expression were determined from a combined analysis of three independent data sets. Differential expression between current and never smokers occurred in 591 of 13,902 measured genes (P < 0.01 and >2-fold change; pooled data)—a profound effect. In contrast, differential expression between current and former smokers occurred in only 145 of the measured genes (P < 0.01 and >2-fold change; pooled data). Nine of these 145 genes showed consistent and significant changes in each of the three data sets (P < 0.01 and >2-fold change), with eight being down-regulated in former smokers. Seven of the eight down-regulated genes, including CYP1B1 and three AKR genes, influence the metabolism of carcinogens and/or therapeutic/chemopreventive agents. Our data comparing former and current smokers allowed us to pinpoint the genes involved in smoking-drug interactions in lung cancer prevention and therapy. These findings have important implications for developing new targeted and dosing approaches for prevention and therapy in the lung and other sites, highlighting the importance of monitoring smoking status in patients receiving oncologic drug interventions.

Clinical implications of granulomatous inflammation detected by endobronchial ultrasound transbronchial needle aspiration in patients with suspected cancer recurrence in the mediastinum

BackgroundGranulomatous inflammation has been previously reported in association with cancer. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is a new minimally invasive test for investigating mediastinal lymphadenopathy. The identification of granulomatous inflammation by EBUS-TBNA and the clinical implications of such detection in a series of patients with previously treated cancer and new mediastinal lymphadenopathy has not previously been performed.MethodsAll 153 consecutive patients undergoing EBUS-TBNA in an academic cancer institution for suspected cancer in the mediastinum (mediastinal lymphadenopathy by CT imaging) were reviewed. Patients with non-caseating granuloma identified by EBUS-TBNA were included.ResultsEBUS-TBNA identified non-caseating granuloma in 17/153 (11%) patients. A subset of 8/153 (5.2%) had sarcoid like lymphadenopathy mimicking cancer recurrence (5/5 PET positive). Another 8/153 (5.2%) patients with new mediastinal lymphadenopathy and no prior history of cancer had a clinical syndrome consistent with sarcoidosis. One other patient with a history of breast cancer was diagnosed with non-tuberculous mycobacteria infection. No patient required mediastinoscopy and there were no complications.ConclusionIn an academic cancer institute, at least 5% of patients undergoing EBUS-TBNA have sarcoid-like lymphadenopathy mimicking cancer recurrence. Further studies to define the precise etiology, natural history and prognosis of this phenomenon are warranted.

Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers

Non–small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non–small cell lung cancer chemoprevention may be warranted. Cancer Prev Res; 3(2); 148–59