Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.

BACKGROUND: The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository. METHODS/DESIGN: Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject. DISCUSSION: Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk. TRIAL REGISTRATION: The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.

Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.

p21waf1/cip1 and transforming growth factor beta 1 protein expression correlate with survival in non-small cell lung cancer.

p21waf1/cip1 encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways. Because p21waf1/cip1, p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21waf1/cip1 and TGF-beta 1 and identified four patient groups with distinct survival outcomes. Concordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and high TGF-beta 1 expression or low p21waf1/cip1 and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and low TGF-beta 1 expression or low p21waf1/cip1 and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21waf1/cip1 protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21waf1/cip1 protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21waf1/cip1 protein. These findings indicate that p21waf1/cip1 immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.

Alpha1-antitrypsin deficiency allele carriers among lung cancer patients.

Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha1-antitrypsin deficiency (alpha1AD) with COPD and COPD with LC, few studies examined the association of alpha1AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the alpha1AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with >70 variants reported. There are at least 10 alleles associated with deficiency in alpha1-antitrypsin. Using an exact binomial test, we compared the alpha1AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). alpha1AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6-16.9%) carried an alpha1AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, P < or = 0.01, respectively). Our preliminary findings suggest that individuals who carry an alpha1AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.

Approach to the solitary pulmonary nodule.

Because many malignant and benign processes may manifest as a solitary pulmonary nodule on a chest roentgenogram, this finding presents a diagnostic challenge. The major concern is whether the lesion is malignant. The likelihood of a malignant tumor correlates with the age of the patient, the size of the nodule, a history of a prior malignant lesion, and a history of smoking. Recent advances in radiologic techniques, such as the detection of calcium or the inference of the presence of calcium by high attenuation values on computed tomography, provide assistance in identifying benign lesions. The history, physical examination, and radiographic information can help determine an appropriate course of action. The goals are to remove malignant nodules promptly and to avoid surgical intervention in patients whose nodules are benign.

Posttransplantation physiologic features of the lung and obliterative bronchiolitis.

Obliterative bronchiolitis remains the major obstacle to long-term survival after lung transplantation. Herein we provide a brief review of the key literature as well as our own experience with this condition. Obliterative bronchiolitis has occurred in up to two-thirds of all lung transplant recipients. The characteristic physiologic changes include declines in (1) forced expiratory volume in 1 second, (2) forced vital capacity, and (3) diffusing capacity of the lungs for carbon monoxide. Lung biopsy in patients with obliterative bronchiolitis reveals occlusion of bronchioles in a patchy but extensive distribution. Mucous plugging and bronchiectasis may also be seen. Furthermore, intimal thickening of pulmonary vessels together with mild arteriosclerotic changes of the muscular and elastic pulmonary arterioles may be observed. To date, the main risk factor for the development of obliterative bronchiolitis is recurrent, severe, and persistent acute lung rejection. The recommended management is prevention because the established fibrotic condition may necessitate retransplantation.

Medical management and complications in the lung transplant recipient.

Lung transplantation has evolved as a viable therapy for patients with end-stage lung disease. Improvements in surgical techniques, avoidance of rejection by effective strategies of immunosuppression, and other aspects of medical management allow successful lung transplantation, with 1-year survivorship of 70 to 93%. In this review, we address the medical management of patients who have undergone lung transplantation. The immunosuppressive protocol used at Mayo Clinic Rochester is presented, along with a discussion of the mechanisms of action and potential complications associated with the various drugs used. The recognition and treatment of early graft dysfunction, infection, rejection, stenosis of the airway anastomosis, and posttransplantation lymphoproliferative disorder are also reviewed. Careful surveillance of patients after lung transplantation helps maintain graft function and facilitates identification, treatment, and potential avoidance of complications.

Lung transplantation: selection of patients and analysis of outcome.

Lung transplantation is an important option for patients with respiratory failure and limited life expectancy. Herein we review the current indications for and outcome after lung transplantation. These results are compared with the natural history of various respiratory diseases, estimated from available databases. Candidates for lung transplantation are generally younger than 60 years of age, have a limited life expectancy because of end-stage lung disease, and have no other major organ dysfunction. Single lung transplantation is performed most commonly for emphysema, pulmonary fibrosis, and pulmonary hypertension. Survival after single lung transplantation is approximately 70% at 1 year, 60% at 2 years, and 40% at 3 years. The median duration of survival for patients with end-stage lung diseases ranges from approximately 2 to 6 years, with wide variation based on the diagnosis and severity of illness. Currently, prolongation of the average survival has not been clearly substantiated after lung transplantation. Further evaluation of outcomes, functional status, and quality of life after lung transplantation is necessary.

Churg-Strauss syndrome complicated by eosinophilic endomyocarditis.

A 34-year-old woman with asthma had increasing dyspnea on exertion for 9 months and new-onset mononeuritis multiplex. An examination demonstrated sinus tachycardia, elevated jugular venous pressure, and a tender nonpulsatile liver. The leukocyte count was 15.8 x 10(9)/L, with 23% eosinophils. Echocardiography revealed a laminated thrombus obliterating much of the right ventricular cavity, with encasement of the tricuspid valve. Ultrafast computed tomography showed no evidence of pulmonary emboli. Biopsy specimens of skin nodules revealed extravascular palisading granulomas. The thrombus was refractory to corticosteroids, and right ventricular thrombectomy was performed. To our knowledge, this is the third reported case of Churg-Strauss syndrome with thrombotic complications from coexistent eosinophilic endomyocarditis. In an asthmatic patient with chronic dyspnea, eosinophilic tissue infiltration, and neuropathy, Churg-Strauss syndrome should be considered; evaluation for cardiac involvement may be warranted.

Reduced work of breathing after single lung transplantation for emphysema.

BACKGROUND: Pulmonary emphysema, with or without chronic bronchitis, has emerged as the most common indication for successful single lung transplantation. Although gas exchange can be expected to improve after successful transplantation, such changes do not adequately explain the improvement in dyspnea experienced by these patients and resulting in improved quality of life. METHODS: We prospectively studied the respiratory mechanics of 14 single lung transplantation recipients with pulmonary emphysema, of whom 10 have been followed up beyond 1 year. The mean age of the group was 48.8 years (range, 42 to 60 years) for the seven men and seven women. Average donor-predicted total lung capacity was 0.6 L (+0.2 [standard error]) greater than recipient-predicted total lung capacity. Comparison of pulmonary resistance, dynamic lung compliance, and static lung compliance were taken to examine the possible role of reduced airways resistance and of improved elastic recoil in the reduced work of breathing. Results were analyzed by means of a one-tailed paired Student t test and linear regression analysis (both stepwise and multivariate); results are tabulated by mean (+/- 1 [standard error]). RESULTS: Between preoperative measurements and 12 months postoperatively, maximum lung elastic recoil increased from 8.1 (+/- 0.7) to 11.3 (+/- 1.0) cm H2O, p < 0.01; pulmonary resistance fell from 8.3 (+/- 0.8) to 5.4 (+/- 0.7) cm H2O sec/L, p < 0.01. Dynamic lung compliance fell from 0.23 (+/- 0.04) to 0.12 (+/- 0.02) L/cm H2O, p < 0.02, and static lung compliance fell from 0.66 (+/- 0.13) to 0.22 (+/- 0.05) L/cm H2O, p < 0.001. CONCLUSIONS: The decline in lung compliance after single lung transplantation reflects the importance of improvement in elastic recoil and reduced chest wall distention, improving the work of breathing. The 67% decline in static lung compliance (300% increase in elastic recoil) is probably the single most important mechanical factor leading to reduced dyspnea after single lung transplantation for emphysema.

Evolving strategies in lung transplantation for emphysema.

Evolving strategies of pulmonary preservation, bronchial revascularization, immunosuppression, and infectious disease management were used in 15 initial consecutive patients undergoing lung transplantation for emphysema. There were 10 women and 5 men with a mean age of 49 years (range, 36 to 60 years). All patients required supplemental oxygen therapy. One bilateral, 9 left, and 5 right transplantations were performed. Mean preoperative forced expiratory volume in 1 second and total lung capacity were 16% and 146%, respectively, of predicted. Quadruple drug immunosuppression was used. Actuarial 1-year survival in this initial series is 93.3% +/- 6.4% (Kaplan-Meier) with one early cardiac death at day 71. Mean forced expiratory volume in 1 second and diffusing capacity for carbon monoxide at discharge were 43% and 62%, respectively, of predicted. Rehabilitation has been excellent, and all survivors are active and free of supplemental oxygen. During the study, the following treatment strategies have evolved: (1) University of Wisconsin solution has replaced Euro-Collins' solution for pulmonary preservation; (2) direct bronchial revascularization with the internal thoracic artery now is used; (3) an algorithm-based variable dose OKT3 induction regimen has resulted in a major reduction in dosage; and (4) infectious disease management focuses on the prophylaxis of cytomegalovirus and fungal infection using prolonged ganciclovir and early itraconazole therapy as well as the avoidance of Epstein-Barr virus mismatches. Single-lung transplantation for emphysema has excellent early results with continuing evolving management strategies.

Endobronchial techniques in lung cancer. Options for nonsurgical care.

Endobronchial techniques may be beneficial in patients with lung cancer. Photodynamic therapy may be used with intent to cure in some operable superficial squamous cell carcinomas and in some cases of high surgical risk or refusal to undergo surgery. Tumor resection with the Nd:YAG laser, implantation of prosthetic airway stents, and brachytherapy are palliative methods used in inoperable disease. These palliative treatments, used alone or concurrently, may result in remarkable but temporary improvement in symptoms.

Outpatient care of COPD patients.

Chronic obstructive pulmonary disease (COPD) is a disorder of airflow limitation that is often progressive. Interventions aimed at slowing this progression include smoking cessation, avoidance of exacerbating factors, and prevention or early treatment of infection. Reversible symptoms can be controlled pharmacologically, with supplemental oxygen prescribed when needed. Finally, quality of life can be improved through education and pulmonary rehabilitation.

Chemotherapy for advanced lung cancer. When to expect a response.

Chemotherapy has been shown to lengthen survival in patients with stage IIIA NSCLC when used pre-operatively (major response rates of 50% to 75%). Chemotherapy in combination with radiation for unresectable stage IIIA or IIIB disease has also improved survival rates. Major response rates of 10% to 30% are reported in cases of stage IV disease. Chemotherapy is now remarkably successful in achieving response in patients with limited SCLC, and 5-year survival rates as high as 10% to 15% are reported. Further increases in the 5-year survival rate will depend on improved chemotherapeutic treatment of nonsurgical disease. Research in the 1990s has presented a number of new chemotherapeutic agents with promising activity against this recalcitrant disease.

Solitary pulmonary nodule: time to think small.

The challenge presented by a solitary pulmonary nodule has faced physicians and patients since the advent of the chest radiograph. Is the nodule malignant or benign? When should something be done about it and what should that be? The majority of solitary nodules are benign, but the detection of a nodule may be the first and only chance for cure in the patient with lung cancer. The expanding availability and use of computed tomography are leading to increased numbers and decreased size of nodules detected. Surgical resection remains the most sensitive and specific method of analysis but introduces morbidity and mortality that may be unnecessary and avoidable. Advances in radiographic techniques have improved the ability to noninvasively identify whether a nodule is likely malignant or benign. Application of these techniques may ease the decision making and reduce the incision making.

Churg-Strauss syndrome.

OBJECTIVES: This article discusses the clinical manifestations and treatment protocols of Churg-Strauss syndrome (CSS). A review of the definition, pathophysiology, and prognosis of CSS is included, as well as more recent evidence of the presumed association between antileukotriene antagonists and CSS. DATA SOURCES: Relevant articles in the medical literature derived from searching the MEDLINE database (1966 to present) with key terms Churg-Strauss syndrome, allergic granulomatosis, and allergic granulomatous angiitis. Sources included review articles, meta-analyses, randomized control trials, case reports, case series, and seminal articles, the majority of which had been published within the past decade. STUDY SELECTION: Studies that described the clinical manifestations, pathophysiology, etiology, treatment, or prognosis of CSS. RESULTS: CSS is a systemic vasculitic disorder with multiorgan involvement and diverse presentations. CONCLUSIONS: Recognition of the multiorgan manifestations of CSS is crucial to clinical management. Whether a causal relationship exists between antileukotriene antagonists and onset of CSS remains unclear.

Clinical strategies for solitary pulmonary nodule.

The solitary pulmonary nodule frequently presents a diagnostic dilemma to the physician and the patient. Is it malignant or benign? Should it be observed, biopsied, or removed? Much has been learned through surgical, biopsy, and radiographic studies to help answer these questions. We review what is known about the solitary nodule and discuss the clinical approach to its evaluation.