Evaluation of Musculoskeletal and Pulmonary Bacterial Infections With [124I]FIAU PET/CT.

PURPOSE: Imaging is limited in the evaluation of bacterial infection. Direct imaging of in situ bacteria holds promise for noninvasive diagnosis. We investigated the ability of a bacterial thymidine kinase inhibitor ([124I]FIAU) to image pulmonary and musculoskeletal infections. METHODS: Thirty-three patients were prospectively accrued: 16 with suspected musculoskeletal infection, 14 with suspected pulmonary infection, and 3 with known rheumatoid arthritis without infection. Thirty-one patients were imaged with [124I]FIAU PET/CT and 28 with [18F]FDG PET/CT. Patient histories were reviewed by an experienced clinician with subspecialty training in infectious diseases and were determined to be positive, equivocal, or negative for infection. RESULTS: Sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of [124I]FIAU PET/CT for diagnosing infection were estimated as 7.7% to 25.0%, 0.0%, 50%, 0.0%, and 20.0% to 71.4% for musculoskeletal infections and incalculable-100.0%, 51.7% to 72.7%, 0.0% to 50.0%, 100.0%, and 57.1% to 78.6% for pulmonary infections, respectively. The parameters for [18F]FDG PET/CT were 75.0% to 92.3%, 0.0%, 23.1% to 92.3%, 0.0%, and 21.4% to 85.7%, respectively, for musculoskeletal infections and incalculable to 100.0%, 0.0%, 0.0% to 18.2%, incalculable, and 0.0% to 18.2% for pulmonary infections, respectively. CONCLUSIONS: The high number of patients with equivocal clinical findings prevented definitive conclusions from being made regarding the diagnostic efficacy of [124I]FIAU. Future studies using microbiology to rigorously define infection in patients and PET radiotracers optimized for image quality are needed.

In Vivo Characterization of the Swine Airway Morphometry and Motion Based on Computed Tomographic Imaging During Respiration.

Swine are a commonly used model in translational pulmonary research. However, in vivo airway morphometry during respiration has not been studied in extensive detail using modern imaging tools. Chest computed tomographic was performed in swine (n = 3) at multiple stages of respiration. Morphometric parameters of each airway segment at end-expiration and end-inspiration were compared as well as among matched anatomical regions (proximal and distal; ventral, lateral, and dorsal). Analysis included segment diameter, length, ellipticity, and the bifurcation angle between daughter branches. Deformation of the airway during respiration was qualitatively visualized using a point-to-point deformation map. Comparison of airway generation showed airway diameter and length were larger at end-inspiration in the fourth and seventh generations compared to end-expiration. Bifurcation angle was larger at end-inspiration compared to end-expiration. Analysis by anatomical region showed that length and bifurcation angle were larger at inspiration in the distal airway regions only. Regardless of respiratory phase, the lateral regions had larger diameters and lengths compared to the ventral and dorsal regions at similar generations and proximal regions had larger bifurcation angles. The findings that morphological changes were more prevalent in distal airways during respiration was confirmed by analysis of a deformation map. Compared to human airway models, the relative diameter may be smaller and length may be greater in swine in similar airway generations. This morphometric description of the swine airways during respiration may guide conduct of preclinical translational studies, revealing advantages and limitations of swine models for specific evaluations. Such morphometric parameters may directly determine the suitability of the swine model for the study of lung interventions, in terms of recapitulation of human morphometry dynamics.

Pleural fluid secondary to pulmonary cryptococcal infection: a case report and review of the literature.

BACKGROUND: Pulmonary Cryptococcosis (PC) is diagnosed with increasing incidence in recent years, but it does not commonly involve the pleural space. Here, we report a HIV-negative case with advanced stage IIIB non-small cell lung cancer (NSCLC) treated with radiation therapy presented with dyspnea, a new PET-positive lung mass and bilateral pleural effusion suspecting progressive cancer. However, the patient has been diagnosed as pulmonary cryptococcal infection and successfully treated with oral fluconazole therapy. CASE PRESENTATION: A 77-year-old male with advanced stage non-small cell lung cancer treated with combined chemo-radiation therapy who presented with progressive dyspnea, a new PET-positive left lower lobe lung mass and bilateral pleural effusions. Initial diagnostic thoracentesis and bronchoscopy yielded no cancer, but instead found yeast forms consistent with cryptococcal organisms in the transbronchial biopsies of the left lower lobe lung mass. Subsequent to this, the previously collected pleural fluid culture showed growth of Cryptococcus neoformans. The same sample of pleural effusion was tested and was found to be positive for crytococcal antigen (CrAg) by a lateral flow assay (LFA). The patient has been treated with oral fluconazole therapy resulting in gradual resolution of the nodular infiltrates. CONCLUSION: PC should be considered in immunosuppressed cancer patients. Additionally, concomitant pleural involvement in pulmonary cryptococcal infections may occur. The incidence of false positive 18FDG-PET scans in granulomatous infections and the use of CrAg testing in pleural fluid to aid in diagnosis are reviewed.

Guideline for the acquisition and preparation of conventional and endobronchial ultrasound-guided transbronchial needle aspiration specimens for the diagnosis and molecular testing of patients with known or suspected lung cancer.

RATIONALE: Conventional transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS)-TBNA are widely accepted tools for the diagnosis and staging of lung cancer and the initial procedure of choice for staging. Obtaining adequate specimens is key to provide a specific histologic and molecular diagnosis of lung cancer. OBJECTIVES: To develop practice guidelines on the acquisition and preparation of conventional TBNA and EBUS-TBNA specimens for the diagnosis and molecular testing of (suspected) lung cancer. We hope to improve the global unification of procedure standards, maximize the yield and identify areas for research. METHODS: Systematic electronic database searches were conducted to identify relevant studies for inclusion in the guideline [PubMed and the Cochrane Library (including the Cochrane Database of Systematic Reviews)]. MAIN RESULTS: The number of needle aspirations with both conventional TBNA and EBUS-TBNA was found to impact the diagnostic yield, with at least 3 passes needed for optimal performance. Neither needle gauge nor the use of miniforceps, the use of suction or the type of sedation/anesthesia has been found to improve the diagnostic yield for lung cancer. The use of rapid on-site cytology examination does not increase the diagnostic yield. Molecular analysis (i.e. EGFR, KRAS and ALK) can be routinely performed on the majority of cytological samples obtained by EBUS-TBNA and conventional TBNA. There does not appear to be a superior method for specimen preparation (i.e. slide staining, cell blocks or core tissue). It is likely that optimal specimen preparation may vary between institutions depending on the expertise of pathology colleagues.

Glycoproteomic analysis of bronchoalveolar lavage (BAL) fluid identifies tumor-associated glycoproteins from lung adenocarcinoma.

Cytological examination of cells from bronchoalveolar lavage (BAL) is commonly used for the diagnosis of lung cancer. Proteins released from lung cancer cells into BAL may serve as biomarkers for cancer detection. In this study, N-glycoproteins in eight cases of BAL fluid, as well as eight lung adenocarcinoma tissues and eight tumor-matched normal lung tissues, were analyzed using the solid-phase extraction of N-glycoprotein (SPEG), iTRAQ labeling, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Of 80 glycoproteins found in BAL specimens, 32 were identified in both cancer BAL and cancer tissues, with levels of 25 glycoproteins showing at least a 2-fold difference between cancer and benign BAL. Among them, eight glycoproteins showed greater than 2-fold elevations in cancer BAL, including Neutrophil elastase (NE), Integrin alpha-M, Cullin-4B, Napsin A, lysosome-associated membrane protein 2 (LAMP2), Cathepsin D, BPI fold-containing family B member 2, and Neutrophil gelatinase-associated lipocalin. The levels of Napsin A in cancer BAL were further verified in independently collected 39 BAL specimens using an ELISA assay. Our study demonstrates that potential protein biomarkers in BAL fluid can be detected and quantified.

Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients.

BACKGROUND: The diagnosis of sarcoidosis is still a significant challenge in China because of the need to exclude other diseases including granulomatous infections and malignancies that may be clinically and radiographically similar. The specific aim of the study is to search for serum protein biomarkers of sarcoidosis and to validate their clinical usefulness in differential diagnosis. METHODS: Serum samples were collected from patients with sarcoidosis (n = 37), and compared to those from patients with tuberculosis (n = 20), other pulmonary diseases (n = 20), and healthy volunteers (n = 20) for determination of sarcoidosis-specific or -associated protein expression profiles. The first part of this study focused on proteomic analysis of serum from patients with sarcoidosis to identify a pattern of peptides capable of differentiating the studied populations using the ClinProt profiling technology based on mass spectrometry. Enzyme Linked Immunosorbent Assay (ELISA) was then used to verify corresponding elevation of the serum protein concentration of the potential biomarkers in the same patients sets. Receiver operating characteristic curve (ROC) analyses was performed to determine the optimal cutoff value for diagnosis. Immunohistochemistry was carried out to further confirm the protein expression patterns of the biomarkers in lung tissue. RESULTS: An unique protein peak of M/Z 3,210 Daltons (Da) was found to be differentially expressed between the sarcoidosis and control groups and was identified as the N-terminal peptide of 29 amino acids (94-122) of serum amyloid A (SAA). ELISA confirmed that the serum SAA level was significantly higher in the sarcoidosis group than that of the other 3 control groups (p < 0.05). The cutoff for serum SAA concentration determined by ROC analysis was 101.98 ng/ml, with the sensitivity and specificity of 96.3% and 52.5%, respectively. Immunohistochemical staining showed that the SAA depositions in lung tissue of the sarcoidosis patients were also significantly more intense than in non-sarcoid lung tissue (p < 0.05). CONCLUSION: This is the first study to investigate serum protein markers in Chinese subjects with sarcoidosis. This study shows that the serum SAA expression profiles were different between the sarcoidosis and non-sarcoidosis groups. SAA may be a potential serum biomarker for ruling-out the diagnosis of sarcoidosis in Chinese subjects.

Economic assessment of home-based COPD management programs.

Home-based exacerbation management programs have been proposed as an approach to reducing the clinical and financial burden of COPD. We demonstrate a framework to evaluate such programs in order to guide program design and performance decisions towards optimizing cost and clinical outcomes. This study models the impact of hypothetical exacerbation management programs through probabilistic Markov simulations. Patients were stratified by risk using exacerbation rates from the ECLIPSE study and expert opinion. Three scenarios were modeled, using base, worst and best case parameters to suggest potential telehealth program performance. In these scenarios, acute exacerbations could be detected early, with sensitivity and specificity ranging from 60-90%. Detected acute exacerbations could be diverted to either a sub-acute pathway (12.5-50% probability), thus entirely avoiding hospitalization, or a lower cost pathway through length-of-stay reduction (14-28% reduction). For a cohort of patients without prior hospitalization, the base case telehealth scenario results in a cumulative per-patient lifetime savings of $2.9 K over ≈ 12 years. For a higher risk cohort of patients with a prior admission and 1 to 2 acute exacerbations per year, a cumulative $16K per patient was saved during the remaining ≈ 3 life-years. Acceptable prices for home-based exacerbation detection testing were highly dependent on patient risk and scenario, but ranged from $290-$1263 per month for the highest risk groups. These results suggest the economic viability of exacerbation management programs and highlight the importance of risk stratification in such programs. The presented model can further be adapted to model specific programs as trial data becomes available.

Clinical analysis of 76 patients pathologically diagnosed with pulmonary cryptococcosis.

The aim of the present study was to investigate the clinical characteristics of pulmonary cryptococcosis patients in China, with analysis of immunocompetent and immunocompromised subjects. We performed a retrospective review of 76 patients diagnosed with tissue-confirmed pulmonary cryptococcosis at the Shanghai Pulmonary Hospital (Shanghai, China) during a 10-yr period (2001-2010). Of 76 patients (54 males and 22 females), 41 (53.95%) were immunocompetent and 35 out of the 41 were asymptomatic. Approximately 80% of the patients had histories suspicious of environmental fungal exposure. Radiological (computed tomography) findings showed predominantly peripheral findings (85.53%, 65 out of 76 patients) including nodular masses (55.26%, 42 out of 76), pneumonic infiltrates (23.68%, 18 out of 76) and mixed type (21.05%, 16 out of 76). 43.42% (33 out of 76) were initially misdiagnosed, often as cancer by false-positive (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) (28 out of 46 cases). 51 patients received antifungal therapy, 25 patients were clinically observed without treatment. As of December 31, 2010, 71 cases showed total recovery and four cases showed improvement (efficacy rate of 98.68%, 75 out of 76). One HIV-positive case died of cryptococcal meningitis. Incidence of pulmonary cryptococcosis in China may be related to environmental fungal exposures. Most presented as asymptomatic peripheral lung lesions. False-positive (18)FDG-PET examinations often lead to initial clinical misdiagnosis of cancer. Unlike immunocompromised or clinically symptomatic patients, all immunocompetent patients had a good response, either to fluconazole monotherapy or observation, with a tendency for spontaneous remissions in the asymptomatic immunocompetent subjects.

Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2.

RATIONALE: The critical innate immune mechanisms that regulate granulomatous inflammation in sarcoidosis are unknown. Because the granuloma-inducing component of sarcoidosis tissues has physicochemical properties similar to those of amyloid fibrils, we hypothesized that host proteins capable of forming poorly soluble aggregates or amyloid regulate inflammation in sarcoidosis. OBJECTIVES: To determine the role of the amyloid precursor protein, serum amyloid A, as an innate regulator of granulomatous inflammation in sarcoidosis. METHODS: Serum amyloid A expression was determined by immunohistochemistry in sarcoidosis and control tissues and by ELISA. The effect of serum amyloid A on nuclear factor (NF)-kappaB induction, cytokine expression, and Toll-like receptor-2 stimulation was determined with transformed human cell lines and bronchoalveolar lavage cells from patients with sarcoidosis. The effects of serum amyloid A on regulating helper T cell type 1 (Th1) granulomatous inflammation were determined in experimental models of sarcoidosis, using Mycobacterium tuberculosis catalase-peroxidase. MEASUREMENTS AND MAIN RESULTS: We found that the intensity of expression and distribution of serum amyloid A within sarcoidosis granulomas was unlike that in many other granulomatous diseases. Serum amyloid A localized to macrophages and giant cells within sarcoidosis granulomas but correlated with CD3(+) lymphocytes, linking expression to local Th1 responses. Serum amyloid A activated NF-kappaB in Toll-like receptor-2-expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-gamma, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2. CONCLUSIONS: Serum amyloid A is a constituent and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2, providing a mechanism for chronic disease and new therapeutic targets.

Alternative methods for local ablation-interventional pulmonology: a narrative review.

OBJECTIVE: To discuss and summarise the background and recent advances in the approach to bronchoscopic ablative therapies for lung cancer, focusing on focal parenchymal lesions. BACKGROUND: This series focusses on the challenges highlighted by increasing recognition of the prognostically more favourable oligometastatic disease rather than the more frequent, but prognostically poor, high tumour burden metastatic disease. While surgery, stereotactic body radiation therapy (SBRT), and trans-thoracic percutaneous ablative techniques such as microwave (MWA) and radiofrequency ablation (RFA) are well recognised options for selected cases of pulmonary oligometastasis, bronchoscopic approaches to pulmonary tumour ablation are becoming realistic alternatives. An underlying tenet driving research and implementation in this domain is that percutaneous ablative techniques are obliged to traverse the pleura leading to a high rate of pneumothorax, and risks also goes up for peri-vascular lesions. Historically low yield bronchoscopic targeting of isolated peripheral tumors have significantly improved by incorporating multi-modality high resolution imaging and processing, including navigation planning and real-time image guidances (ultrasound, electromagnetic navigation, cone-beam CT). Combining advanced image guidance with ablative technology adaptations for bronchoscopic delivery opens up the options for high dose local ablative therapies that may reduce transthoracic complications and provide palliative to curative options for limited stage primary and oligometastatic diseases. METHODS: We conduct a narrative review of the literature summarizing the history of bronchoscopic tumor ablation approaches, technical details including biologic rational for their uses, and current evidence for each modality, as well as investigations into future applications. Because of the relative paucity of prospective studies, we have been very inclusive in our inclusion of experiences from the published clinical databases. CONCLUSIONS: Whilst surgical resection and SBRT remain the current mainstay of curative therapies for peripheral cancers, in the foreseeable future, developments and further research will see bronchoscopic ablative therapies become viable lung sparing alternatives in those deemed suitable. The future is bright.

Epigenetic imprinting alterations as effective diagnostic biomarkers for early-stage lung cancer and small pulmonary nodules.

BACKGROUND: Early lung cancer detection remains a clinical challenge for standard diagnostic biopsies due to insufficient tumor morphological evidence. As epigenetic alterations precede morphological changes, expression alterations of certain imprinted genes could serve as actionable diagnostic biomarkers for malignant lung lesions. RESULTS: Using the previously established quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) method, elevated aberrant allelic expression of imprinted genes GNAS, GRB10, SNRPN and HM13 was observed in lung cancers over benign lesions and normal controls, which were pathologically confirmed among histologically stained normal, paracancerous and malignant tissue sections. Based on the differential imprinting signatures, a diagnostic grading model was built on 246 formalin-fixed and paraffin-embedded (FFPE) surgically resected lung tissue specimens, tested against 30 lung cytology and small biopsy specimens, and blindly validated in an independent cohort of 155 patients. The QCIGISH diagnostic model demonstrated 99.1% sensitivity (95% CI 97.5-100.0%) and 92.1% specificity (95% CI 83.5-100.0%) in the blinded validation set. Of particular importance, QCIGISH achieved 97.1% sensitivity (95% CI 91.6-100.0%) for carcinoma in situ to stage IB cancers with 100% sensitivity and 91.7% specificity (95% CI 76.0-100.0%) noted for pulmonary nodules with diameters ≤ 2 cm. CONCLUSIONS: Our findings demonstrated the diagnostic value of epigenetic imprinting alterations as highly accurate translational biomarkers for a more definitive diagnosis of suspicious lung lesions.

T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.

Sarcoidosis is a systemic granulomatous disease associated with local epithelioid granulomas, CD4(+) T cells, and Th1 cytokines. The tissue Ags that drive this granulomatous inflammation are uncertain. In this study, we used IFN-gamma-ELISPOT assays and flow cytometry to assess lung and blood T cell responses to the candidate pathogenic Ag, Mycobacterium tuberculosis catalase-peroxidase (mKatG) in patients with sarcoidosis from two centers. Despite differences in patient phenotypic, genetic, and prognostic characteristics, we report that T cell responses to mKatG were remarkably similar in these cohorts, with higher frequencies of mKatG-reactive, IFN-gamma-expressing T cells in the blood of sarcoidosis patients compared with nontuberculosis sensitized healthy controls, and (in a subset) in greater numbers than T cells reactive to purified protein derivative. In sarcoidosis, mKatG-reactive CD4(+) Th1 cells preferentially accumulated in the lung, indicating a compartmentalized response. Patients with or without Löfgren syndrome had similar frequencies of mKatG specific IFN-gamma-expressing blood T cells. Circulating mKatG-reactive T cells were found in chronic active sarcoidosis but not in patients with inactive disease. Together, these results demonstrate that T cell responses to mKatG in sarcoidosis fit a profile expected for a pathogenic Ag, supporting an immunotherapeutic approach to this disease.

Novel visualized quantitative epigenetic imprinted gene biomarkers diagnose the malignancy of ten cancer types.

BACKGROUND: Epigenetic alterations are involved in most cancers, but its application in cancer diagnosis is still limited. More practical and intuitive methods to detect the aberrant expressions from clinical samples using highly sensitive biomarkers are needed. In this study, we developed a novel approach in identifying, visualizing, and quantifying the biallelic and multiallelic expressions of an imprinted gene panel associated with cancer status. We evaluated the normal and aberrant expressions measured using the imprinted gene panel to formulate diagnostic models which could accurately distinguish the imprinting differences of normal and benign cases from cancerous tissues for each of the ten cancer types. RESULTS: The Quantitative Chromogenic Imprinted Gene In Situ Hybridization (QCIGISH) method developed from a 1013-case study which provides a visual and quantitative analysis of non-coding RNA allelic expressions identified the guanine nucleotide-binding protein, alpha-stimulating complex locus (GNAS), growth factor receptor-bound protein (GRB10), and small nuclear ribonucleoprotein polypeptide N (SNRPN) out of five tested imprinted genes as efficient epigenetic biomarkers for the early-stage detection of ten cancer types. A binary algorithm developed for cancer diagnosis showed that elevated biallelic expression (BAE), multiallelic expression (MAE), and total expression (TE) measurements for the imprinted gene panel were associated with cell carcinogenesis, with the formulated diagnostic models achieving consistently high sensitivities (91-98%) and specificities (86-98%) across the different cancer types. CONCLUSIONS: The QCIGISH method provides an innovative way to visually assess and quantitatively analyze individual cells for cancer potential extending from hyperplasia and dysplasia until carcinoma in situ and invasion, which effectively supplements standard clinical cytologic and histopathologic diagnosis for early cancer detection. In addition, the diagnostic models developed from the BAE, MAE, and TE measurements of the imprinted gene panel GNAS, GRB10, and SNRPN could provide important predictive information which are useful in early-stage cancer detection and personalized cancer management.

An outbreak of Pseudomonas aeruginosa infections associated with flexible bronchoscopes.

BACKGROUND: Endoscopes, including bronchoscopes, are the medical devices most frequently associated with outbreaks of nosocomial infections. We investigated an outbreak of Pseudomonas aeruginosa infections after bronchoscopic procedures. METHODS: Microbiologic results were reviewed to determine the rates of recovery of P. aeruginosa from bronchoalveolar-lavage specimens. Environmental samples from endoscopes and the endoscopy suite were cultured. Medical records were reviewed to identify infections in the 14 days after a bronchoscopy. RESULTS: The rate of recovery of P. aeruginosa from bronchoalveolar-lavage specimens obtained with use of endoscopy-suite bronchoscopes increased from 10.4 percent at base line to 31.0 percent during the outbreak (relative risk, 2.97; 95 percent confidence interval, 2.28 to 3.90). Cultures of samples from three bronchoscopes grew P. aeruginosa, whereas cultures of samples from the environment, instrument-cleaning machines, and gastrointestinal endoscopes did not. The three bronchoscopes had been part of a nationwide recall. A total of 414 patients underwent bronchoscopy during the outbreak, and there were 48 respiratory tract and bloodstream infections among 39 of these patients (9.4 percent). In 32 infections (66.7 percent), P. aeruginosa was confirmed as a potentially causative organism. Exposure to a potentially contaminated bronchoscope may have had a role in the death of three patients. The rate of recovery of P. aeruginosa returned to base line after the instruments were removed from service. CONCLUSIONS: This large outbreak of P. aeruginosa infections related to bronchoscopy was apparently caused by a loose biopsy-port cap in the bronchoscopes. Instrument safety and surveillance methods for bronchoscopy must be improved, and better recall procedures are needed for medical devices.

Bronchial intraepithelial neoplasia/early central airways lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).

BACKGROUND: An evidence-based approach is necessary for the localization and management of intraepithelial and microinvasive non-small cell lung cancer in the central airways. METHODS: Material appropriate to this topic was obtained by literature search of a computerized database. Recommendations were developed by the writing committee and then reviewed by the entire guidelines panel. The final recommendations were made by the Chair and were voted on by the entire committee. RESULTS: White light bronchoscopy has diagnostic limitations in the detection of microinvasive lesions. Autofluorescence bronchoscopy (AFB) is a technique that has been shown to be a sensitive method for detecting these lesions. In patients with moderate dysplasia or worse on sputum cytology and normal chest radiographic findings, bronchoscopy should be performed. If moderate/severe dysplasia or carcinoma in situ (CIS) is detected in the central airways, then bronchoscopic surveillance is recommended. The use of AFB is preferred if available. In a patient being considered for curative endobronchial therapy to treat microinvasive lesions, AFB is useful. A number of endobronchial techniques as therapeutic options are available for the management of CIS and can be recommended to patients with inoperable disease. In patients with operable disease, surgery remains the mainstay of treatment, although patients may be counseled about these techniques. CONCLUSIONS: AFB is a useful tool for the localization of microinvasive neoplasia. A number of endobronchial techniques available for the curative treatment can be considered first-line therapy in inoperable cases. For operable cases, the techniques may be considered and discussed with the patients.

Less efficient g2-m checkpoint is associated with an increased risk of lung cancer in African Americans.

Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non-small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of gamma-radiation-induced G2-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy gamma-radiation, and harvested at 3 hours after gamma-radiation treatment. gamma-Radiation-induced G2-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in gamma-radiation-treated cultures from the same subject. The mean percentage of gamma-radiation-induced G2-M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P < 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of gamma-radiation-induced G2-M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G2-M arrest was observed (P(trend) = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (P(trend) < 0.01), with a lowest-versus-highest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage-induced G2-M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage-induced G2-M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans.