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1.  Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers 
There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.
doi:10.1158/1940-6207.CAPR-11-0057
PMCID: PMC3251330  PMID: 21636546
2.  Early Detection of Bronchial Lesions Using Lung Imaging Fluorescence Endoscope 
The performance of the Lung Imaging Fluorescence Endoscope (LIFE) system was compared with conventional bronchoscopy in 158 patients: 68 patients with invasive cancer, 42 patients with abnormal sputum cytology findings (12 early cancer and 26 dysplasia), 17 cases with resected lung cancer and 31 smokers with symptoms. The respective results of conventional bronchoscopy and LIFE for detection of dysplasia were; sensitivity 52% and 90% (biopsy basis), 62% and 92% (patient basis). Fluorescence bronchoscopy may be an important adjunct to conventional bronchoscopy to improve the localization of subtle lesions of bronchus.
doi:10.1155/DTE.5.85
PMCID: PMC2362618  PMID: 18493486
3.  Clinical application of the SurePath liquid-based Pap test in cytological screening of bronchial brushing for the diagnosis of lung cancer 
Cytotechnology  2010;62(1):53-59.
The SurePath liquid-based Pap test (LPT) is successfully and widely used to assess sputum cytology. This study aimed to compare the cytological findings and diagnostic sensitivity of LPT with those of the conventional Pap smear (CPS) method for diagnosing lung cancer. Bronchial brushing specimens from 204 patients diagnosed with lung cancer were studied. LPT slides showed decreased areas of cell monolayers, a clearer background and distinct, stereoscopic cytological features. The LPT had a significantly higher diagnostic sensitivity for lung cancer (71.6%) than the CPS method (57.8%, p < 0.05), particularly for small cell lung carcinoma and >2 cm lesions (p < 0.05). Combination of the LPT with the CPS method showed obviously higher diagnostic sensitivity for the detection of adenocarcinoma (63.6%), central lesions (85.0%) and >2 cm lesions (81.4%) compared with the CPS method alone (p < 0.05, p < 0.01). Thus, LPT is a useful and easily performed technique that can be widely applied, and is suitable for the early diagnosis of lung cancer.
doi:10.1007/s10616-010-9261-5
PMCID: PMC3303009  PMID: 20401634
Cytopathology; Liquid-based Pap test; Lung cancer; Bronchial brushing; Cytodiagnosis
4.  Altered miRNA Expression in Sputum for Diagnosis of Non-small Cell Lung Cancer 
SUMMARY
Analysis of molecular genetic markers in biological fluids has been proposed as a useful tool for cancer diagnosis. MicroRNAs (miRNAs) are small regulatory RNAs that are frequently dysregulated in lung cancer and have shown promise as tissue-based markers for its prognostication. The aim of this study was to determine whether aberrant miRNA expression can be used as a marker in sputum specimen for the diagnosis of non-small cell lung cancer (NSCLC). Experimental Design: Expressions of mature miRNAs, mir-21 and mir-155, were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and normalized to that of control miRNA, U6B, in sputum of 23 patients with NSCLC and 17 cancer-free subjects. The data was compared with conventional sputum cytology for the diagnosis of lung cancer. All endogenous miRNAs were present in sputum in a remarkably stable form and sensitively and specifically detected by real-time RT-PCR. Mir-21 expression in the sputum specimens was significantly higher in cancer patients (76.32 ± 9.79) than cancer-free individuals (62.24±3.82) (p<0.0001). Furthermore, overexpression of mir-21 showed highly discriminative receiver-operator characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with areas under the ROC curve at 0.902 ± 0.054. Detection of mir-21 expression produced 69.66% sensitivity and 100.00% specificity in diagnosis of lung cancer, as compared with 47.82% sensitivity and 100.00% specificity by sputum cytology. The measurement of altered miRNA expression in sputum could be a useful noninvasive approach for the diagnosis of lung cancer.
doi:10.1016/j.lungcan.2009.04.004
PMCID: PMC2846426  PMID: 19446359
MicroRNA; sputum; lung cancer; real-time RT-PCR; diagnosis
5.  Sputum cytology in suspected cases of carcinoma of lung (Sputum cytology a poor man's bronchoscopy!) 
Aims:
To evaluate the role of sputum cytology in the diagnostic work-up of patients with suspected lung cancer
Settings and Design:
Spontaneously produced fresh sputum was analyzed in clinically suspected cases of lung cancer.
Materials and Methods:
Spontaneously produced fresh sputum was analyzed in 36 clinically suspected cases of lung cancer. It was carried out using the “fresh pick and smear” method, which employs examination of sputum for blood-tinged, discolored or solid particles and preparation of thin and even smears from these selected portions.
Statistical Analysis Used:
Average and means.
Results:
Sensitivity of sputum cytology was 60%, which increased with an increase in the number of samples examined.
Conclusions:
Sputum cytology in suspected cases of carcinoma of lung is a useful diagnostic tool. It may be called as a poor man's bronchoscopy.
doi:10.4103/0970-2113.92356
PMCID: PMC3276027  PMID: 22345909
Carcinoma of lung; exfoliative cytology; PAP stain; pick and smear method; sputum cytology
6.  Detection and Localization of Intraepithelial Neoplasia and Invasive Carcinoma Using Fluorescence-Reflectance Bronchoscopy 
Objectives
The primary objective of this study was to evaluate the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intraepitheal neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites.
Design
This study was a prospective, multicenter, comparative, single arm trial. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75%, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years.
Materials and Methods
The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in two stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least one nonsuspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, carcinoma in situ (CIS), or invasive carcinoma. A positive patient was defined as having at least one lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy.
Results
There were 115 men and 55 women with median age of 62 years. Seven hundred seventy-six biopsy specimens were included. Seventy-six were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95% confidence interval [CI], 1.26–1.89). The relative sensitivity on a per-patient basis was 1.33 (95% CI, 1.13–1.70). The relative sensitivity to detect intraepithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95% CI, 2.00–16.00) and 3.50 (95% CI, 1.63–12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51% and 80%, respectively, could be achieved for detection of moderate/severe dsyplasia, CIS, and microinvasive cancer.
Conclusions
Using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intraepitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize interobserver variation in grading of abnormal sites should be explored further in future prospective clinical trial.
doi:10.1097/JTO.0b013e3181914506
PMCID: PMC2845524  PMID: 19096306
Autofluorescence; Bronchoscopy; Early detection; Lung neoplasm; Screening; Intraepithelial neoplasm; Dysplasia
7.  Comprehensive epidermal growth factor receptor gene analysis from cytological specimens of non-small-cell lung cancers 
British Journal of Cancer  2007;98(1):154-160.
Epidermal growth factor receptor (EGFR) gene mutations and increased copy numbers are considered as predictors of response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in non-small-cell lung cancer (NSCLC). Lung cancer diagnosis is often based on cytology alone. However, almost all published data on EGFR gene analyses were obtained from biopsies. This study tested the feasibility of EGFR gene analyses on cytological specimens. Eighty-four cytological specimens from NSCLCs were prospectively analysed for EGFR gene mutation in exons 18–21 and EGFR gene copy numbers were evaluated by fluorescence in situ hybridisation (FISH). A FISH-positive result was defined according to the criteria by Cappuzzo et al established for biopsies of NSCLCs. Fluorescence in situ hybridisation results of cytological specimens were compared to the FISH results on matching biopsies (n=33). Initial diagnosis of NSCLC was solely based on cytology in 37 out of 84 (44.0%) patients. Out of 80 NSCLCs, 6 (7.5%) showed EGFR gene mutations. Out of 67 cancers, 45 (67.2%) were FISH positive on cytological specimens. Comparison of FISH showed a FISH-positive result in 21 out of 33 (63.6%) cytological specimens but in only 8 out of 33 (24.2%) matched biopsies. Epidermal growth factor receptor gene analyses are well applicable to cytological specimens. The high FISH-positive rate of NSCLC on cytological specimens contrasts with the low rate on biopsies when previously suggested criteria are used. New criteria for a positive EGFR FISH status to predict response to therapy with EGFR-TKI need to be defined for cytological specimens.
doi:10.1038/sj.bjc.6604142
PMCID: PMC2359717  PMID: 18087280
non-small-cell lung cancer; EGFR; mutation; FISH; cytology
8.  Early detection for lung cancer. New tools for casefinding. 
Canadian Family Physician  2001;47:537-544.
OBJECTIVE: To review data from published population trials and clinical practice guidelines on screening for lung cancer to provide a recommendation for early detection of lung cancer. QUALITY OF EVIDENCE: Literature was searched via MEDLINE using the MeSH headings "lung neoplasm," "mass screening," "thoracic radiography," and "sputum." Only prospective randomized controlled trials with large numbers of subjects were selected. MAIN MESSAGE: Risk of lung cancer among long-term heavy smokers continues even years after stopping smoking. Risk is highest in smokers with chronic obstructive pulmonary disease. Canadian clinical practice guidelines currently recommend that sputum cytology examination and chest radiography (CXR) not be used for lung cancer screening. This guideline was deducted from four randomized population trials in the 1970s that have serious limitations and applies to asymptomatic adults only. A CXR and sputum cytology examination are indicated in symptomatic current and former smokers older than 45 years with a smoking history of 30 pack-years or more and airflow obstruction defined as a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) of 70% or less and a FEV1 lower than 70%. Curative treatment is available for early lung cancer. Substantial advances in innovative technologies for early detection using low-dose spiral CT and newer sputum tests have been made in the last three decades. Additional studies are under way to evaluate these new technologies. CONCLUSION: Primary care physicians have an important role in identifying people at risk of developing lung cancer and in supporting research to evaluate new screening technology.
PMCID: PMC2018399  PMID: 11281087
9.  Fluorescence in situ hybridization as adjunct to cytology improves the diagnosis and directs estimation of prognosis of malignant pleural effusions 
Background
The identification of malignant cells in effusions by conventional cytology is hampered by its limited sensitivity and specificity. The aim of this study was to investigate the value of fluorescence in situ hybridization (FISH) as adjuncts to conventional cytologic examination in patients with malignant pleural effusions.
Methods
We conducted a retrospective cohort study of 93 inpatients with pleural effusions (72 malignant pleural effusions metastatic from 11 different organs and 21 benign) over 23 months. All the patients came from Chinese northeast areas. Aspirated pleural fluid underwent cytologic examination and fluorescence in situ hybridization (FISH) for aneuploidy. We used FISH in single-colour or if appropriate in dual-colour evaluation to detect chromosomal aberrations (chromosomes 7, 11, and 17) in effusion cells as markers of malignancy, to raise the diagnostic yield and identified the efficiency by diagnostic biopsy. Predominant cytogenetic anomalies and patterns of intratumor cytogenetic heterogeneity were brought in relation to overall survival rate.
Results
Cytology alone confirmed malignant pleural effusions in 45 of 72 patients (sensitivity 63%), whereas FISH alone positively identified 48 of 72 patients (sensitivity 67%). Both tests had high specificity in predicting benign effusions. If cytology and FISH were considered together, they exhibited 88% sensitivity and 94.5% specificity in discriminating benign and malignant effusions. Combined, the two assays were more sensitive than either test alone. Although the positive predictive value of each test was 94.5%, the negative predictive value of cytology and FISH combined was 78%, better than 47% and 44% for FISH and cytology alone, respectively. There was a significantly prolonged survival rate for patients with aneuploidy for chromosome 17.
Conclusions
FISH in combination with conventional cytology is a highly sensitive and specific diagnostic tool for detecting malignant cells in pleural effusions . The high sensitivity and specificity may be associated with geographic area and race. Simple numeric FISH anomalies may be prognostic.
doi:10.1186/1749-8090-7-121
PMCID: PMC3514305  PMID: 23148562
Malignant pleural effusions; FISH; Prognosis; Sensitivity; Specificity
10.  Chromosomal aneusomy in sputum, as detected by Fluorescence In Situ Hybridization (FISH) predicts lung cancer incidence 
Lung cancer is usually disseminated at diagnosis making prognosis poor. Smokers are at high risk for lung cancer and are targets for prevention and early detection strategies. Sputum is a potential source for lung cancer biomarkers, but no test is currently available with sufficient sensitivity and specificity for clinical screening utility. Chromosomal aneusomy (CA) was measured in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls matched on age, gender, and date of collection. The CA-FISH assay was performed using a four-target DNA FISH probe including EGFR, MYC, 5p15 and CEP6. Sensitivity for a positive CA-FISH assay (abnormal for ≥ 2 of the 4 markers) was substantially higher for samples collected within 18 months (76%) than >18 months before lung cancer diagnosis (31%). Specificity for a positive FISH by this same definition was 85%. Among subjects providing sputum sample within 18 months before diagnosis, sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). The adjusted odds ratios for specimens collected within 18 months of cancer diagnosis were higher using the CA-FISH assay (OR=27.2, 95% CI 7.8 to 94.1) than previous studies assessing cytologic atypia (OR=2.3, CI 0.8 to 6.4) or gene promoter methylation (OR=6.5; CI 1.2 to 35.5). In conclusion, chromosomal aneusomy in sputum is a promising biomarker for prediction of lung cancer risk. Evaluation of the 4-DNA targets was more effective than any single marker and had highest sensitivity for samples collected ≤ 18 months to lung cancer diagnosis and patients diagnosed with squamous cell carcinoma.
doi:10.1158/1940-6207.CAPR-09-0165
PMCID: PMC2939746  PMID: 20332298
Sputum; Lung Cancer; FISH; biomarker; Chromosomal Abnormality
11.  The Limitations of Exfoliative Cytology for the Detection of Epithelial Atypia in Oral Leukoplakias 
British Journal of Cancer  1971;25(1):21-24.
Two hundred and ninety-nine oral leukoplakias were examined by exfoliative cytology; 83 of these lesions were biopsied because of clinical or previous histological features. Epithelial atypia was found in 16 of these biopsies, exfoliative cytology detecting epithelial atypia in only 6 of these cases. Thus exfoliative cytology used alone would have led to a false negative diagnosis in 10 out of 16 (62%) of the cases with epithelial atypia verified by histology. In addition, in no instance was exfoliative cytology responsible for the detection of an epithelial atypia that had been overlooked by consideration of clinical or previous histological features. Exfoliative cytology was successful in the detection of atypia only in those cases in which the surface of the lesion was either ulcerated or not keratinized; all keratinized lesions with atypia yielded negative cytology. The results of this study lead to the conclusion that exfoliative cytology is not to be recommended as a routine diagnostic or screening procedure for the detection of possibly pre-malignant features in oral leukoplakias.
PMCID: PMC2008553  PMID: 5581297
12.  Combined Genetic Analysis of Sputum and Computed Tomography for Noninvasive Diagnosis of Non–Small-Cell Lung Cancer 
Summary
CT plays an important role in diagnosis of lung cancer, however has been limited by uncertain diagnostic rate for early stage of non–small-cell lung cancer (NSCLC), particularly central tumors. Genetic analysis of sputum has proven to be useful in diagnosis of NSCLC. We proposed to evaluate efficacy of combing CT and genetic analysis of sputum for noninvasive diagnosis of stage I NSCLC. Genomic copy changes of a panel of lung cancer-related genes, HYAL2, FHIT, p16, and SP-A were analyzed by a mini-chip in sputum from 33 patients with stage I NSCLC and 49 cancer-free controls. The genetic and CT diagnoses were compared with surgical-pathologic stage. CT had higher sensitivity (85%) in detection of lung cancer compared with the mini-chip (70%) (p<0.05), while there was no significant difference in specificity between the two tests (89 vs. 92%, p=0.09). Similarly, CT showed considerably higher sensitivity (93%) in identifying peripheral tumors than did the mini-chip (64%) (p<0.05), whereas there was no difference in specificity between them (98 vs. 96%, p=0.28). However, in detecting central tumors, CT had lower specificity (90%) compared with the mini-chip (98%) (P<0.05), although its sensitivity (79%) was higher than that of the mini-chip (73%) (P=0.05). Combining both tests offered higher sensitivity (91%) than did any single one (85%, 70%, all <0.05), while still keeping 92% sensitivity. In particular, this combined approach yielded higher sensitivity, specificity, and accuracy for diagnosing central cancers compared with CT alone (all p<0.05). The integration of the genetic assay with CT led to improvements in noninvasive diagnosis of stage I NSCLCs, especially central tumors.
doi:10.1016/j.lungcan.2009.01.004
PMCID: PMC3544396  PMID: 19181417
Genetic analysis; sputum; CT; lung cancer; diagnosis
13.  Cytologic features of nipple aspirate fluid using an automated non-invasive collection device: a prospective observational study 
BMC Women's Health  2005;5:10.
Background
Detection of cytologic atypia in nipple aspirate fluid (NAF) has been shown to be a predictor of risk for development of breast carcinoma. Manual collection of NAF for cytologic evaluation varies widely in terms of efficacy, ease of use, and patient acceptance. We investigated a new automated device for the non-invasive collection of NAF in the office setting.
Methods
A multi-center prospective observational clinical trial involving asymptomatic women designed to assess fluid production, adequacy, safety and patient acceptance of the HALO NAF Collection System (NeoMatrix, Irvine, CA). Cytologic evaluation of all NAF samples was performed using previously described classification categories.
Results
500 healthy women were successfully enrolled. Thirty-eight percent (190/500) produced fluid and 187 were available for cytologic analysis. Cytologic classification of fluid producers showed 50% (93/187) Category 0 (insufficient cellular material), 38% (71/187) Category I (benign non-hyperplastic ductal epithelial cells), 10% (18/187) Category II (benign hyperplastic ductal epithelial cells), 3% (5/187) Category III (atypical ductal epithelial cells) and none were Category IV (unequivocal malignancy). Overall, 19% of the subjects produced NAF with adequate cellularity and 1% were found to have cytologic atypia.
Conclusion
The HALO system is a simple, safe, rapid, automated method for standardized collection of NAF which is acceptable to patients. Cytologic assessment of HALO-collected NAF showed the ability to detect benign and pre-neoplastic ductal epithelial cells from asymptomatic volunteers.
doi:10.1186/1472-6874-5-10
PMCID: PMC1198234  PMID: 16078997
14.  Chromogenic in situ hybridization to detect EGFR gene copy number in cell blocks from fine-needle aspirates of non small cell lung carcinomas and lung metastases from colo-rectal cancer 
Background
Several studies demonstrated that epidermal growth factor receptor (EGFR) gene copy number (GCN) correlates to the response to tyrosine kinase inhibitors in non small cell lung cancer (NSCLC) and to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (CRC). In the presence of lung nodules, cytology is often the only possible diagnostic approach. Chromogenic in situ hybridization (CISH) is an alternative technique to fluorescence in situ hybridization (FISH), but its feasibility in detecting EGFR GCN in cell blocks from fine-needle aspiration cytology (FNAC) of lung nodules has not yet been established.
Methods
We evaluated the feasibility of CISH on 33 FNAC from 20 primary NSCLC (5 squamous carcinomas, 8 large cell carcinomas and 7 adenocarcinomas) and 13 lung metastases from CRC.
Results
Of the 33 FNAC analyzed by CISH, 27 (82%) presented a balanced increase in EGFR gene and chromosome 7 number: 10 cases (30%) showed a low polysomy, 15 (45%) a high polysomy and 2 (6%) NSCLC were amplified. No significant differences between NSCLC and CRC lung metastases were found in relation to disomic or polysomic status. In addition, no correlation between EGFR GCN and EGFR immunohistochemical overexpression was found. Furthermore, we compared CISH results with those obtained by FISH on the same samples and we found 97% overall agreement between the two assays (k = 0.78, p < 0.0001). Two cases were amplified with both assays, whereas 1 case of NSCLC was amplified by FISH only. CISH sensitivity was 67%, the specificity and positive predictive value (PPV) was 100%, and the negative predictive value (NPV) was 97%.
Conclusions
Our study shows that CISH is a valid method to detect EGFR GCN in cell blocks from FNAC of primary NSCLC or metastatic CRC to the lung.
doi:10.1186/1756-9966-29-125
PMCID: PMC2954880  PMID: 20843314
15.  Application of cytology and molecular biology in diagnosing premalignant or malignant oral lesions 
Molecular Cancer  2006;5:11.
Early detection of a premalignant or cancerous oral lesion promises to improve the survival and the morbidity of patients suffering from these conditions. Cytological study of oral cells is a non-aggressive technique that is well accepted by the patient, and is therefore an attractive option for the early diagnosis of oral cancer, including epithelial atypia and squamous cell carcinoma. However its usage has been limited so far due to poor sensitivity and specificity in diagnosing oral malignancies. Lately it has re-emerged due to improved methods and it's application in oral precancer and cancer as a diagnostic and predictive method as well as for monitoring patients. Newer diagnostic techniques such as "brush biopsy" and molecular studies have been developed. Recent advances in cytological techniques and novel aspects of applications of scraped or exfoliative cytology for detecting these lesions and predicting their progression or recurrence are reviewed here.
doi:10.1186/1476-4598-5-11
PMCID: PMC1448188  PMID: 16556320
16.  Autofluorescence bronchoscopy for lung cancer surveillance based on risk assessment 
Thorax  2006;62(4):335-340.
Background
This is a preliminary report of an ongoing prospective bimodality lung cancer surveillance trial for high‐risk patients. Bimodality surveillance incorporates autofluorescence bronchoscopy (AFB) and spiral CT (SCT) scanning in high‐risk patients as a primary lung cancer surveillance strategy, based entirely on risk factors. AFB was used for surveillance and findings were compared with conventional sputum cytology for the detection of malignancy and pre‐malignant central airway lesions.
Methods
402 patients registering at Roswell Park Cancer Institute were evaluated with spirometric testing, chest radiography, history and physical examination, of which 207 were deemed eligible for the study. For eligibility, patients were required to have at least two of the following risk factors: (1) ⩾20 pack year history of tobacco use, (2) asbestos‐related lung disease on the chest radiograph, (3) chronic obstructive pulmonary disease with a forced expiratory volume in 1 s (FEV1) <70% of predicted, and (4) prior aerodigestive cancer treated with curative intent, with no evidence of disease for >2 years. All eligible patients underwent AFB, a low‐dose SCT scan of the chest without contrast, and a sputum sample was collected for cytological examination. Bronchoscopic biopsy findings were correlated with sputum cytology results, SCT‐detected pulmonary nodules and surveillance‐detected cancers. To date, 186 have been enrolled with 169 completing the surveillance procedures.
Results
Thirteen lung cancers (7%) were detected in the 169 subjects who have completed all three surveillance studies to date. Pre‐malignant changes were common and 66% of patients had squamous metaplasia or worse. Conventional sputum cytology missed 100% of the dysplasias and 68% of the metaplasias detected by AFB, and failed to detect any cases of carcinoma or carcinoma‐in‐situ in this patient cohort. Sputum cytology exhibited 33% sensitivity and 64% specificity for the presence of metaplasia. Seven of 13 lung cancers (58%) were stage Ia or less, including three patients with squamous cell carcinoma. Patients with peripheral pulmonary nodules identified by SCT scanning of the chest were 3.16 times more likely to exhibit pre‐malignant changes on AFB (p<0.001).
Conclusion
Bimodality surveillance will detect central lung cancer and pre‐malignancy in patients with multiple lung cancer risk factors, even when conventional sputum cytology is negative. AFB should be considered in high‐risk patients, regardless of sputum cytology findings.
doi:10.1136/thx.2006.068999
PMCID: PMC2092474  PMID: 17101735
17.  Evaluation of a Cervical Cancer Screening Program Based on HPV Testing and LLETZ Excision in a Low Resource Setting 
PLoS ONE  2010;5(10):e13266.
We conducted studies in Vanuatu to evaluate potential screening and treatment strategies to assist with control of cervical cancer. In a pilot study of 496 women, visual inspection and cytology were evaluated as screening tests for detection of CIN 2 or worse (CIN2+), observed in 21 of 206 subjects biopsied on the basis of abnormal visual inspection or cytology. Sensitivity of visual inspection with Lugol's Iodine for detection of CIN2+ on biopsy was 0.63, specificity was 0.32, and the positive predictive value was 0.09. For HSIL cytology, sensitivity was 0.99, specificity was 0.77, and the positive predictive value was 0.88. HSIL cytology was significantly more sensitive and had a significantly higher PPV for CIN 2+ than visual inspection (p<0.01). In a further study of 514 women, we compared testing for HR HPV and cytology as predictors of biopsy proven CIN 2+. Sensitivity of HSIL cytology for CIN2+ as established by loop excision of the cervix was 0.81, specificity was 0.94, and positive predictive value was 0.48. Sensitivity of a positive test for HR HPV for detection of CIN2+ was non-significantly different from cytology at 0.81, specificity was 0.94, and positive predictive value was 0.42. Combining the two tests gave a significantly lower sensitivity of 0.63, a specificity of 0.98, and a positive predictive value of 0.68. For women over 30 in a low resource setting without access to cytology, a single locally conduced test for high risk HPV with effective intervention could reduce cervical cancer risk as effectively as intervention based on cytology conducted in an accredited laboratory.
doi:10.1371/journal.pone.0013266
PMCID: PMC2951361  PMID: 20949059
18.  Cytological changes in the oral mucosa after use of a mouth rinse with alcohol: A prospective double blind control study 
Aim: The aim of this preliminary study was to detect cytological changes in the oral mucosa after using a mouth wash with alcohol. Material and Methods: A prospective double-blind, controlled study was performed, for 6 months. Group 1 consisted of 30 subjects who used a mouth rinse with 26.9% of alcohol [Listerine®] and Group 2 consisted of 30 subjects who used a mouth rinse with the same ingredients but with no alcohol. We obtained three cytological samples from the oral mucosa. The presence of cytological atypia, binucleation and karyorrhesis, and type of cells were studied. We also used a fluorescent in situ hybridization technique (FISH) in 15 samples in each group, for the micronucleus. Results: We found no clinical mucosal alteration after using the mouth wash at the end of the study in either group. We observed no cytological differences between the groups at the end of the study (p>0.05). Regarding the study of the micronucleus by FISH, we observed no significant difference between the groups (p>0.05). Conclusions: Our results showed no cytological alteration in patients using a mouth rinse with alcohol, but these findings should be considered preliminary results, to be confirmed in a greater sample of patients.
Key words:Mouth wash, oral mucosa, cytological change, alcohol.
doi:10.4317/medoral.18843
PMCID: PMC3505716  PMID: 23085712
19.  Sputum examination for early detection of lung cancer 
Journal of Clinical Pathology  2003;56(11):805-810.
Conventional sputum cytology can be used for the detection of lung cancer, but has shown a low yield in prospective screening trials. This review focuses on the technical aspects relevant to the outcome of DNA and image analysis in sputum. Published articles are discussed in the light of the technical background. Recent developments in DNA analysis and nuclear image analysis show a clear potential to improve or refine diagnosis beyond that achieved with conventional sputum cytology examination. The challenge for future studies in DNA and nuclear analysis of sputum is to ensure high levels of quality control and to confirm these initial encouraging results.
PMCID: PMC1770101  PMID: 14600122
Sputum samples; lung cancer; early diagnosis; cytology; molecular markers
20.  Assessment of oral cytological changes associated with exposure to chemotherapy and/or radiotherapy 
Cytojournal  2009;6:8.
Background:
Death from cancer is high in Sudan, with low survival rates, as most of the patients present with advanced disease. Most patients receive high and repeated doses of radiotherapy or chemotherapy. The aim of this study was to investigate the feasibility of using cytological evaluation to detect oral epithelial atypia amongst these patients. As a part of the continuous development in cancer therapy, this case control study was conducted in Khartoum, Sudan.
Methods:
Papanicolaou stained oral mucosal cells were obtained from 100 cancer patients receiving radiotherapy and/or chemotherapy (ascertained as cases), 50 cancer patients not exposed to either therapy (control 1), and 50 apparently healthy individuals (control 2).
Statistical analysis:
The data was analyzed by using a computer SPSS program, to obtain the Chi-square test.
Results:
Without prior knowledge of the subjects' group, oral epithelial atypia was detected in 7% of the cases. Inconclusive features of cytological atypia were observed in 13% of the cases. Atypia was not observed in both the control groups. Inflammatory infiltrate and viral cytopathic effects were identified in 32% and 8% of the cases respectively.
Conclusion:
Cytological atypia, viral infections, and inflammatory infiltrates were detected after exposure to radiotherapy and/or chemotherapy.
doi:10.4103/1742-6413.51332
PMCID: PMC2686222  PMID: 19495410
Atypia; chemotherapy; cytology; oral; mucosa; radiotherapy
21.  High magnification bronchovideoscopy combined with narrow band imaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer 
Thorax  2003;58(11):989-995.
Background: We investigated the use of high magnification bronchovideoscopy combined with narrow band imaging (NBI) for the detailed examination of angiogenic squamous dysplasia (ASD). This was carried out in relation to bronchial vascular patterns with abnormal mucosal fluorescence in heavy smokers at high risk for lung cancer.
Methods: Forty eight patients with sputum cytology specimens suspicious or positive for malignancy were entered into the study. Conventional white light and fluorescence bronchoscopic examination was first performed. Observations by high magnification bronchovideoscopy with conventional white light were made primarily at sites of abnormal fluorescence, and then repeated with NBI light to examine microvascular networks in the bronchial mucosa. Spectral features on the RGB (Red/Green/Blue) sequential videoscope system were changed from the conventional RGB broadband filter to the new NBI filter. The wavelength ranges of the new NBI filter were B1: 400–430 nm, B2: 420–470 nm, and G: 560–590 nm. ASD tissues were also examined using a confocal laser scanning microscope equipped with argon-krypton (488 nm) and argon (514 nm) laser sources.
Results: The microvessels, vascular networks of various grades, and dotted vessels in ASD tissues were clearly observed in NBI-B1 images. Diameters of the dotted vessels visible on NBI-B1 images agreed with the diameters of ASD capillary blood vessels diagnosed by pathological examination. Capillary blood vessels were also clearly visualised by green fluorescence by confocal laser scanning microscopy. There was a significant association between the frequency of dotted vessels by NBI-B1 imaging and tissues confirmed as ASD pathologically (p=0.002).
Conclusions: High magnification bronchovideoscopy combined with NBI was useful in the detection of capillary blood vessels in ASD lesions at sites of abnormal fluorescence. This may enable the discrimination between ASD and another pre-invasive bronchial lesion.
doi:10.1136/thorax.58.11.989
PMCID: PMC1746520  PMID: 14586056
22.  UroVysion fluorescence in situ hybridization (UroVysion FISH) assay for detection of bladder cancer in voided urine of Turkish patients: a preliminary study 
Contemporary Oncology  2013;17(2):156-160.
Bladder cancer is the fourth most common cancer in men and the fifth most common cancer worldwide. UroVysion FISH has high sensitivity and specificity for urothelial carcinoma detection. We investigated the genetic marker detected by the UroVysion FISH technique in diagnosis of Turkish bladder cancer patients and compared these results with the urine cytology and cystoscopy. Urine specimens were analyzed using UroVysion FISH probes for abnormalities in centromeric chromosomes 3, 7, and 17 and locus-specific 9p21.
Morning fresh voided urine samples were collected from each patient for FISH analysis. Cytology and histopathology analysis were performed by the pathology department. Twenty-seven bladder cancer patients (23 male and 4 female) with a history of bladder cancer who provided informed consent were included in this prospective study.
The results showed that cancer was detected in 8 patients via FISH; 7 via cytology; 12 via cystoscopy. According to the pathology results, 15 were normal, 10 high-grade carcinoma and 2 low-grade carcinoma. Sensitivity of these methods with FISH, cytology, and cystoscopy was 29.6%, 25.9%, and 44.4%, respectively.
In conclusion, all tests have different advantages and disadvantages. Also, larger studies will be needed to confirm these results. But, UroVysion FISH appeared to have good specificity for detecting bladder cancer in urine specimens and also it is important to correlate the FISH results with the cystoscopy and cytological findings.
doi:10.5114/wo.2013.34619
PMCID: PMC3685372  PMID: 23788983
UroVysion FISH; bladder cancer; voided urine; cytology
23.  Genetically Abnormal Circulating Cells in Lung Cancer Patients: An Antigen Independent Fluorescence in-situ Hybridization Based Case-Control Study 
Purpose
We performed a study to determine if a fluorescence in-situ hybridization (FISH)-based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in Non Small Cell Lung Cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).
Experimental Design
We evaluated 59 NSCLC cases with stage I through IV disease and 24 controls. PBMCs and matched tumors were hybridized with 2 two-color (3p22.1/CEP3 and 10q22.3 [SP-A]/CEP10) and 2 four-color (CEP3, CEP7, CEP17, and 9p21.3 [URO]) and (EGFR, c-MYC, 6p11-q11, and 5p15.2 [LAV]) FISH probes. Percentages of cytogenetically abnormal cells (CACs) in peripheral blood and in matched tumor specimens were quantified using an automated fluorescent scanner. Numbers of CACs were calculated based on the percentage of CACs (defined as PBMCs with genetic abnormalities) per mL of blood and expressed per microliter of blood.
Results
Patients with NSCLC had significantly higher numbers of CACs than did controls. Mean number of CACs ranged from 7.23±1.32/μl for deletions of 10q22.3/CEP10 to 45.52±7.49/μl for deletions of 3p22.1/CEP3. Numbers of CACs with deletions of 3p22.1, 10q22.3, and 9p21.3, and gains of URO, increased significantly from early to advanced stage of disease.
Conclusions
We have developed a sensitive and quantitative antigen-independent FISH-based test for detecting CACs in peripheral blood of patients with NSCLC which showed a significant correlation with the presence of cancer. If this pilot study can be validated in a larger study, CACs may have a role in the management of patients with NSCLC.
doi:10.1158/1078-0432.CCR-09-3358
PMCID: PMC2949278  PMID: 20651054
24.  Lung Cancer—Improved Cytologic Detection by Inducing Production of Sputum 
California Medicine  1966;104(1):41-45.
The principle of producing bronchial lavage by deposition of large amounts of heated aerosol has resulted in a significantly greater yield of positive cytologic diagnosis of bronchogenic carcinoma than with repeated “volunteer” specimens of sputum. Positive pressure plus bronchodilators augments greater sputum volume.
Using this technique, cases in which results of bronchoscopy and aspiration biopsy were negative for malignant change, were diagnosed cytologically.
Application of this technique can sometimes detect early lung carcinoma before roentgenographic changes are detectable. Positive tests in clinically far advanced disease may prevent unnecessary surgical intervention.
The simplicity of the technique, the freedom from adverse reactions, and its wide acceptance by the subjects tested, make it valuable in the diagnosis of lung cancer.
PMCID: PMC1516183  PMID: 5909252
25.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Background
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
Methods
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Results
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Conclusions
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
doi:10.1186/1471-2407-13-578
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres

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