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1.  Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer 
Molecular cancer research : MCR  2009;7(3):330-338.
Tumor contains small population of cancer stem cells (CSC) that are responsible for its maintenance and relapse. Analysis of these CSCs may lead to effective prognostic and therapeutic strategies for the treatment of cancer patients. We report here the identification of CSCs from human lung cancer cells using Aldefluor assay followed by fluorescence-activated cell sorting analysis. Isolated cancer cells with relatively high aldehyde dehydrogenase 1 (ALDH1) activity display in vitro features of CSCs, including capacities for proliferation, self-renewal, and differentiation, resistance to chemotherapy, and expressing CSC surface marker CD133. In vivo experiments show that the ALDH1-positive cells could generate tumors that recapitulate the heterogeneity of the parental cancer cells. Immunohistochemical analysis of 303 clinical specimens from three independent cohorts of lung cancer patients and controls show that expression of ALDH1 is positively correlated with the stage and grade of lung tumors and related to a poor prognosis for the patients with early-stage lung cancer. ALDH1 is therefore a lung tumor stem cell-associated marker. These findings offer an important new tool for the study of lung CSCs and provide a potential prognostic factor and therapeutic target for treatment of the patients with lung cancer.
doi:10.1158/1541-7786.MCR-08-0393
PMCID: PMC4255559  PMID: 19276181
2.  Use of Fluorescence in situ Hybridization to Predict Patient Response to BCG Therapy for Bladder Cancer: Results of a Prospective Trial 
The Journal of Urology  2012;187(3):862-867.
Purpose
No reliable methods currently exist to predict patient response to intravesical immunotherapy with bacillus Calmette-Guérin (BCG), given after transurethral resection for high-risk non-muscle-invasive bladder cancer. We initiated a prospective clinical trial to determine whether fluorescence in situ hybridization (FISH) results during BCG immunotherapy can predict therapy failure.
Materials and Methods
Candidates for standard of care BCG were offered participation in a clinical trial. FISH was performed prior to BCG and at 6 weeks, 3 months, and 6 months during BCG therapy with maintenance. Cox proportional hazards regression was used to assess the relationship between FISH results and tumor recurrence or progression; the Kaplan-Meier product limit method was used to estimate recurrence- and progression-free survival.
Results
One hundred twenty-six patients participated. At a median follow-up of 24 months, 31% of patients had recurrent tumors and 14% experienced disease progression. Patients who had positive FISH results during BCG therapy were 3-5 times more likely than those who had negative FISH results to develop recurrent tumors and 5-13 times more likely to experience disease progression (p < 0.01). The timing of positive FISH results also affected outcome; for example, patients with a negative FISH result at baseline, 6 weeks, and 3 months demonstrated an 8.3% recurrence rate, compared to 48.1% in those with a positive FISH result at all three time points.
Conclusions
FISH results can identify patients who are at risk of tumor recurrence and progression during BCG immunotherapy. This information may be used to counsel patients about alternative treatment strategies.
doi:10.1016/j.juro.2011.10.144
PMCID: PMC3278506  PMID: 22245325
bladder cancer; BCG; FISH; response; prediction
3.  AP2β nucleolar localization predicts poor survival after stage I non–small cell lung cancer resection 
The Annals of Thoracic Surgery  2011;92(3):1044-1050.
Background
Activating enhancer-binding protein-2β (AP2β) is a transcription factor involved in apoptosis. The purpose of the current study was to assess the cellular location and level of AP2β in Non-Small Cell Lung Cancer (NSCLC) and normal lung tissue and investigate whether the level and localization of AP2β expression is predictive of overall survival in patients with stage I NSCLC.
Methods
We performed immunohistochemical analysis of tissue microarrays (TMAs) prepared from stage I NSCLC specimens with adjacent normal lung tissue from two independent sets of patients who underwent lung resection with curative intent at our institution. AP2β intensity was assessed in TMAs, and AP2β staining patterns were classified as either diffuseor nucleolar in the TMAs. AP2β intensity and localization were analyzed for correlation with patients' survival.
Results
Immunohistochemical analysis of TMAs showed that the intensity of AP2β immunohistochemical staining did not correlate with overall survival. When location of AP2β was analyzed in TMAs, all of the normal lung tissue had diffuse pattern of AP2β. In the first set of NSCLC, patients with nucleolar pattern had a significantly lower 5-year survival rate than patients with diffuse pattern (67% vs. 100%; P = 0.004); this finding was confirmed in the second set (64% vs. 91%; P = 0.02). Multivariate analysis revealed that nucleolar pattern was an independent predictor of poor overall survival in both sets.
Conclusions
The AP2β which is located in the nucleoplasm in normal lung tissue is found in either nucleoplasm or nucleoli in NSCLC. The patients with AP2β in the nucleoli had poor survival compared to patients with AP2β in the cytoplasm.
doi:10.1016/j.athoracsur.2011.04.029
PMCID: PMC3272351  PMID: 21871297
Lung cancer biology; survival analysis
4.  Fluorescence in situ hybridization for detecting urothelial carcinoma: A clinicopathological study 
Cancer cytopathology  2010;118(5):259-268.
BACKGROUND
Because urothelial carcinoma (UC) is associated with a significant high risk of recurrence and progression, patients with UC require long-term surveillance. Fluorescence in situ hybridization (FISH) has been shown to be more sensitive than cytology in the detection of UC. This study evaluated the use of FISH for detecting UC.
METHODS
We used a pathology database to identify patients who had urine cytology and FISH performed at our institution between 2004 and 2006. Urinary specimens were analyzed using UroVysion FISH probes for abnormalities in centromeric chromosomes 3, 7 and 17 and locus specific 9p21. FISH results were correlated with cytologic findings and a minimal clinical follow-up of 24 months.
RESULTS
We identified 1006 consecutive urinary specimens from 600 patients (448 men and 152 women) who were monitored for recurrent UC (915 specimens) or evaluated for urinary symptoms (91 specimens). On FISH analysis, 669 specimens were negative for UC and 272 specimens were positive for UC. Sixty-five (6%) specimens were insufficient for FISH analysis. The sensitivity and specificity of FISH for UC were 58% and 66%, respectively, and 59% and 63% when FISH and cytology results were combined. Factors contributing to decreased FISH sensitivity included the paucity or absence of tumor cells, low-grade tumors, degenerated cells, method of specimen collection, type of specimen, and obscuring inflammatory cells or lubricant.
CONCLUSIONS
We found UroVysion FISH had good sensitivity and specificity for detecting UC in urinary specimens. It is important to correlate the FISH results with the cytologic findings.
doi:10.1002/cncy.20099
PMCID: PMC2993817  PMID: 20665656
Urothelial carcinoma; fluorescence in situ hybridization; chromosomal abnormalities; urine; cytology; multitarget FISH; bladder neoplasms; UroVysion
5.  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

Results 1-5 (5)