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Background: New methods are needed to detect precancerous lesions in lung tissue. We conducted a study to determine the utility of LIFE[TM] (laser-induced fluorescence emission) autofluorescence bronchoscopy for the detection of squamous metaplasia and dysplasia in current and former smokers. Methods: In this prospective, single-center study, 53 participants underwent standard white-light bronchoscopy and 39 underwent both white-light and LIFE bronchoscopy. Bronchial biopsy specimens were obtained from all participants at six predetermined sites using white-light bronchoscopy and from all other sites that appeared to be abnormal in participants who underwent LIFE bronchoscopy. Relationships between LIFE imaging and histologic findings were examined for 245 biopsy specimens obtained from those participants who had undergone LIFE bronchoscopy. Results: LIFE imaging revealed abnormalities designated as either class II or class III in 89 (36.3%) and 16 (6.5%) of the 245 sites examined, respectively, and histopathologic examination showed dysplasia and metaplasia in eight (3.3%) and in 52 (21.2%) of the 245 specimens, respectively. Among the 105 biopsy specimens obtained from sites with abnormal LIFE imaging, only 26 (24.8%) exhibited squamous metaplasia and/or dysplasia, similar to the findings for sites with normal LIFE imaging (34 [24.3%] of 140). Comparison of individuals examined by LIFE imaging with those who underwent white-light bronchoscopy alone revealed no increase in the detection of dysplasia or metaplasia with LIFE bronchoscopy. Conclusion: In this population of current and former smokers, abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dysplasia. [J Natl Cancer Inst 1998; 90:991-5]

Background: Retinoids, analogues of vitamin A, are required for the normal growth and differentiation of human bronchial epithelium. They are also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). These effects are thought to result from modulation of cell growth, differentiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which mediate most retinoid actions, are suppressed, abnormal activity may result that could enhance cancer development. Purpose: This study was designed to determine whether there are abnormalities in the expression of retinoid receptors in surgical specimens from patients with NSCLC. Methods: Transcripts of nuclear retinoid receptors were detected in formalin-fixed, paraffin-embedded specimens by use of digoxigenin-labeled riboprobes specific for RAR[Alpha], RAR[Beta], RAR[Gamma], RXR[Alpha], RXR[Beta], and RXR[Gamma] for in situ hybridization to histologic specimens from 79 patients with NSCLC and as control from 17 patients with non-lung cancer. The quality and specificity of the digoxigenin-labeled probes were determined by northern blotting, and the specificity of the binding of antisense riboprobes was verified by use of sense probes as controls. Results: All receptors were expressed in at least 89% of control normal bronchial tissue specimens from 17 patients without a primary lung cancer and in distant normal bronchus specimens from patients with NSCLC. RAR[Alpha], RXR[Alpha], and RXR[Gamma] were expressed in more than 95% of the NSCLC specimens. In contrast, RAR[Beta], RAR[Gamma], and RXR[Beta] expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. Conclusions: These data suggest that the expression of RAR[Alpha], RXR[Alpha], and RXR[Gamma] is not altered in NSCLC; however, expression of RAR[Beta] and possibly also of RAR[Gamma] and RXR[Beta] is suppressed in a large percentage of patients with lung cancer. Implications: The loss of expression of one or more of these nuclear retinoid receptors may be associated with lung carcinogenesis. [J Natl Cancer Inst 1997;89:624-9]

The survival rate for head and neck squamous cell carcinoma remains poor despite therapeutic advances over the last two decades. For patients with disease confined to the head and neck, there are two major and biologically distinct patterns of treatment failures after definitive therapy: recurrence of primary disease and development of second primary tumors. Understanding the biological basis of patterns of treatment failure after definitive therapy is needed to guide the development of adjuvant treatment and strategies to prevent second primary tumors. Purpose: To determine whether expression of the p53 protein has prognostic significance and/or is associated with patterns of treatment failure, we examined protein expression in primary tumor specimens of patients with head and neck squamous cell carcinoma. Methods: Immunohistochemical analysis with a monoclonal antibody (D07) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 69 head and neck cancer patients treated with definitive local therapy (surgery and/or radiotherapy) between January 1980 and October 1983 at The University of Texas M. D. Anderson Cancer Center. We quantitated p53 protein expression and assessed its association with duration of patient survival, patterns of treatment failure (recurrence of primary tumor and development of second primary tumor), and other clinical parameters. All reported P values resulted from two-sided statistical tests. Results: We found detectable levels of p53 protein expression in the tumor cell nuclei of 41 of 69 patients. Thirty-six (52%) of 69 patients whose tumors exhibited p53 protein expression in greater than or equal to 10% of the cell nuclei were grouped as p53 positive, and 33 (48%) of 69 patients whose tumors exhibited less than 10% nuclear expression were grouped as p53 negative. The clinical characteristics of the patients in the p53-positive and p53-negative groups were well balanced. Overall survival was significantly lower, and the times to tumor recurrence, to second primary tumors, and to any treatment failure were significantly shorter in the p53-positive group than in the p53-negative group (P = .0002, P = .047, P = .003, and P = .0009, respectively), mainly because the p53 positivity was associated with earlier development of tumor recurrence and second primary tumors. The rate of second primary tumor development per person per year was also significantly higher in the p53-positive group than in the p53-negative group. By use of multivariate analysis according to the Cox regression model, p53 expression status was identified as the most significant predictor of overall survival duration (P = .007), time to tumor recurrence (P = .053), time to second primary tumors (P = .035), and time to any treatment failure (P = .004). Conclusions: The expression of p53 protein in primary head and neck squamous cell carcinoma was significantly predictive of shorter survival because of its association with earlier development of both tumor recurrence and second primary tumors. Thus, p53 expression may be a valuable marker for identifying individuals at high risk of developing a recurrence of primary disease and second primary tumors who may benefit from adjuvant therapy and chemoprevention after definitive local therapy. [J Natl Cancer Inst 1996;88:519-291

Background: Proliferating cell nuclear antigen (PCNA) is a 36-kd nuclear protein whose expression is associated with DNA synthesis and cell proliferation. Tumorigenesis in head and neck squamous cell carcinoma is proposed to be a multistep process; dysregulation of proliferation is a potential marker of this process. Purpose: PCNA dysregulation was analyzed in squamous cell carcinoma tissue samples containing premalignant lesions (hyperplasia and/or dysplasia) and in adjacent normal epithelium to better understand proliferative changes during head and neck tumor development. Methods: Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded sections by using a monoclonal anti-PCNA antibody. PCNA expression was analyzed in 33 head and neck squamous cell carcinomas and in their adjacent premalignant lesions from different sites and compared with that in the control samples, which had never been exposed to first-hand tobacco smoke. PCNA expression was assessed by semiquantitative scoring (scale 0-3) in three epithelial layers (basal, parabasal, and superficial). The labeling index and the weighted mean index of PCNA expression were calculated. Results: Normal epithelium adjacent to the tumor had much more proliferative activity than the controls: The weighted mean index of PCNA expression was fourfold higher in the basal layer and sixfold higher in the parabasal layer. PCNA expression increased as tissues progressed from adjacent normal epithelium to hyperplasia (P

Background: Telomerase activation plays a critical role in tumorigenesis. To determine the role of telomerase in early lung carcinogenesis and as a potential biomarker in chemoprevention trials, we analyzed the expression of the human telomerase reverse transcriptase catalytic subunit (hTERT) in bronchial biopsy specimens from cigarette smokers who were enrolled in a randomized, double-blinded, placebo-controlled chemoprevention trial of N-(4-hydroxyphenyl) retinamide (4-HPR). Methods: We obtained biopsy specimens from six predetermined sites in the bronchial tree from the 57 participants, before treatment and 6 months after treatment with 4-HPR or placebo. We used in situ hybridization to examine hTERT messenger RNA (mRNA) expression in 266 pretreatment (baseline) and post-treatment site-paired biopsy specimens from 27 patients in the 4-HPR-treated group and from 30 patients in the placebo-treated group. All statistical tests were two-sided. Results: At baseline, 62.4% (95% confidence interval [CI] = 53.9% to 71%) of the biopsy specimens obtained from the group treated with 4-HPR and 65.2% (95% CI = 57.4% to 73.1%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. After 6 months, 45.6% (95% CI = 36.9% to 54.3%) of the biopsy specimens obtained from the 4-HPR-treated group and 68.1% (95% CI = 60.4% to 75.8%) of the biopsy specimens obtained from the placebo-treated group expressed hTERT mRNA. The reduction in hTERT expression observed between the two treatment groups over time was statistically significant (P = .01) when we used the biopsy site as the unit of analysis, but not when we used the individual as the unit of analysis (P = .37). Conclusions: Telomerase is frequently reactivated in the lungs of cigarette smokers. The modulation of hTERT expression in 4-HPR-treated smokers suggests that a novel molecular mechanism underlies the potential chemopreventive properties of 4-HPR. hTERT expression is a promising potential biomarker for risk assessment and for the evaluation of the efficacy of chemopreventive agents in lung carcinogenesis. [J Natl Cancer Inst 2001;93: 1257-63]