Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer.

PURPOSE: Bronchial carcinogenesis is a multistep process characterized by accumulation of genetic and molecular abnormalities, which precedes and accompanies the preinvasive lesions known as dysplasia and carcinoma in situ (CIS). We hypothesized that the level of accumulated molecular abnormalities in dysplasia assessed by immunohistochemical markers might reflect the severity of the carcinogenic process, thus allowing for risk assessment in smokers. EXPERIMENTAL DESIGN: We performed a prospective analysis of bronchial biopsies in 48 former smokers who had at least one area of metaplasia. Twenty-two of the patients had a previous history of lung cancer. Eighty bronchial lesions were recorded at baseline, including 31 metaplasia, 12 mild dysplasia, 9 moderate dysplasia, 9 severe dysplasia, and 19 CISs. Forty-one percent of the patients had multiple preinvasive lesions. Immunohistochemical analysis of P53, cyclin D1, cyclin E, Bax, and Bcl2 was performed. Aberrant expression of one of these proteins as compared with normal bronchi was recorded as one molecular alteration. RESULTS: After 18 months, 17 patients were diagnosed with lung cancer. No isolated parameter, including dysplastic grade or any isolated molecular alteration, was significantly associated with cancer occurrence at 18 months follow-up, using a logistic regression statistical analysis. In contrast, considering CIS and cancer as end point, more than two immunohistochemical abnormalities were associated with cancer or CIS occurrence (P = 0.02). CONCLUSIONS: We concluded that the cumulative index of immunohistochemical abnormalities in a random dysplasia is associated with CIS or lung cancer in the cancerization field of symptomatic smokers, independently of the histopathological grade of dysplasia. This set of histopathological biomarkers might be useful in risk assessment and provide intermediate end points for chemopreventive trials.

Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study.

STUDY OBJECTIVES: Intrapleural immunotherapy has shown some activity in patients with malignant mesothelioma. We conducted a multicentric pilot phase II study to evaluate the tolerance and the activity of intrapleurally infused autologous human activated macrophages (AM Phi) in patients with stage IA, IB, and IIA malignant pleural mesothelioma (MPM). DESIGN: AM Phi derived from in vitro monocyte culture were infused into the pleura of patients every week for 8 consecutive weeks. Each infusion was followed 3 days later by an intrapleural injection of 9 millions units of gamma-interferon (gamma-IFN) in an attempt to prolong the in vivo activation of infused AM Phi. Response was assessed by CT scan and thoracoscopy when possible. If the patient's disease progressed after AM Phi treatment, an additional treatment was left to the choice of the investigator. PATIENTS: Nineteen patients with histologically proven stage IA, IB, or IIA MPM were enrolled. Two patients were excluded before any AM Phi infusion because of complications impeding infusion. Seventeen patients were actually treated. After completion of the AM Phi cellular therapy, 10 patients were treated with chemotherapy as their diseases progressed. RESULTS: The overall response rate of patients actually treated was 14%. When including the two patients enrolled but not treated, the overall response "in intention to treat" was 11%; two patients had a partial response, with a duration of response of 30 months and 3 months, respectively. One patient, who could not be evaluated by thoracoscopy because of pleural symphysis, is still alive without any clinical or radiologic sign of disease 69 months after treatment. No major adverse effects were observed during the infusion of either AM Phi or gamma-IFN, and there was no interruption of treatment because of toxicity. However, symphysis was observed in 7 of 14 patients who received the complete treatment. The median survival of patients actually treated, including those who received chemotherapy after AM Phi, was 29.2 months. CONCLUSION: Combined infusion of AM Phi and gamma-IFN was well tolerated in patients with MPM; however, it had limited antitumor activity.