Gregory M. Loewen

Regular aspirin use and lung cancer risk.

BackgroundAlthough a large number of epidemiological studies have examined the role of aspirin in the chemoprevention of colon cancer and other solid tumors, there is a limited body of research focusing on the association between aspirin and lung cancer risk.MethodsWe conducted a hospital-based case-control study to evaluate the role of regular aspirin use in lung cancer etiology. Study participants included 868 cases with primary, incident lung cancer and 935 hospital controls with non-neoplastic conditions who completed a comprehensive epidemiological questionnaire. Participants were classified as regular aspirin users if they had taken the drug at least once a week for at least one year.ResultsResults indicated that lung cancer risk was significantly lower for aspirin users compared to non-users (adjusted OR = 0.57; 95% CI 0.41–0.78). Although there was no clear evidence of a dose-response relationship, we observed risk reductions associated with greater frequency of use. Similarly, prolonged duration of use and increasing tablet years (tablets per day × years of use) was associated with reduced lung cancer risk. Risk reductions were observed in both sexes, but significant dose response relationships were only seen among male participants. When the analyses were restricted to former and current smokers, participants with the lowest cigarette exposure tended to benefit most from the potential chemopreventive effect of aspirin. After stratification by histology, regular aspirin use was significantly associated with reduced risk of small cell lung cancer and non-small cell lung cancer.ConclusionsOverall, results from this hospital-based case-control study suggest that regular aspirin use may be associated with reduced risk of lung cancer.

Preoperative Exercise Vo2 Measurement for Lung Resection Candidates: Results of Cancer and Leukemia Group B Protocol 9238

Introduction: A stepwise approach to the functional assessment of lung resection candidates is widely accepted, and this approach incorporates the measurement of exercise peak Vo2 when spirometry and radionuclear studies suggest medical inoperability. A new functional operability (FO) algorithm incorporates peak exercise Vo2 earlier in the preoperative assessment to determine which patients require preoperative radionuclear studies. This algorithm has not been studied in a multicenter study. Methods: The CALGB (Cancer and Leukemia Group B) performed a prospective multi-institutional study to investigate the use of primary exercise Vo2 measurement for the prediction of surgical risk. Patients with known or suspected resectable non-small cell lung cancer (NSCLC) were eligible. Exercise testing including measurement of peak oxygen uptake (Vo2), spirometry, and single breath diffusion capacity (DLCO) was performed on each patient. Nuclear perfusion scans were obtained on selected high-risk patients. After surgery, morbidity and mortality data were collected and correlated with preoperative data. Mortality and morbidity were retrospectively compared by algorithm-based risk groups. Results: Three hundred forty-six patients with suspected lung cancer from nine institutions underwent thoracotomy with or without resection; 57 study patients did not undergo thoracotomy. Patients who underwent surgery had a median survival time of 30.9 months, whereas patients who did not undergo surgery had a median survival time of 15.6 months. Among the 346 patients who underwent thoracotomy, 15 patients died postoperatively (4%), and 138 patients (39%) exhibited at least one cardiorespiratory complication postoperatively. We found that patients who had a peak exercise Vo2 of <65% of predicted (or a peak Vo2/kg <16 ml/min/kg) were more likely to suffer complications (p = 0.0001) and were also more likely to have a poor outcome (respiratory failure or death) if the peak Vo2 was <15 ml/min/kg (p = 0.0356). We also found a subset of 58 patients who did not meet FO algorithm criteria for operability, but who still tolerated lung resection with a 2% mortality rate. Conclusions: Our data provide multicenter validation for the use of exercise Vo2 for preoperative assessment of lung cancer patients, and we encourage an aggressive approach when evaluating these patients for surgery.

Peak Oxygen Consumption and Long-Term All-Cause Mortality in Nonsmall Cell Lung Cancer

Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with nonsmall cell lung cancer (NSCLC). The authors investigated the prognostic significance of preoperative cardiorespiratory fitness (peak oxygen consumption [VO2peak]) among operable candidates with NSCLC.

Detection and Localization of Intraepithelial Neoplasia and Invasive Carcinoma Using Fluorescence-Reflectance Bronchoscopy: An International, Multicenter Clinical Trial

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.

HER-2/neu Protein Expression and Gene Alteration in Stage I-IIIA Non-Small-Cell Lung Cancer: A Study of 140 Cases Using a Combination of High Throughput Tissue Microarray, Immunohistochemistry, and Fluorescent In Situ Hybridization

Regarding HER-2/ neu expression (gene or protein level) in lung cancer, several studies with inconsistent results have been recently reported, partially due to variable techniques used and/or heterogeneous populations examined. The objective of this study was to examine HER-2/ neu expression in a well-defined cohort of non–small-cell lung cancers (NSCLC) and in nonneoplastic lung tissue utilizing a combination of high-density tissue microarray, immunohistochemistry (IHC), and fluorescent in situ hybridization (FISH) under uniform test conditions. One hundred forty stage I-IIIA primary NSCLCs and 38 non-neoplastic lung samples were examined. IHC, using an FDA-approved Hercept monoclonal antibody kit, was performed and HER-2/ neu gene alteration was assessed by FISH. The association of expression of HER-2/ neu with clinicopathologic parameters was analyzed. Ninety-four percent of tumor samples (131/140) were fully interpretable after tissue processing. Twenty-five of them (19%) overexpressed (2+, 3+) HER-2/ neu, while 106 (81%) had no or weak expression. All thirty-four interpretable non-neoplastic lung samples were negative for HER-2/ neu alteration at protein and gene level. HER-2/ neu protein overexpression correlated well with HER-2/ neu gene amplification (r =.83, P < 0.001). HER-2/ neu overexpression was significantly associated with histologic subtype: 19 adenocarcinomas (19/82, 23%) versus 4 squamous cell carcinomas (4/44, 9%) overexpressed Her-2/ neu (P = 0.04). Statistical significance was observed between HER-2/ neu expression and tumor differentiation, with strong positive (3+) expression observed more frequently in poorly differentiated tumors (P = 0.01). Patients with HER-2/ neu abnormalities, particularly HER-2/ neu gene amplification, exhibited a shorter survival (P = 0.043). The statistically significant difference (P < 0.005) between HER-2/ neu alteration in tumor samples(25/131, 19%) and in the nonneoplastic tissue (0/34, 0%) implies that HER-2/ neu may have a role in the carcinogenesis of NSCLC. The findings provide evidence supporting the hypothesis that the HER-2/ neu receptor may represent a useful molecular target in the treatment of NSCLC. The significant association of HER-2/ neu expression and gene amplification with poorly differentiated carcinoma compared with well differentiated carcinoma suggests that HER-2/ neu may be involved in NSCLC tumor evolution. Patients with HER-2/ neu gene amplification and strong positive expression of HER-2/ neu protein showed a strong tendency toward shorter survival.

MCM2 - a promising marker for premalignant lesions of the lung: a cohort study

BackgroundBecause cells progressing to cancer must proliferate, marker proteins specific to proliferating cells may permit detection of premalignant lesions. Here we compared the sensitivities of a classic proliferation marker, Ki-67, with a new proliferation marker, MCM2, in 41 bronchial biopsy specimens representing normal mucosa, metaplasia, dysplasia, and carcinoma in situ.MethodsParallel sections were stained with antibodies against MCM2 and Ki-67, and the frequencies of staining were independently measured by two investigators. Differences were evaluated statistically using the two-sided correlated samples t-test and Wilcoxon rank sum test.ResultsFor each of the 41 specimens, the average frequency of staining by anti-MCM2 (39%) was significantly (p < 0.001) greater than by anti-Ki-67 (16%). In metaplastic lesions anti-MCM2 frequently detected cells near the epithelial surface, while anti-Ki-67 did not.ConclusionsWe conclude that MCM2 is detectable in 2-3 times more proliferating premalignant lung cells than is Ki-67. The promise of MCM2 as a sensitive marker for premalignant lung cells is enhanced by the fact that it is present in cells at the surface of metaplastic lung lesions, which are more likely to be exfoliated into sputum. Future studies will determine if use of anti-MCM2 makes possible sufficiently early detection to significantly enhance lung cancer survival rates.

Autofluorescence bronchoscopy for lung cancer surveillance based on risk assessment

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.

Vitamin D Receptor Expression in Normal, Premalignant, and Malignant Human Lung Tissue

Background: There is a strong interest in identifying chemopreventive agents that might help decrease the burden of lung cancer. The active metabolite of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), has been shown to have antiproliferative effects in several tumor types, mediated by the vitamin D receptor (VDR). This is the first comprehensive survey of VDR expression in a series of human lung tissues, including normal and premalignant central airway biopsies and lung tumors. Methods: Immunohistochemical expression of nuclear and cytoplasmic VDR was examined in 180 premalignant or malignant bronchial biopsies from bronchoscopy of 78 high-risk individuals at the Roswell Park Cancer Institute and also in 63 tumor samples from 35 lung cancer patients from the University of Chicago Hospitals. Associations between clinicopathologic data and VDR expression were examined. Results: VDR expression was present in many samples. In biopsies, VDR was commonly detected throughout the full epithelial layer. Most histologically normal (60%, 53 of 88) and metaplastic (61%, 39 of 64) samples had moderate to high nuclear intensity; dysplastic samples mostly had low nuclear intensity (10 of 18, 55%). In tumor samples, 62% (38 of 61) were lacking cytoplasmic VDR, with nuclear expression present in 79%(49 of 62). Analysis of all samples revealed a positive linear trend between proportion of samples with greater nuclear than cytoplasmic intensity and increasing histologic grade (P < 0.01). Conclusions: VDR expression spanned the lung carcinogenesis spectrum. Nuclear expression was similar across various histologies, whereas cytoplasmic expression decreased with increasing histologic grade. These results indicate that there is potential for the use of calcitriol as a chemopreventive agent against the development of lung cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1104–10)

Unusual central nervous system toxicity in a phase I study of N1N11diethylnorspermine in patients with advanced malignancy

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search.Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h.We conclude that great caution is warranted in administering DENSPM on this schedule at doses of ≥ 83 mg/m2/day.

Cross-Linking of Signal Transducer and Activator of Transcription 3—A Molecular Marker for the Photodynamic Reaction in Cells and Tumors

Purpose: Photodynamic therapy (PDT) depends on the delivery of a photosensitizer to the target tissue that, under light exposure, produces singlet oxygen and other reactive oxygen species, which in turn cause the death of the treated cell. This study establishes a quantitative marker for the photoreaction that will predict the outcome of PDT. Experimental Design: Cells in tissue culture, murine s.c. tumors, and endobronchial carcinomas in patients were treated with PDT, and the noncleavable cross-linking of the latent signal transducer and activator of transcription 3 (STAT3) was determined. Results: Murine and human cancer cell lines reacted to PDT by an immediate covalent cross-linking of STAT3 to homodimeric and other complexes. The magnitude of this effect was strictly a function of the PDT reaction that is determined by the photosensitizer concentration and light dose. The cross-link reaction of STAT3 was proportional to the subsequent cytotoxic outcome of PDT. An equivalent photoreaction as detected in vitro occurred in tumors treated in situ with PDT. The light dose-dependent STAT3 cross-linking indicated the relative effectiveness of PDT as a function of the distance of the tissue to the treating laser light source. Absence of cross-links correlated with treatment failure. Conclusions: The data suggest that the relative amount of cross-linked STAT3 predicts the probability for beneficial outcome, whereas absence of cross-links predicts treatment failure. Determination of STAT3 cross-links after PDT might be clinically useful for early assessment of PDT response.