Tobacco, alcohol use, and risks of laryngeal and lung cancer by subsite and histologic type in Turkey

Effects of tobacco smoking and alcohol use on risks of cancers of thelarynx and lung have been evaluated extensively in industrialized countries.Few studies on the effect of these risk factors have been reported fromdeveloping countries. We conducted a case-control study to evaluate risks oflaryngeal and lung cancers in men by subsite and cell type in relation tosmoking and alcohol drinking in Turkey, a country where smoking and alcoholconsumption patterns are different from those in industrialized countries. Weidentified 832 laryngeal and 1,210 lung cancer cases and 829 controls withinformation on smoking and alcohol use (amount and duration) and histologiccell type from an oncology treatment center of a Social Security Agencyhospital in Istanbul, Turkey, admitted between 1979 and 1984. Both laryngealand lung cancer showed significant associations with smoking and alcoholdrinking, but no monotonic dose-response was obtained for alcohol drinking.Among smokers, the highest risks were observed in the supraglottis region ofthe larynx (odds ratio [OR] = 4.1) after adjustment for age and alcohol use.Among alcohol drinkers, the highest risks were observed in the glottis regionof the larynx (OR = 1.7) after adjustment for age and smoking. In theanalysis by the cell type of lung cancer among ever-smokers, small cell typeshowed the highest risk (OR = 5.4), while it showed no association withalcohol drinking. Cumulative cigarette use (pack-years) and number ofcigarettes per day showed stronger associations than years smoked for bothcancer sites. The relative risks of joint exposure to smoking and alcoholwere 12.2 for laryngeal cancer and 14.1 for lung cancer among heavy smokersand heavy alcohol drinkers. This study provides epidemiologic evidence fromTurkey that smoking and alcohol use are associated with risks of cancers ofthe larynx and lung.     

Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene

Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are presumed to be specific biomarkers of exposure to benzene. We analyzed BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a subsample consisting of 19 workers and 19 controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. The adducts were analyzed by gas chromatography-mass spectrometry following reaction of the protein with trifluoroacetic anhydride and methanesulfonic acid. When subjects were divided into controls (n = 42) and workers exposed to < or =31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were 32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure: Spearman r = 0.67, P < 0.0001). To our knowledge, these results represent the first observation in humans that BO-Hb levels are significantly correlated with benzene exposure. Median BO-Alb levels in these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb, respectively, also reflecting a significant correlation with exposure (Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from both Hb and Alb adducts was very similar. These results clearly affirm the use of both Hb and Alb adducts of BO as biomarkers of exposure to high levels of benzene. As part of our investigation of the background levels of BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g) and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the observed background adducts reflect an artifact of the assay, while other portions are indicative of either unknown exposures or endogenous production of adducts.      

Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene

Two of the most common cytogenetic changes in therapy- and chemical- related leukemia are the loss and long (q) arm deletion of chromosomes 5 and 7. The detection of these aberrations in lymphocytes of individuals exposed to potential leukemogens may serve as useful biomarkers of increased leukemia risk. We have used a novel fluorescence in situ hybridization (FISH) procedure to determine if specific aberrations in chromosomes 1, 5 and 7 occur at an elevated rate in the blood cells of workers exposed to benzene. Forty-three healthy workers exposed to a wide range of benzene concentrations (median 31 p.p.m., 8 h time-weighted average) and 44 unexposed controls from Shanghai were studied. Whole blood was cultured and metaphase spreads were harvested at 72 h. Benzene exposure was associated with increases in the rates of monosomy 5 and 7 but not monosomy 1 (P < 0.001, P < 0.0001 and P = 0.94, respectively) and with increases in trisomy and tetrasomy frequencies of all three chromosomes. Long arm deletion of chromosomes 5 and 7 was increased in a dose-dependent fashion (P = 0.014 and P < 0.0001) up to 3.5-fold in the exposed workers. These results demonstrate that leukemia-specific changes in chromosomes 5 and 7 can be detected by FISH in the peripheral blood of otherwise healthy benzene-exposed workers. We suggest that aberrations in chromosomes 5 and 7 may be useful biomarkers of early biological effect for benzene exposure.      

Dietary factors and the risk of squamous cell esophageal cancer among black and white men in the United States

Objectives: To investigate dietary factors for squamous cell esophageal cancer and whether these factors may contribute to the five-fold higher incidence of this cancer in the black versus white population of the United States.Methods: Data from a food frequency questionnaire were analyzed for 114 white men and 219 black men with squamous cell esophageal cancer, and 681 white and 557 black male controls from three areas of the United States who participated in a population-based case-control study of esophageal cancer.Results: Protective effects were associated with intake of raw fruits and vegetables (odds ratio for high versus low consumers=0.3 in both white and black men) and use of vitamin supplements (especially vitamin C; odds ratio for high versus low consumers=0.4 in both races), with the frequency of consumption of raw fruits and vegetables and vitamin supplements being greater for white than black controls. In addition, elevated risks were associated with high versus low intake of red meat (OR=2.7 for blacks and 1.5 for whites) and processed meat (OR=1.6 for blacks and 1.7 for whites), with the levels of consumption being greater for black than white controls.Conclusions: In the United States, these dietary factors may contribute in part to the much higher incidence of squamous cell esophageal cancer among black compared to white men.     

MR imaging of anterior cruciate ligament reconstruction graft

OBJECTIVE. The objective was to determine the MR imaging findings that differentiate intact anterior cruciate ligament reconstruction graft, partial-thickness tear, and full-thickness tear, using arthroscopy as the gold standard. MATERIALS AND METHODS. Sixteen consecutive MR imaging examinations were retrospectively and independently evaluated by two musculoskeletal radiologists for primary signs (graft signal, orientation, fiber continuity, complete discontinuity, and thickness) and secondary signs (anterior tibial translation, uncovered posterior horn lateral meniscus, posterior cruciate ligament hyperbuckling, and abnormal posterior cruciate ligament line) of anterior cruciate ligament reconstruction graft tear in 15 patients with follow-up arthroscopy. Results were compared with arthroscopy, and both receiver operating characteristic curves and kappa values for interobserver variability were calculated. RESULTS. Arthroscopy revealed four full-thickness graft tears, seven partial-thickness tears, and five intact grafts. Of the primary signs, graft fiber continuity in the coronal plane and 100% graft thickness in the sagittal or coronal plane were most valuable in excluding full-thickness tear. Complete discontinuous graft in the coronal plane also was valuable in diagnosis of full-thickness tear. Of the secondary signs, anterior tibial translation and uncovered posterior horn lateral meniscus assisted in differentiating graft tear (partial or full thickness) from intact graft. The other primary and secondary signs were less valuable. Kappa values were highest for graft fiber continuity and graft discontinuity in the coronal plane. CONCLUSION. Full-thickness anterior cruciate ligament graft tear can be differentiated from partial-thickness tear or intact graft by evaluating for graft fiber continuity (coronal plane), complete graft discontinuity (coronal plane), and graft thickness (coronal or sagittal plane).     

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 +/- 0.9 h for imatinib, 20.6 +/- 1.7 h for CGP74588, and 57.3 +/- 12.5 h for (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 h) (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.     

Light and confocal microscopic studies of evolutionary changes in neurofilament proteins following cortical impact injury in the rat

Previous studies have shown that traumatic brain injury (TBI) produces progressive degradation of cytoskeletal proteins including neurofilaments (e.g., neurofilament 68 [NF68] and neurofilament 200 [NF200]) within the first 24 h after injury. Thus, we employed immunofluorescence (light and confocal microscopy) to study the histopathological correlates of progressive neurofilament protein loss observed at 15 min, 3 h, and 24 h following unilateral cortical injury in rats. TBI produced significant alterations in NF68 and NF200 immunolabeling in dendrites and cell bodies at contusion sites ipsilateral to injury, as well as in the noncontused contralateral cortex. Changes in immunolabeling were associated with, but not exclusively restricted to, regions previously shown to contain dark shrunken neurons labeled by hematoxylin and eosin staining, a morphopathological response to injury suggesting impending cell death. Immunofluorescence microscopic studies of neurofilament proteins in the ipsilateral cerebral cortex detected prominent fragmentation of apical dendrites of pyramidal neurons in layers 3-5 and loss of fine dendritic arborization within layer 1. While modest changes were observed 15 min following injury, more pronounced loss of dendritic neurofilament immunofluorescence was detected 3 and 24 h following injury. Confocal microscopy also revealed progressive alterations in NF68 immunoreactivity in dendrites following TBI. While some evidence of structural alterations was observed 15 min following TBI, dendritic breaks were readily detected in confocal micrographs from 3 to 24 h following injury. However, disturbances in axonal NF68 by immunofluorescence microscopy in the corpus callosum were not detected until 24 h after injury. These studies confirmed that derangements in dendritic neurofilament cytoskeletal proteins are not exclusively restricted to sites of impact contusion. Moreover, changes in dendritic cytoskeletal proteins are progressive and not fully expressed within the first 15 min following impact injury. These progressive dendritic disruptions are characterized by disturbances in the morphology of neurofilament proteins, resulting in fragmentation and focal loss of NF68 immunofluorescence within apical dendrites. In contrast, alterations in axonal cytoskeletal proteins are more restricted and delayed with no pronounced changes until 24 h after injury.     

Use of a reusable shielded marker to enhance the accuracy, safety, and efficacy of nuclear medicine procedures

Three cases illustrate the use of a reusable, shielded marker to identify anatomic structures and mark pathologic lesions. No other nuclear medicine marker is available with a shutter mechanism designed to interrupt radiation, thus protecting the patient and technologist from unnecessary radiation and minimizing image artifacts.     

Circulating HER-2/erbB-2/c-neu (HER-2) extracellular domain as a prognostic factor in patients with metastatic breast cancer: Cancer and Leukemia Group B Study 8662.

PURPOSE: The HER-2/erbB-2/c-neu (HER-2) proto-oncogene is a M(r) 185,000 transmembrane tyrosine kinase that is amplified and/or overexpressed by 20-40% of breast cancers. HER-2 has been associated with worse prognosis and resistance or sensitivity to specific treatment. We evaluated circulating levels of extracellular domain of HER-2 (ECD/HER-2) in metastatic breast cancer patients and investigated the prognostic and predictive significance of circulating HER-2 levels regarding endocrine therapy or chemotherapy. EXPERIMENTAL DESIGN: Plasma samples from 242 patients were assayed for circulating ECD/HER-2 levels, using a sandwich enzyme immunoassay. ECD/HER-2 was correlated with clinical data gathered from these patients while they were participating in prospective Cancer and Leukemia Group B (CALGB) therapeutic protocols for metastatic breast cancer. RESULTS: Eighty-nine (37%) of 242 patients had elevated ECD/HER-2 levels (> or =10.5 ng/ml). ECD/HER-2 was significantly associated with tumor burden, progesterone receptor levels, and presence of visceral metastases. Patients with elevated pretreatment levels had a significantly shorter OS but not time-to-progression than did those with ECD/HER-2 levels <10.5 ng/ml in univariate analysis. In univariate but not multivariate subset analyses, among patients treated with endocrine therapy (megestrol acetate), elevated initial ECD/HER-2 was associated with worse OS compared with nonelevated patients. However, among patients treated with chemotherapy (mainly anthracycline-containing regimens), OS did not differ significantly. Rates of response to either endocrine therapy or chemotherapy were similar for patients with elevated and nonelevated ECD/HER-2 levels. CONCLUSIONS: ECD/HER-2 levels are elevated in 35-40% of patients with metastatic breast cancer. Elevated ECD/HER-2 levels are associated with a poorer prognosis in these patients. However, no predictive role for ECD/HER-2 was identified, either for endocrine therapy or for anthracycline-based chemotherapy in the metastatic setting.     

Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME‐ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene‐based and pathway‐based analyses by applying the summary‐based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME‐ON and PLCO, after Bonferroni correction (p_pathway < 0.00625). The two most significant genes were NPAS2 (p_gene = 0.0062) and AANAT (p_gene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME‐ON (p_pathway = 0.021); this association was not confirmed in GECCO (p_pathway = 0.76) or the combined data (p_pathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.