Faculty Bibliography

AIMS: Osteopontin (OPN) is a matricellular protein involved in tissue remodelling, cell-mediated immunity and malignant transformation. High OPN serum levels predict poor prognosis in non-small cell carcinoma and set patients with malignant pleural mesothelioma (MM) apart from disease-free asbestos-exposed individuals. Yet neither the spectrum of tissue expression nor the signalling pathways of OPN in MM and pulmonary adenocarcinoma have been characterized, although in vitro evidence links OPN to the epidermal growth factor receptor (EGFR) pathway. The aim of this study was to address these deficiencies. METHODS AND RESULTS: OPN expression was investigated immunohistochemically in 104 adenocarcinomas and 38 MM and correlated with histological features, including tumour type, grade and proliferation and with expression of activated intermediary EGFR signalling pathway molecules p65, p-AKT, p-ERK, p-STAT-3, and of metalloproteinase (MMP)-1, MMP-2 and MMP-9. In MM, OPN expression was widespread (36/38) and independent of the molecular parameters studied. In adenocarcinoma, high OPN expression was correlated with expression of p65, p-ERK and MMP-9. CONCLUSIONS: Frequent OPN expression is typical of, but not specific for MM, whereas it appears to select adenocarcinoma cases with p65 and MMP-9 expression, suggesting a link with EGFR signalling pathways

BACKGROUND: Soluble mesothelin-related peptides (SMRP)have been reported to be potential biomarkers for malignant pleural mesothelioma (MPM). We report analytical and preliminary clinical studies of MESOMARK, a quantitative assay for SMRP. METHODS: The MESOMARK assay is a 2-step immunoenzymatic assay in an ELISA format with a 6-point calibration curve (0-32 nmol/L). We assessed analytical imprecision, analyte stability, and analytical interferences. We measured SMRP by this assay in 409 apparently healthy individuals (reference interval study), 177 patients with nonmalignant conditions, and 500 cancer patients, including 88 with MPM. RESULTS: The limit of detection was 0.16 nmol/L. At 2-19 nmol/L, intraassay imprecision (CV) was 1.1%-5.3%, and total imprecision was 4.0%-11.0%. The mean dilution recovery for 5 samples was 109% (range, 99%-113%). No interference was seen from added bilirubin (200 mg/L), hemoglobin (500 mg/L), triglycerides (30 g/L), chemotherapeutic agents, or other tested substances. Recombinant mesothelin was stable in serum upon freeze/thaw at -70 degrees C and upon storage for at least 7 days at 2-8 degrees C. The 99(th) percentile of the reference group was 1.5 nmol/L [95% confidence interval (CI), 1.2-1.6 nmol/L; n = 409], and mean SMRP was significantly higher in sera from patients with MPM (7.5 nmol/L; 95% CI, 2.8-12.1 nmol/L; n = 88). SMRP was increased in 52% and 5% of MPM patients and asbestos-exposed individuals, respectively. Concentrations in other nonmalignant and malignant conditions were similar to those in healthy controls. CONCLUSIONS: The MESOMARK assay is analytically robust and may be useful for the detection and management of mesothelioma

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined

In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government

According to the American Cancer Society, there will be an estimated 14,520 new cases of esophageal cancer and 174,470 new cases of lung cancer in 2005. Close to 60% of these patients with esophageal cancer will present at an advanced stage not amenable to cure, but still will require palliation of their dysphagia. Conventional plastic stents (CPS) were used initially, and with continuous improvement in technology, insertion of self-expanding metal stents (SEMS) has become the palliative treatment of choice in the majority of these patients. SEMS are effective in palliating malignant dysphagia in 85%-100% of patients. More recently, a new self-expanding plastic stent (SEPS) has been designed which in early studies has been very effective in palliating dysphagia. Similarly, the majority of patients with lung cancer will present at an advanced stage and approximately 20% of these patients will have an endobronchial component requiring some form of palliation for relief of airway obstruction. Currently airway stents are either made of self-expanding metal for more permanent use, orl silicone if a more temporary solution is needed. Complications similar to the esophageal stents may arise. The purpose of this article is to provide an evidence based review of stents in the palliative setting for esophageal and lung cancer and briefly explore their potential use and expanding indications in the neoadjuvant setting

Individuals concerned about their risk of lung cancer are recommended to talk with their physicians about computed tomographic screening for lung cancer. To provide the necessary information, the survival benefit of the screening, specific to a particular person for a particular round of screening, is needed. The probability of survival gain from the first, baseline, round of screening was addressed as the product of: 1) the screening resulting in a diagnosis of lung cancer; 2) not dying from some other cause for a sufficiently long period of time; and 3) cure resulting from pre-symptomatic treatment of lung cancer. These probabilities were estimated using the International Early Lung Cancer Action Program data on individuals aged 40-85 yrs with a cigarette smoking history of 0-150 pack-yrs. The estimated probability of survival gain ranged from 0.4% for a 60-yr-old with a 10-pack-yr smoking history who quit smoking 20 yrs ago, to 3.1% for a 70-yr-old current smoker with a 100 pack-yr history and 2.0% for an 85-yr-old current smoker with a 150-pack-yr history. When seeking counsel about initiation of screening for lung cancer, an estimate of the probability of survival gain from the first round of computed tomographic screening, specific to the person's age and history of smoking, can be provided

BACKGROUND: Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS: VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS: Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS: A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality

Lobectomy and mediastinal lymph node dissection is the standard surgical management of early stage non-small cell lung cancer (NSCLC) because more limited resections have been associated with a higher risk of local recurrence. Nevertheless, recent lung cancer screening studies have led to the detection of an increasing number of 'very early' NSCLC (defined as less than 2 cm in size) and of good-prognosis histologic subtypes, bronchioloalveolar carcinoma (BAC), and adenocarcinoma (AC), mixed subtypes that are potentially appropriate for sublobar resection. The precise indications for sublobar resection remain unclear and are the subject of ongoing clinical trials, but it seems that very early, peripherally located, node-negative AC of a predominantly BAC pattern may be adequately treated in this manner. Multifocal AC and BAC, either synchronous or metachronous, are also effectively treated by complete resection, using limited resections whenever possible. The pneumonic form of BAC, the rarest variant of this disease spectrum, continues to have a poor prognosis despite complete resection. Very limited experience suggests that lung transplantation leads to prolonged survival in highly selected patients with this histologic subtype. To improve our management of very early AC, much more information is needed about the molecular abnormalities of AC and their relationship to clinical outcomes

Peritoneal mesothelioma is a rare cancer of the peritoneum with about 250 new cases diagnosed each year in the United States. It is the second most common site for mesothelioma development and accounts for 10-20% of all mesotheliomas diagnosed in the United States. A meeting sponsored by the NIH Office of Rare Diseases was held in Bethesda, Maryland on September 13 and 14, 2004. The objective of this meeting was to review the epidemiology, biology and current surgical and medical management of peritoneal mesothelioma. In addition, the meeting also discussed clinical and pre-clinical evaluation of novel treatments for mesothelioma as well as ongoing laboratory research to better understand this disease. This report summarizes the proceedings of the meeting as well as directions for future clinical and basic research