National Cancer Institute®
Last Modified: August 1, 2002
UI - 12082623
AU - Toyooka S; Carbone M; Toyooka KO; Bocchetta M; Shivapurkar N; Minna JD;
TI - Gazdar AF Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells.
SO - Oncogene 2002 Jun 20;21(27):4340-4
AD - Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, TX 75390, USA.
Mesotheliomas are tumors arising from mesothelial cells and are associated with asbestos exposure and approximately 50% contain simian virus 40 (SV40) DNA sequences. SV40 infection of human mesothelial cells (HM) causes early cellular immortalization and late transformation. Aberrant methylation is a major mech-anism for loss of function of tumor suppressor genes (TSGs). We recently reported that of seven genes frequently methylated in epithelial tumors, only RASSF1A gene was frequently methylated in mesotheliomas, and its methylation was correlated with loss of RASSF1A expression and the presence of SV40. We studied whether SV40 infection of normal HM induces aberrant methylation of the genes previously studied in mesotheliomas. Of six infected foci examined at early passages (passages 8-30) there was no methylation of the seven genes examined. Of two foci examined at late passages (passages 51-86) after the appearance of morphological changes suggestive of transformation, methylation and loss of expression of RASSF1A was detected. Sequencing of the CpG dense region around the transcription start site and semi-quantitative real-time methylation specific PCR (MSP) assay for RASSF1A methylation demonstrated progressive methylation during late passages. Exposure to the demethylating agent 5-aza-2'-deoxycytidine restored RASSF1A expression, while exposure to the histone deacetylation inhibitor trichostatin A had no effect. These data, together with our previous findings, support a causal relationship between SV40 infection, progressive RASSF1A methylation and its silencing, and the pathogenesis of mesothelioma.
UI - 1793109
AU - Enterline PE
TI - Changing attitudes and opinions regarding asbestos and cancer 1934-1965.
SO - Am J Ind Med 1991;20(5):685-700
AD - Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, PA 15261.
Literature published in the years 1934-1965 was reviewed to determine attitudes and opinions of scientists as to whether asbestos is a cause of cancer. In Germany, the issue was decided in 1943 when the government decreed that lung cancer, when associated with asbestosis (of any degree), was an occupational disease. In the United States, however, there was no consensus on the issue until 1964. Opinions of scientists over a 22 year period are shown and the contributions of various cultural, social, economic and political factors to these opinions are discussed. A lack of experimental and epidemiological evidence played a major role in delaying a consensus. Other important factors included a rejection of science conducted outside of the U.S. during this period, particularly a rejection of German scientific thought during and after WWII, and a rejection of clinical evidence in favor of epidemiological investigations. Individual writers rarely changed their minds on the subject of asbestos as a cause of cancer.
UI - 11948138
AU - Gelderblom H; Verweij J; van Zomeren DM; Buijs D; Ouwens L; Nooter K;
TI - Stoter G; Sparreboom A Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel.
SO - Clin Cancer Res 2002 Apr;8(4):1237-41
AD - Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, the Netherlands.
It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p. and i.v. dosing. Patients received an i.p. tracer dose of [G-(3)H]paclitaxel in ethanol without CrEL (100 microCi diluted further in isotonic saline) on day 1, i.p. paclitaxel formulated in CrEL (Taxol; 125 mg/m(2)) on day 4, an i.v. tracer of [G-(3)H]paclitaxel on day 22, and i.v. Taxol (175 mg/m(2)) on day 24. Four patients (age range, 54-74 years) were studied, and serial plasma samples up to 72 h were obtained and analyzed for total radioactivity, paclitaxel, and CrEL. In the presence of CrEL, i.v. paclitaxel clearance was 10.2 +/- 3.76 liters/h/m(2) (mean +/- SD), consistent with previous findings. The terminal disposition half-life was substantially prolonged after i.p. dosing (17.0 +/- 11.3 versus 28.7 +/- 8.72 h), as was the mean residence time (7.28 +/- 2.76 versus 40.7 +/- 13.8 h). The bioavailability of paclitaxel was 31.4 +/- 5.18%, indicating insignificant systemic concentrations after i.p. treatment. CrEL levels were undetectable after i.p. dosing (<0.05 microl/ml), whereas after i.v. dosing, the mean clearance was 159 +/- 58.4 ml/h/m(2), in line with earlier observations. In the absence of CrEL, the bioavailability and systemic concentrations of i.p. paclitaxel were significantly increased. This finding is consistent with the postulated concept that CrEL is largely responsible for the pharmacokinetic advantage for peritoneal cavity exposure to total paclitaxel compared with systemic delivery.
UI - 12063622
AU - Sohrab S; Konietzko N
TI - [Diagnosis and staging of malignant pleural mesothelioma]
SO - Pneumologie 2002 Jun;56(6):382-7
AD - Ruhrlandklinik Essen, Abteilung Pneumologie, Universitatsklinik, Germany. firstname.lastname@example.org
Malignant pleural mesothelioma (MPM) is an aggressive solid tumor with rising incidence and mortality. Due to a long latency period after asbestos exposure until tumor manifestation the peak of newly diagnosed MPM cases is to be expected for the year 2017 in Germany. One deciding factor for the poor prognosis with a median survival of 4 - 18 month is a late diagnosis at an advanced stage. Therefore, apart of improved stage related therapeutic options, early diagnostic procedures in suspected MPM play a key role. The diagnosis of MPM is made by the clinician as a synopsis of clinical, imaging and pathological findings. Computed tomography of the thorax and thoracoscopy with biopsy are the most important diagnostic procedures. Staging is recommended to be made as TNM description according to the International Mesothelioma Interest Group (IMIG) to allow a better comparability of various data in MPM.
UI - 12065358
AU - Monnet I; Breau JL; Moro D; Lena H; Eymard JC; Menard O; Vuillez JP;
TI - Chokri M; Romet-Lemonne JL; Lopez M Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study.
SO - Chest 2002 Jun;121(6):1921-7
AD - Department of Pneumology, Center Hospitalier Intercommunal de Creteil, Creteil, France.
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.
UI - 12111199
AU - Muller AM; Weichert A; Muller KM
TI - E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma?
SO - Virchows Arch 2002 Jul;441(1):41-6
AD - Institut fur Pathologie, Berufsgenossenschaftliche Kliniken Bergmannsheil-Universitatsklinik, Burkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. email@example.com
Pleural mesotheliomas, especially pure epithelioid mesotheliomas, may histologically be easily confused with peripheral pulmonary adenocarcinomas or pleural carcinosis. As there is no specific antibody for mesotheliomas, today a panel of immunohistochemical markers is used for the differential diagnosis of these two tumour entities. In search of further significant antibodies for application onto formalin-fixed, paraffin-embedded tissue, we immunohistochemically investigated the expression pattern of three adhesion molecules: vascular cell adhesion molecule (VCAM), E-selectin and E-cadherin. A comparatively large number of 44 mesotheliomas (15 epithelioid, 15 biphasic, 14 sarcomatoid) and 18 peripheral pulmonary adenocarcinomas were analysed. While for these two tumour entities there were no significant differences of the staining patterns for VCAM and E-selectin, there were significant differences in the expression of E-cadherin: while nearly all adenocarcinomas stained positively, there was almost no staining reaction of the mesotheliomas. Therefore, E-cadherin -- in contrast to E-selectin and VCAM -- appears to be a further relevant immunohistochemical marker for the distinction between adenocarcinomas and mesotheliomas.
UI - 12117769
AU - Hirao T; Bueno R; Chen CJ; Gordon GJ; Heilig E; Kelsey KT
TI - Alterations of the p16(INK4) locus in human malignant mesothelial tumors.
SO - Carcinogenesis 2002 Jul;23(7):1127-30
AD - Department of Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115, USA.
The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16(INK4a) and p14(ARF). The p16(INK4a) protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14(ARF) protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16(INK4a) and p14(ARF), are candidates for inactivation. In this study, we have examined p16(INK4a) and p14(ARF) alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14(ARF) 5'-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14(ARF) is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population.
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