Prognostic importance of RASSF2 expression in patients with gastric cancer who had undergone radical gastrectomy

Background: Although Ras-association domain family of gene 2 (RASSF2) has been shown to undergo promoter methylation at high frequency in some cancer types and in brain metastases, its clinical utility as a useful prognostic molecular marker remains unclear in gastric cancer. Methods: Prognostic significance of RASSF2 expression was retrospectively analysed by immunohistochemically in 105 patients with gastric cancer who underwent curative gastrectomy. Results: Low RASSF2 expression was detected in 58 (55 %) patients, whereas 47 patients (45 %) had high RASSF2 expression. Lymph node involvement, pT stage, TNM stage, vascular invasion, perineural invasion and the presence of recurrence were found to be significantly related to RASSF2 expression levels. Low PRL-3 expression was closely correlated with lymph node metastasis (p = 0.001), advanced pT stage (p = 0.021), advanced TNM stage (p < 0.001), the presence of vascular invasion (p < 0.001), perineural invasion (p = 0.018) and high prevalence of recurrence (p = 0.003) compared with high RASSF2 expression. The median disease-free survival (DFS) time for patients with low RASSF2 expression was significantly worse than that of patients with high RASSF2 expression (10.2 vs. 50.6 months, p < 0.001). In addition, patients with high RASSF2 expression had the higher overall survival (OS) interval compared to patients with low RASSF2 expression (NR vs. 14.9 months, p < 0.001). In the multivariate analysis, the rate of RASSF2 expression levels was an independent prognostic factor, for DFS [p < 0.001, HR 0.12 (0.10-0.88)] and OS [p < 0.001, HR 0.10 (0.04-0.46)], as were pT stage and TNM stage, respectively. Conclusions: RASSF2 may be an important molecular marker for carcinogenesis, prognosis and progression in gastric cancer, but the potential value of RASSF2 expression as a useful molecular marker in gastric cancer progression should be evaluated, comprehensively. It would be possible to develop treatments targeting RASSF2 and advance new treatment strategies for gastric cancer

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A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma.

PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

Inhibition of beta-catenin and KRAS expressions by Piper betle in azoxymethane-induced colon cancer of male Fischer 344 rats.

OBJECTIVE: To investigate the chemopreventive effect of Piper betle (PB) on preneoplastic lesions (aberrant crypt foci [ACF]) induced by azoxymethane (AOM) in rats and its effect on colorectal cancer biomarkers (beta-catenin, KRAS, p53 and p21). STUDY DESIGN: A total of 32 male Fischer 344 rats were divided into phase 1 and phase 2 groups (8 and 24 weeks of AOM administration, respectively). Each phase was divided into 4 groups: control or normal saline (NS) (1 mL/kg), AOM (15 mg/kg body weight, once weekly for 2 weeks), PB (75 mg/kg body weight) and AOM + PB. PB was force-fed to rats a week after the second dose of AOM and NS. The colon was cut open longitudinally for methylene blue and immunohistochemistry staining. RESULTS: AOM administration showed formation of ACF at 8 and 24 weeks. PB, however, did not reduce ACF formation at either week, but it managed to reduce beta-catenin expression and KRAS found highly expressed in the AOM group of phase 1 rats. No immunoreactivities of p53 and p21 were detected in phase 2 rats, but instead inflammatory cells were visible in between the lesions. CONCLUSION: PB may act as a potential chemopreventive agent in the early stage of colon carcinogenesis by suppressing the expressions of beta-catenin and KRAS.

Hypericum androsaemum water extract inhibits proliferation in human colorectal cancer cells through effects on MAP kinases and PI3K/Akt pathway.

MAP kinase and PI3K/Akt signalling pathways are commonly altered in colorectal carcinoma (CRC) leading to tumor growth due to increased cell proliferation and inhibition of apoptosis. Several species of the genus Hypericum are used in Portugal to prepare herbal teas to which digestive tract effects are attributed. In the present study, the antiproliferative and proapoptotic effects of the water extracts of H. androsaemum (HA) and H. perforatum (HP) were investigated in two human colon carcinoma-derived cell lines, HCT15 and CO115, which harbour activating mutations of KRAS and BRAF, respectively. Contrarily to HP, HA significantly inhibited cell proliferation and induced apoptosis in both cell lines. HA decreased BRAF and phospho-ERK expressions in CO115, but not in HCT15. HA also decreased Akt phosphorylation in CO115 and induced p38 and JNK in both cell lines. HA induced cell cycle arrest at S and G2/M phases as well as caspase-dependent apoptosis in both cell lines. Chlorogenic acid (CA), the main phenolic compound present in the HA extract and less represented in the HP water extract, did, however, not show any of those effects when used individually. In conclusion, water extract of HA, but not of HP, controlled CRC proliferation and specifically acted on mutant and not wild-type BRAF. The effect of HA was, however, not due to CA alone.

[Glioblastoma treatment in 2010]. / Traitement des glioblastomes à l'aube de 2010.

The treatment of glioblastomas requires a multidisciplinary approach because despite the progresses in surgical and iconographic managements associated with research knowledge this disease presently remains incurable and progresses during the 6 months after its diagnose. Current recommendations are that patients with glioblastoma should undergo maximum surgical resection followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide, followed subsequently by additional adjuvant temozolomide for a period of up to 6 months. Temozolomide mechanism of action is complex and we have recently evidenced a temozolomide-associated anti-angiogenic activity in vitro and in vivo on preclinical human glioblastoma models. We describe in the current review the temozolomide-associated antiangiogenic activity. We also describe here the major signaling pathways that can be constitutively activated in migrating glioma cells, and which render these cells resistant to proapoptotic insults such as conventional chemotherapies. In light of this resistance, we therefore describe the targeted therapies and local drug delivery systems which could be used to complement conventional treatments. We have reviewed more than 400 ongoing clinical trials with respect to these new targeted therapy approaches alone or in combination for glioblastoma therapy and we also emphasize the importance of vaccinotherapy. We conclude our review with a therapeutic model that could be used in the light of the present knowledge.

Oncoprotein expression in human synovial tissue: an immunohistochemical study of different types of arthritis.

Based on the fact that synovial lining cells have some properties of transformed-appearing cells, we have examined the expression of Myc, Myb, Fos, Jun and Ras oncoproteins in synovial tissues from patients with different types of arthritis. Formalin-fixed and paraffin-embedded sections of synovial tissue from 12 patients with rheumatoid arthritis (RA), 14 with reactive arthritis (ReA), nine with other seronegative arthritis (OSA), seven with bacterial arthritis (BA), eight with probable bacterial arthritis (PBA) and eight with osteoarthritis (OA) were studied using the immunoperoxidase staining technique. The oncoproteins studied were expressed both in the synovial lining layer and in the sublining layer, consisting of lymphocytes, other inflammatory cells and blood vessels. Among the six disease entities, RA and OA appeared to be the most distinct, whereas the results obtained for ReA and OSA, and on the other hand for BA and PBA, closely resembled each other. The expression of Myc, Myb, Fos and Jun was significantly correlated both to the degree of synovial hypercellularity and the synovial lymphocytic infiltration. For Ras, such a correlation could not be seen. We conclude that we find no evidence of a cell lineage-specific or a disease-specific abnormality of proto-oncogene products in RA, and the expression of these oncoproteins is consistent with inflammation rather than with any primary abnormality of cell growth.

Biological monitoring of workers exposed to emissions from petroleum plants.

This paper presents some of the results from the Commission of the European Communities collaborative research program (contract number EV5V-CT92-0221), whose aim is to investigate the relationship between exposure to petroleum emissions, benzene, and induction of genetic damage in human cells. Twenty-four workers from petroleum plants in Poland and 35 unexposed controls were examined for cytogenetic effects and ras oncoprotein levels and their relationship to confounding factors (e.g., smoking habit, sex family cancer history, and seasonal influence). Preliminary data of chromosome aberrations (CA) and sister chromatid exchanges (SCE) showed differences among sampling subgroups. In this present study, the levels of ras p21 proteins were determined and further analyses of CA, SCE, high frequency cells (HFC), and proliferative rate index (PRI) have been undertaken. Results show that the exposed group has statistically significant increases in CA, and percent of aberrant cells. There were no differences between exposed and unexposed groups in SCE, HFC, PRI, or the levels of ras p21 proteins. Smoking was found to statistically significantly affect levels of CA, percent of aberrant cells, SCE, HFC, and ras proteins. Sister chromatid exchanges were also statistically significantly sex dependent (7.5 breaks/cells for females and 6.8 breaks/cell for males). There were no statistically significant differences for CA, percent aberrant cells, SCE, HFC, or ras p21 protein levels in subgroups characterized according to cancer cases reported in the immediate family. A seasonal variability was shown with statistically significant increases in various biomarkers in the winter. Unexposed groups also showed increases due to smoking and season. The nonsmoking group individuals also showed statistically significant increases in cytogenetic damage with exposure.