ABSTRACT
The malignant tumors including oral cancer, colorectal cancer, pancreatic cancer, and esophageal cancer, of the digestive system are a common high-fatal malignancy. Porphyromonas gingivalis, as the most important pathogen of periodontal disease, has been gradually proved that its invasiveness occurs not only in the mouth but also in other parts of the digestive system. Moreover, the relevant pathogenic mechanism is increasingly attracting the reseachers' attention. In this study, the role and possible pathogenesis of Porphyromonas gingivalis in the digestive system are described in a systematic and comprehensive way.
Subject(s)
Humans , Mouth Neoplasms , Periodontal Diseases , Porphyromonas gingivalisABSTRACT
<p><b>OBJECTIVE</b>To investigate the prognostic values of HIF-1α, APE1, VEGF, and COX-2 protein expressions and their predictive value of tumor necrosis rate and prognosis in osteosarcoma, as well as their interrelationships.</p><p><b>METHODS</b>Formalin-fixed paraffin-embedded tissue samples were obtained from patients with osteosarcoma. Immunohistochemical assay was performed in pre-chemotherapy samples to determine the HIF-1α, VEGF, APE1, and COX-2 protein expression levels. Hematoxylin-eosin staining was used in post-operative samples to determine the tumor necrosis rate. Univariate and multivariate analyses were used to assess the impact of protein expression on prognosis.</p><p><b>RESULTS</b>Tumor tissues were obtained from 49 patients. Their median follow up was 29 months. HIF-1α was significantly correlated to every protein we tested: VEGF (P = 0.032), APE1 (P < 0.001), and COX-2 (P < 0.001). HIF-1α protein expression had a significant impact on disease free survival (P = 0.006). Expression of HIF-1α had a sensitivity of 64.7% and a specificity of 71.9% for poor pathological response (< 90% of tumor necrosis) versus good pathological response to chemotherapy (≥ 90% necrosis).</p><p><b>CONCLUSION</b>Expression of HIF-1α is a predictor of tumor response to neoadjuvant chemotherapy and outcome in osteosarcoma and is correlated with VEGF, APE1, and COX-2 expression.</p>
Subject(s)
Adolescent , Adult , Aged , Child , Female , Humans , Male , Middle Aged , Young Adult , Antineoplastic Combined Chemotherapy Protocols , Therapeutic Uses , Bone Neoplasms , Drug Therapy , Metabolism , Pathology , Chemotherapy, Adjuvant , Cyclooxygenase 2 , Metabolism , DNA-(Apurinic or Apyrimidinic Site) Lyase , Metabolism , Disease-Free Survival , Follow-Up Studies , Hypoxia-Inducible Factor 1, alpha Subunit , Metabolism , Neoadjuvant Therapy , Neoplasm Staging , Osteosarcoma , Drug Therapy , Metabolism , Pathology , Vascular Endothelial Growth Factor A , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To characterize oncogenic KIT signaling mechanisms in gastrointestinal stromal tumor(GIST), and to determine which signaling pathway might be of potential relevance to imatinib acquired resistance.</p><p><b>METHODS</b>The mutations of KIT and PDGFRa gene were evaluated and KIT downstream signaling profiles were evaluated in 8 specimen from 5 GIST patients who were evaluated treated between 2003 and 2008 in our hospital. Biochemical inhibition of the expression of related proteins in Ras/Raf/MAPK and PI3-K/AKT pathways, such as KIT, mitogen-activated protein kinase(MAPK),mammalian target of rapamycin(MTOR), AKT, Proliferating cell nuclear antigen (PCNA) and BCL-2, were determined by Western blotting for protein activation.</p><p><b>RESULTS</b>Three cases who showed response to imatinib carried primary mutations in KIT gene, with 2 cases possessing mutation in exon 11, 1 case in exon 13. One case with imatinib-resistance developed KIT secondary mutation, but all the cases had no PDGFRa mutation. p-KIT and p-AKT expressions were higher in the samples of imatinib-resistant GIST than those of imatinib-responsive GIST. Total KIT, MAPK, p-MAPK, p-MTOR expressions were strong and comparable in all varied GISTs, which had no significant difference between imatinib-resistant and imatinib-responsive samples. PCNA and BCL-2 expression varied in samples of different therapy cycles and different location.</p><p><b>CONCLUSIONS</b>Ras/Raf/MAPK and PI3-K/AKT/MTOR pathways are essential to GIST pathogenesis. The KIT secondary mutation and PI3-K/AKT/MTOR pathway are particularly relevant for therapeutic targeting in imatinib-resistant GIST.</p>
Subject(s)
Humans , Benzamides , Drug Resistance, Neoplasm , Genetics , Gastrointestinal Stromal Tumors , Drug Therapy , Genetics , Metabolism , Imatinib Mesylate , Mutation , Piperazines , Pharmacology , Proto-Oncogene Proteins c-kit , Genetics , Pyrimidines , Pharmacology , Signal Transduction , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To explore the role of surgery and its long-term outcome in patients with advanced gastrointestinal stromal tumor(GIST) treated with imatinib preoperatively.</p><p><b>METHODS</b>Thirteen patients receiving imatinib therapy preoperatively, were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection.</p><p><b>RESULTS</b>Thirteen patients, including 3 patients with locally advanced primary GIST and 10 patients with recurrent or metastatic GIST, underwent surgery after preoperative treatment with imatinib. Complete resections were accomplished in 4 of the 5 responsive disease(RD) patients, and in 1 of the 8 progression disease(PD) patients (38.5%). The progression-free survival(PFS) time for patients with RD and PD were 24.8 months and 2.8 months respectively. The difference of PFS between patients with RD and those with PD was significant(P<0.01). Median overall survival(OS) was not reached in both patients with RD and PD. The difference of OS between patients with RD and those with PD was not significant(P>0.05).</p><p><b>CONCLUSION</b>Surgical intervention following imatinib is feasible and can be considered for patients with advanced GIST responsive to imatinib.</p>
Subject(s)
Female , Humans , Male , Middle Aged , Antineoplastic Agents , Benzamides , Disease-Free Survival , Gastrointestinal Stromal Tumors , Drug Therapy , General Surgery , Imatinib Mesylate , Piperazines , Prognosis , Pyrimidines , Retrospective Studies , Treatment OutcomeABSTRACT
Objective: The application of the tyrosine kinase inhibitor imatinib changed the treatment style and the prognosis foreground of gastrointestinal stromal tumor (GIST). The prognosis of advanced GIST was improved significantly. However, the number of patients with imatinib resistance increased continuously with enlongation of treatment period. Imatinib resistance became a hot point recently. This study aimed to explore the mechanism responsible for the acquired resistance to imatinib. Methods: With the bidirectional DNA sequencing and the analysis of an ABI PRISM 310 capillary electrophoresis system, this work sequenced the extrons 9, 11, 13, and 17 of KIT gene and the extron 12 and 18 in platelet derived growth factor receptor (PDGFR) α gene in the 9 GIST patients who were resistant to imatinib or obtained stable disease (SD) during imatinib treatment. Results: Activating mutations of KIT gene existed in 7 of 9 cases of GIST patients. Six cases had the KIT gene mutation in exon 11 encoding the juxtamembrane domain and 1 case had mutation in exon 13. Secondary KIT mutations were identified in the 4 imatinib-resistant patients. This work found an identical novel missense mutation in exon 17, T2467T-→T2467G, which caused a substitution of Tyr by Asp at codon 823 (Y823 D) in tyrosine kinase domain of KIT. Conclusion: The imatinib resistance may be related with missense mutation in exon 17, T2467T→T2467G, in tyrosine kinase domain of KIT.