Solid Tumor Size Research Articles

VEGF/VEGFR Pathway Inhibitors as Anti-Angiogenic Agents: Present and Future

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types. The key signaling system that regulates proliferation and migration of endothelial cells are vascular endothelium growth factor (VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with higher affinity and greater kinase activity, is more important in the direct regulation of angiogenesis, mitogenic signaling, and permeability-enhancing effects. VEGFRs are expressed at high levels in many types of human solid tumors, including glioma, lung, breast, renal, ovarian and gastrointestinal tract carcinomas. Inhibition of VEGFR has emerged as a potential therapy method for cancers and it has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib. Consequently, a number of small molecules with VEGFR inhibitory properties have been developed. Many of these have been evaluated as potent inhibitors and some are currently in clinical-trials for various angiogenic related disorders including inflammatory diseases, retinopathies and age related macular degeneration. This review reports various VEGF/VEGFR pathway inhibitors such as small molecules and monoclonal antibodies, along with their reported activities.

Role of solid tumor size compared with whole tumor size to predict pathologic malignant grade or prognosis in clinical stage IA lung adenocarcinoma: A multicenter study.

7058 Background: Small lung adenocarcinoma often contains non-solid component (ground glass opacity: GGO), which is known to be low grade malignancy, on high-resolution computed tomography (HRCT). This study evaluates the usefulness of solid tumor size compared with whole tumor size on preoperative HRCT to predict pathological high-grade malignancy (positive for lymphatic invasion or vascular invasion or pleural invasion) or prognosis for clinical stage IA lung adenocarcinoma in the setting of multicenter study. Methods: We performed HRCT and fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) on 502 patients with clinical stage IA lung adenocarcinoma before they underwent curative surgical resection. Preoperative whole tumor size or solid tumor size on HRCT and surgical results were analyzed. Results: The median values of whole tumor size and solid tumor size were 2.0 cm and 1.2 cm, respectively. Receiver operating characteristics (ROC) area under the curve (AUC) values to predict pathological high-grade malignancy for whole tumor size and solid tumor size were 0.590 and 0.829 respectively. Multiple logistic regression analyses demonstrated that solid tumor size (p < 0.001) and maximum standardized uptake value (SUVmax) on FDG-PET/CT (p < 0.001) were independent variables relative to the prediction of pathological high-grade malignancy. Although three-year disease-free survival (DFS) rates were 92.5% for whole tumor size < 2.0 cm and 86.7% for whole tumor size > 2.0 cm (p = 0.51), three-year DFS rates were 92.0% for solid tumor size < 2.0 cm and 78.9% for solid tumor size > 2.0 cm (p = 0.048), and particularly, 100% for solid tumor size = 0 cm (pure GGO). Based on the multivariate Cox analyses, solid tumor size (p < 0.001) was a significantly independent factor for DFS as well as SUVmax (p = 0.05), but whole tumor size was not. Conclusions: Solid tumor size on HRCT has higher predictive values of pathological high-grade malignancy and prognosis than whole tumor size in clinical stage IA lung adenocarcinoma. Solid tumor size on HRCT should be considered to select therapeutic strategies for treating clinical stage IA lung adenocarcinoma.

Safrole Induces Apoptosis in Human Oral Cancer HSC-3 Cells

Phytochemicals have been used as potential chemopreventive or chemotherapeutic agents. However, there are data suggesting a mutagenic effect of some phytochemicals. We hypothesized that safrole would have anticancer effects on human oral squamous cell carcinoma HSC-3 cells. Safrole decreased the percentage of viable HSC-3 cells via induction of apoptosis by an increased level of cytosolic Ca2+ and a reduction in the mitochondrial membrane potential (ΔΨ m ). Changes in the membrane potential were associated with changes in the Bax, release of cytochrome c from mitochondria, and activation of downstream caspases-9 and -3, resulting in apoptotic cell death. In vivo studies also showed that safrole reduced the size and volume of an HSC-3 solid tumor on a xenograft athymic nu/nu mouse model. Western blotting and flow cytometric analysis studies confirmed that safrole-mediated apoptotic cell death of HSC-3 cells is regulated by cytosolic Ca2+ and by mitochondria- and Fas-dependent pathways.

New indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic surgery

The aim of this work was to analyze parameters to determine the possibility for detection of tumor location, and clarify the indication for preoperative marking of small peripheral pulmonary nodules in thoracoscopic resection. In a series of 97 patients who underwent video-assisted thoracoscopic surgery, information on standard uptake values (SUVs) and the detectability of tumor location was assessed. In patients whose lesions were <15 mm in diameter and where the distance to the pleura was >10 mm, lesions were not detected. Multivariate analysis to determine the factors related to the possibility of detecting tumor localization revealed that the distance to the pleural surface (P=0.0001), and the ratio of solid portion (P=0.0104) were statistically significant. In the non-solid tumor group, we should perform preoperative marking for tumors located more than 3 mm in depth from the visceral pleura. In the solid tumor group, the linear function (depth=0.4×size-0.9) may be used to separate detectable and undetectable groups. However, the sensitivity was 90.3% even if this formula was applied. Here we advocate the algorithm for detection of indication for preoperative marking using the ratio of solid portion, tumor size and SUV of fluorodeoxyglucose positron emission tomography.

Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug Resistance

The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and associated with tumor malignancy. However, the mechanism of this metabolic switch remains largely unknown. Herein, we reported that hypoxia-inducible factor-1 (HIF-1) induced pyruvate dehydrogenase kinase-3 (PDK3) expression leading to inhibition of mitochondrial respiration. Promoter activity assay, small interference RNA knockdown assay, and chromatin immunoprecipitation assay demonstrated that hypoxia-induced PDK3 gene activity was regulated by HIF-1 at the transcriptional level. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drugs resistance, whereas knocking down PDK3 inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. These data demonstrated that increased PDK3 expression due to elevated HIF-1alpha in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy.

Immunotherapy of established murine tumors with large multivalent immunogen and cyclophosphamide.

Plasma membrane vesicles isolated from tumor cells can be incorporated onto 5-microns diameter microspheres and antigen in this form, termed large multivalent immunogen (LMI), augments generation of tumor-specific cytotoxic T lymphocyte (CTL) responses in vivo. Treatment of mice with LMI at the time of challenge with tumor significantly reduced growth of several tumors in their syngeneic hosts. Our report describes the effects of LMI on established progressing tumors, including P815 solid tumor and two fibrosarcomas in a lung-metastasis model. Treatment of mice bearing established tumors (7 to 12 days) with LMI alone did not significantly reduce tumor growth or extend host survival, but highly synergistic effects of combined treatment with cyclophosphamide (Cy) and LMI were found. Cy alone reduced the size of P815 solid tumors, but within a few days, the tumors began to grow progressively, and survival was only marginally extended. However, Cy followed 2 to 3 days later by a single injection of LMI resulted in prolonged reduction of tumor growth and significant extension of survival; in some experiments, tumors became undetectable in the majority of treated mice, and the mice survived indefinitely. Essentially the same results were obtained in experiments examining survival of mice bearing established MCA-203 fibrosarcoma. LMIs were uniquely effective in acting synergistically with Cy; antigen in the form of irradiated tumor cells or plasma membrane in adjuvant were ineffective, and free plasma-membrane antigen (not on microspheres) had only marginal effects. There has been considerable interest in the possibility of using tumor antigen to enhance tumor-specific immune responses, and clinical trials using this approach are showing some promise. The results described here suggest that altering the form of antigen by purifying plasma membranes and incorporating them onto microspheres might significantly improve the efficacy of tumor immunotherapy with antigen.