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Magnetic resonance spectroscopy as an early indicator of response to anti-angiogenic therapy in patients with recurrent glioblastoma: RTOG 0625/ACRIN 6677.
Ratai, EM, Zhang, Z, Snyder, BS, Boxerman, JL, Safriel, Y, McKinstry, RC, Bokstein, F, Gilbert, MR, Sorensen, AG, Barboriak, DP
Neuro-oncology. 2013;(7):936-44
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Abstract
BACKGROUND The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy. METHODS Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values. RESULTS NAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression-free survival and 1-year survival. CONCLUSION Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment.
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Anti-angiogenic effects of epigallocatechin-3-gallate in human skin.
Domingo, DS, Camouse, MM, Hsia, AH, Matsui, M, Maes, D, Ward, NL, Cooper, KD, Baron, ED
International journal of clinical and experimental pathology. 2010;(7):705-9
Abstract
Epigallocatechin-3-gallate (EGCG) is the main polyphenol component of green tea. This compound exhibits antioxidant, immunomodulatory, photoprotective, anti-angiogenic, and anti-inflammatory properties. We conducted a small randomized, double blind, split face trial using a cream containing 2.5% w/w of EGCG. Four healthy volunteers with significant erythema and telangiectasia on the face applied EGCG cream to one side of the face, and vehicle control cream to the other, twice daily for six weeks. After six weeks, biopsies were taken from EGCG and vehicle treated sites. Immunohistochemistry was used to measure VEGF and HIF-1 α. HIF-1 α expression was decreased in EGCG treated sites, such that 28.4% of the epidermis showed positive staining in vehicle treated vs. 13.8% in EGCG treated sites (p<0.001). A similar decrease in VEGF expression was found (6.7% in EGCG vs. 11.0%in in vehicle-treated skin (p<0.005). EGCG topical treatments influence HIF-1 α induction and VEGF expression and may serve as a potential agent in the prevention of telangiectasias.
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The effect of different doses of intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma.
Gupta, V, Jha, R, Rao, A, Kong, G, Sihota, R
European journal of ophthalmology. 2009;(3):435-41
Abstract
PURPOSE To prospectively evaluate the effect of 1.25 mg and 2.5 mg intracameral bevacizumab on surgical outcomes of trabeculectomy for neovascular glaucoma (NVG), with primary outcome measures being the regression of neovascularization of iris (NVI) and reduction of intraocular pressure (IOP). METHODS Consecutive patients with neovascular glaucoma from December 2006 to March 2007 were randomized into two cohorts assigned to receive 1.25 mg (Group 1) or 2.5 mg (Group 2) intracameral bevacizumab prior to undergoing mitomycin C (MMC) trabeculectomy. Surgical outcome measures were evaluated following initial injection and during follow-up post-surgery. RESULTS The most common causes for iris neovascularization were central retinal vein occlusion (47.3%) and proliferative diabetic retinopathy (36.8%). Following intracameral bevacizumab, there was a reduction in IOP compared to baseline in both treatment groups (Group 1, n=9: -10.4+/-4.5 mmHg, p=0.57; Group 2, n=10: -12.1+/-5.5 mmHg, p=0.1). The reduction in IOP was not statistically significant between the two groups (p=0.55). None of the eyes underwent further retinal ablation post trabeculectomy. Reappearance of NVI was seen in three eyes (Group 1, n=2; Group 2, n=1) after 3 months. There was no statistically significant difference in regression of NVI grade between the treatment groups (p=0.1). CONCLUSIONS The efficacy of an intracameral dose of 2.5 mg of bevacizumab prior to trabeculectomy for eyes with NVG is not significantly different from a 1.25 mg dose. Intracameral bevacizumab followed by trabeculectomy results in good surgical outcomes. Longer follow-up would be needed to evaluate differences in recurrence rates of iris neovascularization using different dosages.
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Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes.
Vijay, SK, Mishra, M, Kumar, H, Tripathi, K
Acta diabetologica. 2009;(1):27-33
Abstract
The purpose of this study was to assess the effects of PPAR-gamma agonists (pioglitazone and rosiglitazone) on mediators of endothelial dysfunction and markers of angiogenesis in patients with type-2 diabetes. Pioglitazone group showed favorable reductions in serum total cholesterol, triglycerides, LDL cholesterol, VLDL cholesterol and increase in HDL cholesterol as compared to rosiglitazone group, after 16 weeks of treatment and also with control group. There was significant reduction of CRP level in pioglitazone and rosiglitazone group. The level of serum TNF-alpha decreased significantly in pioglitazone and mildly decreased in rosiglitazone group. The level of VEGF, IL-8 and Angiogenin were increased in pioglitazone than rosiglitazone group. There were no significant changes observed in the serum angiogenin and IL-8 levels in the control group. Pioglitazone and rosiglitazone therapy in type-2 diabetes subjects have additional benefits of reducing mediators of endothelial dysfunction. Increase in angiogenesis markers in patients receiving pioglitazone could have variable effects in diabetic nephropathy and retinopathy as there may be increased vascular neogenesis. Pioglitazone has advantage over rosiglitazone in lowering lipid and proinflammatory cytokines.
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Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma.
Flaherty, KT, Rosen, MA, Heitjan, DF, Gallagher, ML, Schwartz, B, Schnall, MD, O'Dwyer, PJ
Cancer biology & therapy. 2008;(4):496-501
Abstract
BACKGROUND The investigation of angiogenesis inhibitors is of particular interest in renal cell carcinoma (RCC), in which dysregulated blood vessel formation has been correlated with shortened survival. Sorafenib is a novel RAF and VEGF receptor tyrosine kinase inhibitor. We conducted this study to (a) determine if sorafenib is anti-angiogenic, and (b) to relate anti-angiogenic effect to outcome. RESULTS Four patients achieved partial response by WHO criteria (ORR 24%). Median time to progression (TTP) was 12.9 months. K(trans) decreased significantly during treatment with sorafenib (60.3% decline, 95% CI 46.1-74.6%). The percent decline in K(trans) and change in tumor size by CT scan were significantly associated with progression-free survival (p = 0.01 and 0.05, respectively). In addition, K(trans) at baseline was also significantly associated with progress-free survival (p = 0.02). PATIENTS AND METHODS Seventeen patients with metastatic RCC underwent dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI was used to calculate the gadolinium exchange constant between blood and tumor interstitial tissue, K(trans). CONCLUSIONS In patients with RCC, inhibition of tumor vascular permeability by sorafenib was associated with improved outcome. Moreover, baseline tumor vascular permeability, expected to be a poor prognosis factor, was a predictive marker of favorable response to therapy.
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Optimizing scan delays of fixed duration contrast injection in contrast-enhanced biphasic multidetector-row CT for the liver and the detection of hypervascular hepatocellular carcinoma.
Kanematsu, M, Goshima, S, Kondo, H, Nishibori, H, Kato, H, Yokoyama, R, Miyoshi, T, Hoshi, H, Onozuka, M, Moriyama, N
Journal of computer assisted tomography. 2005;(2):195-201
Abstract
OBJECTIVE To determine the optimal scan delay required for fixed duration contrast injection in contrast-enhanced biphasic multidetector-row CT for the liver and the detection of hypervascular hepatocellular carcinoma (HCC). METHODS CT images (2.5-mm collimation, 5-mm thickness with no intersectional gap) were obtained after an intravenous bolus injection of 2 mL/kg of nonionic iodine contrast material (300 mg I/mL) for a fixed 30-second injection in 206 patients, who were prospectively randomized into four groups, for which scans were initiated at -5, 15, and 35 seconds; at 0, 20, and 40 seconds; at 5, 25, and 45 seconds; or at 10, 30, and 50 seconds for the first (acquisition time: 4.3 seconds), second (4.3 seconds), and third (9.1 seconds) phases, respectively, after the completion of contrast injection. Mean CT values (HU) of the abdominal aorta, spleen, main portal veins, liver parenchyma, and hepatic veins were measured. Increases in CT values between pre- and post-contrast CTs (DeltaHU) for the organs, and spleen-to-liver and HCC-to-liver contrast differences (deltaHU) were assessed. RESULTS Abdominal aorta reached 273-301 DeltaHU at -5 to 10 seconds with a peak (301 DeltaHU) at 5 seconds. Spleen peaked (115 DeltaHU) at 10 seconds. Liver parenchyma were enhanced weakly (11-34 DeltaHU) at -5 to 10 seconds, exceeded 50 DeltaHU at 20 seconds, peaked (61 DeltaHU) at 30 seconds, and then plateaued (54-58 DeltaHU) at 35-50 seconds. Hepatic veins were enhanced weakly (14-37 DeltaHU) at -5 to 10 seconds, and reached 67 DeltaHU at 15 seconds. Spleen-to-liver (65-69 deltaHU) and HCC-to-liver (31-34 deltaHU) contrast differences were highest at 5-10 seconds. Qualitative results corresponded well with quantitative results. CONCLUSIONS For the detection of hypervascular HCCs, the optimal scan delay after a 30-second contrast injection of the hepatic arterial phase, was found to range from 5 to 10 seconds, and that of the portal venous phase was 35 seconds or somewhat longer.
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Low glucose degradation products dialysis solution modulates the levels of surrogate markers of peritoneal inflammation, integrity, and angiogenesis: preliminary report.
Kim, YL, Do, J, Park, SH, Cho, K, Park, J, Yoon, K, Cho, DK, Lee, EG, Kim, IS
Nephrology (Carlton, Vic.). 2003;:S28-32
Abstract
The presence of glucose degradation products (GDPs) in peritoneal dialysis (PD) fluids has many adverse effects, namely clinically significant abdominal pain or discomfort during infusion, inhibition of cell proliferation, impairment of inflammatory cell function, cytotoxicity, and the induction of vascular endothelial growth factor (VEGF). In a prospective, randomized, controlled trial comparing a low GDP PD solution (pH 7.0, two compartment bag: low GDP) to conventional PD solution (pH 5.5: high GDP), the overnight dialysate levels of the markers of inflammation/wound healing (hyaluronic acid (HA)), mesothelial cell mass/membrane integrity (cancer antigen 125 (CA125)), and angiogenesis (VEGF) were assessed over a 12-month period. Twenty-six newly commencing continuous ambulatory peritoneal dialysis (CAPD) patients were randomly assigned to either the Low GDP group (n = 16) or the High GDP group (n = 10). Standard peritoneal permeability analysis for membrane transport characteristics and dialysis adequacy with nutritional status (serum albumin, nPCR) were evaluated at 1, 6, and 12 months. In patients treated with high GDP solution, there was significant increase in VEGF with time (time = 1 month, 67.2 +/- 10.8; time = 6 months, 189.8 +/- 90.2; and time = 12 months, 169.3 +/- 83.1 pg/mg of protein; P < 0.05). There was no significant change of VEGF with time in the low GDP group. Significantly higher concentrations of CA125 (65.5 +/- 10.4 vs. 19.7 +/- 2.6 at 1 month, P < 0.0001; 66.6 +/- 9.8 vs. 29.7 +/- 5.0 at 6 months, P < 0.01; 68.7 +/- 10.5 vs. 30.7 +/- 10.0 U/mL at 12 months, P < 0.01) and lower concentrations of HA (114.6 +/- 18.8 vs. 254.3 +/- 69.2 at 1 month, P < 0.05; 417.5 +/- 57.2 vs. 1277.5 +/- 367.9 ng/mg of protein at 12 month, P < 0.05) were observed in the low GDP group compared with the high GDP group. In conclusion, continuous therapy with the low GDP solution modulates the levels of surrogate markers of peritoneal inflammation, integrity and angiogenesis. The results strongly suggest that the use of a low GDP solution would be beneficial to maintain the function and structural integrity of the peritoneal membrane.