Association Analysis of VEGF Inhibitors with Vascular Calcification: A Retrospective Study of Patients with Colorectal or Renal Cancer Treated with Bevacizumab
Ontology highlight
ABSTRACT:
DISEASE(S): Vascular Calcification Occurs In Patients With Colorectal Or Kidney Cancer
PROVIDER: 80658 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:There is sparse literature demonstrating effective treatments for metastatic chromophobe renal cell carcinoma (ChRCC). The tyrosine kinase inhibitor (TKI) sunitinib selectively inhibits the VEGF pathway and it is a standard care for metastatic clear cell renal cell carcinoma (ccRCC), although data supporting its use in ChRCC is much more limited. A 56-year-old underwent palliative nephrectomy for locally-advanced ChRCC with sarcomatoid differentiation. Tumor gene expression profiling using Affymetrix HG-U133 Plus 2.0 GeneChip platform demonstrated significantly elevated VEGF-C expression compared to normal renal tissue (n = 12) and other types RCC (n = 158). Adjuvant sunitinib was used to treat his residual unresectable retroperitoneal lymph nodes. He demonstrated an exceptional response and underwent complete surgical resection four months later. He has been managed with TKIs for nearly nine years with only minimal disease progression. Additional studies exploring treatment options for patients with non-clear cell RCC are needed; in their absence, we would recommend TKIs for patients whose tumors bear a similar molecular profile.
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Project description:Several studies have reported an association between vascular endothelial growth factor (VEGF) gene polymorphisms rs2010963, rs3025039 and rs699947 and renal cell carcinoma (RCC). However, the results remain inconclusive and controversial. We therefore conducted a meta-analysis to evaluate this association. Electronic databases were searched for relevant case-control studies up to November 2016. RevMan 5.2 software and STATA version 12.0 were used for statistical analysis in our meta-analysis. Heterogeneity was assessed using the I2 value. Nine eligible studies were retrieved for detailed evaluation. The pooled estimates indicated that the GG genotype of VEGF rs2010963 polymorphism significantly decreased RCC risk [GG vs. GC+CC; GG vs. GC]. There was also a significant association between VEGF rs3025039 polymorphism and RCC susceptibility [CC+CT vs. TT; CC vs. TT]. Furthermore, a significant association between VEGF rs699947 polymorphism and RCC susceptibility was detected [A vs. C; AA+AC vs. CC; AA vs. AC+CC; AA vs. CC; AA vs. AC; AC vs. CC]. Subgroup analysis revealed that these associations held true especially for Asians. Our meta-analysis suggested that there may be a relationship between the VEGF rs2010963, rs3025039 and rs699947 polymorphisms and RCC susceptibility.
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Project description:Rheumatoid arthritis (RA), is marked by joint inflammation leading to pannus formation which results in cartilage destruction promoting bone erosion. The pathological hallmark of RA includes synovial hyperplasia and synovial angiogenesis. Active tissue neovascularization is observed in RA. Vascular endothelial Growth factor A (VEGFA), an endothelial cell-specific proangiogenic molecule is triggered by hypoxic cells and its levels are upregulated in RA. The aim of this study was to investigate functional and pathogenic VEGFA variants and to identify the impact of point mutation in VEGFA's interaction with VEGFR2 and how these polymorphisms affect the susceptibility and severity of RA. We investigated impact of these point mutations on the stability of VEGFA using various computational tools. These mutations were further identified by conservational profile as they are highly involved as structural and functional mutations. Furthermore, these selected variants were modelled and docked against targeted domain regions IGD2 and IGD3 of VEGFR2. Further molecular dynamic simulations were performed using Gromacs. Out of 168 nsSNPS, 19 were highlighted as highly pathogenic using insilico prediction tools. InterPro and ConSurf revealed domains and conserved variants respectively. After stability analysis, we concluded that almost all the mutations were responsible for decreasing the protein stability. HOPE predicted that all the selected damaging nsSNPs were present in the domain which is essential for the functioning of VEGFA protein. Constructed Ramachandran plot and ERRAT validated the quality of all the models. Based on the interactions predicted by STRING database, we performed Protein-Protein docking between VEGFA and VEGFR2. We found few conserved interactions and new polar contacts among wild-type and mutants with VEGFR2. From the simulations, we concluded that mutant R108Q was the most stabilizing mutant among all others whereas R82Q, C86Y, and R108W complexed with VEGFR2 were comparatively less stabilizing as compared to the wild type. This study provides insight into pathogenic nsSNPs that can affect VEGFA protein structure and function. These high-risk variants must be taken into consideration for genetic screening of patients suffering from RA.
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Project description:VEGF (vascular endothelial growth factor) receptor tyrosine kinase inhibitors have become first-line therapy for metastatic renal cell carcinoma. Their use commonly leads to hypertension, but their effects on long-term renal function are not known. In addition, it has been suggested that the development of hypertension is linked to treatment efficacy. The objective of this study was to determine the effects of these drugs on long-term renal function, especially in those with renal dysfunction at baseline, and to examine the role of hypertension on these effects. Serum creatinine measurements were used to calculate the estimated glomerular filtration rate for 130 renal cell carcinoma patients who were treated with this class of tyrosine kinase inhibitors. New or worsening hypertension was defined by documented start or addition of antihypertensive medications. Overall, the use of tyrosine kinase inhibitors in patients with estimated glomerular filtration <60 or ?60 mL/min per 1.73 m2 was not associated with a decline in long-term renal function. During follow-up, 41 patients developed new or worsening hypertension within 30 days from first drug administration, and this was not linked to further reductions in glomerular filtration. These patients seemed to survive longer than those who did not develop hypertension within 30 days, although this was not statistically significant (P=0.07). Our findings suggest that the use of VEGF tyrosine kinase inhibitors does not adversely affect long-term renal function even in the setting of new-onset hypertension or reduced renal function at baseline.
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Project description:Interventions: Single arm:None
Primary outcome(s): Dice Similarity Coefficient
Study Design: Single arm
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Project description:Background:Manual analysis of tissue sections, such as for pathological diagnosis, requires an analyst with substantial knowledge and experience. Reproducible image analysis of biological samples is steadily gaining scientific importance. The aim of the present study was to employ image analysis followed by machine learning to identify vascular endothelial growth factor (VEGF) in kidney tissue that had been subjected to hypoxia. Methods:Light microscopy images of renal tissue sections stained for VEGF were analyzed. Subsequently, machine learning classified the cells as VEGF+ and VEGF- cells. Results:VEGF was detected and cells were counted with high sensitivity and specificity. Conclusion:With great clinical, diagnostic, and research potential, automatic image analysis offers a new quantitative capability, thereby adding numerical information to a mostly qualitative diagnostic approach.
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Project description:Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n?=?70). Bevacizumab (10?mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression?=?3.01, p?=?0.00014; median PFS 248 vs. 348 days p?=?0.0008) and the modeling of progressive disease (p?<?0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.
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