scholarly journals Examination of Micro Vascular Density on Metastatic Colorectal Cancer of RAS Mutant-Type as Anti Vegf Therapy Predictor

2021 ◽  
Vol 57 (2) ◽  
pp. 111
Author(s):  
Heru Sulistyo ◽  
Vicky Sumarki Budipramana
Keyword(s):  
Gold Standard ◽  
Microvascular Density ◽  
Vascular Density ◽  
Research Subjects ◽  
Academic Hospital ◽  
Mutant Type ◽  
Targeting Therapy ◽  
Nccn Guidelines ◽  
Anti Vegf ◽  
Ras Status

According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Colon Cancer Version 2.2019, mCRC patients with mutant type RAS were treated with anti-VEGF. However, the use of the targeting therapy still had inconsistent results. Neoangiogenesis studies had been used as a basis to assess the prognosis of mCRC. Microvascular density (MVD) had become the morphological gold standard to assess neovascularization in human tumors. This study proved the existence of low microvascular density (MVD) in mCRC patients with mutant type RAS status as a predictor of failure of anti-VEGF therapy. There were 29 patients at Dr. Soetomo Academic Hospital from 2015-2018 who had their RAS status checked and tested for microvascular density (MVD). The results of this study were analyzed using SPSS 23.0. In the Mutant-type of RAS group, this study examined microvascular density (MVD). 11 (73%) research subjects with high MVD scores and 4 (27%) research subjects had low MVD scores. Besides, 27% microvascular density (MVD) was low, in the mutant-type of RAS mCRC patient which could be a predictor factor for the failure of anti-VEGF therapy.

Withholding anti-EGFR, the impact on outcome in RAS wild-type metastatic colorectal tumors (WAIT or ACT trial).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 626-626
Author(s):  
Lola-Jade Palmieri ◽  
Laurent Mineur ◽  
David Tougeron ◽  
Benoit Rousseau ◽  
Victoire Granger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Propensity Score ◽  
Cohort Analysis ◽  
Wild Type ◽  
First Line ◽  
Anti Vegf ◽  
Ras Status ◽  
Metastatic Sites ◽  
The Impact ◽  
Doublet Chemotherapy

626 Background: First line of RAS wild-type (WT) unresectable metastatic colorectal cancer (mCRC) can be doublet chemotherapy with an anti-VEGF (Vascular Endothelial Growth Factor), or an anti-EGFR (Epidermal Growth Factor Receptor). Waiting for RAS status, many oncologists initiate chemotherapy and add the anti-EGFR secondly. The objective was to compare the delayed introduction of the anti-EGFR to the immediate introduction of the anti-VEGF in first-line treatment of RAS WT mCRC. Methods: This was a retrospective cohort analysis from 2013 to 2016, multicentric with 28 health care centers. We included patients with RAS WT unresectable mCRC treated between 2013 and 2016 by a doublet chemotherapy with the anti-VEGF introduced immediately or with the anti-EGFR introduced at C2 or C3. Progression free survival (PFS), overall survival (OS) and response rate (RR) for the two cohorts were compared. Hazard ratios (HR) with 95% confidence interval (95%CI) were estimated with cox regression models weighted on propensity score to deal with potential confounders. Results: A total of 262 patients were included, 129 in the immediate anti-VEGF group and 133 in the delayed anti-EGFR group. Median follow-up was 37.9 months. Ninety-two patients had the anti-EGFR introduced at C2, 40 at C3. The median delay of RAS analysis was 19 days (q1-q3: 13-26). Patients treated with anti-VEGFs were more likely men (68% versus 56%), with more metastatic sites ( > 2 sites: 15% versus 9%). A propensity score including the number of metastatic sites and a possible previous treatment was built. Delayed anti-EGFRs were associated with longer PFS compared to immediate anti-VEGFs: 13.8 versus 11.0 months, p = 0.0244. After weighting, delayed anti-EGFRs were still associated with better PFS: HR 0.74, 95%CI [0.61 – 0.90], p = 0.0024. OS was not different between the two arms (30.5 for anti-VEGF versus 29.9 months, p = 0.3934), even after weighting (HR 0.86, 95%CI [0.69 – 1.08], p = 0.2024). There was a better RR with delayed anti-EGFRs: 66.7% versus 45.6%, p = 0.0007. Conclusions: Our findings suggest that, while waiting for RAS status, the delayed introduction of the anti-EGFR is a valid option, compared to the immediate introduction of the anti-VEGF.

scholarly journals Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40−/−mice

2013 ◽  
Vol 304 (6) ◽  
pp. H816-H827 ◽  
Author(s):  
Jennifer S. Fang ◽  
Stoyan N. Angelov ◽  
Alexander M. Simon ◽  
Janis M. Burt
Keyword(s):  
Blood Pressure ◽  
Inflammatory Response ◽  
Tissue Perfusion ◽  
Microvascular Density ◽  
Macrophage Infiltration ◽  
Vascular Density ◽  
Distal Limb ◽  
Poor Recovery ◽  
Ischemic Tissue ◽  
Collateral Vessels

Recently, we reported that recovery of tissue perfusion in the ischemic hindlimb was reduced, inflammatory response increased, and survival of distal limb tissue compromised in connexin 40 (Cx40)-deficient (Cx40−/−) mice. Here we evaluate whether genotype-specific differences in tissue perfusion, native vascular density, arteriogenesis, blood pressure, and chronic ANG II type 1 receptor (AT1R) activation contribute to poor recovery of ischemic hindlimb tissue in Cx40−/−mice. Hindlimb ischemia was induced in wild-type (WT), Cx40−/−, and losartan-treated Cx40−/−mice by using surgical procedures that either maintained (mild surgery) or compromised (severe surgery) perfusion of major collateral vessels supplying the distal limb. Pre- and postsurgical hindlimb perfusion was evaluated, and tissue survival, microvascular density, and macrophage infiltration were documented during recovery. Hindlimb perfusion was compromised in presurgical Cx40−/−versus WT mice despite comparable native microvascular density. Hindlimb perfusion 24 h postsurgery in Cx40−/−and WT mice was comparable after mild surgery (collateral vessels maintained), but compromised arteriogenesis in Cx40−/−animals nevertheless limited subsequent recovery of tissue perfusion and compromised tissue survival. Prolonged pre- and postsurgical treatment of Cx40−/−mice with losartan (an AT1R antagonist) normalized blood pressure but did not improve tissue perfusion or survival, despite reduced macrophage infiltration. Thus it appears Cx40 is necessary for normal tissue perfusion and for recovery of perfusion, arteriogenesis, and tissue survival in the ischemic hindlimb. Our data suggest that Cx40−/−mice are at significantly greater risk for poor recovery from ischemic insult due to compromised regulation of tissue perfusion, vascular remodeling, and prolonged inflammatory response.

Military Medical Research and Experimentation

2021 ◽  
pp. 159-180
Author(s):  
Michael L. Gross
Keyword(s):  
Informed Consent ◽  
Medical Research ◽  
Gold Standard ◽  
Military Medicine ◽  
Experimental Studies ◽  
Research Subject ◽  
Research Subjects ◽  
Undue Influence ◽  
Effective Drugs ◽  
Modern War

Medicine is often unprepared for the physical and psychological wounds of modern war. Military medicine requires urgent research to treat traumatic brain injury, develop resuscitation techniques, upgrade surgical procedures, and acquire effective drugs. Retrospective, observational, and survey studies dominate the literature. However, clinically controlled experimental studies, the gold standard of medical research, are rare in military medicine. Stringent informed consent requirements to protect service members from coercion and undue influence make it difficult to enlist them for in-theater clinical studies. When a research subject is unconscious and his representative is unavailable to give consent, investigators can request waivers. But due to concerns about patient vulnerability, waivers are rarely granted to allow researchers to recruit injured soldiers in the field. Easing informed consent requirements to match those of civilian medical research, and intensifying efforts to recruit civilian research subjects during war will improve the prospects of clinical research.

Aflibercept: A review of its effect on the treatment of exudative age-related macular degeneration

2019 ◽  
Vol 29 (4) ◽  
pp. 368-378 ◽  
Author(s):  
Zois Papadopoulos
Keyword(s):  
Macular Degeneration ◽  
Gold Standard ◽  
Age Related Macular Degeneration ◽  
Great Length ◽  
Positive Effects ◽  
Anti Vegf ◽  
Age Related ◽  
High Level ◽  
Endothelial Growth Factor ◽  
The Impact

Considerable improvement has been achieved in the way in which exudative age-related macular degeneration is conventionally treated and in the associated visual outcomes and prognosis, thanks to the agents with effects against vascular endothelial growth factor (anti-VEGF). By comparison to earlier treatment approaches that involved the use of lasers, the anti-VEGF agents have made it possible to accomplish more positive visual and anatomical outcomes in cases of exudative age-related macular degeneration. Indeed, owing to their positive effects, anti-VEGF agents have quickly come to be considered the gold standard for the treatment of wet age-related macular degeneration. Aflibercept, the most recently approved intravitreally administered anti-VEGF, seems to mark another milestone in the treatment of wet age-related macular degeneration. This anti-VEGF agent presents a series of singular pharmacodynamic and pharmacokinetic attributes that provide it a number of biological benefits in relation to the treatment of choroidal neovascularization compared to other agents. These attributes include high level of affinity for the VEGF-A factor, an intravitreal half-life of great length, as well as the ability to serve as an antagonist for other growth factors besides VEGF. The impact of Aflibercept on the manner in which exudative age-related macular degeneration is managed was demonstrated by thoroughly reviewing the related literature. The present review article highlights the pharmacology, pharmacokinetics, safety and effectiveness of this anti-VEGF agent as well as the landmark clinical studies that have been carried out to establish this drug as a gold standard in the therapy of neovascular age-related macular degeneration. In addition, studies regarding the outcomes and effectiveness of the various dosage regimens, either as monotherapy or in combination with other agents, are also reviewed.

scholarly journals The role of optical coherence tomography angiography biomarkers in assessing the outcome of long-term anti-VEGF therapy of diabetic macular edema

2022 ◽  
Vol 14 (4) ◽  
pp. 95-102
Author(s):  
A. Zh. Fursova ◽  
A. S. Derbeneva ◽  
M. S. Tarasov ◽  
M. V. Vasil’eva ◽  
J. A. Gamza ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Macular Edema ◽  
Diabetic Macular Edema ◽  
Optical Coherence Tomography Angiography ◽  
Antiangiogenic Therapy ◽  
Initial Density ◽  
Average Density ◽  
Vascular Density ◽  
Optical Coherence ◽  
Anti Vegf

The purpose of the study was to assess the changes of biomarkers of diabetic macular edema activity by optical coherence tomography angiography (OCTA) data and the relationship of these biomarkers with the response to anti-VEGF therapy during a two-year follow-up. Material and methods. The study included 59 patients (101) eyes, averagely aged 60.27 ± 9.50 years. The average number of intravitreal injections of aflibercept over the treatment period was 12.87 ± 3.50. The initial size of the foveolar avascular zone (FAZ) area — 0.37 ± 0.22 mm2 , and the acircularity index — 0.56 ± 0.14 remained unchanged after 5 months: 0.36 ± 0.24 mm2  and 0.56 ± 0.12, respectively, and being practically in the same level in 12 and 24 months. The large FAZ area, noted in the group where disorganization of retinal inner layers (DRIL) was observed (0.39 ± 0.21 mm2 ), correlated with a lower visual acuity (r = 0.67, p = 0.003). The acircularity index remained unchanged; no significant differences were found in the DRIL patient groups. After 5 loading injections, the average initial density of vessels in the macular region increased from 12.33 ± 3.86 mm to 12.75 ± 1.14 mm, after 1 year it was 13.48 ± 1.15 mm, after 2 years — 13.25 ± 3.39 mm. The average density of retinal perfusion increased at the 5th month from 29.81 ± 10.85 % to 31.55 ± 2.34 %, after 12 months to 32.91 ± 3.45, and by the end of the observation period to 31.41 ± 9.79 %. In the DRIL group, the baseline vascular density and mean perfusion volume were significantly lower: 11.17 ± 2.09 mm vs. 13.49 ± 1.14 mm and 28.40 ± 4.53 % vs. 31.20 ± 2.44 %). Conclusion. DRIL, a biomarker reflecting impaired capillary blood flow in the superficial capillary plexus and correlating with functional results, can be used as a predictor of antiangiogenic therapy effectiveness. After antiangiogenic therapy with DMO, the microcirculation indices (FAZ and acircularity) remained stable, and the vascular density and perfusion volume tended to increase, which testifies to the absence of ischemic damage.

scholarly journals Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tetsuo Mashima ◽  
Takeru Wakatsuki ◽  
Naomi Kawata ◽  
Myung-Kyu Jang ◽  
Akiko Nagamori ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Combination Treatment ◽  
Xenograft Model ◽  
Vegf Receptor ◽  
Antibody Treatment ◽  
Targeting Therapy ◽  
Normal Tissues ◽  
Anti Vegf ◽  
Mouse Xenograft Model

AbstractThe vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.

Choriocapillary vascular density changes in choroidal neovascularization associated with choroidal nevus after anti-VEGF injections

2020 ◽  
pp. 112067212098294
Author(s):  
Luca D’andrea ◽  
Federica Fossataro ◽  
Gilda Cennamo
Keyword(s):  
Choroidal Neovascularization ◽  
Optical Coherence Tomography Angiography ◽  
Vascular Density ◽  
Non Invasive ◽  
Anti Vegf ◽  
Pigmented Lesion ◽  
Before And After ◽  
Choroidal Nevus ◽  
Sd Oct

Purpose: To evaluate choriocapillary vascular density changes in choroidal neovascularization (CNV) type 2 associated with choroidal nevus using optical coherence tomography angiography (OCT-A) before and after anti-VEGF treatment. Methods: Observational case report. Results: A 25-year-old woman, was referred to Eye Clinic and presented a decreased visual acuity in right eye. Fundus examination showed a pigmented lesion located in macular region associated with subretinal hemorrhages adjacent to the mass in right eye. The diagnosis of choroidal nevus-associated with CNV was made and confirmed by spectral domain (SD)-OCT, OCT-A, and ultrasound examination. Two monthly ranibizumab intravitreal injections (IVT) were performed and a regression of the activity of neovascular lesion was noted. OCT-A showed a reduction of choriocapillaris vessel density (VD) before the treatment and an increase of VD after IVT injections. Conclusion: OCT-A could be a non-invasive and diagnostic tool to evaluate choriocapillaris vascular changes after IVT injections in CNV associated with choroidal nevus.

Quantitative Vascular Density Changes in Choriocapillaris Around CNV After Anti-VEGF Treatment: Dark Halo

2018 ◽  
Vol 49 (12) ◽  
pp. 918-924 ◽  
Author(s):  
Marco Rispoli ◽  
Maria Cristina Savastano ◽  
Bruno Lumbroso
Keyword(s):  
Vascular Density ◽  
Dark Halo ◽  
Anti Vegf

scholarly journals Imaging Hyperreflective Foci as an Inflammatory Biomarker after Anti-VEGF Treatment in Neovascular Age-Related Macular Degeneration Patients with Optical Coherence Tomography Angiography

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Jing Wu ◽  
Chaoyang Zhang ◽  
Qian Yang ◽  
Hai Xie ◽  
Jingting Zhang ◽  
...  
Keyword(s):  
Optical Coherence Tomography Angiography ◽  
Age Related Macular Degeneration ◽  
Vascular Density ◽  
Neovascular Amd ◽  
Outer Retina ◽  
Inflammatory Biomarker ◽  
Hyperreflective Foci ◽  
Anti Vegf ◽  
Age Related ◽  
Capillary Plexus

Purpose. To investigate the hyperreflective foci (HRF) as an inflammatory biomarker using optical coherence tomography angiography (OCTA) in neovascular age-related macular degeneration (AMD) patients after antivascular endothelial growth factor (anti-VEGF) treatment and its association with the retinal microcapillary density. Methods. Twenty-five eyes from 25 patients with neovascular AMD were included in the study. All eyes were imaged with OCTA at baseline (M0) and after 3 consecutive injections (M3; injection performed each month) of anti-VEGF. The number of HRF in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and outer retina was counted. The vascular density of the fovea, parafovea, and the whole macula, as well as the area of the foveal avascular zone (FAZ), was measured. Results. The mean interval between baseline and follow-up with OCTA was 93.08 ± 5.00 (range, 85-101) days. Compared with the baseline, the number of HRF significantly decreased in DCP ( 7.52 ± 3.06 vs. 3.76 ± 1.48 , P < 0.01 ) and outer retina ( 12.04 ± 4.91 vs. 5.88 ± 3.32 , P < 0.01 ) after treatment. There was no significant difference for HRF number in the SCP, the vascular density (containing foveal, parafoveal, and whole macular), and FAZ area before and after treatments. Conclusion. The number of HRF in DCP and outer retina might serve as an inflammatory biomarker in patients with neovascular AMD. The reduced HRF possibly represents the alleviation of inflammation after anti-VEGF treatment in patients with AMD.

scholarly journals Kebugaran Jasmani menurut instrument GPAQ dibandingkan dengan VO2max pada wanita umur 25 sampai 54 tahun

2019 ◽  
Vol 21 (4) ◽  
Author(s):  
Olwin Nainggolan ◽  
Lely Indrawati ◽  
Julianty Pradono
Keyword(s):  
Physical Activity ◽  
Positive Predictive Value ◽  
Negative Predictive Value ◽  
Predictive Value ◽  
Gold Standard ◽  
Area Under The Curve ◽  
Research Subjects ◽  
Cross Sectional ◽  
Activity Questionnaire ◽  
Receiver Operating

The Global Physicall Activity Questionnaire (GPAQ) is the most commonly used tool for measuring physical activity in surveys. Receiver Operating Analysis (ROC) is performed to see the GPAQ instrumen's diagnostic ability to physical activity with VO2max as a comparison. The aims of study is to determine the distribution of METs minutes / weeks of each activity domain, cut off point METs, area under the curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value of GPAQ instrumen measurement with gold standard VO2max. Examination of fitness level using a bicycle static (ergocycle) with astrand method. Research subjects were women aged 25 to 54 years as many as 117 people in Central Bogor District. It is descriptive research with cross sectional design. The measurement of physical activity is done by interview using GPAQ instrumen version 2 which consists of 16 questions on 3 domains of activities ie work, travel and recreation. The results showed that all respondents did not have heavy category activity either job or recreation domain. Average METs score with moderate job domain 4271,69 ± 2874,34; travel domain 1058 ± 1730; medium category recreation domain with METs value of 181.23 ± 471,594 and the overall average total METs were 5511.11 ± 3440.48. Cut off point value of GPAQ instrumen is 4,668 / week; sensitivity = 50,0; specificity = 43,3; a positive predictive value of 75.9%; negative predictive value of 29.3%. The concluded that the average value of METs for each domains over estimate activity, the level of physical activity using GPAQ instrumen is not accurate and there is no correlation between the level of physical activity with GPAQ instrumen compared with fitness V02max with P = 0.451. An alternative instrumen for the assessment of physical activity in a population-based survey is required. Abstrak Instrumen Global Physicall Activity Questionnaire (GPAQ) adalah tools yang paling sering digunakan untuk mengukur aktifitas fisik dalam survei yang dilakukan oleh Kementrian Kesehatan. Analisis Receiver Operating (ROC) dilakukan untuk melihat kemampuan diagnostik instrumen GPAQ terhadap aktifitas fisik dengan nilai VO2max sebagai pembanding. Penelitian ini bertujuan untuk mengetahui sebaran nilai METs menit/minggu setiap domain aktifitas, nilai cut off point METs, luas daerah di bawah kurva (AUC), sensitifitas, spesifisitas, nilai prediksi positif dan nilai prediksi negatif dari pengukuran GPAQ dengan gold standard pemerikaan VO2max. Pemeriksaan tingkat kebugaran menggunakan sepeda statis (ergocycle) dengan metoda astrand. Subyek penelitian adalah wanita umur 25 sampai dengan 54 tahun sebanyak 117 orang di Kecamatan Bogor Tengah. Penelitian ini merupakan penelitian deskriptif dan uji diagnostik dengan disain potong lintang. Pengukuran aktifitas fisik dilakukan dengan wawancara secara terstruktur menggunakan instrumen GPAQ versi 2 yang terdiri dari 16 pertanyaan pada 3 domain aktifitas yaitu pekerjaan, perjalanan dan rekreasi. Hasil penelitian menunjukkan seluruh responden tidak memiliki  aktifitas kategori berat baik domain pekerjaan maupun rekreasi. Rata-rata nilai METs  dengan domain pekerjaan level sedang 4271,69±2874,34; domain perjalanan 1058±1730; domain rekreasi kategori sedang dengan  nilai METs 181,23±471,594 dan nilai rata-rat total keseluruhan METs adalah 5511,11±3440,48. Nilai cut off point instrumen GPAQ sebesar 4.668/minggu, sensitifitas=50,0; spesifisitas=43,3; nilai prediksi positif 75,9%; nilai prediksi negatif 29,3%. Dapat  disimpulkan bahwa nilai rata-rata METs tiap domain aktifitas  over estimate, tingkat aktifitas fisik menggunakan instrumen GPAQ tidak akurat dan tidak ada korelasi antara tingkat aktifitas fisik dengan  instrumen GPAQ dibandingkan dengan kebugaran V02max dengan P=0.451. Perlu alternatif instrumen lain untuk penilaian aktifitas fisik dalam survei berbasis populasi diluar instrumen GPAQ.

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