Vascular Endothelial Growth Factor Antibody Research Articles

Biofabricated adipose-derived mesenchymal cell sheets recover cryo-injured kidneys in rats.

This study aimed to develop a treatment for chronic kidney disease (CKD) by investigating whether transplantation of biofabricated adipose-derived mesenchymal cell (AMC) sheets could improve renal tissue and function. Thirty-nine 10-week-old male Sprague-Dawley rats underwent the harvesting of adipose tissues and right nephrectomy. AMCs that were collected from adipose tissues were labeled and cultured on temperature-responsive dishes, and applied to a gelatin hydrogel sheet. Subsequently, two identical AMC-gelatin sheets were attached together to biofabricate a bilayered AMC-gelatin sheet. Further, 3 weeks after nephrectomy, the renal artery and vein of the left kidney were clamped, and the kidney was sprayed with liquid nitrogen for 60 seconds. The biofabricated AMC sheet was autologously transplanted into the renal capsule of the cryo-injured region (n = 14). Control rats were given acellular sheet (n = 25). One day before and four weeks after transplantation, blood and 24-hour urinary specimens were collected. Histological analysis of the experimental kidneys was performed four weeks after transplantation. Four weeks after transplantation, in the acellular control-transplanted rats, creatinine clearance levels tended to increase, while serum creatinine levels significantly increased. However, in the biofabricated AMC sheet-transplanted rats, creatinine clearance levels significantly increased, and serum creatinine levels remained unchanged and were significantly lower than that of the control rats. The ratio of damaged to undamaged renal tubules in the AMC sheet-transplanted rats was lower than that in the control rats. In addition, the occupancy rate of fibrotic areas in the renal cortex under the AMC sheet-transplanted regions was significantly lower than that in the control regions. After transplantation, while the expressions of transforming growth factor-beta 1 and hypoxia-inducible factor-1 alpha were observed in both the control- and AMC sheet-transplanted regions, these expressions tended to be lower in the AMC sheet-transplanted rats than in the control rats. The labeled transplanted AMCs were detected in the transplanted regions, with some of them also showing positive staining for the vascular endothelial growth factor antibody. In conclusion, the biofabricated AMC sheets improved renal functions by ameliorating renal tubule disorders and renal fibrosis. Therefore, biofabricated AMC sheets would serve as a potential treatment for CKD.

A Glucose-Responsive Hydrogel Inhibits Primary and Secondary BRB Injury for Retinal Microenvironment Remodeling in Diabetic Retinopathy.

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

Intravitreal Lucentis (Ranibizumab) as A Treatment for Diffuse Diabetic Macular Edema

Introduction: Humanized anti-VEGF (Vascular endothelial growth factor) antibody fragment Lucentis (Ranibizumab) is prescribed to treat neovascular (wet) age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization. It is also used to treat macular edema following retinal vein occlusion. Objective: This study was carried out to evaluate the anatomic effect and visual acuity response following intravitreal Lucentis (Ranibizumab). Methodology: In this investigation, diffuse diabetic macular edema was present in 30 eyes belonging to 30 patients with stable diabetes mellitus. Every eye had undergone argon laser photocoagulation, either Focal, Grid, or pan-retinal photocoagulation (PRP), for a minimum of three months. The patients with a mean age was 58.13±5.17 years were treated with two intravitreal injections of 0.5 mg of ranibizumab in 0.05 ml spaced four weeks apart. A skilled ophthalmologist assessed each patient's best-corrected visual acuity (BCVA), also assessed their central macular thickness (CMT) using optical coherence tomography, and assessed their diabetic retinopathy at both the baseline and follow-up sessions. The results: The results showed that the means of BCVA were significantly (P<0.01) decreased from baseline (1.189±0.077 logMAR) to 1 month (0.162±0.058 logMAR) and 3 months (1.109±0.049 logMAR) after injection. Also the results revealed that the mean of CMT were significantly (P<0.01) declined from the baseline (477.47±151.32 µm) to 1 month (438.27±115.68 µm) and 3 month (396.80±115.26 µm) after treatment. Conclusions: The study concluded that after three months of the second injection of Lucentis (ranibizumab) significantly reduced central macular thickness and improved visual acuity, then diffuse diabetic macular edema is significantly improved and treated using Lucentis (ranibizumab).

Interaction between VEGF-A and immune checkpoint targets in triple-negative breast cancer and mechanisms of immune evasion and tumor progression.

1096 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment triple negative breast cancer (TNBC). However, not all patients with TNBC benefit from the addition of ICIs due to factors such as intrinsic and acquired resistance to ICIs, and complex interplay between tumor and immune cells in the tumor microenvironment (TME). Vascular endothelial growth factor (VEGF) promotes angiogenesis and potentially modulates tumor immune evasion. A phase I clinical trial has shown that a bispecific antibody to VEGF-A and PD-L1 produces encouraging tumor responses in advanced TNBC. In this study, we investigated the interaction between VEGF and various immune gene expression signatures including PD-L1 in a real-world breast cancer patient population. Methods: Comprehensive immune profiling, including the RNA-seq based gene expression assessment of 395 immune-associated genes, was performed on 120 formalin-fixed paraffin-embedded breast cancer samples. PD-L1 expression (Combined Positive Score, CPS ≥ 10%) was measured by immunohistochemistry (IHC; 22C3). Clinicopathologic variables were collected. Statistical associations between quantitative biomarkers, including 28 immune checkpoint genes, were calculated using Pearson correlations (r), and comparisons of quantitative biomarkers between groups were performed using the proportions test. For statistical significance, p<0.05 was required. Results: The study cohort included 29 patients (24.2%) with TNBC and 91 (75.2%) with non-TNBC (including ER+/HER2- and HER2+). Most patients had metastatic tumors (n=92, 76.7%) and invasive ductal carcinoma (n=83, 69.2%). Among the TNBC group, 21 patients had PD-L1 positive tumors (72.4%), defined by CPS ≥ 10.In non-TNBC, VEGF has significant, though weak (r<0.35) correlations with the expression of three checkpoint genes: AKT1 (r=0.35, p=0.00063), ICOS (r=0.34, p=0.00099), and TIM3 (r=0.29, p=0.0061). In TNBC, VEGF has significant, strong (r>0.47) correlations with the expression of three other checkpoint genes: PD-1 (r=0.47, p=0.0094), PD-L1 (r=0.57, p=0.0012), and PIK3CA (r=0.6, p=0.00051) However, in TNBC, VEGF gene expression does not have a statistical association with PD-L1 IHC (CPS ≥/< 10 (p=0.9)). Conclusions: Our findings suggest that there is an interplay between angiogenesis and an immunosuppressive tumor immune microenvironment in TNBC to a greater degree than in non-TNBCs. This supports the notion that angiogenesis mediators such as VEGF-A may enhance the expression of immunosuppressive checkpoint molecules, leading to immune evasion and tumor progression. Combination treatments of ICIs, especially anti-PD-1 therapy, with VEGF antibodies may be promising approaches to enhance the immune responses in TNBC, especially in tumors with CPS<10, where the current frontline treatment is cytotoxic chemotherapy.

Biodistribution and pharmacokinetics of [89Zr]-anti-VEGF mAbs using PET in glioblastoma rat models

IntroductionGlioblastomas present intensive angiogenesis, thus anti–Vascular Endothelial Growth Factor (VEGF) antibodies (mAbs) have been proposed as promising therapies. However, the results of clinical trials reported moderate toxicity and limited effectiveness. This study evaluates the in vivo pharmacokinetics and biodistribution of these mAbs in a growing model of glioblastoma in rats using Positron Emission Tomography (PET). Material&Methods:mAbs were radiolabeled with zirconium-89. Four days after the model induction, animals were injected with 2.33 ± 1.3 MBq of [89Zr]-DFO-bevacizumab (n = 8) or 2.35 ± 0.26 MBq of [89Zr]-DFO-aflibercept (n = 6). PETs were performed at 0H, 48H, 168H, 240H, and 336H post-injection. Tumor induction was confirmed using [18F]-Fluorodeoxyglucose-PET and immunohistochemistry. Radiotracer uptake was estimated in all pre-defined Volumes-of-Interest. ResultsAnti-VEGF mAbs showed 100 % Radiochemical-Purity. [89Zr]-DFO-bevacizumab showed a significantly higher bioavailability in whole-blood. A significant increase in the tumor uptake was detectable at 168H PET with [89Zr]-DFO-bevacizumab meanwhile with [89Zr]-DFO-aflibercept it was only detectable at 336H. [89Zr]-DFO-bevacizumab tumor uptake was significantly higher than that of [89Zr]-DFO-aflibercept in all the scans. Tumor induction was confirmed in all animal models. ConclusionMAbs detect VEGF-expression in glioblastoma models. Tumors were earlier targeted by Bevacizumab. The lower blood availability of aflibercept resulted in a lower tumor uptake than bevacizumab in all the scans.

Application of Targeted Nano-Bubble Ultrasound Contrast Agent in the Detection of Arterial Intima Inflammation in Rats

Tumor-specific antibodies or ligands were connected to the surface of nano-bubbles to form a targeted nano-bubble ultrasound contrast agent (UCA), which can accumulate in tumor tissues, enhance tumor tissue visualization, and realize extravascular disease detection and ultrasound molecular imaging. In this research, the positive and negative charges were attracted to promote the self-assembly connection between the targeted vascular endothelial growth factor (VEGF) antibody and the envelope surface of the nano-bubble, thereby obtaining a tumor-specific targeted nano-bubble UCA. Then, from the basic characterization, in vivo and in vitro ultrasound contrast performance analysis, a rat model of arterial intima inflammation in vivo was constructed. 16 Wistar rats were screened and divided into a control group and a contrast-enhanced ultrasound group. The imaging performance of the targeted molecules was analyzed by preparing an UCA. in vitro contrast-enhanced ultrasound found that the contrast intensity of self-made targeted nano-bubbles was greatly affected by concentration, but there was no linear relationship between the two. in vivo experiments were performed to observe rat liver contrast. The results showed that the contrast intensity and contrast time of the targeted nano-bubbles in vivo were greatly affected by the dose, and the stability in vivo was lower than the stability in vitro. Immunohistochemical tests found that P-selectin was expressed in large amounts in the intima of damaged blood vessels. Compared with ordinary contrast agents, the prepared targeted nano-UCA after modeling can enhance the video intensity of the inner membrane (P <0.05) and prolong the imaging time (P <0.05). It suggested that the contrast agent can specifically bind to P-selectin on the surface of vascular endothelial cells, and it was expected to be used for the detection of early inflammatory lesions in atherosclerotic diseases.

Oxidative Stress Participates in Age-Related Cataract Formation by Disrupting Connection between Lens Epithelial Cells through c-Src/VEGF Pathway

Purpose To observe the effects of oxidative stress on vascular endothelial growth factor (VEGF) and connections of lens epithelial cells. Methods Human lens epithelium of patients with age-related cataract (ARC), both SRA01/04 cells and whole mice lens stimulated by H2O2 were employed. VEGF in human aqueous humor of ARC-patients and the supernatant of SRA01/04 cells was determined by ELISA. The expressions of VEFG in human lens epithelium were detected by immunofluorescence staining. Multiple linear regression analysis and spearman rank-order correlation were used to determine the associations between VEGF and parameters of ARC individuals. In H2O2-induced SRA01/04 cells, Catalase (CAT), PP1 (inhibitor of c-Src kinase) and Avastin (VEGF antibody) were used to inhibit the effects of H2O2, activation of c-Src kinase and VEGF, which were detected by Western blot. The alterations of ZO-1 and N-cadherin were tested by immunofluorescence staining and Western blot. In H2O2-induced whole lens, the changes of opacification area in different treatment of inhibitors were observed. Results The secretion of VEGF in aqueous humor and expression of VEGF in the lens epithelium of ARC patients increased significantly with age. In H2O2-induced SRA01/04 cells, the VEGF in the supernatant was increased with the culture duration and the dose of H2O2. The expressions of p-Src418 and VEGF were also up-regulated, whereas the expressions of ZO-1 and N-cadherin were down-regulated. CAT effectively prevented these changes induced by H2O2, while PP1 inhibited not only p-Src418 but also up-regulation of VEGF, Avastin partially inhibited VEGF up-regulation. Both PP1 and Avastin prevented down-regulation of ZO-1 and N-cadherin, respectively, but Avastin combined with PP1 had no significant synergistic effects. In H2O2-induced cataract, CAT prevented development of opacification area effectively, and PP1 and Avastin did partially. Conclusions Oxidative stress disrupts connections of lens epithelial cells by activating c-Src/VEGF, inhibiting which may prevent cataract.

Microvesicles released from ectopic endometrial foci as a potential biomarker of endometriosis.

Angiogenesis is engaged in endometriosis. It is regulated by regulatory factors and cytokines, transported in microvesicles. The purpose was to investigate the presence of MVs with vascular endothelial growth factor (VEGF) and metalloproteinase-9 (MMP-9) in peripheral blood and peritoneal fluid of women operated on for endometrioma or teratoma Material and methods:Microvesicles (MVs) were determined in blood samples and peritoneal fluid samples collected from women aged 20-60 years operated on for endometriosis (test group) and teratoma (control group). The final investigations were performed on 47 patients, who qualified for the study based on the meticulous inclusion criteria. MVs were analyzed by flow cytometry (FACS) using annexin V, antibodies for molecules characteristic of cells from endometriosis foci (keratin 18 (K18), CD105, CD146), and antibodies for intraepithelial vascular growth factor VEGF and metalloproteinase-9 (MMP-9). The sample was double "reading" using flow cytometry (FACSCantoII). Cytometry analysis confirmed MVs' presence in plasma and peritoneal fluid collected from patients with both endometriosis and teratomas. A statistically significant higher level of AnnexinV (+) MVs were observed in plasma samples of endometriosis patients. In the control group, there was a higher percentage of double-positive VEGF (+)/MMP-9 (+) and single MMP-9 (+) positive MVs in the serum. In the peritoneal fluid higher frequency of double-positive VEGF (+)/MMP-9 (+) MVs were found in the control group. However, the amount of VEGF (+) / MMP-9 (+) MVs object did not enable to differentiate between the test and control groups. The study was the first, in which MVs were confirmed in plasma and peritoneal fluid in benign adnexa tumors. Microvesicles are present in peripheral blood and peritoneal fluid samples collected from patients with endometriosis and teratomas. Microvesicles with proangiogenic factors (VEGF and MMP-9) are more abundant in blood and peritoneal fluid samples from patients with teratomas.

Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells.

JZL184, an inhibitor of monoacylglycerol lipase (MAGL) and thus of the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), mediates various anticancer effects in preclinical studies. However, studies on the effect of this or other MAGL inhibitors under hypoxia, an important factor in tumor biology and response to cancer therapy, have not yet been performed in cancer cells. In the present study, the impact of the conditioned media (CM) of A549 and H358 lung cancer cells incubated with JZL184 under hypoxic conditions on the angiogenic properties of human umbilical vein endothelial cells (HUVECs) was investigated. Treatment of HUVECs with CM derived from cancer cells cultured for 48 h under hypoxic conditions was associated with a substantial increase in migration and tube formation compared with unconditioned medium, which was inhibited when cancer cells were incubated with JZL184. In this process, JZL184 led to a significant increase in 2-AG levels in both cell lines. Analysis of a panel of proangiogenic factors revealed inhibition of hypoxia-induced vascular endothelial growth factor (VEGF) expression by JZL184. Antiangiogenic and VEGF-lowering effects were also demonstrated for the MAGL inhibitor MJN110. Receptor antagonist experiments suggest partial involvement of the cannabinoid receptors CB1 and CB2 in the antiangiogenic and VEGF-lowering effects induced by JZL184. The functional importance of VEGF for angiogenesis in the selected system is supported by observations showing inhibition of VEGF receptor 2 (VEGFR2) phosphorylation in HUVECs by CM from hypoxic cancer cells treated with JZL184 or when hypoxic cancer cell-derived CM was spiked with a neutralizing VEGF antibody. On the other hand, JZL184 did not exert a direct effect on VEGFR2 activation induced by recombinant VEGF, so there seems to be no downstream effect on already released VEGF. In conclusion, these results reveal a novel mechanism of antiangiogenic action of JZL184 under conditions of hypoxic tumor-endothelial communication.

Electrochemical determination of vascular endothelial growth factor using functional metal-polymer nanocomposites

Vascular endothelial growth factor (VEGF) is a homo-dimeric glycoprotein that plays a prominent part in the pathophysiology of angiogenesis and vasculargenesis, such as tumorigenesis, vascular permeability and metastasis. Quantification of VEGF in the body is significant for clinical diagnosis and treatment. An electrochemical sensor for the sensitive determination of VEGF was developed. Functional metal-polymer nanocomposites, gold nanoparticles@poly(o-phenylenediamine) (AuNPs@PoPD), and AuNPs@PoPD-labeled VEGF antibodies (Ab-AuNPs@PoPD) were synthesized. The glassy carbon electrode modified with graphene nanoribbons (GNRs), AuNPs and VEGF, GCE/GNRs-AuNPs/VEGF, was fabricated and it was employed to capture Ab-AuNPs@PoPD. Free VEGF proteins had an inhibitory action on the assembly of GCE/GNRs-AuNPs/VEGF/Ab-AuNPs@PoPD, leading to the decrease of the electrochemical probe, PoPD, on the modified electrode and the decline of current signal in the voltammetic measurement. Under the optimal experimental conditions, the peak current difference was proportional to the VEGF concentration in the range of 0.500–500 ng mL−1 and the limit of detection was 300 pg mL−1. The proposed sensor exhibited a good selectivity, reproducibility and stability. High-salt microenvironment induced the dysfunction of human umbilical vein endothelial cells (HUVECs). Electrochemical measurements reveal that increasing NaCl concentration in the growth medium promoted the release of VEGF from dysfunctional HUVECs.

Vascular Endothelial Growth Factor Expression in Breast Carcinoma and its Association with Expression of Estrogen Receptors, Progesterone Receptors and HER-2/neu and Molecular Subtypes

Background: The management of breast carcinoma depends on several molecular markers and tumor stages. In the last decades, estrogen receptors (ER), progesterone receptors (PR), and HER-2/neu have shown good therapeutic responses. Among other molecular markers, vascular endothelial growth factor (VEGF) is becoming more widely used as a prognostic indicator in patients with breast carcinoma. Anti-VEGF therapy already has been proven as an effective chemotherapeutic agent in some other carcinomas. The study aimed to find out the immunohistochemical expression of Vascular Endothelial Growth Factor (VEGF) in breast carcinoma and its possible correlation with the expression of ER, PR, and HER-2/neu and molecular subtypes to evaluate its prognostic value. Material & Methods: This study was conducted in the Department of Pathology, BIRDEM General Hospital, Dhaka, from March 2018 to January 2020. In this study, 45 diagnosed cases of breast carcinoma were enrolled. Slides of all cases were stained with ER, PR, HER-2/neu, and VEGF antibodies following the avidin-biotin-peroxidase staining method. Results: Among 45 cases, 60% showed positive immunohistochemical expression of VEGF. Most of these cases (71.1%) were ER/PR positive. VEGF did not show a significant association with other molecular markers or molecular subtypes. Conclusion: Although, the potential prognostic value of VEGF has not been confirmed. Based on the findings of the current study, it can be assumed that VEGF plays an important role in the pathogenesis of breast cancer. So, it may serve as a useful biomarker for immuno-targeting therapy in patients with breast cancer.

The Effect of Induction Chemotherapy with VEGF Inhibition on Tumor Response in Synchronously Metastasized Potentially Resectable Colorectal Cancer.

(1) Background: The pathological tumor response of the primary tumor to induction chemotherapy in synchronously metastasized colorectal cancer (mCRC) patients has not been investigated. The aim of this study was to compare patients treated with induction chemotherapy combined with vascular endothelial growth factor (VEGF) or with epidermal growth factor receptor (EGFR) antibodies. (2) Methods: We present a retrospective analysis, where we included 60 consecutive patients with potentially resectable synchronous mCRC who received induction chemotherapy combined with either VEGF or EGFR antibodies. The primary endpoint of this study was the regression of the primary tumor, which was assessed by the application of the histological regression score according to Rödel. The secondary endpoints were recurrence-free survival (RFS) and overall survival (OS). (3) Results: A significantly better pathological response and a longer RFS for patients treated with the VEGF antibody therapy compared to those treated with the EGFR antibodies was demonstrated (p = 0.005 for the primary tumor and log-rank = 0.047 for RFS). The overall survival did not differ. The trial was registered with clinicaltrial.gov, number NCT05172635. (4) Conclusion: Induction chemotherapy combined with a VEGF antibody revealed a better pathological response of the primary tumor, leading to a better RFS compared to that with EGFR therapy; this has clinical relevance in patients with potentially resectable synchronously mCRC.

Mandibular Condylar Hyperplasia and its correlation with Vascular endothelial growth factor.

Condylar hyperplasia (CH) is a rare condition characterized by excessive unilateral growth of the mandibular condyle after cessation of growth on the contralateral side causing facial asymmetry, being more prevalent in the second and third decades. The aim of this study was to determine the utility of vascular endothelial growth factor (VEGF-A) as a diagnostic and prognostic factor in condylar hyperplasia, and to determine its potential viability as a therapeutic target. This is a case-control study, where seventeen mandibular condyles specimens were collected from seventeen patients treated for active mandibular condyle hyperplasia and three unaffected human mandibular condyles from cadavers will serve as the control group. The samples were immunostained with VEGF-A antibody and evaluated on both quantity and intensity of staining. VEGF-A was qualitatively found to be greatly upregulated in patients with condylar hyperplasia. VEGF-A was qualitatively found to be upregulated in patients affected by CH, validating VEGF-A as a potential diagnostic, prognostic, and therapeutic target.

Incidence of Hyper Progressive Disease in Combination Immunotherapy and Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Monotherapy for Unresectable Hepatocellular Carcinoma

Introduction: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods: This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4. Results: The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05–3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25–33.79) when compared to the combined VEGF antibody group. Conclusion: The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.

Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody

BackgroundSuccess of T cell immunotherapy hinges on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors and associated with immune evasion. The efficacy of...

Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade

Recent clinical trials revealed that immune checkpoint inhibitors and antiangiogenic reagent combination therapy improved the prognosis of various cancers. We investigated the roles of fibrocytes, collagen-producing monocyte-derived cells, in combination immunotherapy. Anti-VEGF (vascular endothelial growth factor) antibody increases tumor-infiltrating fibrocytes and enhances the antitumor effects of anti-PD-L1 (programmed death ligand 1) antibody invivo. Single-cell RNA sequencing of tumor-infiltrating CD45+ cells identifies a distinct "fibrocyte cluster" from "macrophage clusters" invivo and in lung adenocarcinoma patients. A sub-clustering analysis reveals a fibrocyte sub-cluster that highly expresses co-stimulatory molecules. CD8+ Tcell-costimulatory activity of tumor-infiltrating CD45+CD34+ fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockade invivo; CD86-/- fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor β (TGF-β)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-βR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade.

Mechanism of sac expansion without evident endoleak analyzed with X ray phase-contrast tomography

ObjectiveSynchrotron radiation-based X ray phase-contrast tomography (XPCT) was used in this study to evaluate abdominal aorta specimens from patients with sac expansion without evidence of an endoleak (endotension) following endovascular aortic repair (EVAR) for an abdominal aortic aneurysm (AAA). The aim of this study was to analyze the morphologic structure of the aortic wall in patients with this condition and to establish the cause of the endotension. MethodsHuman aortic specimens of the abdominal aorta were obtained during open repair, fixed with formalin, and analyzed among three groups. Group A was specimens from open abdominal aortic aneurysm repairs (n = 7). Group E was specimens from sac expansion without an evident endoleak after EVAR (n = 7). Group N was specimens from non-aneurysmal “normal” cadaveric abdominal aortas (n = 5). Using XPCT (effective voxel size, 12.5 μm; density resolution, 1 mg/cm3), we measured the density of the tunica media (TM) in six regions of each sample. Then, any changes to the elastic lamina and the vasa vasorum were analyzed pathologically. The specimens were immunohistochemically examined with anti-CD31 and vascular endothelial growth factor antibodies. ResultsThe time from EVAR to open aortic repair was 64.2 ± 7.2 months. There were significant differences in the thickness of the TM among three groups: 0.98 ± 0.03 mm in Group N; 0.31 ± 0.01 mm in Group A; and 0.15 ± 0.03 mm in Group E (P < .005). There were significant differences in the TM density among the groups: 1.087 ± 0.004 g/cm3 in Group N; 1.070 ± 0.001 g/cm3 in Group A; and 1.062 ± 0.007 g/cm3 in Group E (P < .005). Differences in the thickness and density of the TM correlated with the thickness of the elastic lamina; in Group N, uniform high-density elastic fibers were observed in the TM. By contrast, a thinning of the elastic lamina in the TM was observed in Group A. A marked thinness and loss of elastic fibers was observed in Group E. CD31 immunostaining revealed that the vasa vasorum was localized in the adventitia and inside the outer third of the TM in Group N, and in the middle of the TM in Group A. In Group E, the vasa vasorum advanced up to the intima with vascular endothelial growth factor-positive cells in the intimal section. ConclusionsXPCT could be used to demonstrate the densitometric property of the aortic aneurysmal wall after EVAR. We confirmed that the deformation process that occurs in the sac expansion after EVAR without evidence of an endoleak could be explained by hypoxia in the aortic wall.

Structural characteristics of chronic subdural hematomas in elderly and senile patients and their prognostic significance

o account morphological characteristicsMaterials and methods. Retrospective analysis of the results of diagnosis and treatment of patients with CSDH treated in the neurotrauma department of the Romodanov Institute of Neurosurgery NAMS of Ukraine and the City Hospital for Emergency and Emergency Medicine of Zaporizhzhya in 2010‒2019. Among the patients were 80 elderly people, 32 senile and 6 long-lived people. Multispiral computed tomography (MSCT) was performed in 86.7 % of patients, magnetic resonance imaging (MRI) in 13.3 %. In 118 cases, surgical intervention was performed (various types and volume), in 67 % ‒ a morphological study of the fragments of the capsule of the CSDH was performed.Results. The indication for surgery in elderly and senile persons with CSDH is the presence of hematomas with a volume of ≥100 cm3, regardless of the severity of the dislocation syndrome. In 95 % of observations, accompanying somatic diseases were detected. Control of treatment effectiveness was carried out with the help of MRI (in 73.5 % of cases) and CT (in 26.5 %). According to the results of histological studies, three variants of the structure of the capsule of CSDH have been established (according to the density of the location of vessels (the level of expression of the vascular endothelial growth factor (VEGF)) and the ratio of mesenchymal cells), which, together with clinical data, makes it possible to determine the genesis of CSDH. Also, several variants of the structure of the capsule of CSDH were identified, depending on the timing of the diagnosis and morphological examination. Analysis of the relative number and ratio of different cell pools (lymphocytes, fibroblasts, fibrocytes), quantification of immunopositive cells with a reaction to VEGF antibodies, as well as determination of the number of newly formed vessels per unit area makes it possible to predict the course and risk of recurrence of CSDH. Conclusions. The clinical and diagnostic characteristic of CSDH, characteristic of the elderly and senile, is the presence of hematomas with a volume of ≥100 cm3 and the discrepancy between the severity of the condition, clinical and neurological manifestations, and the degree of expressiveness of dislocation-compression changes according to MSCT/MRI data. It is effective to remove CSDH through 1 – 2 milling holes. Microcraniotomy is considered appropriate for a hematoma with complex neuroimaging architecture (multiple septa, layers, trabeculae), in some cases of hematoma recurrence. If the inner surface of the capsule is turned to the blood clot and is represented by a layer of spindle-shaped cells, this indicates a non-traumatic origin of the hematoma. A staged complex clinical and diagnostic examination for CSDH has both clinical and purely practical significance (especially expert), justifying the costs of treatment and insurance payments, ensures the social adaptation of the patient and brings the solution of these issues closer to international standards. Indications, criteria for choosing tactics and the sequence of performing procedures taking into account risks, prognostic clinical-radiological and structural signs are based mainly on recommendations and consensuses and require further detailed study.

Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.

LW-1 MY LIFE WORK : MY RESEARCH WORK FOCUSING ON TUMOR-ASSOCIATED ENDOTHELIAL CELLS ALONG WITH VEGF FOR 30 YEARS

Abstract When I was a medical student, I happened to see the typical histopathology of glioblatoma (GBM) containing expanding necrosis surrounded by enormous glomerulous microvasculature with endothelial proliferation resembling glomeruli in the kidney. It looks like tumor cells starving out due to lack of blood supply with accelerating growth. Since then, I have been fascinated by tumor angiogenesis that might be an attractive therapeutic target.In 1989, vascular endothelial growth factor (VEGF) and vascular permeability factor (VPF) turned out to be identical. In 1992, VEGF expression was distributed surrounding necrosis area in GBM. In 1993, anti-tumor effect of monoclonal antibody for VEGF via inhibition of angiogenesis on various tumor models including glioma was verified in vivo. In 1996, VEGF was found to inhibit the functional maturation of dendritic cells, suggesting that therapeutic blockade of VEGF may improve prospect for immunotherapy as well as inhibition of angiogenesis. Those findings made me excited with visionary idea that combination therapy of anti-VEGF therapy and dendritic cell-based immunotherapy might be a potential therapeutic approach for GBM. Currently, I am dedicated in clinical study of dendritic cell-based immunotherapy and bevacizumab for GBM.Since graduating from medical school and discovery of VEGF in the same era, my clinic and research have been supported by serendipity of a vast of experiences and many people. I would give take-home message to next generation that originality and creativity were cultivated in real-world, and that serendipity and integration were precious for development of basic and clinical research.