Treatment outcomes of central retinopathy of prematurity with localization in the Moscow regional perinatal center

BACKGROUND: Ranibizumab is widely used in retinopathy of prematurity. Therefore, it is necessary to evaluate the effectiveness, the risk of complications, and recurrence of the disease by antiangiogenic therapy. AIM: To demonstrate the experience of using anti-VEGF drugs in the Moscow Regional Perinatal Center and the effectiveness of different approaches to retinopathy of prematurity (ROP) treatment in the central retinal zone. MATERIAL AND METHODS: The case histories of 17 deeply premature infants with threshold ROP stages and localization in the posterior pole were retrospectively analyzed. Children were treated with intravitreal VEGF inhibitor (total 9 children), 5 children underwent laser coagulation of the retina, and 3 children received combined treatment (laser and intravitreal administration of a VEGF inhibitor). RESULTS: The average age of development of threshold stages was 35.2 weeks (range: 30.539 weeks) in our study. The frequency of promising outcomes after using anti-VEGF drugs alone or in conjunction with peripheral laser treatment was 100%. In comparison, the only laser treatment generated a promising result in 70% of the eyes. However, ROP relapses after anti-VEGF therapy developed at 37, 43, 44,5 weeks. In addition, 1 out of 9 children developed a recurrence of ROP and required laser treatment 7 weeks after using anti-VEGF. CONCLUSION: The use of anti-VEGF therapy is an effective method for the treatment of ROP of the posterior pole. However, there is the ambiguity of the available recommendations on the further management of children. Therefore, it is necessary to monitor the children who have received antiangiogenic therapy for as long as possible.

Structure-Based Virtual Screening, Molecular Docking, MolecularDynamics Simulation of VEGF Inhibitors for the Clinical Treatment of Ovarian Cancer

VEGF and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identified in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential VEGF inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumour cells of ovary and to examine for an effectiveness of identified inhibitor for treatment of ovarian cancer using various In silico approaches. 12 established VEGF inhibitors were collected from various literature. The compound AEE788 displays the great affinity towards the target protein as a result of docking study. AEE78 was further used for structure base virtual screening in order to obtain more structurally similar compound with high affinity. Among the 80 Virtual screened compounds, CID 88265020, explicates much better affinity than established compound AEE788. Based on Molecular Dynamics Simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 have the high affinity with the lowest re-rank score, and holds a huge potential to inhibit the VGFR and can be implemented for prospective of future investigations in Ovarian Cancer.

Prevention of VEGF inhibitor-induced toxicity by salt restriction: the SUN-SALT study

Introduction Vascular endothelial growth factor (VEGF) inhibitors target the formation of new blood vessels required for growth and metastatic spread of a malignant tumor. Although this is an effective anticancer treatment, many patients develop cardiovascular side effects such as hypertension, requiring dose reduction or early termination of treatment. In animals, VEGF inhibitor-induced hypertension is salt-sensitive. Aim To prospectively study whether salt restriction can prevent or attenuate the rise in blood pressure in response to anti-cancer treatment with VEGF inhibitors. Method This is a single centre prospective open-label intervention study. Patients are eligible when treated with a VEGF inhibitor according to standard of care and developing hypertension or a blood pressure rises of 20 mmHg or more during the first treatment cycle. A salt restricted diet (<4 grams/day) including provided salt-less bread is started during the off-treatment period under guidance of a specialized dietitian. The primary endpoint is mean difference in blood pressure rise between the treatment cycle with and the treatment cycle without salt restriction. We aim for a total of 16 patients with a blood pressure rise of at least 20mmHg and/or development of hypertension undergoing the intervention. Results Between 28 November 2019 and 25 March 2021, 45 patients gave informed consent. Fourteen patients developed hypertension and/or a blood pressure rise of at least 20 mmHg after three- four weeks of treatment making them eligible for the intervention. In 10 patients, salt restriction was the only intervention to reduce the blood pressure rise during the following treatment cycle, leading to a reduction in blood pressure rise of 17 mmHg (10 vs 27 mmHg; p<0.001). In four patients antihypertensive treatment was started during the first treatment cycle due to blood pressure rise above 170 mmHg. Salt restriction did not appear to have an important further blood pressure lowering effect, although in one patient the antihypertensive treatment was interrupted during the stop week and salt restriction was sufficient to limit the blood pressure rise in the second cycle. Importantly, the intervention was well tolerated and most patients continued salt restriction after the study finished. Conclusion Applying salt restriction might be an effective and well tolerated intervention to decrease blood pressure rise during treated with VEGF inhibitors. More importantly, this gives important information about the pathogenesis. Further studies of collected blood and 24h urine samples will allow conclusions on the role of endothelin-1, the renin aldosterone system and prostacyclins. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): De Merel (Charity aiming for research directly benefiting patients; yearly award, success rate ∼30% “Stichting De Merel”)

Abstract 44: VEGF Inhibitor-induced Vascular Dysfunction Is Ameliorated By PARP/TRPM2 Inhibition

Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi), which are used as anti-angiogenic drugs in cancer treatment. Clinical observations suggest that the combination of VEGFi with another anti-cancer drug, olaparib (PARP inhibitor [PARPi]), may attenuate the development of hypertension. However putative vascular mechanisms are unknown. PARP plays a major role in the activation of TRPM2, a redox-sensitive Ca 2+ channel, which is associated with hypertension-induced vascular dysfunction. We hypothesized that PARPi attenuates VEGFi-induced vascular injury through TRPM2/Ca 2+ -dependent pathways. Human vascular smooth muscle cells (hVSMC), human aortic endothelial cells (HAEC), and mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone (3μM) or in combination with olaparib (1μM). Wire myography was used to assess vascular function. Axitinib reduced ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), an effect blocked by olaparib. U46619- and ET-1-induced vasoconstriction were increased by axitinib (% KCl- U4 : 101.2 [Ct] vs. 141.4 [Axi]; ET-1 : 122.6 [Ct] vs. 152.5 [Axi]), an effect not observed with axitinib plus olaparib. TRPM2 channel blocker (8-Br-cADPR; 1μM) attenuated the hypercontractile effects and endothelial dysfunction induced by axitinib. Axitinib increased ROS production in hVSMC (RUL: 0.8±0.2 [Ct] vs. 1.1±0.09 [Axi]) and HAEC (0.7±0.4 [Ct] vs. 1.2±0.1 [Axi]), stimulated phosphorylation of the inhibitory site of eNOS (a.u.: 0.99±0.35 [Ct] vs. 1.35±0.10 [Axi]) and induced exaggerated Ca 2+ influx (AUC: 17541±4708 [Ct] vs. 22249±1438 [Axi]) in hVSMC. These effects were blocked by olaparib and 8-Br-cADPR. Axitinib also induced phosphorylation of MLC20 in hVSMC (a.u.: 0.028±0.02 [Ct] vs. 0.04±0.01 [Axi]) and aorta (a.u.: 0.3±0.01 [Ct] vs. 0.5±0.001 [Axi]). Our data indicate that PARP/TRPM2 inhibition attenuates axitinib-mediated vascular dysfunction and normalizes impaired hVSMC and HAEC signalling induced by VEGFi. We define a putative vasoprotective effect of olaparib that may ameliorate vascular injury and hypertension induced by VEGFi in cancer treatment.

Mechanisms and Clinical Trials of Hepatocellular Carcinoma Immunotherapy

Hepatocellular carcinoma (HCC), one of the most common and lethal tumors worldwide, is usually not diagnosed until the disease is advanced, which results in ineffective intervention and unfavorable prognosis. Small molecule targeted drugs of HCC, such as sorafenib, provided only about 2.8 months of survival benefit, partially due to cancer stem cell resistance. There is an urgent need for the development of new treatment strategies for HCC. Tumor immunotherapies, including immune check point inhibitors, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb), have shown significant potential. It is known that the expression level of glypican-3 (GPC3) was significantly increased in HCC compared with normal liver tissues. A bispecific antibody (GPC3-S-Fabs) was reported to recruit NK cells to target GPC3 positive cancer cells. Besides, bispecific T-cell Engagers (BiTE), including GPC3/CD3, an aptamer TLS11a/CD3 and EpCAM/CD3, were recently reported to efficiently eliminate HCC cells. It is known that immune checkpoint proteins programmed death-1 (PD-1) binding by programmed cell death-ligand 1 (PD-L1) activates immune checkpoints of T cells. Anti-PD-1 antibody was reported to suppress HCC progression. Furthermore, GPC3-based HCC immunotherapy has been shown to be a curative approach to prolong the survival time of patients with HCC in clinically trials. Besides, the vascular endothelial growth factor (VEGF) inhibitor may inhibit the migration, invasion and angiogenesis of HCC. Here we review the cutting-edge progresses on mechanisms and clinical trials of HCC immunotherapy, which may have significant implication in our understanding of HCC and its immunotherapy.

Treatment of Coates retinitis in both eyes in a 5-year-old girl

Purpose. To present a rare clinical case of bilateral Coates retinitis in a 5-year-old girl. Material and methods. A clinical case of a 5-year-old girl with rare Coat's retinitis in both eyes is described. The disease occurred abruptly: the child's parents noted the appearance of leukocoria in the right eye. After the examination Coates ' retinitis was diagnosed. At the time of examination in the clinic, there was a retinal detachment in the right eye, the surgical treatment was performed: lensvitrshvartectomy, plastic surgery of the anterior chamber, with the melting of the retina with perfluoroorganic compounds, drainage of subretinalfluid, endolaser coagulation on the right eye. A month after the first symptoms appeared in the right eye, the patient complained of decreased vision in the left eye. Examination on the pediatric retinal camera showed an increase in vascular activity in the left eye, and signs of Coats' retinitis were revealed. Results. As a therapy for this disease, the patient was twice injected intravitreally inhibitor of vascular endothelial growth factor (VEGF inhibitor) into the left eye with positive dynamics noted as a decrease in the activity of retinal vessels and leveling of the exudative component, as well as with an increase in visual acuity in the left eye. Conclusion. This clinical case demonstrates that intravitreal administration of inhibitor VEGF with traditional methods of treatment can be used as a treatment for patients with Coates retinitis. Key words: Coat's retinitis, Coats' disease, vascular endothelial growth factor inhibitor, aflibercept, intravitreal injection, anti-VEGF, retinal detachment.

A new approach to the treatment of macular edema associated with toxocaral uveitis in remission in pediatric ophthalmology using a VEGF inhibitor

Purpose. To demonstrate the results of treatment with the use of a VEGF inhibitor (anti-VEGF) in a clinical case of severe edema of the macular and paramacular regions against the background of toxocaral uveitis in remission. Material and methods. This article presents a clinical case of an 11-year-old female patient with increasing severe macular edema with neovascularization, which appeared against the background of toxocaral uveitis in remission. In connection with the progression of the disease, the patient was injected intravitreally with an inhibitor of vascular endothelial growth factor aflibercept. Results. At discharge, the patient showed positive dynamics in the form of an increase in visual acuity in the left eye from 0.04 to 0.07. According to the results of ophthalmoscopy and OCT of the left eye, a decrease in the area of exudation is determined, which confirms the effectiveness of the treatment. Conclusion. The description of this case can be provided as information about the possibility of using a VEGF inhibitor for exudative processes of the macular region of various etiologies in the absence of the effectiveness of conservative treatment methods. Key words: toxocariasis, uveitis, macular edema, aflibercept, anti-VEGF, OCT.

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.