Leukocyte telomere length and response to antiangiogenic therapy in patients with neovascular age-related macular degeneration

Возрастная макулярная дегенерация (ВМД) становится основной причиной потери зрения людьми старше 60 лет. Неоваскулярная форма ВМД характеризуется хориоидальной неоваскуляризацией, основным триггером которой является фактор роста эндотелия сосудов (VEGF), ингибирование которого - современный стандарт лечения. Значительная вариабельность ответа на анти-VEGF-терапию определяет актуальность поиска биологических маркеров - прогностических критериев ответа на лечение. Проведен анализ зависимости ответа 110 пациентов с нВМД на анти-VEGF-терапию от функциональных и анатомических параметров сетчатки (по данным оптической когерентной томографии) и длины теломер лейкоцитов (ДТЛ, оценивали методом количественной ПЦР). В 100 % глаз наблюдали положительную динамику максимально корригированной остроты зрения (МКОЗ). Центральная толщина сетчатки (ЦТС) снизилась после третьей инъекции до 265 [234-306] мкм, к концу периода наблюдения - до 211 [190-262] мкм. Сохранение активности субретинальной неоваскулярной мембраны (СНМ) в конце периода наблюдения коррелировало с более низкими показателями исходной МКОЗ и высокими значениями исходной ЦТС. Выявлена ассоциация ДТЛ с ответом на лечение: у пациентов с большей ДТЛ чаще наблюдали переход активной формы СНМ в неактивную уже после трех инъекций, в то время как при меньшей ДТЛ чаще сохранялась активность СНМ, что определяло потребность в большем числе интравитреальных инъекций. Age-related macular degeneration (AMD) is becoming the leading cause of vision loss in people over 60 years of age. The neovascular form of AMD (nVMD) is characterized by choroidal neovascularization (CNV), the main trigger of which is vascular endothelial growth factor (VEGF), the inhibition of which is the current standard of treatment. Significant variability of response to anti-VEGF therapy determines the relevance of the search for biological markers - prognostic criteria of treatment response. We analyzed the response of 110 nVMD patients to anti-VEGF therapy depending on the functional and anatomical parameters of the retina (according to optical coherence tomography, OCT) and leukocyte telomere length (LTL, was assessed by quantitative PCR). Positive dynamics of best corrected visual acuity (BCVA) was observed in 100 % of eyes. The central retinal thickness (CRT) decreased after the 3rd injection to 265 [234-306] µm, by the end of the observation period - to 211 [190-262] µm. The retention of activity of the subretinal neovascular membrane (SNM) at the end of the observation period correlated with lower values of the initial BCVA and high values of the initial CRT. An association of LTL with response to treatment was revealed: in patients with higher LTL the active form of SNM was more often switched to inactive after three injections, while with lower LTL, the activity of SNM was more often preserved, which determined the need for more intravitreal injections.

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

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.

Myopic choroidal neovascularization: management issues remain

In the modern world, myopia continues to be one of the most common refractive errors and is considered a socially signifi cant problem, since it is a common cause of decreased vision. In connection with the growth of myopia, the risk of developing complications in the fundus increases, leading to the development of degenerative changes in the retina and an irreversible decrease in visual functions in young and middle-aged people. One of these complications is myopic choroidal neovascularization, which leads to a progressive, irreversible decrease in visual acuity and poor prognosis, and the process is often bilateral in nature. The tactics of managing patients with such complications has been determined: antiangiogenic therapy is used – intravitreal therapy with anti-VEGF drugs, which is currently the fi rst choice therapy for this pathology. But in some cases, antiangiogenic therapy is contraindicated, and the question arises about the tactics of managing such patients. The aim: to study treatment options for myopic choroidal neovascularization in patients with myopia in different situations.Material and methods. The paper presents two clinical observations of patients with mChNV, considers the tactics of their management. The patients underwent standard ophthalmological examination, optical coherence tomography (OCT) and OCT-Angio (OPTOPOL Technology, Poland).Conclusions. Women with myopia planning pregnancy need a thorough examination not only by a clinician, but also by an ophthalmologist, since it is necessary to take into account not only the degree of myopia and choose the optimal delivery method, but also to study the state of the retina for the timely diagnosis of degenerative changes in the fundus.

Galectins as Emerging Glyco-Checkpoints and Therapeutic Targets in Glioblastoma

Despite recent advances in diagnosis and treatment, glioblastoma (GBM) represents the most common and aggressive brain tumor in the adult population, urging identification of new rational therapeutic targets. Galectins, a family of glycan-binding proteins, are highly expressed in the tumor microenvironment (TME) and delineate prognosis and clinical outcome in patients with GBM. These endogenous lectins play key roles in different hallmarks of cancer by modulating tumor cell proliferation, oncogenic signaling, migration, vascularization and immunity. Additionally, they have emerged as mediators of resistance to different anticancer treatments, including chemotherapy, radiotherapy, immunotherapy, and antiangiogenic therapy. Particularly in GBM, galectins control tumor cell transformation and proliferation, reprogram tumor cell migration and invasion, promote vascularization, modulate cell death pathways, and shape the tumor-immune landscape by targeting myeloid, natural killer (NK), and CD8+ T cell compartments. Here, we discuss the role of galectins, particularly galectin-1, -3, -8, and -9, as emerging glyco-checkpoints that control different mechanisms associated with GBM progression, and discuss possible therapeutic opportunities based on inhibition of galectin-driven circuits, either alone or in combination with other treatment modalities.

A Retrospective Analysis of the Effect of Anlotinib in Patients With Lung Cancer With or Without Previous Antiangiogenic Therapy

ObjectiveThe purpose of this study was to initially investigate the effect of previous antiangiogenic therapy (bevacizumab and endostatin) on the efficacy of anlotinib in patients with advanced or metastatic lung cancer (LC).MethodsWe retrospectively collected the clinical data of patients with LC treated with anlotinib and divided them into group A (treated with anlotinib after the failure of previous antiangiogenic drugs and group B (no prior use of antiangiogenic drugs). We used propensity score matching (PSM) for confounding factors between the groups. Progression-free survival (PFS) and overall survival (OS) were also recorded.ResultsA total of 160 patients were included in the analysis. The median OS in groups A and group B was 11.8 months and 16.1 months (P=0.120), whereas the median PFS was 3.1 months and 4.7 months (P=0.009), respectively. Moreover, the objective response rate (ORR) of the two groups was 9.6% and 10.4% (P=0.874), and the disease control rate (DCR) was 71.1% and 80.5% (P=0.165).After PSM (n=46), baseline characteristics were comparable between groups A and B. Furthermore, the median OS of the two groups was 14.6 months and 16.2 months (P=0.320), whereas the median PFS was 3.5 months and 4.5 months (P=0.040), respectively. Moreover, the ORR of the two groups were 13.0% and 10.9% (P=0.748), and the DCR were 78.3% and 82.6% (P=0.599), respectively.ConclusionsPrevious antiangiogenic treatments may affect the PFS of patients who receive anlotinib later, but it might not affect the patient’s ORR and OS.

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.

A New Antitumor Direction: Tumor-Specific Endothelial Cells

Targeting tumor blood vessels is an important strategy for tumor therapies. At present, antiangiogenic drugs are known to have significant clinical effects, but severe drug resistance and side effects also occur. Therefore, new specific targets for tumor and new treatment methods must be developed. Tumor-specific endothelial cells (TECs) are the main targets of antiangiogenic therapy. This review summarizes the differences between TECs and normal endothelial cells, assesses the heterogeneity of TECs, compares tumorigenesis and development between TECs and normal endothelial cells, and explains the interaction between TECs and the tumor microenvironment. A full and in-depth understanding of TECs may provide new insights for specific antitumor angiogenesis therapies.

Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.

Scintigraphic Imaging of Neovascularization With 99mTc-3PRGD2 for Evaluating Early Response to Endostar Involved Therapies on Pancreatic Cancer Xenografts In Vivo

BackgroundMolecular imaging targeting angiogenesis can specifically monitor the early therapeutic effect of antiangiogenesis therapy. We explore the predictive values of an integrin αvβ3-targeted tracer, 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2), for monitoring the efficacy of Endostar antiangiogenic therapy and chemotherapy in animal models.MethodsThe pancreatic cancer xenograft mice were randomly divided into four groups, with seven animals in each group and treated in different groups with 10 mg/kg/day of Endostar, 10 mg/kg/day of gemcitabine, 10 mg/kg/day of Endostar +10 mg/kg/day of gemcitabine at the same time, and the control group with 0.9% saline (0.1 ml/day). 99mTc-3PRGD2 scintigraphic imaging was carried out to monitor therapeutic effects. Microvessel density (MVD) was measured using immunohistochemical staining of the tumor tissues. The region of interest (ROI) of tumor (T) and contralateral corresponding site (NT) was delineated, and the ratio of radioactivity (T/NT) was calculated. Two-way repeated-measure analysis of variance (ANOVA) was used to assess differences between treatment groups.ResultsTumor growth was significantly lower in treatment groups than that in the control group (p < 0.05), and the differences were noted on day 28 posttreatment. The differences of 99mTc-3PRGD2 uptakes were observed between the control group and Endostar group (p = 0.033) and the combined treatment group (p < 0.01) on day 7 posttreatment and on day 14 posttreatment between the control group and gemcitabine group (p < 0.01). The accumulation of 99mTc-3PRGD2 was significantly correlated with MVD (r = 0.998, p = 0.002).ConclusionWith 99mTc-3PRGD2 scintigraphic imaging, the tumor response to antiangiogenic therapy, chemotherapy, and the combined treatment can be observed at an early stage of the treatments, much earlier than the tumor volume change. It provides new opportunities for developing individualized therapies and dose optimization.

Dual sEH/COX-2 Inhibition Using PTUPB—A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague–Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%–70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improved in vitro the viability of human mesangial cells. Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.