Vascular Endothelial Growth Factor Inhibitors Research Articles

Three-year outcome of photodynamic therapy combined with VEGF inhibitor for pachychoroid neovasculopathy.

Long-term results of photodynamic therapy (PDT) combined with vascular endothelial growth factor (VEGF) inhibitors for pachychoroid neovasculopathy (PNV) are not yet clear. This study is a retrospective, observational case series. We retrospectively examined untreated PNV cases (22 cases, 22 eyes, mean age of 71.0years) who underwent PDT therapy in combination with VEGF inhibitors followed by additional treatments with pro re nata protocol. Visual acuity, number of treatments, and time to recurrence were examined. In addition, foveal choroidal thickness and choroidal vascularity index (CVI) were evaluated in 13 of 22 patients who were followed up with SpectralisOCTR from baseline. Fifteen (68%) cases had polyps at baseline. LogMAR visual acuity averaged 0.24 ± 0.20 (range, - 0.079 to 0.82) at baseline and significantly improved after 1, 2, and 3years (p = 0. 004, 0.0003, 0.002, respectively). Fourteen patients (64%) recurred, with an average time to recurrence of 1.8 ± 0.9years. Foveal choroidal thickness decreased significantly after 1year (average from 326μm to 263μm) and remained unchanged up to 3years (255μm). CVI also decreased after 1year (average from 0.62 to 0.61) and remained unchanged until 3years later (0.60). We examined the 3-year course of PDT in combination with the VEGF inhibitor for untreated PNV. Visual acuity was improved, foveal choroidal thickness and CVI were decreased after 3years.

Beyond VEGF: Angiopoietin–Tie Signaling Pathway in Diabetic Retinopathy

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin–Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial

ObjectiveCytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of...

Alginate-Encapsulated Mesenchymal Stromal Cells Improve Hind Limb Ischemia in a Translational Swine Model.

Cellular therapies have been investigated to improve blood flow and prevent amputation in peripheral artery disease with limited efficacy in clinical trials. Alginate-encapsulated mesenchymal stromal cells (eMSCs) demonstrated improved retention and survival and promoted vascular generation in murine hind limb ischemia through their secretome, but large animal evaluation is necessary for human applicability. We sought to determine the efficacy of eMSCs for peripheral artery disease-induced limb ischemia through assessment in our durable swine hind limb ischemia model. Autologous bone marrow eMSCs or empty alginate capsules were intramuscularly injected 2 weeks post-hind limb ischemia establishment (N=4/group). Improvements were quantified for 4 weeks through walkway gait analysis, contrast angiography, blood pressures, fluorescent microsphere perfusion, and muscle morphology and histology. Capsules remained intact with mesenchymal stromal cells retained for 4 weeks. Adenosine-induced perfusion deficits and muscle atrophy in ischemic limbs were significantly improved by eMSCs versus empty capsules (mean±SD, 1.07±0.19 versus 0.41±0.16, P=0.002 for perfusion ratios and 2.79±0.12 versus 1.90±0.62 g/kg, P=0.029 for ischemic muscle mass). Force- and temporal-associated walkway parameters normalized (ratio, 0.63±0.35 at week 3 versus 1.02±0.19 preligation; P=0.17), and compensatory footfall patterning was diminished in eMSC-administered swine (12.58±8.46% versus 34.85±15.26%; P=0.043). Delivery of eMSCs was associated with trending benefits in collateralization, local neovascularization, and muscle fibrosis. Hypoxia-cultured porcine mesenchymal stromal cells secreted vascular endothelial growth factor and tissue inhibitor of metalloproteinase 2. This study demonstrates the promise of the mesenchymal stromal cell secretome at improving peripheral artery disease outcomes and the potential for this novel swine model to serve as a component of the preclinical pipeline for advanced therapies.

Efficacy and safety of atezolizumab and bevacizumab in appendiceal adenocarcinoma.

Appendiceal Adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors (ICIs) have not been previously explored. We conducted a prospective, single arm phase 2 study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. Patients treated with the Atezo+Bev combination had 100% disease control rate (1 PR, 15 SD) with progression free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, p = .041). In light of recent data demonstrating a lack of efficacy of 5-FU based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted.

QbD Enabled Development and Evaluation of Pazopanib Loaded Nanoliposomes for PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7nm and 182.0nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

Aqueous Extracts of Cannabis sativa: Cytotoxicity and Effects on Angiogenesis, Oxidative Stress and Nitric Oxide Production

AbstractCannabis sativa has been used in local medicine to manage cancer, ache, inflammation, diabetes, and other conditions. The aqueous extract of Cannabis sativa leaves collected from two geographical locations (South Africa, EC and Lesotho, LS) was assessed for their potential against angiogenesis, nitric oxide (NO) production, oxidative stress and cytotoxicity. The EC extract showed better angiogenesis and vascular endothelial growth factor suppression than the LS extract at 20 and 100 µg/mL. EC and LS displayed their highest NO inhibitory effects (91 and 76%) at the most negligible 1.6 µg/mL concentration. The glutathione and Catalase levels increased significantly in the MCF-7 cells following administration with EC and LS. In contrast, a decrease in the malondialdehyde (MDA) level in the cells' supernatant was found compared to the untreated cells. High-performance liquid chromatography analysis reveals the presence of cannabidiol (CBD) and tetrahydrocannabinoilic acid (THCA), with EC and LS having a considerable number of similar peaks. The extracts were relatively non-cytotoxic within the concentration range evaluated (0.78125 -100–µg/mL), though selective effects on cell survival at some concentrations were observed. The study provides information to support the extensive folkloric use of the aqueous extract of C. sativa in cancer and other associated ailments, as well as diseases linked to oxidative stress. Studies on the aqueous extract using animal models or other relevant in vivo models are recommended.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial

Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2mg and 0.1mg doses) with laser therapy in very low birthweight infants (<1500g) with ROP. Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms-66.8 (62.9-70.7) following ranibizumab 0.2mg, 64.6 (60.6-68.5) following ranibizumab 0.1mg and 62.1 (57.8-66.4) following laser therapy; differences in means: ranibizumab 0.2mg v laser: 4.7 (95% CI:-1.1, 10.5); 0.1mg v laser: 2.5 (-3.4, 8.3); 0.2mg v 0.1mg: 2.2 (-3.3, 7.8). High myopia (worse than-5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2mg, 8/55 (15%) following ranibizumab 0.1mg and 11/45 (24%) following laser therapy (0.2mg versus laser: odds ratio: 3.99 (1.16-13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. 5-year outcomes confirm the findings of the original RAINBOW trial and a planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected. Novartis Pharma AG.

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma.

ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly. Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia. ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.

Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors

BackgroundStudies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a...

Evaluating the docetaxel effect in an animal model of polyarthritis.

To evaluate the anti-inflammatory effects of DTX in RA and the effect of methotrexate on PAD4 to investigate its potential as an RA biomarker. Forty male Wistar rats were divided into five groups of eight rats. Healthy rats formed the control group. The Second Group to Fifth group were induced with Complete Freund's adjuvant. The third group received DTX at a dosage of 1mg/kg on alternate days, as determined by a preliminary experiment. The fourth group was given 1mg/kg/week of methotrexate intraperitoneally. The fifth group was treated with a half dose of DTX and methotrexate simultaneously. Significant Arthritis index and knee joint circumference decrease in the DTX group. No significant difference in body weight, platelet-lymphocyte ratio, and white blood cell count between the groups. Neutrophile lymphocyte ratio showed weak correlation with ACPA, while PAD4 showed good correlation with RA markers. Level of ACPA, PAD4, TNF-α, IL-1β, and VEGF significantly decreased in the DTX group than induction group (p < 0.05). DTX reduces the progression and joint destruction in rats induced by Complete Freund's Adjuvant which may due to inhibition of PAD4, TNF-α, IL-1β, VEGF, and ACPA. Also, methotrexate exhibited anti PAD4 effect.

Abstract CT275: A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC)

Abstract Background: Chemotherapy in combination with bevacizumab (Bev) has been a standard first-line treatment for RAS-mutated mCRC patients for the last 2 decades. The prognosis of these patients remains poor. Onvansertib is an orally available, highly potent, and selective inhibitor of Polo-like kinase 1 (PLK1), currently in clinical development. In a Phase 1b/2 study, onvansertib in combination with FOLFIRI + Bev demonstrated safety and promising efficacy in the second-line treatment of KRAS-mutated mCRC patients (NCT03829410). A subgroup analysis showed that patients not exposed to Bev (Bev-naïve) in the first-line setting had superior clinical benefit compared to Bev-exposed patients. Based on this data, we propose to investigate the combination of onvansertib with SoC (chemo + Bev) in the first-line treatment of RAS-mutated, Bev-naïve mCRC patients. Methods: This exploratory Phase 2, open-label, randomized study is designed to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of 2 doses of onvansertib (20 mg and 30 mg) in combination with SoC (FOLFIRI + Bev or FOLFOX + Bev) versus SoC alone in patients with RAS-mutated metastatic and unresectable CRC in the first-line setting. Eligible participants must have histologically confirmed mCRC, KRAS or NRAS mutation, no previous systemic therapy in the metastatic setting, ECOG performance status of 0 or 1, measurable disease as defined per RECIST v1.1. Exclusion criteria include patients with BRAF-V600 mutations or microsatellite instability high/deficient mismatch repair, prior treatment with a VEGF inhibitor, previous oxaliplatin treatment within 12 months prior to randomization. The primary endpoint is objective response as determined according to RECIST v1.1 by an independent central review. Key secondary endpoints include progression-free survival and duration of response per independent central review. The study will enroll approximately 90 patients. Each patient will be randomized to be treated with onvansertib (20 mg or 30 mg) + SoC or SoC alone. The enrollment period for this study is approximately 12 months. Patients will be followed for overall survival for up to 1 year after the end of treatment. Trial is open and recruiting as of November 2023. This trial is registered as NCT06106308. Citation Format: Heinz-Josef Lenz, Benjamin Kuritzky, Anu Thummala, Stephan Kendall, Ravindranath Patel, Sreenivasa R. Chandana, Alisha H. Bent, Nancy Sherman, Ramanand Arun Subramanian, Fairooz Kabbinavar, Joel Randolph Hecht. A phase 2, randomized, open-label study of onvansertib in combination with standard-of-care (SoC) versus SoC alone for first-line treatment of RAS-mutant metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT275.

Three-Year Outcomes of VEGF Inhibitors in Naïve Branch Retinal Vein Occlusion: Fight Retinal Blindness!

To evaluate the 3-year outcomes of vascular endothelial growth factor (VEGF) inhibitors in the treatment of cystoid macular oedema (CME) due to branch retinal vein occlusion (BRVO) in an international multicenter cohort of eyes. Multicenter, international, BRVO database study. Seven hundred forty-seven patients (760 eyes) undergoing intravitreal therapy for BRVO for 3 years in a multicenter international setting. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters, central subfield thickness (CST), treatments, number of injections and visits data was collected using a validated web-based tool. Visual acuity (VA) gain at 3 years in LogMAR letters. Secondary outcome measures included anatomical results, treatment pattern and percentage of completers. A subgroup analysis by study drug was conducted for clinical outcomes. Mean adjusted VA change was +11 letters (95% CI 9,13), mean adjusted change in CST was -176μm (-193, -159). Median number of injections/visits was 16/24 at 3 years of follow-up. Most eyes received VEGF inhibitors exclusively (89%, n=677) and as a monotherapy in 71% (n=538). Few eyes were switched to steroids (11%, n=83). Suspensions in treatment >180 days occurred in 26% of study eyes. Aflibercept showed greater CST reductions (-147 vs -128 vs -114μm; p< 0.001) and significantly lower switching rates (14% vs 38% vs 33%, p< 0.001) compared with ranibizumab and bevacizumab, respectively. This international study of 3-year BRVO outcomes after starting treatment with VEGF inhibitors found adequate visual and anatomical results in routine clinical care. Visual outcomes were similar amongst the different initiating VEGF inhibitors, although eyes starting with aflibercept had better anatomical outcomes and a lower switching rate.

One-Year Anti-VEGF Therapy Outcomes in Diabetic Macular Edema Based on Treatment Intensity: Data from the Fight Retinal Blindness! Registry

PurposeTo compare one-year outcomes of eyes with diabetic macular edema (DME) treated in routine clinical practice based on the proportion of visits where intravitreal vascular endothelial growth factor (VEGF) inhibitor injections were delivered. DesignCohort study ParticipantsThere were 2288 treatment-naïve eyes with DME starting intravitreal VEGF inhibitor therapy from 31 October 2015 to 31 October 2021 from the Fight Retinal Blindness! international outcomes registry. MethodsEyes were grouped according to the proportion of visits at which an injection was received, Group A with less than the median of 67% (n=1172) versus Group B with greater than the median (n=1116). Main Outcome MeasureMean visual acuity (VA) change after 12 months of treatment. ResultsThe mean (95% confidence interval [CI]) VA change after 12 months of treatment was 3.6 (2.8, 4.4) letters for eyes in Group A versus 5.2 (4.4, 5.9) letters for eyes in Group B (p=0.005). The mean (95% CI) central subfield thickness (CST) change was -69 (-76, -61) μm and -85 (-92, -78) μm for eyes in Group A versus Group B, respectively (p=0.002). A moderate positive correlation was observed between the number of injections received over 12 months of treatment and the change in VA (p<0.001). Additionally, eyes that received more injections had a moderately greater CST reduction. ConclusionsThis registry analysis found that overall VA and anatomic outcomes tended to be better in DME eyes treated at a greater proportion of visits in the first year of intravitreal VEGF inhibitor therapy.

Rediscovering AMD with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture

Swept-source optical coherence tomography angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross-sectional and en face imaging strategies. Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30, 2022 PARTICIPANTS: Patients with AMD METHODS: Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. SS-OCTA imaging of AMD at different stages of disease progression. Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid. Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD.

501 Systemic Immunological Suppression in Glioblastoma Is Targeted by Concurrent VEGF and PD-1 Inhibition in a Dose-Dependent Manner: Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) From a Randomized Controlled Trial

INTRODUCTION: Anti-PD1 blockade has had poor efficacy in recurrent glioblastoma (rGBM) across three RCTs. VEGF, a proangiogenic factor that is upregulated in rGBM, contributes to tumor-associated immunosuppression and is widely targeted through bevacizumab. Preclinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD-1 and anti-VEGF agents is a promising approach for rGBM, for which an RCT was conducted. METHODS: Patients with rGBM were administered nivolumab (240mg IV q2weeks) plus either standard dose bevacizumab (10mg/kg) or low dose bevacizumab (3mg/kg) IV q2weeks, with 1:1 randomization. Stratification factors were age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months. CITE-Seq was performed on 16 patients across trial arms, both pre- and on-therapy, yielding total 32 immunological profiles. For control, CITE-seq was done on three patients receiving anti-VEGF therapy alone. RESULTS: 90 patients were enrolled with median age of 60.6 years and 45 patients per arm. Both arms had similar OS at 12 months (P = 0.14). Significantly higher OS was found in posthoc analysis for patients aged = 60 years with standard dose. Distinct immune cell populations were identified and differential changes in myeloid-derived suppressor cells (MDSCs) found across trial arms on-therapy. Network medicine approach identified VEGF as target to reduce MDSCs, with VEGF primarily expressed by responders’ MDSCs. Differential gene expression analysis identified increased pro-inflammatory signatures in standard dose arm. CONCLUSIONS: Standard dose bevacizumab was associated with increased inflammatory response and reduction of immunosuppressive MDSC. These mechanistic insights potentially explain survival benefit seen with concurrent VEGF and PD-1 inhibition in elderly rGBM patients.

Suppression of inflammation in ulcerative colitis rats by avocado and pomegranate

BackgroundPomegranate seed oil (PSO) and avocado seed oil (ASO) are natural polyphenols with established anti-inflammatory activity. PurposeThis study aimed to investigate the molecular mechanisms underlying the therapeutic efficacy of PSO and ASO in experimental ulcerative colitis (UC) with reference to sulfasalazine (SLZ). MethodsEighty male albino rats were divided equally into 8 groups; Normal, PSO, ASO, SLZ, UC-control, (UC+PSO), (UC+ASO) and (UC+SLZ) groups. Colitis was induced by intra-rectal injection of acetic acid. PSO (0.5ml/ 200g), ASO (1ml/ 250g) and SLZ (100mg/kg) were administered orally once/day for 14 days, 24h after colitis induction. Colitis was evaluated by measuring disease activity index (DAI), colon weight/length ratio and histologic inflammatory score. Vascular endothelial growth factor receptor-2 (VEGFR-2), colonic macrophage migration inhibitory factor (MIF), and malondialdehyde (MDA) were determined. Colonic gene expression of TNF-α, VEGF and heme oxygenase-1 (HO-1) were also estimated. ResultsPSO and ASO treatments to UC rats significantly reduced DAI, weight/length ratio, VEGFR-2, and colon histologic inflammatory score versus UC-controls. ASO significantly suppressed MIF levels and TNF-α expression greater than PSO. However, PSO was more significant than ASO in reducing MDA levels and up-regulating HO-1 expression. Both oils significantly down-regulated VEGF expression. The obtained biochemical and histological changes induced by UC were nearly corrected by SLZ. ConclusionThe proved beneficial effect of PSO and ASO as anti-inflammatory, anti-angiogenic, and antioxidant in UC rats could be mediated by suppression of TNF-α, VEGF, and MIF and up-regulation of HO-1.

A Network Meta-analysis of the Efficacy of Drug Therapy in First-line Treatment of Advanced Hepatocellular Carcinoma.

Systemic therapy is mainly recommended for advanced hepatocellular carcinoma (HCC). Considering the variety of treatments available for HCC, there is a need to understand their relative benefits and risks, especially for the newly approved combination of immune checkpoint inhibitors and vascular endothelial growth factor inhibitors represented by atezolizumab in combination with bevacizumab. A reticulated meta-analysis was used to evaluate the efficacy and safety of atezolizumab-bevacizumab combination therapy compared with other first-line systemic therapies for the treatment of patients advanced HCC. PubMed, The Cochrane Library, Web of Science, and Embase databases were searched from the time of library construction to 01 December 2022, and the data were extracted and analyzed using Stata16.0 for Meta-analysis. The data were extracted separately, and a meta-analysis was performed using the software Stata16.0. 16 clinical studies with 8,779 subjects were identified from 13,417 records and were used to build the evidence network for all trials. TThe combination therapy of atezolizumab and bevacizumab has the advantage of prolonging the OS of patients when treating advanced HCC [HR=5.71, 95%CI (4.30, 7.12), p<0.05] Also, the combination therapy has the advantage of prolonging the patient's progression free survival [HR=1.60, 95%CI (0.89, 2.49), p<0.05]. Atezolizumab-bevacizumab combination therapy can improve clinical outcomes such as OS and PFS in patients with advanced HCC.

Acute aortic catastrophe caused by cardiovascular oncological manipulation by tyrosine kinase inhibitors with immune checkpoint blockades: a case report and literature review

Abstract Background Tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) inhibitor pathway with immune checkpoint blockade have shown promising outcomes in managing metastatic renal cancer. However, they increase the risk of a person developing high blood pressure and cardiovascular complications. Case summary In this study, we report the case of a 73-year-old woman on axitinib and pembrolizumab for her Stage 4 renal cell carcinoma. She presented with intractable chest pain and high systolic blood pressure, not responding to opiates. Her computed tomography angiography results showed an acute intra-mural haematoma with a rupture in the descending thoracic aorta. She underwent emergency thoracic endovascular aortic repair. Post-operatively, she recovered fully without any neurological or cardiovascular issues. Discussion The severity of cardiovascular haemodynamic complications arising from the consumption of VEGF inhibitors and from immunotherapy and the lack of anti-hypertensive strategies to adequately manage such events require an unequivocal and urgent assessment of their cardiovascular safety. This case highlights the crucial role of cardiovascular oncology in managing such acute aortic catastrophes.

Клинико-лабораторные факторы риска рецидива (реактивации) ретинопатии недоношенных после интравитреального введения афлиберцепта

Purpose. To study the causes of reactivation of retinopathy of prematurity (ROP) after intravitreal aflibercept injections. Material and methods. This study was carried out at V.F. Voino-Yasenetsky Scientific and Practical Center for Specialized Medical Care in Children from September 2021 to February 2023. The study included 101 premature infants (202 eyes) with retinopathy of prematurity who received intravitreal administration of aflibercept. The patients were divided into two groups: the control group included patients who received a single intravitreal injection of a VEGF inhibitor (aflibercept) with a positive effect. The main group included children who received two or more intravitreal injections of VEGF inhibitors (aflibercept) after reactivation of ROP. All patients were monitored for reactivation of retinopathy of prematurity after intravitreal injection of aflibercept. Results. The study noted a statistically significant difference in blood pH levels, stage of ROP, and APROP. In the group with reactivation ROP, APROP was noted 2 times more often (48.94% versus 27.78% in the control group). The group with more intravitreal aflibercept injections had lower blood pH levels (7.348±0.044 versus 7.372±0.030 in the control group). Conclusion. The study showed that clinical and paraclinical risk factors for the development of recurrent (reactivation) of ROP after intravitreal treatment with aflibercept are: severe eye disease (stage of ROP, aggressive posterior ROP), a change in the acid-base balance of the blood towards increased acidity. Blood acidity reflects a generalized process of impaired angiogenesis throughout the body. The more severe the patient’s initial eye condition, the higher the incidence of reactivation of ROP. Key words: recurrence, reactivation, retinopathy of prematurity, risk factor, clinical and paraclinical, aflibercept