Antiangiogenic Therapy In Patients Research Articles

Pathological evaluation of tumor immune microenvironment before first-line anti-PD1 plus anti-angiogenic therapy in patients with unresectable hepatocellular carcinoma (HCC): Towards a prediction for treatment efficacy.

e14662 Background: Immune checkpoint inhibitor (ICI) combined with anti-angiogenic therapy is the standard first-line treatment for unresectable HCC patients. However, most patients do not derive durable benefit and will progress faster. Simultaneously, sufficient clinically validated biomarkers to stratify patients are lacking in HCC. Recent studies have shed a light on the strong connection between immunotherapy efficacy and tumor immune microenvironment (TIME) in HCC. Thus, this study aims to investigate TIME features before treatment to develop a potential way for survival prediction which may optimize risk stratification. Methods: A total of 84 unresectable HCC patients who received first-line ICI plus anti-angiogenic therapy at Nanjing Drum Tower Hospital were included. 4 multiplex immunohistochemistry (mIHC) panels containing 18 biomarkers were developed to thoroughly evaluate immune cells in TIME before therapy, such as cytotoxic T cells, tissue-resident memory T cells, macrophages and neutrophils. TIME features were then extracted from raw image by digital pathology, including cell subpopulation abundance and spatial profiling. We identified a list of TIME features associated with objective response rate (ORR), progression free survival (PFS) and overall survival (OS), and developed a TIME-based risk score (TIS) in our cohort using machine-learning. Results: After data cleaning, a total of 78 patients with complete clinical information and TIME features were included and split into training and validation sets. A higher positive rate of CD103+ cells and CD8+ cells were observed in responder, while patients with higher CD66b+ positive rate showed shorter PFS and OS. In terms of spatial profiling, tumor cells accompanied with more CD8+ cells were associated with longer PFS and OS, while longer distance from CD14+ cells and CD66b+ cells to tumor cells favored longer PFS and OS. Regarding PFS prediction, our machine-learning model TIS included both immune cell abundance and spatial features. Stratifying patients in the low- and high-risk groups using TIS revealed prolonged PFS (p<0.0001, HR: 0.24, 95%CI [0.13-0.45]) and OS (p = 0.00057, HR: 0.27, 95%CI [0.12-0.60]) in TIS low-risk group. Moreover, ORR in TIS low-risk group was 52.9% (17/34) and 15.9% (7/44) in TIS high-risk group. Univariable and multivariable analysis demonstrated that TIS was an independent predictor for ORR (p = 0.0017), PFS (p = 0.00065) and OS (p = 0.00042). Independent validation is still awaited. Conclusions: This study demonstrates that our machine-learning based risk score can improve treatment response and survival prediction using TIME features, which provides the potential to optimize risk stratification before first-line treatment for unresectable HCC patients.

Real world effectiveness of immunotherapy combined with anti-angiogenic therapy in patients with anthracycline-resistant soft tissue sarcomas.

e23543 Background: Soft tissue sarcomas are a heterogeneous group of malignant tumors of mesenchymal origin with more than 50 histologic subtypes. They have distinct molecular, genetic and clinical features and account for 1% of adult malignancies, the most common being liposarcoma, undifferentiated pleomorphic sarcoma and leiomyosarcoma. Immune checkpoint inhibitors (ICIs) have limited efficacy in sarcomas compared to other solid tumors; however, they have shown some activity in certain subtypes. The use of immunotherapy in sarcoma faces many challenges due to tumor heterogeneity, scarcity of therapeutic antibodies and chimeric antigen receptors to target antigens in sarcoma subtypes. However, combining ICIs with other therapies seems to improve the therapeutic efficacy to some extent. Antiangiogenic targeted therapy has been recommended by major guidelines as the treatment of choice for second-line soft tissue sarcomas. However, there are limited results from large clinical studies on whether immunotherapy combined with antiangiogenic therapy improves the efficacy. Methods: In this real-world single-center retrospective cohort study conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, the efficacy of immunotherapy combined with antivascular therapy was assessed by progression-free survival (PFS) and overall survival (OS). Safety was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Results: In this study, we enrolled a total of 21 eligible patients, of which 6 were liposarcoma, 4 were leiomyosarcoma, 4 were rhabdomyosarcoma, and 7 were other types. The immunotherapy used in all patients was anti-PD-1 antibody, with bevacizumab as the antivascular therapy drug in four of them and antiangiogenic tyrosine kinase inhibitors in the others. 12(57%) patients had received one-line therapy, 9 (43%) had received ≥ second-line therapy. Median progression-free survival (mPFS) was 5.5 months and median overall survival (mOS) 16.1 months in the total population. mPFS was significantly longer in 2nd-line V.S. ≥3rd-line patients (9.6 months V.S. 3.1 months, P = 0.0007), with a tendency to be prolonged mOS in 2nd-line treatment (16.1 months V.S. 9.3 months), but with no statistically significant difference. The most common grade ≥3 adverse events were hypertension, hand-foot syndrome, and abnormal thyroid function. Conclusions: This study confirms that immunotherapy combined with antiangiogenic therapy is effective and tolerable in anthracycline-resistant soft tissue sarcomas in the real world.It is possible that use in the second line may lead to better efficacy than use in multiple lines, and more clinical studies are expected.

Efficacy of PD-1 Inhibitors Combined with Anti-Angiogenic Therapy in Driver Gene Mutation Negative Non-Small-Cell Lung Cancer with Brain Metastases.

Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs). A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs. 11.8 months; p = 0.004), with no significant difference in iPFS (p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (p = 0.005) but not the iORR (p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (p = 0.003) was an independent prognostic indicator of OS. Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.

Варианты антиангиогенной терапия субретинальных кровоизлияний на фоне возрастной макулодистрофии

Purpose. To evaluate the effectiveness of various options for anti-angiogenic therapy in patients with subretinal hemorrhage (SRH) by of age-related macular degeneration (AMD). Material and methods. A total of 15 patients (15 eyes) with SRH by of AMD were treated. The mean duration of a hemorrhage from its onset to the start of treatment was 18.8 ± 10.0 days. The size of the SRH varied from 0.5 to 5 DD. The best corrected visual acuity (BCVA) before treatment varied from hand movement near the face to 0.1. Patients underwent the following treatment options for SRH: 1) anti-VEGF intravitreal injection (IVI) – 8 (53.3%); 2) IVI anti-VEGF + IVI prourokinase + IVI ophthalmic gas (SF6, C2F6) – 7 (46.7%). The average follow-up period for patients after treatment was 10.8 ± 6.3 months. Results and discussion. With the maximum follow-up period after the treatment in 2nd group it was possible to achieve hemorrhage displacement: partial – in 2 (58%) patients, complete – in 5 (71.5%) patients. At the maximum follow-up period, an improvement in BCVA in comparison with the preoperative one was observed in 8 (53.3%) cases, no dynamics – in 4 (26.7%) cases, and negative dynamics – in 3 (20%) cases. All patients underwent anti-VEGF therapy after the start of SRH treatment. Conclusions. The data obtained indicate that the use of antiangiogenic therapy of SRH by of AMD has positive results in improving BCVA and reducing the volume of hemorrhage. The choice of treatment method is determined by the size and duration of the existence of the SRH. It is necessary to continue anti-VEGF therapy in all patients after the start of treatment with SRH by of AMD. Keywords: submacular hemorrhage, age-related macular degeneration, pneumodislocation, anti-VEGF inhibitors, tissue plasminogen activator

Protein disulfide-isomerase A4 confers glioblastoma angiogenesis promotion capacity and resistance to anti-angiogenic therapy

IntroductionIncreasing evidence has revealed the key activity of protein disulfide isomerase A4 (PDIA4) in the endoplasmic reticulum stress (ERS) response. However, the role of PDIA4 in regulating glioblastoma (GBM)-specific pro-angiogenesis is still unknown.MethodsThe expression and prognostic role of PDIA4 were analyzed using a bioinformatics approach and were validated in 32 clinical samples and follow-up data. RNA-sequencing was used to search for PDIA4-associated biological processes in GBM cells, and proteomic mass spectrum (MS) analysis was used to screen for potential PDIA4 substrates. Western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assays (ELISA) were used to measure the levels of the involved factors. Cell migration and tube formation assays determined the pro-angiogenesis activity of PDIA4 in vitro. An intracranial U87 xenograft GBM animal model was constructed to evaluate the pro-angiogenesis role of PDIA4 in vivo.ResultsAberrant overexpression of PDIA4 was associated with a poor prognosis in patients with GBM, although PDIA4 could also functionally regulate intrinsic GBM secretion of vascular endothelial growth factor-A (VEGF-A) through its active domains of Cys-X-X-Cys (CXXC) oxidoreductase. Functionally, PDIA4 exhibits pro-angiogenesis activity both in vitro and in vivo, and can be upregulated by ERS through transcriptional regulation of X-box binding protein 1 (XBP1). The XBP1/PDIA4/VEGFA axis partially supports the mechanism underlying GBM cell survival under ER stress. Further, GBM cells with higher expression of PDIA4 showed resistance to antiangiogenic therapy in vivo.ConclusionsOur findings revealed the pro-angiogenesis role of PDIA4 in GBM progression and its potential impact on GBM survival under a harsh microenvironment. Targeting PDIA4 might help to improve the efficacy of antiangiogenic therapy in patients with GBM.

L1CAM promotes vasculogenic mimicry formation by miR-143-3p-induced expression of hexokinase 2 in glioma.

In recent decades, antiangiogenic therapy, which blocks the supply of oxygen and nutrition to tumor cells, has become a promising clinical strategy for the treatment of patients with tumors. However, recent studies revealed that vasculogenic mimicry (VM), which is the process by which vascular morphological structures are formed by highly invasive tumor cells, has been considered a potential factor for the failure of antiangiogenic therapy in patients with tumors. Thus, inhibition of VM formation might be a potential target for improving the outcome of antiangiogenic strategies. However, the mechanism underlying VM formation is still incompletely elucidated. Herein, we report that L1CAM might be a critical regulator of VM formation in glioma, and might be associated with the resistance of glioma to antiangiogenic therapy. We found that the tumor-invasion and tube-formation capabilities of L1CAM-overexpressing cells were significantly enhanced invitro and invivo. In addition, the results indicated that miR-143-3p, which might directly target the 3'UTR of the hexokinase 2 (HK2) gene to regulate its protein expression, was subsequently involved in L1CAM-mediated VM formation by glioma cells. Further study revealed that the regulation of MMP2, MMP9, and VEGFA expression was involved in this process. Moreover, we identified that activation of the downstream PI3K/AKT signaling pathway of the L1CAM/HK2 cascade is critical for VM formation by glioma cells. Furthermore, we found that the combined treatment of anti-L1CAM neutralizing monoclonal antibody and bevacizumab increases efficacy beyond that of bevacizumab alone, and suppresses glioma growth invivo, indicating that the inhibition of L1CAM-mediated VM formation might efficiently improve the effect of antiangiogenic treatment for glioma patients. Together, our findings demonstrated a critical role of L1CAM in regulating VM formation in glioma, and that L1CAM might be a potential target for ameliorating tumor resistance to antiangiogenic therapy in glioma patients.

Albuminuria as a biomarker of severity in diabetic retinopathy and in the response to intravitreal treatment in diabetic macular edema.

Diabetic macular edema (DME) presents a suboptimal response to antiangiogenic treatment in approximately 30% of patients. We analyzed the relationship between renal function and response to antiangiogenic therapy in patients with DME. A total of 367 patients were collected and distributed into three main groups: uncomplicated diabetic retinopathy (DR) group (n = 97), proliferative diabetic retinopathy (PDR) group (n = 94) and DME group (n = 175). Likewise, patients with DME were divided into two groups: responders to antiangiogenic drugs (n = 96) and non-responders to antiangiogenic drugs (n = 79). Age, type of diabetes, arterial hypertension (AHT), creatinine, HbA1c, albuminuria and glomerular filtration rate were analyzed. In the statistical analysis, chi-square test and t student were used to compare each group. The relationship between albuminuria and response to treatment in the DME group was studied with a binary logistic regression model, estimating odds ratio and their confidence intervals. There are differences between the three main groups in terms of the presence or not of albuminuria. The presence of albuminuria is greater in the group of patients with more severe DR (PDR and DME), compared to the uncomplicated DR group (p < 0.009). In the logistic regression analysis model, a positive relationship was found and the odds ratio for the albuminuria variable and is 2.78 (CI: 1.42-5.36). The presence of albuminuria is associated with a higher degree of DR and worse response to antiangiogenic therapy in patients with DME in our series. Multidisciplinary teams would be necessary to reduce albuminuria and thus optimize the treatment of patients with DME.

Efficacy and safety of immune checkpoint inhibitors combined anti-angiogenic therapy in patients with unresectable hepatocellular carcinoma: A meta-analysis.

This study aimed to compare the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents in patients with unresectable hepatocellular carcinoma (HCC). We conducted a systematic literature search of articles published between the establishment of the database and February 2022. Data were extracted and analyzed using STATA 14.0. Six randomized controlled trials (RCTs) (980 patients for combination therapy and 565 patients for monotherapy) and 5 single-arm studies (246 patients for ICIs combination therapy) were enrolled. The objective response rate (ORR) and disease control rate (DCR) were 26% and 70%, respectively, after ICIs combination therapy. Compared with monotherapy in RCTs, ICIs combination therapy resulted in higher progression-free survival (PFS) and overall survival (OS), but also increased the incidence of adverse events (AEs). Increased incidences of fatigue, hypertension, hyperbilirubinemia, proteinuria, and nausea were more common after ICIs combination therapy. The analysis results reveal that ICI-combined anti-angiogenesis therapy has higher efficacy than either ICIs or anti-angiogenesis options for unresectable HCC, but it is necessary to manage the AEs.

Leukocyte Telomere Length and Response to Antiangiogenic Therapy in Patients with Neovascular Age-Related Macular Degeneration

Leukocyte Telomere Length and Response to Antiangiogenic Therapy in Patients with Neovascular Age-Related Macular Degeneration

The Role of Retinal Plasticity in the Formation of Irreversible Retinal Deformations in Age-Related Macular Degeneration

Purpose To construct a realistic physical model of viscoelastic retinal stretching and, on its basis, derive a universal quantitative criterion of irreversible retinal deformations during age-related macular degeneration. Methods In this work, standard methods of nonlinear fracture mechanics of ductile and viscoelastic materials were applied to study the evolution of retinal deformation progress in patients with neovascular age-related macular degeneration in the area of large druses or subretinal or sub-retinal pigment epithelium fluid accumulation. A two-dimensional rhombic model of viscoelastic Kelvin-Feucht primitives was used to reconstruct the parameters included in the approximation of the creep strain growth rate. A clinical case of a patient with age-related macular degeneration and retinal pigment epithelium detachment in the macula was taken as a basis for theoretical research. The patient underwent retinal optical coherent tomography on DRI Swept-Source OCT. Results A closed realistic theoretical model of retinal stretching in the projection of retinal pigment epithelium elevation due to its detachment or drusen based on a two-dimensional rhombic Kelvin-Feucht primitives model was constructed. The calculation of stress in the retinal tissue with consistent consideration of creep effects was performed. Conclusions The time of critical retinal loading – a new quantitative criterion for the irreversibility of retinal stretching in age-related macular degeneration is proposed. This criterion allows the prediction of the functional outcome of antiangiogenic therapy in patients with age-related macular degeneration with identical initial retinal morphometric parameters.

Resistance to anti-angiogenic therapy in patients with neovascular age-related macular degeneration

Resistance to anti-angiogenic therapy in patients with neovascular age-related macular degeneration

Endometrial blood vessel morphometry in patients presenting with abnormal uterine bleeding.

: Abnormal uterine bleeding (AUB) is one of the most common problems encountered in gynecological practice. Various benign and malignant disorders of the endometrial tissue show vascular changes such as congestion, dilatation, and vessel wall irregularities. To evaluate the vascular morphometry of the endometrial tissue in AUB. : A descriptive cross-sectional study of the endometrial tissue in patients presented with AUB was undertaken for vascular morphometric analysis. Histopathological processing of the endometrial tissue samples was done as per the standard format, and the slides were evaluated for vascular morphometry. Out of 150 cases of endometrial tissue in patients presented with AUB, 80 cases were reported as proliferative phase, 41 as secretory phase, 15 as disordered proliferative endometrium, 6 as atrophic phase endometrium, and 4 each of endometrial hyperplasia without atypia and endometrial carcinoma. An average number of endometrial blood vessels and large-sized blood vessels were more in endometrial carcinoma and endometrial hyperplasia without atypia as compared to proliferative phase, secretory phase, atrophic endometrium, and disordered proliferative endometrium. Vessel shape irregularities and vascular congestion were observed in all the cases of atrophic endometrium, endometrial carcinoma, and endometrial hyperplasia without atypia. Endometrial carcinoma showed severe dilatation of the endometrial blood vessels. Vascular morphometry changes were noted in endometrial hyperplasia, endometrial carcinoma, disordered proliferative endometrium, and atrophic phase endometrium. These findings suggest that studies or trials related to anti-angiogenic therapy may help to plan anti-angiogenic therapy in patients with AUB.

CircMAN1A2 promotes vasculogenic mimicry of nasopharyngeal carcinoma cells through upregulating ERBB2 via sponging miR-940.

Nasopharyngeal carcinoma (NPC) is the most prevalent human primary malignancy of the head and neck, and the presence of vasculogenic mimicry (VM) renders anti-angiogenic therapy ineffective and poorly prognostic. However, the underlying mechanisms are unclear. In the present study, we used miR-940 silencing and overexpression for in vitro NPC cell EdU staining, wound healing assay and 3D cell culture assay, and in vivo xenograft mouse model and VM formation to assess miR-940 function. We found that ectopic miR-940 expression reduced NPC cell proliferation, migration and VM, as well as tumorigenesis in vivo. By bioinformatic analysis, circMAN1A2 was identified as a circRNA that binds to miR-940. Mechanistically, we confirmed that circMAN1A2 acts as a sponge for miR-940, impairs the inhibitory effect of miR-940 on target ERBB2, and then activates the PI3K/AKT/mTOR signaling pathway using RNA-FISH, dual luciferase reporter gene and rescue analysis assays. In addition, upregulation of ERBB2 expression is associated with clinical staging and poor prognosis of NPC. Taken together, the present findings suggest that circMAN1A2 promotes VM formation and progression of NPC through miR-940/ERBB2 axis and further activates the PI3K/AKT/mTOR pathway. Therefore, circMAN1A2 may become a biomarker and therapeutic target for anti-angiogenic therapy in patients with nasopharyngeal carcinoma.

Safety Profile of Immunotherapy Combined With Antiangiogenic Therapy in Patients With Melanoma: Analysis of Three Clinical Studies.

Objective: To describe the frequency and spectrum of treatment-related adverse events (TRAEs) of immunotherapy combined with antiangiogenic therapy in patients with melanoma. Methods: This retrospective cohort study included three clinical trials on patients with stage III/IV melanoma treated with anti–PD 1 and antiangiogenic therapy. Results: We analyzed data from 72 patients with a median follow-up time of 25.9 months (95% CI, 9.1–42.7 m). The median treatment duration was 7.5 months (range, 0.7–42.8 m), and the median of treatment cycles was 11.0 (range, 1–90). Most patients (70 of 72 or 97.2%) experienced TRAEs (mostly grades 1 or 2). No drug-related deaths were reported. Most TRAEs were hepatic (75%), endocrine (72.2%), skin (65.3%), and gastrointestinal tract (59.7%) manifestations, followed by myelosuppression (55.6%), renal dysfunction (55.6%), and dyslipidaemia (54.2%). The adverse event (AE) spectra were similar between regimens. Using multivariate Cox proportional risk models showed that hypertension was associated with a long PFS. According to our multivariable logistic regression models, TRAEs were not associated with ORR. Conclusion: We found that the prevalence of AEs was higher than that of anti–PD-1 monotherapy. Most of the AEs were mild. The AE spectra were similar to those seen after anti–PD-1 or antiangiogenic therapy monotherapy, without unexpected AEs. Immunotherapy combined with antiangiogenic therapy was well tolerated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03955354.

To the Question of Terminology, Expert Criteria for Evaluating the Effectiveness of Antiangiogenic Therapy and the Prevalence of Refractory Forms of Neovascular Age-Related Macular Degeneration. Review

The authors presented a review of studies aimed at assessing the effectiveness of antiangiogenic therapy in patients with neovascular form of age-related macular degeneration. The purpose of this review was to clarify the prevalence of true refractory forms of WMD on literary data. The vast majority of experts consider the marker of “refractory” the exit of the dye from the vessels on fluorescent angiography (FAG), fibrovascular detachment of pigment epithelium with intraretinal and/or subretinal fluid on optical coherent tomography, an increase in hemorrhage on the eye compared to the initial level of post-loading phase therapy. The analysis showed a wide corridor of indicators, due to different approaches and timing of the assessment of the respondent’s status, as well as expert criteria for the effectiveness of antiangiogenic therapy. In addition, the authors drew attention to the different understanding of the terms tahiphylaxis and tolerance, presented by the researchers. Many papers are replacing these perceptions. The our work presents the fundamental differences of these biological phenomena in the clinic and morphometric data, as well as the timing of development. Meanwhile, overcoming resistance involves an accurate diagnosis of the pharmacological cause and a subsequent differentiated approach to solving the problem. An overview of the work on overcoming refractory to antiangiogenic drugs in various ways is presented.

Пахихориоидальная неоваскулопатия при нормальной субфовеолярной толщине хориоидеи

Pachychoriod neovasculopathy and typical neovascular age-related macular degeneration often look similar, but some differences have been described both genotypically and in the level of cytokine profile, which explains the difference in response to antiangiogenic therapy. It is known that pachychoriod diseases are characterized by choroidal subfoveolar thickening. However, there is currently no data on the structural features of the choroid in the presence of pachychoriod neovasculopathy outside the fovea. Purpose. To perform a detailed analysis of choroial structure on OCT scans of patients with neovascular AMD with normal choroidal subfoveolar thickness and to reveal the frequency of pachychoriodal neovasculopathy identification. Material and methods. In retrospective study, the data of 30 treatment-naive patients (30 eyes) aged 71.5±7.6 years with CNV type 1 were analyzed, including 18 women and 12 men, with a subfeolar thickness of the choroidal membrane not exceeding 250 µm. The patients underwent OCT and OCT-angiography using a Spectralis device (Heidelberg Engineering, Germany). In the foveolar zone and under the neovascular complex, if it is located outside the fovea, the structure of the choroid was analyzed: the choroidal thickness, Haller layer and choriocapillaries / layer of Sattler vessels were measured. Results. The average thickness of the choroid in the fovea in all patients was 170.1±40 µm. The thickness of Haller vessels layer was on average 112.3±20 μm, and the layer of choriocapillaries / Sattler vessels was 57.8±12 μm. In 22 eyes, the structure of the choroid and the ratio of all layers were similar in all analyzed OCT scans. However, in 8 eyes, under the CNV located extrafoveally, a thickening of the choroid was revealed up to 210.5±51 µm, the main volume of the choroid was presented by pachyvessels – dilated and enlarged vessels of the Haller layer which thickness was 189.4 ± 48 µm, and thinning of the choriocapillary / Sattler layer to 21.1±16 µm. Conclusion. Among 30 patients with normal subfoveolar thickness of the choroid, the frequency of PNV was 26.6%. Taking into account the literature data on different responses to antiangiogenic therapy in patients with PNV and typical AMD, we can once again emphasize the importance of a detailed assessment of changes in the choroid not only in the foveolar zone, but also specifically in the area of the neovascular complex. Key words: pachychoriod neovasculopathy, choroid, OCT.

Clinical observation of local intervention combined with camrelizumab and apatinib in the treatment of metastatic soft-tissue sarcoma.

The study aimed to investigate the effectiveness and safety of the combination of immune checkpoint inhibitor, local interventional therapy, and anti-angiogenic therapy in patients with metastatic soft-tissue sarcoma (mSTS). We retrospectively evaluated the medical records of patients with mSTS who started treatment between September 2018 and June 2020 at our hospital. Overall, 33 patients with different subtypes of mSTS were included. Most primary tumors originated from the lungs, and the rest were scattered throughout the body. All patients were treated with camrelizumab combined with apatinib within 5 days of local interventional therapy using transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Primary end point was progression-free survival (PFS), and secondary end points were objective response rate (ORR), disease control rate (DCR), and patient safety. The median PFS, median overall survival (OS), ORR, and DCR were 8.8 months, 18.5 months, 36.4%, and 75.8%, respectively. Patients (n = 20) treated with RFA combined with TACE showed better responses than those treated with RFA alone (n = 13), with mPFS of 9.3 and 7.9 months (P = 0.044) and mOS of 19.0 and 16.2 months (P = 0.043), respectively. Patients (n = 8) with alveolar soft part sarcomas showed excellent efficacy, with ORR, DCR, mPFS, and mOS of 62.5%, 87.5%, 11.5 months, and 22.5 months, respectively. Grades 3 or 4 treatment-related adverse events occurred in 12 of 33 patients. Local intervention therapy combined with camrelizumab and apatinib is effective and safe for patients with mSTS and should be investigated in future clinical trials.

Predictors of functional outcome of antiangiogenic therapy in neovascular age-related macular degeneration

Aim.To study predictive factors for functional outcome of aflibercept intravitreal antiangiogenic therapy in patients with neovascular age-related macular degeneration (nAMD).&#x0D; Material and methods.Thirty-six treatment naive nAMD patients (45 eyes, 26 females and 10 males, with a mean age of 74.4 10.9 years) were included in this study. All patients received 3 monthly aflibercept injections followed by 4 bimonthly aflibercept injections. Demographic characteristics, baseline best corrected visual acuity (BCVA), central retinal thickness (CRT), and structural retinal changes on optical coherence tomography (OCT) scans were evaluated for the correlation with BCVA after 10 months follow-up.&#x0D; Results.At the end of the follow-up period, the mean BCVA increased statistically significantly from 31 15 (~0.32) letters at baseline to 37 14 (~0.4) letters (p= 0.003). CRT at baseline and at the end of follow-up was 357 110 and 269 70 m (p 0.001), respectively. Final BCVA correlated statistically significantly with baseline BCVA (r= 0.62,p 0.0001), baseline CRT (r= 0.48,p= 0.001), and disease duration from the appearance of complaints until the therapy start (r= 0.32,p= 0.03). Structural macular changes on the OCT scans were not related to final BCVA (p 0.05) apart from the status of the ellipsoid zone (p 0.001). Final BCVA was statistically significantly lower in males than in females (34.7 14.0 (~0.4) and 45.0 9.2 (~0.63) letters, respectively,p= 0.03).&#x0D; Conclusion.Baseline visual acuity, gender, CRT, disease duration from the appearance of complaints until the therapy start, and status of the ellipsoid zone are predictive for the functional outcome in wet AMD patients.

Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: A two-center retrospective study

BackgroundThe synergistic effects of immunotherapy and antiangiogenic therapy in advanced non–small cell lung cancer (NSCLC) have been reported in both preclinical and clinical trials. Herein, we evaluated the preliminary efficacy and safety of combined immunotherapy and antiangiogenic therapy in patients with previously treated advanced NSCLC in a real-world setting. MethodsWe conducted a 2-center, retrospective study of previously treated advanced NSCLC patients who received any anti-programmed death-1 antibody combined with antiangiogenic agent between May 2018 and March 2020. ResultsIn total, 57 patients were included in this study, and the objective response rate and disease control rate were 19.3% and 63.2%, respectively. The median progression-free survival (PFS) was 4.2 months (95% confidence interval [CI]: 3.2–5.2 months). Bone metastases (odds ratio [OR] not available; P < .01) and ≥ 3 treatment lines (OR 6.8; 95% CI: 1.6–29.6; P < .05) were independent negative predictors of objective response. Additionally, liver metastases (hazard ratio [HR] 3.7; 95% CI: 1.6–8.5; P < 0.01), poor performance status score (PS) (HR 3.4; 95% CI: 1.6–7.5; P < 0.01) and ≥ 3 treatment lines (HR 3.5; 95% CI: 1.7–7.4; P < 0.01) were found to be negative predictors of PFS. Eighty-nine percent of the patients experienced an adverse event. ConclusionsMetastatic sites (bone and liver), ≥3 treatment lines and poor PS were potential negative predictors of the efficacy of immunotherapy combined with antiangiogenic therapy for treating NSCLC. Further investigations and randomized controlled trials are needed.

Sirolimus for the treatment of vascular anomalies in children

Vascular anomalies (VA) comprise a heterogeneous group of diseases associated with congenital angiogenesis disorder. There are no currently developed unified protocols and treatment regimens for systemic forms of VA. Numerous advantages show sirolimus, an mTOR inhibitor, as a well tolerated and effective antiproliferative and antiangiogenic therapy in patients with VA. The article presents the results of treatment of 211 patients with VA (6 patients with vascular tumors and 205 patients with vascular malformations) aged 2 months to 17 years (median – 9 years), who received sirolimus therapy for 1–86 months (median – 24 months). Sirolimus was administered at a starting dose of 0.8 mg/m2/day orally in two doses with an interval of 12 hours. The concentration of the blood preparation was maintained in the therapeutic range of 6–15 ng/ml. Since 2015, concomitant therapy with co-trimoxazole for the prevention of Pneumocystis pneumonia has been prescribed only to tracheostomy carriers. When infectious episodes occurred in patients, sirolimus therapy continued without changes in the dose of the drug and did not affect the disease, provided that the therapeutic concentration was maintained. A positive response to therapy was observed in 89.1 % of patients with VA in the form of the size of the vascular mass according to the data of visual examination and instrumental control. All patients showeda clinical response to therapy in the form of relief of painsyndrome, reduction/relief of lymphorrhea, reduction/improvement of hemostasis parameters, and an increase in functional activity and quality. For the entire observation period 2012–2020, when taking sirolimus, not a single severe adverse event occurring in post-transplant patients has been reported that would require discontinuation of the drug. The article presents two clinical cases of sirolimus use in the treatment of patients with kaposiform hemangioendothelioma and extensive venous malformation. Parents are encouraged to use the information in scientific research and publications.