Effects Of Anti-angiogenic Therapy Research Articles

Analysis of the effectiveness of antiangiogenic therapy in the complex treatment of patients with diabetic macular edema

Analysis of the effectiveness of antiangiogenic therapy in the complex treatment of patients with diabetic macular edema

Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development

Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.

Cavitation in an antivascular cancer therapy setting

Focused ultrasound in combination with circulating microbubbles is being widely investigated as a means to promote spatially targeted drug delivery. This approach has considerable potential in oncology for a range of therapeutic agents. At sufficiently high pressures, above those typically employed in drug delivery, tumor microvessel damage can be induced to an extent that leads to perfusion shutdown and subsequent ischemic tissue necrosis. This approach is often referred to as antivascular ultrasound (AVUS), which has been shown in preclinical work to be capable of enhancing the effects of radiation therapy, antiangiogenic therapy, chemotherapy, and immunotherapy. At present, the mechanisms of AVUS are not well established. It is important to gain a more detailed understanding of the bubble–microvessel interactions that lead to perfusion shutdown, along with the cavitation signatures associated with these behaviors to enable the rational development of effective cavitation based control methods. This talk will provide a brief overview of AVUS therapy in oncology and highlight recent efforts employing two-photon microscopy, high speed optical imaging, and acoustic emission monitoring to gain insights into bubble behavior within small channels and in vivo microvessels under AVUS exposure conditions.

Антиангиогенная терапия в сочетании с ферментным тромболизисом – новый перспективный способ лечения тромбоза вен сетчатки

Сentral retinal vein occlusion (CRVO), the first mention of which was made more than 200 years ago, today is characterized by a sufficiently fully and in detail studied pathogenesis and a detailed clinical picture [1]. It should be noted that currently, when studying certain aspects of the pathogenesis of this disease, preference is given to studying the role of various angiogenic factors, in particular, vascular endothelial growth factor (VEGF) [2, 3]. At the same time, the assessment of the influence of coagulation, hemodynamic and immune-inflammatory factors of retinal vein occlusion to a certain extent fades into the background. However, it is a holistic understanding of the pathogenesis of CRVO based on the principles of systemic methodology that is the basis for the development of effective, pathogenetically substantiated methods of treating this disease. Purpose. To study the effectiveness of anti-angiogenic therapy in combination with epiretinal thrombolysis in the treatment of «fresh» CRVO. Methods. A clinical study was conducted among 106 patients with retinal vein occlusion with a disease development period up to 7 days, divided depending on the method of treatment into 2 groups: the main one – 56 patients (56 eyes), who were intravitreally injected with the anti-VEGF drug aflibercept with simultaneous epiretinal injection of recombinant prourokinase, and a comparison group – 50 patients (50 eyes) who received monotherapy with an angiogenesis inhibitor. All patients were matched for age and gender. Ophthalmological examination included: visometry, pneumotonometry, ophthalmoscopy, optical coherence tomography of the macular retina. Statistical processing of the obtained results was carried out using the IBM SPSS Statistics 27 program. Differences were considered statistically significant at p<0.05. Results. The use of a new combined method for thrombosis treatment, including intravitreal injection of an antiVEGF drug in combination with epiretinal injection of prourokinase, provides high and stable clinical and functional results in the postoperative period with an increase in visual acuity by 1.8 times, as well as an acceleration of hemorrhage lysis and resorption of macular edema by 2.0 times. Key words: central retinal vein occlusion; branch central retinal vein occlusion; anti-VEGF therapy; thrombolytics; prourokinase.

Correlation between IVIM parameters and microvessel architecture: direct comparison of MRI images and pathological slices in an orthotopic murine model of rhabdomyosarcoma.

This study aimed to explore the correlation between intravoxel incoherent motion (IVIM) parameters and microvessel architecture (microvessel density (MVD), vasculogenic mimicry (VM), and pericyte coverage index (PCI)) in an orthotopic murine model of rhabdomyosarcoma. The murine model was established by injecting rhabdomyosarcoma-derived (RD) cells into the muscle. Nude mice underwent routine magnetic resonance imaging (MRI) and IVIM examinations with ten b values (0, 50, 100, 150, 200, 400, 600, 800, 1000, and 2000 s/mm2). D, D*, and f values were calculated with the ADW4.7 workstation. MRI images and pathological slices were directly compared to ensure that radiology parameters accurately reflect pathology. MVD, VM, PCI, and cellularity were obtained by histological analysis. The correlations were assessed between IVIM parameters (D, D*, f, and fD* values) and pathological markers (MVD, VM, PCI, and cellularity). The average of D, D*, f, and fD* values were 0.55 ± 0.07 × 10-3mm2/s, 5.25 ± 0.73 × 10-3mm2/s, 13.39 ± 7.68%, and 0.73 ± 0.49 × 10-3mm2/s, respectively. The average of MVD, VM, PCI, and cellularity were 41.91 ± 10.98, 1.16 ± 0.83, 0.49 ± 0.18, and 39.15 ± 9.00%. D*, f, and fD* values showed a positive correlation with MVD separately, while the D value did not correlate with MVD. D value negatively correlated to VM moderately, and other parameters did not associate with VM. D* and fD* values were positively correlated with PCI, but no correlation was observed between other parameters and PCI. IVIM may evaluate the tumor microvessel architecture. D*, f, and fD* may reflect the endothelial lining blood vessel; D could indirectly reflect the VM; D* and fD* could reflect PCI(the normal degree of the tumor blood vessel). An intravoxel incoherent motion may be useful in assessing rhabdomyosarcoma microvessel structure to predict the target and effectiveness of anti-angiogenic therapy. • IVIM may be used to evaluate the tumor microvessel architecture in the mouse rhabdomyosarcoma model. • The MRI-pathology control method achieves correspondence between MRI slices and pathology slices, which ensures the consistency of the ROI of MRI and the pathology observation region.

O-266 Anti-angiogenic therapy as treatment for adenomyosis in mice

Abstract Study question What is the effect of anti-angiogenic therapy on adenomyosis in mice Summary answer Commencing treatment at six weeks with angiogenesis inhibitor axitinib successfully reduced the severity of adenomyosis by approximately 50% at 9 weeks. What is known already Adenomyosis is a gynecological disorder characterized by abnormal uterine bleeding, dysmenorrhea, pelvic pain and subfertility. Increased expression of angiogenic markers, as well as increased microvascular density (MVD) in adenomyosis suggest a pivotal role for angiogenesis in the pathophysiology of adenomyosis, which presents an opportunity for treatment. Study design, size, duration The effect of angiogenesis inhibition was studied in a tamoxifen-induced adenomyosis mouse model. 102 Mice received oral treatment with axitinib 3 mg/kg (‘dose I/AX3 treatment group’, n = 34), axitinib 25 mg/kg (‘dose II/AX25 treatment group’ n = 34), or with vehicle-only (‘placebo group’, n = 34) from week 6 until week 9. After termination of the mice at week 9, all uteri were analyzed for the presence of adenomyosis. Participants/materials, setting, methods The prevalence and severity of adenomyosis were assessed by; (i) grade of adenomyosis (0/1/2/3), based on the depth of endometrial gland infiltration into the myometrium in H&E-stained sections, (ii) percentage of adenomyosis-affected tissue in vimentin-stained sections and (iii) degree of myometrium that is affected in α-SMA-stained sections. The adenomyosis severity index was calculated by multiplying mean grade/mouse with the percentage affected surface area. Changes in angiogenesis-related gene expression were evaluated using real-time quantitative PCR. Main results and the role of chance 101 mice completed adenomyosis induction and could be analyzed. The prevalence of adenomyosis was 30/33 (90.0%) in dose I (3mg/kg), 29/34 (85.3%) in dose II (25mg/kg) and 30/34 (88.2%) in placebo treated mice (p=0.78). The prevalence of high grade (2/3) adenomyosis was significantly lower in mice treated with axitinib dose II (N = 19, 55.9%) than in the placebo group (N = 27, 79.4%, p<0.05). The grade of adenomyosis per mouse after treatment was 0.7 point lower in the groups treated with axitinib dose I and dose II, than in the placebo treated group (dose I and II both median of 1.0 compared to 1.7, p < 0.05). The adenomyosis severity index was reduced by 48% in the axitinib-treated groups (dose I p<0.05). In the placebo-treated group, the myometrium adjacent to the affected site (as a marker for hypertrophy) was thicker in the placebo- than in the axitinib-treated groups. There were no signs of fibrosis. MVD was reduced in myometrium of dose I treated mice by 14% compared with Ax25-treated mice (p<0.05), as well as compared to 6-week-old tamoxifen-treated mice (p<0.05). Expression of angiogenic growth factors and their receptors was markedly reduced in the dose I and II axitinib-treated groups compared to the placebo-treated group. Limitations, reasons for caution Limitations of this study include the uncertainty on the optimal timing to start treatment, and the assessment of the presence and severity of adenomyosis. Further research should focus on commonality among different angiostatic drugs, as well as the method and timing of application. Wider implications of the findings Since there is currently no treatment option for premenopausal women who wish to retain their uterus and their fertility, treatment with an angiogenesis inhibitor might provide a solution. The major requirement in further development of anti-angiogenesis therapy is a safety and side-effect profile tolerable for this population. Trial registration number Not applicable

The Interplay between Microbiota and Chemotherapy-Derived Metabolites in Breast Cancer.

The most common cancer in women is breast cancer, which is also the second leading cause of death in this group. It is, however, important to note that some women will develop or will not develop breast cancer regardless of whether certain known risk factors are present. On the other hand, certain compounds are produced by bacteria in the gut, such as short-chain fatty acids, secondary bile acids, and other metabolites that may be linked to breast cancer development and mediate the chemotherapy response. Modeling the microbiota through dietary intervention and identifying metabolites directly associated with breast cancer and its complications may be useful to identify actionable targets and improve the effect of antiangiogenic therapies. Metabolomics is therefore a complementary approach to metagenomics for this purpose. As a result of the combination of both techniques, a better understanding of molecular biology and oncogenesis can be obtained. This article reviews recent literature about the influence of bacterial metabolites and chemotherapy metabolites in breast cancer patients, as well as the influence of diet.

Correlation between Microvessel Density Based on CD31 Immunohistochemical Expression and Clinicopathology of Invasive Breast Carcinoma

Background
 Breast carcinoma is the most common malignancy in women worldwide. Tumor size, metastases, lymph node involvement (KGB), stage and histopathological grade are significant prognostic factors in invasive breast carcinoma. Microvessel density (MVD) assessment is used to measure angiogenesis which helps predict tumor behavior and the effect of antiangiogenic therapy. MVD is a quantitative calculation of intratumoral capillary blood vessels which reflects the results of the process of angiogenesis. The aim of this study was to analyze the relationship between MVD based on CD31 immunohistochemical expression and the clinicopathology of invasive breast carcinoma.
 
 Method
 Cross sectional analytic study with 42 samples diagnosed with invasive breast carcinoma at H. Adam Malik General Hospital Medan. MVD is the number of small blood vessels in terms of size and diameter (arterioles and venules) with a round lumen that is positively stained with CD31 at 10 large visual fields, categorized as low if <45 blood vessels/10 LPB and high if ≥45 blood vessels/10 LPB. The relationship between MVD and several clinicopathological parameters was analyzed using the Chi-Square, Fisher's Exact and Mann-Whitney tests.
 
 Results
 There was a significant relationship between tumor size (p=0.029), metastasis (p=0.014), stage (p=0.002), histopathological grade (p=0.0043), LVI (p=0.002), TILs (p=0.007). Large tumor size, metastases, high histopathological stage and grade, positive LVI and high TILs were significantly associated with MVD. However, there was no significant relationship between KGB involvement (p=0.570) and MVD.
 
 Conclusion
 MVD is significantly related to tumor size, metastases, stage, histopathological grade, LVI and TILs, and not significantly related to lymph node involvement. MVD plays a role in the angiogenesis of invasive breast carcinoma clinicopathology.

Anti-angiogenic therapy in the treatment of diabetic macular edema in various variants of the vitreoretinal interface

BACKGROUND: Anti-angiogenic therapy for diabetic macular edema (DME), recognized as the gold standard, is not always effective. When compensating for the general somatic status, it is necessary to search for local causes of DME resistance to anti-angiogenic therapy.
 AIM: To study the effectiveness and features of anti-angiogenic therapy for DME in normal and pathological vitreoretinal interface (VRI).
 MATERIALS AND METHODS: Patients who received anti-angiogenic therapy for 12 months, in addition to the standard examination, underwent optical coherence tomography with an assessment of morphometric parameters and VRI.
 RESULTS: In addition to the groups of normal and pathological VRI, a group of transformation from pathological to normal VRI was identified. Visual acuity increases with normal VRI, decreases with pathological. OCT scores decrease in both groups. In the transformation group, an increase in vision and a decrease in OCT parameters were observed only after VRI transformation.
 CONCLUSION: The pathologic condition of the VRI reduces effectiveness of anti-angiogenic therapy for DME, except for 10% of cases in which VRI is transformed into normal within 5-6 months from the start of treatment. These data should be taken into account when choosing a treatment strategy for DME.

Three-year follow-up study of clinical effectiveness of antiangiogenic therapy for neovascular age-related macular degeneration

The study analyzes long-term (three years) clinical effectiveness of anti-VEGF treatment of neovascular age-related macular degeneration (nAMD) and attempts to identify the most clinically significant associations between the functional and structural parameters. The study included 122 patients (122 eyes) diagnosed with nAMD, mean age -73.4±6.6 years old. Prospective follow-up lasted 144 weeks. All patients were treated with angiogenesis inhibitor (aflibercept 2 mg), and most of them (72.9%) - according to the Treat-and-Extend protocol. The average number of injections was 7.39±1.28, 4.63±0.97 and 4.06±0.81 during the first, second and third years of the follow-up, respectively. The mean baseline best-corrected visual acuity (BCVA) was 0.24±0.21. After three loading doses, BCVA increased to 0.33±0.26 (+0.09; 37.5%), by the end of follow-up BCVA was 0.35±0.27 (+0.11; 45.8%). Central retinal thickness (CRT) decreased from 314.89±88.07 μm to 234.4±42.8 μm (a 25.5% decrease) by the end of the follow-up. After three loading injections baseline functional and anatomical parameters had the most significant correlations (r≥0.7, p<0.05) with intraretinal fluid, ellipsoid zone integrity and the area of macular atrophy. Analysis of the morphological and functional outcomes by the end of the first year demonstrates the feasibility of preserving the results while reducing the number of visits and injections according to the Treat-and-Extend protocol. Achieving maximum improvement of functional parameters most significantly correlated with changes in such biomarkers as central retinal thickness, area of macular atrophy and integrity of the ellipsoid zone.

The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy

The vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) axis is indispensable in the process of angiogenesis and has been implicated as a key driver of tumor vascularization. Consequently, several strategies that target VEGF and its cognate receptors, VEGFR-1 and VEGFR-2, have been designed to treat cancer. While therapies targeting full-length VEGF have resulted in an improvement in both overall survival and progression-free survival in various cancers, these benefits have been modest. In addition, the inhibition of VEGFRs is associated with undesirable off-target effects. Moreover, VEGF splice variants that modulate sprouting and non-sprouting angiogenesis have been identified in recent years. Cues within the tumor microenvironment determine the expression patterns of these variants. Noteworthy is that the mechanisms of action of these variants challenge the established norm of VEGF signaling. Furthermore, the aberrant expression of some of these variants has been observed in several cancers. Herein, developments in the understanding of the VEGF/VEGFR axis and the splice products of these molecules, as well as the environmental cues that regulate these variants are reviewed. Furthermore, strategies that incorporate the targeting of VEGF variants to enhance the effectiveness of antiangiogenic therapies in the clinical setting are discussed.

ANGI-05. VASCULAR NORMALIZATION IN MURINE GLIOBLASTOMA IS CONTROLLED BY APLN-SIGNALING AND CAN BE MONITORED BY DCE-MR IMAGING IN VIVO

Abstract OBJECTIVE Glioblastoma (GBM) expansion is accompanied by aberrant tumor vascularization. We demonstrated that the peptide hormone Apelin (APLN) controls GBM neo-vascularization and that the APLN-receptor antagonist Apelin-F13A improved the efficiency and reduced the invasive side effect of established antiangiogenic therapy. Here we investigated if Apelin-F13A blunts the formation of vasogenic edema, which can be monitored by MRI in vivo. METHODS To investigate the role of APLN -signaling in regulating the tightness of the tumor vasculature we performed in vivo leakage assays using Evans-Blue dye and fluorescent dextran. By confocal immunofluorescence, we characterized the maturation of the tumor vasculature with respect to pericyte-coverage and established a dynamic contrast enhanced (DCE) MR imaging protocol to follow vascular edema formation. RESULTS We found that Evans-Blue extravasation is significantly increased by 3-fold in APLNKO tumors compared to controls. Uptake of fluorescent Dextran by CD31+ endothelia was quantified and increased massively from 200μm2 per high magnification field (HMF) in wildtype to 3500μm2 per HMF in APLNKO tumors. Interestingly, intracerebral infusion of Apelin-F13A enhanced pericyte coverage of the tumor vasculature by 50%, decreased Evans-Blue extravasation from 25 μg/ml in controls to 8 μg/ml in treated tumors significantly and efficiently reversed the APLN-dependent vasogenic edema assessed by comparison of T2w-MRI to HE tumor volumes. To follow vasogenic edema formation in vivo, T1w 3D FLASH images were acquired every second over a 360s time course after gadolinium-based MR-contrast agent injection and demonstrated a delayed washout of the contrast in APLN-deficient GBM. CONCLUSION Together, our study shows that DCE-MRI can document APLN-dependent intratumoral vascular normalization and allows inspecting vasogenic edema formation in vivo. In addition to its anti-angiogenic / anti-invasive effect, Apelin-F13A can potently reduce vasogenic edema and might thus serve as a multimodal therapy for the treatment of human GBM in the future.

WZB117 enhanced the anti-tumor effect of apatinib against melanoma via blocking STAT3/PKM2 axis.

Background: Melanoma is the most lethal skin malignant tumor with a short survival once stepping into the metastatic status and poses a therapeutic challenge. Apatinib (a tyrosine kinase inhibitor) is a promising antiangiogenic agent for the treatment of metastatic melanoma. However, antiangiogenic monotherapy is prone to acquired drug resistance and has a limited therapeutic effect. The persistence dependence of glycolytic metabolism in antiangiogenic therapy-resistant cells provides evidence that glycolysis inhibitors may enhance the effect of antiangiogenic therapy. So, this study aimed to investigate whether WZB117 (a specific GLUT1 inhibitor) could enhance the anti-tumor effect of apatinib against melanoma and its potential mechanisms. Methods: We investigated the anti-tumor effects of apatinib alone or in combination with WZB117 on human melanoma cell lines (A375 and SK-MEL-28). The MTT assay determined cell viability and the half-maximal inhibitory concentration (IC50). Multiple drug effect/combination indexes (CI) analysis was conducted to assess interactions between apatinib and WZB117. Signal transducer and activator of transcription 3 (STAT3) pathway measured by western blotting and immunofluorescence staining. RNA expression analyses were performed using the reverse transcription-quantitative PCR method. Results: Apatinib and WZB117 showed dose and time-dependent growth inhibitory effects in both melanoma cells. The IC50 of apatinib at 48 h in A375 and SK-MEL-28 cells was 62.58 and 59.61 μM, respectively, while the IC50 of WZB117 was 116.85 and 113.91 μM, respectively. The CI values of the two drugs were 0.538 and 0.544, respectively, indicating a synergistic effect of apatinib combined with WZB117. We also found that glucose consumption and lactate production were suppressed by apatinib plus WZB117 in a dose-dependent manner, paralleled by reducing glycolytic enzyme pyruvate kinase M2 (PKM2). The potential mechanism of the combination was to suppress the phosphorylation of STAT3. Knockdown of STAT3 by siRNA inhibited the expression of PKM2, while the activation of STAT3 by IL-6 increased the expression of PKM2. The effects of IL-6 were attenuated by apatinib combined with WZB117 treatment. Conclusion: WZB117 enhanced the anti-tumor effect of apatinib against melanoma via modulating glycolysis by blocking the STAT3/PKM2 axis, which suggested the combination of apatinib with WZB117 could be a potential therapeutic candidate for melanoma.

Inhibition of infection-induced vascular permeability modulates host leukocyte recruitment to Mycobacterium marinum granulomas in zebrafish.

Mycobacterial granuloma formation involves significant stromal remodeling including the growth of leaky, granuloma-associated vasculature. These permeable blood vessels aid mycobacterial growth, as antiangiogenic or vascular normalizing therapies are beneficial host-directed therapies in preclinical models of tuberculosis across host-mycobacterial pairings. Using the zebrafish-Mycobacterium marinum infection model, we demonstrate that vascular normalization by inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) decreases granuloma hypoxia, the opposite effect of hypoxia-inducing antiangiogenic therapy. Inhibition of VE-PTP decreased neutrophil recruitment to granulomas in adult and larval zebrafish, and decreased the proportion of neutrophils that extravasated distal to granulomas. Furthermore, VE-PTP inhibition increased the accumulation of T cells at M. marinum granulomas. Our study provides evidence that, similar to the effect in solid tumors, vascular normalization during mycobacterial infection increases the T cell:neutrophil ratio in lesions which may be correlates of protective immunity.

Application of Intravoxel Incoherent Motion Diffusion-Weighted Imaging in Predicting and Monitoring Early Efficacy of Anti-Angiogenic Therapy in the C6 Glioma Rat Model.

ObjectiveTo investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in evaluating early effects of anti-angiogenic therapy in the C6 glioma rat model.MethodsTwenty-six rats of the C6 glioma model were randomly divided into a treatment group (received bevacizumab) and a control group (physiological saline). IVIM-DWI was performed on days 0, 1, 3, 5, and 7 after anti-angiogenic therapy and tumor growth and IVIM-DWI parameters were dynamically observed. Hematoxylin and eosin, CD34 microvessel density (MVD), proliferation of cell nuclear antigen (PCNA), and Hif-α staining were performed on day 7. One-way ANOVA was used to compare intra-group differences and an independent-samples t-test was used to compare inter-group differences of MRI parameters. Correlations between IVIM-DWI parameters, tumor size, and pathological results were analyzed.ResultsThe relative change in tumor volume (ΔVolume) in the two groups differed significantly on days 5 and 7 (p = 0.038 and p < 0.001). The perfusion-related parameters D*- and f-values decreased in the treatment group and demonstrated significant differences compared with the control group on days 3, 5, and 7 (p = 0.033, p < 0.001, and p < 0.001, respectively). The diffusion-related parameters ADC and D-values increased in the treatment group and were found to be significantly differently different from the control group on days 5 and 7 (both p < 0.001). The initial D-value showed a negative correlation with ΔVolume (γ = −0.744, p < 0.001), whereas the initial D*-value and relative change of D-value had a positive correlation with ΔVolume (γ = 0.718, p < 0.001 and γ = 0.800, p < 0.001, respectively). MVD was strongly positively correlated with D*-value (r = 0.886, p = 0.019), PCNA was negatively correlated with ADC- and D-values (r = −0.848, p = 0.033; and r = −0.928 p = 0.008, respectively), and Hif-1α was strongly negatively correlated with D*-value (r = −0.879, p = 0.010).ConclusionIVIM-DWI was sensitive and accurate in predicting and monitoring the effects of early anti-angiogenesis therapy in a C6 glioma rat model.

Long time dynamics of a phase-field model of prostate cancer growth with chemotherapy and antiangiogenic therapy effects

&lt;p style='text-indent:20px;'&gt;We consider a phase-field model of prostate cancer growth with chemotherapy and antiangiogenic therapy effects which is introduced in [&lt;xref ref-type="bibr" rid="b2"&gt;2&lt;/xref&gt;]. It is comprised of phase-field equation to describe tumor growth, which is coupled to a reaction-diffusion type equation for generic nutrient for the tumor. An additional equation couples the concentration of prostate-specific antigen (PSA) in the prostatic tissue and it obeys a linear reaction-diffusion equation. The system completes with homogeneous Dirichlet boundary conditions for the tumor variable and Neumann boundary condition for the nutrient and the concentration of PSA. Here we investigate the long time dynamics of the model. We first prove that the initial-boundary value problem generates a strongly continuous semigroup on a suitable phase space that admits the global attractor in a proper phase space. Moreover, we also discuss the convergence of a solution to a single stationary state and obtain a convergence rate estimate under some conditions on the coefficients.&lt;/p&gt;

New criteria of effectiveness of anti-VEGF therapy in exudative age-related macular degeneration

To evaluate the effectiveness of anti-angiogenic therapy using fluctuation and variability in patients with exudative age-related macular degeneration (AMD). This study included 200 patients with types 1, 2, 3 neovascularization and polypoidal choroidal vasculopathy (PCV). All patients underwent standard ophthalmological examination, as well optical coherence tomography (OCT) and OCT angiography (OCT-A). Patients were divided into 4 quartiles based on fluctuation and variability. All patients underwent intravitreal administration of the anti-VEGF drug aflibercept (Eylea) manufactured by Bayer, Germany, using the Treat-and-Extend regimen. As a result of the study, a significant increase in visual acuity was revealed on the second year of treatment in patients in the 2nd and 3rd quartiles, best corrected visual acuity (BCVA) decreased in the 1st and 4th quartiles. In the group with paracentral fluctuation, a significant increase in BCVA by the end of the second year of treatment was observed in the 1st (p=0.05) and 3rd quartiles. As a result of a 2-year follow-up, it was found that BCVA values were lower in patients with the greatest variability (2nd, 3rd, and 4th quartiles). A significant increase in BCVA was observed in the 1st quartile (p=0.047). The largest number of patients with subretinal fibrosis that had fluctuations in the central zone and peripheral fluctuations was observed in the 4th quartile, the smallest - in the 2nd quartile. Similar pattern was observed in the variability group. In the setting of anti-VEGF therapy, a significant increase in BCVA was observed in patients with the lowest variability - in the 1st quartile (p=0.047), but in patients with fluctuations the highest BCVA values were observed in the 2nd and 3rd quartiles, while in the 4th quartile BCVA decreased (p=0.0562). The results of this study indicate that when treating patients with neovascular AMD, clinicians should aim for a treatment strategy that minimizes fluctuation and variability.

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.

The treatment of advanced pulmonary sarcomatoid carcinoma.

Pulmonary sarcomatoid carcinoma (PSC) is a pathological subtype of non-small-cell lung cancer. Although the incidence of PSC in lung cancer is very low, it is an aggressive cancer, leading to a poor prognosis. Currently, there is no standard treatment for advanced PSC. Targeted therapy can be used for patients with METex14 mutations and patients with other driver gene mutations may also benefit from treatment. The emergence of immune checkpoint inhibitors also provides potential options for advanced PSC treatment, but more clinical data is needed. Additionally, more research may be warranted to explore the effects of chemotherapy, radiotherapy and antiangiogenic therapy. In this review, the authors summarize the research regardingthe treatment of advanced PSC.

Tomographic Parameters of Recurrent Macular Edema Due to Retinal Vein Occlusion during Antiangiogenic Therapy

Purpose: to establish the tomographic parameters to predict the recurrent of macular edema due to retinal vein occlusion.Patients and methods. This is a retrospective study of 54 patients (54 eyes) with macular edema, no more than 3 months old, who had recurrent of macular edema after 3 intravitreal injections of aflibercept. Standard ophthalmological examination, spectral optical coherence tomography, intravitreal injections of aflibercept according to instruction, and statistical analysis of the data were conducted.Results. Recurrence of macular edema developed on average 6.3 ± 1.2 weeks after three injections of aflibercept. We identified of the most significant prognostic tomographic parameters affecting the recurrent of macular edema during intravitreal injections of aflibercept — central foveal thickness &gt; 500 μm (OR 2.1, p = 0.01), the presence of serous retinal detachment (OR 5.1, p = 0.001), the presence of hyperreflective foci (OR 3.7, p = 0.03), alteration of external limiting membrane (OR 4.7, p = 0.01), disruption of the photoreceptor innersegment/outer segment junction (OR 3.4, p = 0.01), disruption of retinal pigment epithelium (OR 2.1, p = 0.02).Conclusion: the recurrent of macular edema with retinal vein occlusion during antiangiogenic therapy depends on baseline tomographic parameters. Our results can be important in predicting the duration and effectiveness of antiangiogenic therapy in a particular patient at the beginning of the disease, which makes the approach to management more personalized, promising in economic, social and psychological aspects.