Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Retinopathy of prematurity(ROP)is a pathological neovascularization with fibrotic changes in the fundus of premature infants.It is a major cause of preventable blindness in children in both developing and developed countries.Treatment of ROP has long been a hot research topic in ophthalmology and pediatrics.With a clearer knowledge of the pathogenesis of ROP,more basic and clinical studies have been carried out.The anti-vascular endothelial growth factor therapy and surgical treatment have become mature strategies,and a variety of therapeutic drugs including insulin-like growth factor-1,transforming growth factor-β,polyunsaturated fatty acids,and β-adrenergic receptor blockers have been developed.This article reviews the recent advances in ROP.
Child ; Humans ; Infant, Newborn ; Infant, Premature ; Neovascularization, Pathologic ; therapy ; Retinopathy of Prematurity ; drug therapy ; surgery ; Vascular Endothelial Growth Factor A ; antagonists & inhibitors

OBJECTIVE: To evaluate the effect of anti-vascular endothelial growth factor (VEGF) on juxtafoveal choroidal neovascularization (CNV) secondary to multifocal choroiditis (MFC) and wet age-related macular degeneration (AMD). METHODS: In this retrospective, comparative study, 20 unique eyes with CNV were divided into two groups: 10 patients affected by MFC and 10 patients diagnosed with wet AMD. They all received local intravitreal (IVT) injections of ranibizumab, with 6 months of follow-up. Retreatment injections were performed based on findings suggestive of active neovascularization. RESULTS: Significant improvements were observed in the juxtafoveal CNV lesions, and average central macular thickness decreased in both groups following the anti-VEGF therapy (P<0.05). The average number of injections used in MFC patients was 1.6, while three injections on average were used in wet AMD patients (Z=-2.844, P=0.009). Best-corrected visual acuity was significantly improved in MFC patients after anti-VEGF therapy (P<0.05), and there was no significant difference in wet AMD patients between before anti-VEGF therapy and 6 months later (P>0.05). CONCLUSIONS IVT ranibizumab resulted in good clinical outcomes for juxtafoveal CNV secondary to MFC and wet AMD, but the average number of injections used in MFC was fewer than that used in wet AMD over a 6-month observation period. Compared with the wet AMD group, visual acuity was obviously improved in the MFC group at 6 months.
Adult ; Aged ; Angiogenesis Inhibitors/therapeutic use* ; Choroidal Neovascularization/drug therapy* ; Female ; Humans ; Inflammation ; Intravitreal Injections ; Macular Degeneration/drug therapy* ; Male ; Middle Aged ; Ranibizumab/therapeutic use* ; Treatment Outcome ; Vascular Endothelial Growth Factor A/antagonists & inhibitors* ; Vision, Ocular ; Wet Macular Degeneration/drug therapy*

PURPOSE: To evaluate the visual and anatomical outcomes for neovascular age-related macular degeneration with submacular hemorrhage after intravitreal injections of tenecteplase (TNK), anti-vascular endothelial growth factor (VEGF) and expansile gas. METHODS: This study was a retrospective clinical case series following 25 eyes of 25 patients. All patients received a triple injection using 0.05 mL TNK (50 µg), 0.05 mL anti-VEGF and 0.3 mL of perfluoropropane gas. Retreatment with anti-VEGF was performed as needed. Preoperative and postoperative best-corrected visual acuity and central retinal thickness were analyzed. RESULTS: The mean logarithm of the minimum angle of resolution of best-corrected visual acuity improved significantly from 1.09 ± 0.77 at baseline to 0.52 ± 0.60 at 12 months (p < 0.001). The mean central retinal thickness also improved significantly from 545 ± 156 at baseline to 266 ± 107 at 12 months (p < 0.001). A visual improvement of 0.3 logarithm of the minimum angle of resolution unit or more was achieved in 15 eyes (60%). During the 12 postoperative months, an average of 4.04 intravitreal anti-VEGF injections was applied. CONCLUSIONS: A triple injection of TNK, anti-VEGF, and a gas appears to be safe and effective for the treatment of submacular hemorrhage secondary to neovascular age-related macular degeneration.
Acute Disease ; Aged ; Aged, 80 and over ; Female ; Fibrinolytic Agents/administration & dosage ; Fluorescein Angiography ; Fluorocarbons/*administration & dosage ; Follow-Up Studies ; Fundus Oculi ; Humans ; Intravitreal Injections ; Macula Lutea/*diagnostic imaging ; Male ; Middle Aged ; Retinal Hemorrhage/diagnosis/*drug therapy ; Retrospective Studies ; Tissue Plasminogen Activator/*administration & dosage ; Tomography, Optical Coherence ; Treatment Outcome ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Visual Acuity

PURPOSE: To evaluate 12-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with grape-like polyp clusters. METHODS: This retrospective observational study included 23 eyes of 23 patients who were newly diagnosed with PCV with grape-like polyp clusters, and who were subsequently treated with anti-VEGF monotherapy. The study compares the best-corrected visual acuity (BCVA) of the patients at diagnosis, at 3 months, and at 12 months after diagnosis. In addition, 12-month changes in BCVA values were compared between cases with subfoveal or juxtafoveal polyps and cases with extrafoveal polyps. RESULTS: The baseline, 3-month, and 12-month logarithm of the minimal angle of resolution BCVA was 0.62 ± 0.35, 0.50 ± 0.43, and 0.58 ± 0.48, respectively. Compared to the baseline, patient BCVA was not significantly different at 12 months after diagnosis (p = 0.764). Six eyes (26.1%) gained ≥0.2 logarithm of the minimal angle of resolution BCVA. In cases with subfoveal or juxtafoveal polyps, BCVA values at baseline and at 12 months after diagnosis were 0.66 ± 0.37 and 0.69 ± 0.53, respectively. In cases with extrafoveal polyps, the values were 0.54 ± 0.33 and 0.37 ± 0.31, respectively. Changes in BCVA values were significantly different between the two groups (p = 0.023). CONCLUSIONS: Although anti-VEGF therapy has favorable short-term efficacy for treating PCV with grape-like polyp clusters, long-term visual improvements are generally limited in the majority of afflicted eyes. The presence of subfoveal or juxtafoveal polyps may suggest unfavorable treatment outcomes.
Aged ; Angiogenesis Inhibitors/*administration & dosage ; Choroid/blood supply/*diagnostic imaging ; Choroidal Neovascularization/diagnosis/*drug therapy ; Female ; Fluorescein Angiography ; Follow-Up Studies ; Fundus Oculi ; Humans ; Intravitreal Injections ; Male ; Polyps/diagnosis/*drug therapy ; Retrospective Studies ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/*antagonists & inhibitors

PURPOSE: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) is the first choice of treatment for age-related macular degeneration. However, quite a few eyes treated using conventional dose anti-VEGF (CDAV) have persistent pigment epithelial detachment (PED) on optical coherence tomography. This study investigated the efficacy and safety of high dose anti-VEGF (HDAV) for refractory PED. METHODS: In this retrospective study, 31 eyes of neovascular age-related macular degeneration patients with persistent PED findings despite six or more intravitreal injections of CDAV (bevacizumab 1.25 mg or ranibizumab 2.5 mg) were analyzed. Changes in visual outcome, central foveal thickness, and PED height were compared before and after HDAV (bevacizumab 5.0 mg) for these refractory PED cases. RESULTS: The mean age of patients was 67.7 years. The number of CDAV injections was 12.1. The number of HDAV injections was 3.39. Best-corrected visual acuity in logarithm of the minimum angle of resolution before and after HDAV was 0.49 and 0.41 (p < 0.001), respectively. Central foveal thickness before and after HDAV was 330.06 and 311.10 µm (p = 0.125), respectively. PED height before and after HDAV was 230.28 and 204.07 µm (p = 0.014), respectively. There were no serious adverse reactions in all the eyes. CONCLUSIONS: Increasing the dose of bevacizumab in refractory PED may be a possible treatment option.
Aged ; Angiogenesis Inhibitors/administration & dosage ; Bevacizumab/*administration & dosage ; Dose-Response Relationship, Drug ; Female ; Fluorescein Angiography ; Fundus Oculi ; Humans ; Intravitreal Injections ; Macular Degeneration/*complications/diagnosis/drug therapy ; Male ; Middle Aged ; Retinal Detachment/diagnosis/*drug therapy/etiology ; Retinal Pigment Epithelium/*diagnostic imaging/drug effects ; Retrospective Studies ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/antagonists & inhibitors

OBJECTIVETo investigate the effect of extracellular signal-regulated kinase (ERK) signaling pathway on the endothelial differentiation of periodontal ligament stem cells (PDLSC).

METHODSHuman PDLSC was cultured in the medium with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) to induce endothelial differentiation. Endothelial inducing cells was incubated with U0126, a specific p-ERK1/2 inhibitor. PDLSC from one person were randomly divided into four groups: control group, endothelial induced group, endothelial induced+DMSO group and endothelial induced+U0126 group. The protein expression of the p-EKR1/2 was analyzed by Western blotting at 0, 1, 3, 6 and 12 hours during endonthelial induction. The mRNA expressions of CD31, VE-cadherin, and VEGF were detected by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) after a 7-day induction. The proportion of CD31(+) to VE-cadherin(+) cells was identified by flow cytometry, and the ability of capillary-like tubes formation was detected by Matrigel assay after a 14-day induction. The measurement data were statistically analyzed.

RESULTSPhosphorylated ERK1/2 protein level in PDLSC was increased to 1.24±0.12 and 1.03±0.24 at 1 h and 3 h respectively, during the endothelial induction (P<0.01). The mRNA expressions of CD31 and VEGF in induced+U0126 group were decreased to 0.09±0.18 and 0.49±0.17, which were both significantly different with those in induced group (P<0.05). The proportion of CD31(+) to VE-cadherin(+) cells of induced+U0126 group were decreased to 5.22±0.85 and 3.56±0.87, which were both significantly different with those in induced group (P<0.05). In Matrigel assay, the branching points, tube number and tube length were decreased to 7.0±2.7, 33.5±6.4, and (15 951.0±758.1) pixels, which were all significantly different with those in induced group (P<0.05).

CONCLUSIONSThe endothelial differentiation of PDLSC is positively regulated by ERK signaling pathway. Inhibition of ERK1/2 phosphorylation could suppress endothelial differentiation of PDLSC.

Antigens, CD ; genetics ; metabolism ; Butadienes ; pharmacology ; Cadherins ; genetics ; metabolism ; Cell Differentiation ; Endothelial Cells ; cytology ; physiology ; Enzyme Inhibitors ; pharmacology ; Extracellular Signal-Regulated MAP Kinases ; physiology ; Fibroblast Growth Factor 2 ; pharmacology ; Humans ; Mitogen-Activated Protein Kinase 3 ; antagonists & inhibitors ; metabolism ; Nitriles ; pharmacology ; Periodontal Ligament ; cytology ; metabolism ; Phosphorylation ; Platelet Endothelial Cell Adhesion Molecule-1 ; genetics ; metabolism ; RNA, Messenger ; metabolism ; Random Allocation ; Signal Transduction ; Stem Cells ; cytology ; physiology ; Time Factors ; Vascular Endothelial Growth Factor A ; genetics ; metabolism ; pharmacology

PURPOSE: To evaluate the effects of posterior subtenon triamcinolone acetonide injection on refractory diabetic macular edema (DME) after intravitreal bevacizumab (IVB) injection failure. METHODS: Patients with DME and central subfield thickness (CST) >300 microm who did not respond to IVB injections were retrospectively included. Specifically, we enrolled patients who were diagnosed with refractory DME and who experienced an increase in CST after 1 to 2 IVB injections or no decrease after > or =3 consecutive IVB injections. One clinician injected 20 mg of triamcinolone acetonide into the posterior subtenon space. All patients received ophthalmic examinations at baseline and at 2, 4, and 6 months post-baseline. Examinations included Snellen visual acuity, intraocular pressure, and spectral-domain optical coherence tomography. RESULTS: Forty eyes of 34 patients were included. The average baseline CST was 476 microm. The average CST decreased to 368 microm at 2 months, 374 microm at 4 months, and 427 microm at 6 months (p < 0.001 for all results, Wilcoxon signed-rank test). The average intraocular pressure increased from 15.50 to 16.92 mmHg at 2 months but decreased to 16.30 mmHg at 4 months and 15.65 mmHg at 6 months. Logarithm of the minimum angle of resolution visual acuity improved from 0.56 to 0.50 at 2 months (p = 0.023), 0.50 at 4 months (p = 0.083), and 0.48 at 6 months (p = 0.133, Wilcoxon signed-rank test). No complications were detected. CONCLUSIONS: Posterior subtenon triamcinolone acetonide is an effective and safe treatment for reducing CST in DME refractory to IVB.
Aged ; Angiogenesis Inhibitors/*therapeutic use ; Bevacizumab/*therapeutic use ; Diabetic Retinopathy/diagnostic imaging/*drug therapy/physiopathology ; Female ; Glucocorticoids/*administration & dosage ; Humans ; Injections, Intraocular ; Intraocular Pressure/physiology ; Intravitreal Injections ; Macular Edema/diagnostic imaging/*drug therapy/physiopathology ; Male ; Middle Aged ; Retrospective Studies ; Tenon Capsule/*drug effects ; Tomography, Optical Coherence ; Treatment Failure ; Triamcinolone Acetonide/*administration & dosage ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Visual Acuity/physiology

PURPOSE: To describe the changes of fundus autofluorescence (FAF) in patients with age-related macular degeneration before and after intravitreal injection of anti-vascular endothelial growth factor according to the type of choroidal neovascularization (CNV) and to evaluate the correlation of FAF with spectral domain optical coherence tomography (SD-OCT) parameters and vision. METHODS: This was a retrospective study. Twenty-one treatment-naive patients with neovascular age-related macular degeneration were included. Study eyes were divided into two groups according to the type of CNV. Fourteen eyes were type 1 CNV and seven eyes were type 2 CNV. All eyes underwent a complete ophthalmologic examination, including an assessment of best-corrected visual acuity, SD-OCT, fluorescein angiography, and FAF imaging, before and 3 months after intravitreal anti-vascular endothelial growth factor injection. Gray scales of FAF image for CNV areas, delineated as in fluorescein angiography, were analyzed using the ImageJ program, which were adjusted by comparison with normal background areas. Correlation of changes in FAF with changes in SD-OCT parameters, including CNV thickness, photoreceptor inner and outer segment junction disruption length, external limiting membrane disruption length, central macular thickness, subretinal fluid, and intraretinal fluid were analyzed. RESULTS: Eyes with both type 1 and type 2 CNV showed reduced FAF before treatment. The mean gray scales (%) of type 1 and type 2 CNV were 52.20% and 42.55%, respectively. The background values were 106.72 and 96.86. After treatment, the mean gray scales (%) of type 1 CNV and type 2 CNV were changed to 57.61% (p = 0.005) and 57.93% (p = 0.008), respectively. After treatment, CNV thickness, central macular thickness, and inner and outer segment junction disruption length were decreased while FAF increased. CONCLUSIONS: FAF was noted to be reduced in eyes with newly diagnosed wet age-related macular degeneration, but increased after anti-vascular endothelial growth factor therapy regardless of CNV lesion type.
Aged ; Angiogenesis Inhibitors/*therapeutic use ; Choroidal Neovascularization/classification/diagnostic imaging/*drug therapy ; Female ; Fluorescein Angiography ; Fundus Oculi ; Humans ; Intravitreal Injections ; Male ; Middle Aged ; Optical Imaging ; Ranibizumab/*therapeutic use ; Retrospective Studies ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/*antagonists & inhibitors ; Visual Acuity ; Wet Macular Degeneration/classification/diagnostic imaging/*drug therapy

No abstract available.
Angiogenesis Inhibitors/administration & dosage ; Bevacizumab/*administration & dosage ; Follow-Up Studies ; Humans ; Intravitreal Injections ; Male ; Middle Aged ; Optic Disk/*pathology ; POEMS Syndrome/*complications/diagnosis ; Papilledema/diagnosis/*drug therapy/etiology ; Tomography, Optical Coherence ; Vascular Endothelial Growth Factor A/*antagonists & inhibitors