Differences between pathologic and non-pathologic high myopia in 4-year outcomes of anti-VEGF therapy for macular neovascularization.

This retrospective observational study aimed to investigate the difference in 4-year outcomes of ranibizumab or aflibercept therapy for macular neovascularization (MNV) with high myopia between pathologic myopia (PM) and non-PM. This study was conducted at Kyoto University Hospital and included consecutive treatment-naïve eyes with active myopic MNV, in which a single intravitreal ranibizumab or aflibercept injection was administered, followed by a pro re nata (PRN) regimen for 4 years. Based on the META-PM study classification, eyes were assigned to the non-PM and PM groups. This study analyzed 118 eyes of 118 patients (non-PM group, 19 eyes; PM group, 99 eyes). Baseline, 1-year, and 2-year best-corrected visual acuity (BCVA) were significantly better in the non-PM group (P = 0.02, 0.01, and 0.02, respectively); however, the 3-year and 4-year BCVA were not. The 4-year BCVA course was similar in both groups. However, the total number of injections over 4 years was significantly higher in the non-PM than in the PM group (4.6 ± 2.6 vs. 2.9 ± 2.6, P = 0.001). Four-year BCVA significantly correlated only with baseline BCVA in both non-PM (P = 0.047, ß = 0.46) and PM groups (P < 0.001, ß = 0.59). In conclusion, over the 4-year observation period, the BCVA course after anti-VEGF therapy for myopic MNV was similar in the eyes with non-PM and those with PM; however, more additional injections in a PRN regimen were required in the eyes with non-PM compared to those with PM. Thus, more frequent and careful follow-up is required for the eyes with non-PM compared with those with PM to maintain long-term BCVA.

Short-Term Outcomes of 3 Monthly intravitreal Faricimab On Different Subtypes of Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the efficacy and safety of faricimab injections for treatment-naïve neovascular age-related macular degeneration (nvAMD) patients, including subtypes and pachychoroid phenotypes, and identify predictive factors for visual outcomes. Methods: nvAMD patients were prospectively recruited, receiving three monthly faricimab (6 mg) injections. Best-corrected visual acuity (BCVA) two months after the last injection (month 4) was compared between subtypes, and between pachychoroid neovasculopathy (PNV) and non-PNV eyes. Regression analysis determined factors influencing month 4 BCVA. Results: The study involved 23 patients (12 typical AMD [tAMD], 10 polypoidal choroidal vasculopathy [PCV], 1 retinal angiomatous proliferation [RAP]). Eleven exhibited PNV phenotype. Significant BCVA (P = 4.9 × 10-4) and central retinal thickness (CRT) (P = 1.3 × 10-5) improvements were observed post-faricimab treatment. The therapy demonstrated favourable results for both tAMD and PCV eyes, and non-PNV and PNV eyes. Faricimab achieved dry macula in 77.3% of eyes, with subretinal fluid resolution in most cases, although intraretinal fluid (IRF) often persisted. Multivariable analysis identified external limiting membrane (ELM) presence and IRF as BCVA contributors at month 4. Conclusion: Faricimab demonstrated significant effectiveness and safety in treatment-naïve nvAMD patients, particularly for PCV and PNV eyes. ELM presence and IRF is predictive of visual outcomes.

Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

MACULAR CHORIORETINAL ATROPHY AND VISUAL OUTCOMES IN RANIBIZUMAB- OR AFLIBERCEPT-TREATED MYOPIC CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To investigate the predictors of macular chorioretinal atrophy, consisting of patchy atrophy (PA) at the macula and choroidal neovascularization (CNV)-related macular atrophy (CNV-MA), during treatment with ranibizumab or aflibercept for myopic CNV (mCNV) and its impact on visual outcomes. METHODS: This retrospective study included 82 eyes with treatment-naïve mCNV who were treated with pro re nata injections of ranibizumab or aflibercept. RESULTS: Nine eyes (11.0%) presented with macular PA at baseline (PA group), and 73 eyes (89.0%) did not (non-PA group). VA improved during the first year in the non-PA group; a similar trend was noted in the PA group until 3 months after initial treatment. This improvement was maintained until 24 months ( P < 0.001) in the non-PA group, but not in the PA group. In the PA group, macular chorioretinal atrophy progressed faster ( P < 0.0001), and CNV-MA was more frequent during the 2 years of treatments ( P = 0.04). Even non-PA group eyes sometimes developed CNV-MA (42% at Month 24) if they had a larger CNV and thinner subfoveal choroidal thickness at baseline, resulting in poorer visual prognosis ( P < 0.01). CONCLUSION: Macular PA at baseline was a risk factor for CNV-MA development and was associated with poor visual outcomes.

Annual trends of ophthalmic surgeries in Japan's super-aged society, 2014-2020: a national claims database study.

This study aimed to analyze the trends and factors influencing the number of ophthalmic surgeries in Japan using the open data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan published by the Ministry of Health, Labour and Welfare. We calculated the number of cataract, glaucoma, and vitreoretinal surgeries, categorized by sex, age, and surgical type, for the fiscal years (FY) 2014 to 2020. The number of cataract surgeries remained stable at approximately 1.45 million cases from FY 2014 to 2018, increased to nearly 1.6 million cases in FY 2019, and decreased to 1.45 million cases in FY 2020. Among glaucoma surgeries, surgical treatments were increased 1.8 times over 7 years, from 33,000 to 60,000 cases. Laser treatment remained steady at around 55,000 cases from FY 2014 to 2017 and then increased to approximately 60,000 cases. The number of vitreoretinal surgeries was increased 1.2 times from FY 2014 to 2019, from 120,000 to 140,000, and decreased to 130,000 by FY 2020. Trends in ophthalmic surgeries over the past 7 years may be influenced by population aging, minimally invasive surgery, and the coronavirus disease pandemic. These findings have implications on surgical decision-making and resource allocation.

Therapeutic effects of faricimab on aflibercept-refractory age-related macular degeneration.

Though vascular endothelial growth factors (VEGF) and other proangiogenic factors, such as angiopoietins (Ang), may be involved in the development of neovascular age-related macular degeneration (nvAMD), only drugs that inhibit the VEGF family are available for the treatment. The newly approved anti-VEGF drug faricimab, which also inhibits Ang-2, is expected to be effective in patients with AMD refractory to conventional anti-VEGF drugs. Therefore, we prospectively investigated the efficacy of faricimab in the treatment of aflibercept-refractory nvAMD. Patients with nvAMD who had been treated with aflibercept in the last year and required bimonthly injections were recruited. 25 eyes showed persistent exudative changes immediately before the faricimab injection (baseline). In these 25 eyes, switching to faricimab did not change visual acuity or central retinal thickness 2 months after the injection; however, 56% of eyes showed reduction or complete absorption of fluid. Notably, 25% of the eyes that showed dry macula at month 2 had no fluid recurrence for up to 4 months. These results indicate that faricimab could benefit some patients with aflibercept-refractory nvAMD.

A case of Epstein-Barr virus-associated primary vitreoretinal lymphoma in an immunosuppressed patient.

PURPOSE: To describe a rare case of Epstein-Barr virus (EBV)-positive primary vitreoretinal lymphoma (PVRL) in an immunosuppressed patient. METHODS: Observational case report. RESULTS: A 64-year-old man under immunosuppressive therapy for rheumatic arthritis was referred for 2-month of blurred vision and decreased visual acuity in the right eye. Only mutton-fat keratic precipitates and mild vitreous opacity were found in the right eye without (sub-)retinal or sub-retinal pigment epithelial lesions. Vitreous biopsy and systemic workup suggested the diagnosis of PVRL of diffuse large B cell lymphoma (DLBCL) subform. Neoplastic cells stained positive for EBV antigens, EBV-encoded small RNA and Epstein-Barr nuclear antigen 2, consistent with EBV-positive DLBCL. Intravitreal methotrexate was effective in improving ocular symptoms. CONCLUSION: Our case provided evidence on the association of EBV infection with PVRL.

PREDICTORS OF 3-MONTH AND 1-YEAR VISUAL OUTCOMES AFTER VITRECTOMY WITH SUBRETINAL TISSUE PLASMINOGEN ACTIVATOR INJECTION FOR SUBMACULAR HEMORRHAGE.

PURPOSE: To investigate factors associated with 3-month or 1-year best-corrected visual acuity (BCVA) after vitrectomy with subretinal tissue plasminogen activator injection for submacular hemorrhage (SMH) and to identify the predictors of early displacement. METHODS: This prospective cohort study included consecutive eyes with SMH complicating neovascular age-related macular degeneration or retinal macroaneurysm that underwent vitrectomy with subretinal tissue plasminogen activator injection and were followed up for at least 3 months. Parameters that correlated with 3-month BCVA, 1-year BCVA, and 2-week displacement grade (0-3) were identified. RESULTS: Twenty-nine eyes of 29 patients (73.1 ± 8.4 years; neovascular age-related macular degeneration, 25 eyes) were included. Logarithm of the minimum angle of resolution BCVA improved 3 months after the surgery (baseline, 0.76 [20/115] ± 0.35; 3-month, 0.51 [20/65] ± 0.32; P = 0.006). In multivariable analyses, 1-year logarithm of the minimum angle of resolution BCVA correlated with age ( P = 0.007, ß = 0.39) and SMH recurrence within 1 year after surgery ( P < 0.001, ß = 0.65). Two-week displacement grade correlated with the contrast-to-noise ratio of SMH ( P = 0.001, ß = -0.54). Macular hole occurred in three eyes (10%) with small SMH size and was closed in all eyes via additional vitrectomy with an inverted internal limiting membrane flap technique. CONCLUSION: The recurrence of SMH negatively affected the 1-year visual outcome after vitrectomy with subretinal tissue plasminogen activator injection for SMH. The contrast-to-noise ratio was a useful predictor of early SMH displacement, but not of 1-year BCVA. Further research is necessary to determine the optimal treatment to prevent SMH recurrence.

TEN-YEAR VISUAL OUTCOME AND CHANGE IN CHORIORETINAL ATROPHY AFTER INTRAVITREAL RANIBIZUMAB FOR MACULAR NEOVASCULARIZATION IN PATHOLOGIC MYOPIA.

PURPOSE: To investigate the 10-year visual outcome and chorioretinal atrophy after a single intravitreal ranibizumab injection followed by a pro re nata regimen for myopic macular neovascularization in pathologic myopia, and to identify the factors associated with 10-year best-corrected visual acuity (BCVA). METHODS: This retrospective observational study evaluated 26 consecutive treatment-naïve eyes (26 patients) with myopic macular neovascularization in pathologic myopia who underwent a single intravitreal ranibizumab followed by a pro re nata regimen of intravitreal ranibizumab and/or intravitreal aflibercept injection and observed over 10 years. We assessed changes in BCVA and morphological parameters, including the META-PM Study category as a chorioretinal atrophy index. RESULTS: The logarithm of the minimum angle of resolution BCVA changed from 0.36 (Snellen, 20/45) ± 0.39 to 0.39 (20/49) ± 0.36 over 10 years of observation. Compared to baseline, 1-year BCVA improved ( P = 0.002), whereas 2 to 10-year BCVA was not significantly different. Total injection frequency was 3.8 ± 2.6. In none of the eyes, 10-year BCVA was 20/200 or less. Ten-year BCVA correlated with baseline BCVA ( P = 0.01, r = 0.47). The META-PM Study category progressed in 60% of eyes. There were no drug-induced complications. CONCLUSION: Best-corrected visual acuity in eyes with myopic macular neovascularization in pathologic myopia was maintained for 10 years after a single intravitreal ranibizumab followed by a pro re nata regimen without drug-induced complications. The META-PM Study category progressed in 60% of eyes, especially those with older baseline age. Early diagnosis and treatment of myopic macular neovascularization are essential to maintain good long-term BCVA.

Computational Screening of Inhibitory Compounds for SARS-Cov-2 3CL Protease with a Database Consisting of Approved and Investigational Chemicals.

Computational screening is one of the fundamental techniques in drug discovery. Each compound in a chemical database is bound to the target protein in virtual, and candidate compounds are selected from the binding scores. In this work, we carried out combinational computation of docking simulation to generate binding poses and molecular mechanics calculation to estimate binding scores. The coronavirus infectious disease has spread worldwide, and effective chemotherapy is strongly required. The viral 3-chymotrypsin-like (3CL) protease is a good target of low molecular-weight inhibitors. Hence, computational screening was performed to search for inhibitory compounds acting on the 3CL protease. As a preliminary assessment of the performance of this approach, we used 51 compounds for which inhibitory activity had already been confirmed. Docking simulations and molecular mechanics calculations were performed to evaluate binding scores. The preliminary evaluation suggested that our approach successfully selected the inhibitory compounds identified by the experiments. The same approach was applied to 8820 compounds in a database consisting of approved and investigational chemicals. Hence, docking simulations, molecular mechanics calculations, and re-evaluation of binding scores including solvation effects were performed, and the top 200 poses were selected as candidates for experimental assays. Consequently, 25 compounds were chosen for in vitro measurement of the enzymatic inhibitory activity. From the enzymatic assay, 5 compounds were identified to have inhibitory activities against the 3CL protease. The present work demonstrated the feasibility of a combination of docking simulation and molecular mechanics calculation for practical use in computational virtual screening.

Effects of Metastatic Sites on Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer.

PURPOSE: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS/BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P < .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.

Rescue photodynamic therapy for age-related macular degeneration refractory to anti-vascular endothelial growth factor monotherapy.

BACKGROUND: To evaluate the 3-year outcome in eyes with neovascular age-related macular degeneration (nAMD) treated with intravitreal anti-vascular endothelial growth factor monotherapy or rescue therapy using standard verteporfin photodynamic therapy (PDT), and corroborate efficacy of rescue PDT. METHODS: Patients were administered aflibercept injections once a month for 3 months followed by once every 2 months in the first year. After year 1, treatment with aflibercept monotherapy as indicated or in combination with PDT at the retinal specialist's discretion. Only cases completing the three-year follow-up were included. Regression analysis with visual acuity and macular atrophy at year 3 was performed for the dependent variable. RESULTS: Of the 292 eyes, 15 eyes underwent rescue PDT following year 1. The best-corrected visual acuity (logarithm of minimal angle of resolution, mean/Snellen equivalent ± SD) was 0.35 (20/45) ± 0.38, 0.23 (20/30) ± 0.36, 0.26 (20/35) ± 0.38, and 0.31 (20/40) ± 0.42 at baseline, year 1, year 2, and year 3, respectively. Multiple regression analysis revealed that the rescue PDT was significantly associated with macular atrophy and poor visual outcome at year 3 (odds ratio = 1.2, p < 0.001; ß = 0.23, p = 0.0029, respectively). CONCLUSIONS: The visual outcome in eyes with nAMD retained baseline levels at year 3; however, patients treated with rescue PDT developed macular atrophy more frequently and poor visual outcomes.

Pachychoroid-phenotype effects on 5-year visual outcomes of anti-VEGF monotherapy in polypoidal choroidal vasculopathy.

PURPOSE: To investigate whether the efficacy of anti-vascular endothelial growth factor (VEGF) monotherapy for polypoidal choroidal vasculopathy (PCV) differs between pachychoroid and non-pachychoroid phenotypes in the long term. METHODS: This retrospective longitudinal study included 115 treatment-naïve eyes in 115 consecutive patients with symptomatic PCV who were treated with anti-VEGF monotherapy and were followed up for 5 years. Eligible eyes were assigned to either a pachy-PCV group, with a pachychoroid phenotype, or a non-pachy-PCV group, without a pachychoroid phenotype. Best-corrected visual acuity (BCVA) and other parameters over a 5-year period were compared between the groups. RESULTS: Forty-eight eyes and 67 eyes were classified into the pachy-PCV and non-pachy-PCV groups respectively. Baseline and 5-year BCVA (logarithm of the minimum angle of resolution) were 0.19 ± 0.20 and 0.16 ± 0.28 in the pachy-PCV group, respectively, and 0.25 ± 0.26 and 0.26 ± 0.36 in the non-pachy-PCV group respectively. BCVA did not change significantly in either group (p = 0.18 and 0.08 respectively). BCVA did not differ between the groups at any observation time-point. Subfoveal choroidal thickness (SFCT) at baseline and at 5 years was significantly higher in the pachy-PCV group than in the non-pachy-PCV group (both p < 0.001); however, the mean rate of decrease in SFCT did not differ in either group over the 5-year period (22% vs. 23%, p = 0.81). CONCLUSION: Our findings suggest that anti-VEGF monotherapy was similarly effective for pachychoroid- and non-pachychoroid-phenotype eyes with PCV, for at least 5 years, although further studies are required.

Efficacy of combined anti-VEGF and photodynamic therapy for bilateral diffuse uveal melanocytic proliferation: Case series.

RATIONALE: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an extremely rare retinal exudative disease with physical disorders and no established treatment standard. We describe treatment courses in 3 cases of BDUMP. PATIENTS CONCERNS: Three male patients complained active vision loss. One male patient in his 70s (patient 1) was treated with prednisolone, mesalazine, and ciclosporin for hypoplastic anemia and ulcerous colitis. One male patient in his 60s (patient 2) was on prednisolone therapy for adult Still disease. Another male patient in his 70s (patient 3) was on prednisolone therapy for polymyalgia rheumatica, giant cell arteritis, and pancreatic body tumor. DIAGNOSES: Retinal specialists diagnosed these patients with BDUMP based on characteristic fundus findings of multiple red patches and retinal exudate. INTERVENTIONS: Two patients (patients 1 and 2) with poor response to anti-vascular endothelial growth factor (VEGF) monotherapy and/or triamcinolone acetonide sub-Tenon injection were treated with combined anti-VEGF therapy and photodynamic therapy. One patient (patient 3) was treated with 3 rounds of monthly anti-VEGF monotherapy. OUTCOMES: Retinal exudates were resolved in all patients. No recurrence of retinal exudates was observed for at least 10 months, 2 years, or 4 months after the therapy in patients 1, 2, and 3, respectively. However, best-corrected visual acuity of the right eye was low (20/200) compared with that of the left eye (20/22) in patient 2 despite exudate resolution, due to permanent outer retinal damage secondary to long-term retinal exudate. LESSONS SUBSECTIONS: Combined anti-VEGF therapy and photodynamic therapy may be a feasible therapeutic option for treatment-resistant exudate in patients with BDUMP. Early diagnosis of BDUMP and prompt administration of combination therapy are crucial.

Visual acuity outcomes of anti-VEGF treatment for neovascular age-related macular degeneration in clinical trials.

Anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) has been evaluated in clinical trials. To select the best anti-VEGF drug and the best treatment regimen for nAMD, a thorough understanding of the characteristics of each anti-VEGF drug and treatment regimen is essential. In this review, we summarized visual acuity (VA) changes in 30 previous clinical trials of anti-VEGF treatment for nAMD. In most studies, ranibizumab, aflibercept, and brolucizumab improved the VA by 6 to 12 letters from the baseline VA of 50-65 letters and maintained the VA improvement regardless of the treatment regimen; the VA improved from 0.2-0.4 to 0.3-0.7 in Snellen equivalents. The improvement was rapid during the first month and became slower after the second injection, and 60% to 90% of the VA improvement was attained within the first 3 months. The upper limit of the VA improvement should be determined according to eyes with nAMD themselves, not according to anti-VEGF drugs or treatment regimens. Since a fixed regimen can result in overtreatment, whilst a pro re nata regimen can result in insufficient treatment, a treat-and-extend regimen would be optimal to treat nAMD. Insufficient treatment fails to improve VA to the upper limit and/or to maintain the improved VA, whereas overtreatment can cause macular atrophy. One study reported no difference in the risk of macular atrophy between ranibizumab and aflibercept, whilst many studies have suggested that aflibercept causes more choroidal thinning, one of the risk factors for macular atrophy, than does ranibizumab. Further evaluation of drugs and regimens should be performed from the viewpoint of complications and minimum number of injections required to improve and maintain VA.

Myeloid-resident neuropilin-1 promotes choroidal neovascularization while mitigating inflammation.

Age-related macular degeneration (AMD) in its various forms is a leading cause of blindness in industrialized countries. Here, we provide evidence that ligands for neuropilin-1 (NRP1), such as Semaphorin 3A and VEGF-A, are elevated in the vitreous of patients with AMD at times of active choroidal neovascularization (CNV). We further demonstrate that NRP1-expressing myeloid cells promote and maintain CNV. Expression of NRP1 on cells of myeloid lineage is critical for mitigating production of inflammatory factors such as IL6 and IL1ß. Therapeutically trapping ligands of NRP1 with an NRP1-derived trap reduces CNV. Collectively, our findings identify a role for NRP1-expressing myeloid cells in promoting pathological angiogenesis during CNV and introduce a therapeutic approach to counter neovascular AMD.

Effects of Intravitreous Aflibercept Injection in Pachychoroid Neovasculopathy: Comparison with Typical Neovascular Age-Related Macular Degeneration.

PURPOSE: To compare the 12-month efficacy of intravitreous aflibercept (IVA) injection between eyes with pachychoroid neovasculopathy and neovascular age-related macular degeneration (AMD). METHODS: Retrospective, comparative case series analysis. Twenty-seven eyes with pachychoroid neovasculopathy and sixty-three eyes with neovascular AMD. All patients received three initial monthly, followed by bimonthly, IVA injections. RESULTS: Twelve months after initial treatment, the mean best-corrected visual acuity (BCVA) had improved both in pachychoroid neovasculopathy (from 0.28 to 0.14 logMAR; P = 0.001) and neovascular AMD (from 0.40 to 0.29 logMAR; P < 0.001). Twelve months after initial treatment, eyes with pachychoroid neovasculopathy exhibited decreased mean central retinal thickness (CRT) and subfoveal choroidal thickness (both, P < 0.001) and presence of polyps (P = 0.039) and improved integrity of external limiting membrane (ELM) (P = 0.008) and ellipsoid zone band (P = 0.001). At the 12-month follow-up, 77% and 68% of eyes with pachychoroid neovasculopathy and neovascular AMD, respectively, exhibited dry macula (P = 0.30). Baseline CRT was correlated with 12-month BCVA in eyes with pachychoroid neovasculopathy (P = 0.02). In eyes with neovascular AMD, CRT (P = 0.005) and presence of intact ELM (P = 0.007) were significant predictors of 12-month BCVA. CONCLUSION: Periodic IVA injection leads to anatomical and functional improvement in eyes with pachychoroid neovasculopathy and in eyes with neovascular AMD.

Deterioration of phagocytosis in induced pluripotent stem cell-derived retinal pigment epithelial cells established from patients with retinitis pigmentosa carrying Mer tyrosine kinase mutations.

Retinitis pigmentosa (RP) is an incurable retinal degenerative disease with an unknown mechanism of disease progression. Mer tyrosine kinase (MERTK), which encodes a receptor of the Tyro3/Axl/Mer family of tyrosine kinases, is one of the causal genes of RP. MERTK is reportedly expressed in the retinal pigment epithelium (RPE) and is essential for phagocytosis of the photoreceptor outer segment. Here, we established induced pluripotent stem cells (iPSC) from patients with RP having homozygous or compound heterozygous mutations in MERTK, and from healthy subjects; the RP patient- and healthy control-derived iPSCs were differentiated into RPE cells. Although cytoskeleton staining suggested that polarity may have been disturbed mildly, there were no apparent morphological differences between the diseased and normal RPE cells. The internalization of photoreceptor outer segments in diseased iPSC-RPE cells was significantly lower than that in normal iPSC-RPE cells. This in vitro disease model may be useful for elucidating the mechanisms of disease progression and screening treatments for the disease.

Characteristics of pachychoroid neovasculopathy.

Recently, several research groups have reported a newly recognized clinical entity of choroidal neovascularization, termed pachychoroid neovasculopathy. However, its characteristics have yet to be well described. The purpose of this study was to investigate the clinical and genetic characteristics of pachychoroid neovasculopathy regardless of treatment modality. This study included 99 eyes of 99 patients with treatment-naïve pachychoroid neovasculopathy. Mean initial best-corrected visual acuity (BCVA) was 0.20 ± 0.32 logMAR, and did not change (P = 0.725) during follow-up period (mean ± SD, 37.0 ± 17.6 months). Subretinal hemorrhage (SRH) (≥ 4 disc areas in size) occurred in 20 eyes (20.2%) during follow-up. Age, initial BCVA, central retinal thickness, SRH (≥ 4 disc areas in size) and treatment (aflibercept monotherapy) were significantly associated with the final BCVA (P = 0.024, < 0.001, 0.031, < 0.001, and 0.029, respectively). Multiple regression analysis showed initial BCVA and presence of SRH to be significant predictors of final BCVA (both P < 0.001). Polypoidal lesions were more common in the SRH group than in the non-SRH group (85.0% vs 48.1%, P = 0.004). There was no significant difference in the frequency of the risk allele in ARMS2 A69S, CFH I62V, CFH Y402H between these groups (P = 0.42, 0.77, and 0.85, respectively). SRH (29.1% vs 9.1%, P = 0.014) and choroidal vascular hyperpermiability (65.5% vs 43.2%, P = 0.027) were seen more frequently in the polypoidal lesion (+) group than in the polypoidal lesion (-) group. There was considerable variation in lesion size and visual function in patients with pachychoroid neovasculopathy, and initial BCVA and presence of SRH at the initial visit or during the follow-up period were significant predictors of final BCVA.

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.