FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer.

Estrogen receptor α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. The molecular mechanisms underlying the up-regulation of ERα activity, however, remain poorly understood. We identified FK506-binding protein 52 (FKBP52) as a factor associated with poor prognosis of individuals with ERα-positive breast cancer. We found that FKBP52 interacts with breast cancer susceptibility gene 1 and stabilizes ERα, and is essential for breast cancer cell proliferation. FKBP52 depletion resulted in decreased ERα expression and proliferation in breast cancer cell lines, including MCF7-derived fulvestrant resistance (MFR) cells, suggesting that inhibiting FKBP52 may provide a therapeutic effect for endocrine therapy­resistant breast cancer. In contrast, FKBP51, a closely related molecule to FKBP52, reduced the stability of ERα. Consistent with these findings, FKBP51 was more abundantly expressed in normal tissues than in cancer cells, suggesting that these FKBPs may function in the opposite direction. Collectively, our study shows that FKBP52 and FKBP51 regulate ERα stability in a reciprocal manner and reveals a regulatory mechanism by which the expression of ERα is controlled.

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

BACKGROUND: The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. METHODS: Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78 Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n = 197). In principle, patients received androgen deprivation therapy for 3-6 months before radiation, concurrently, and for 2 years after completion of intensity-modulated radiation therapy. RESULTS: The median follow-up period was 96 months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P = 0.023). Grade Group 5 and younger age (cutoff: 70 years old) were independent predictors of recurrence (P = 0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18 months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P = 0.039) when contrasted with those who had a longer interval to biochemical failure. CONCLUSIONS: Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

Prednisolone improves hippocampal regeneration after trimethyltin-induced neurodegeneration in association with prevention of T lymphocyte infiltration.

The endogenous regenerative capacity of the brain is quite weak; however, a regenerative reaction, the production of new neurons (neurogenesis), has been reported to occur in brain lesions. In addition, leukocytes are well known to infiltrate brain lesions. Therefore, leukocytes would also have a link with regenerative neurogenesis; however, their role has not been fully elucidated. In this study, we investigated leukocyte infiltration and its influence on brain tissue regeneration in a trimethyltin (TMT)-injected mouse model of hippocampal regeneration. Immunohistochemically, CD3-positive T lymphocytes were found in the hippocampal lesion of TMT-injected mice. Prednisolone (PSL) treatment inhibited T lymphocyte infiltration and increased neuronal nuclei (NeuN)-positive mature neurons and doublecortin (DCX)-positive immature neurons in the hippocampus. Investigation of bromodeoxyuridine (BrdU)-labeled newborn cells revealed the percentage of BrdU/NeuN- and BrdU/DCX-positive cells increased by PSL treatment. These results indicate that infiltrated T lymphocytes prevent brain tissue regeneration by inhibiting hippocampal neurogenesis.

Disseminated histiocytic sarcoma in a squirrel monkey (Saimiri sciureus).

A 14-years-old squirrel monkey was euthanized due to weakness. Histopathological examination revealed multifocal growth of oval cells with severe atypia in the liver, spleen, and bone marrow. The neoplastic cells were positive for histiocytic markers (Iba1, HLA-DR, CD204). This is the fourth case of histiocytic sarcoma in non-human primates.

Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system.

Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because αV ß3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS-RC-2 tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2 tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that biglycan was knocked down by biglycan siRNA-containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA-containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.

Influence of radiation dose and predicted tumor invasion depth on local recurrence after definitive chemoradiotherapy for stage 0-I esophageal squamous cell carcinoma: a propensity score-weighted, retrospective, observational study.

BACKGROUND: The optimal radiation dose for treating non-metastatic superficial esophageal squamous cell carcinoma is unknown. In this retrospective observational study, we investigated the influence of radiation dose and pretreatment endoscopic prediction of tumor invasion depth on local recurrence after definitive chemoradiotherapy in patients with superficial esophageal squamous cell carcinoma. METHODS: We analyzed 134 patients with clinical Tis-T1N0M0 esophageal squamous cell carcinoma who underwent chemoradiotherapy at our institution between 2006 and 2019. Patients were grouped into standard-dose (50.0-50.4 Gy) and high-dose (60.0 Gy) radiotherapy groups. The outcomes of interest were local recurrence and major local recurrence (endoscopically unresectable local recurrent tumors). Kaplan-Meier analysis and the log-rank test were used with propensity score and inverse probability of treatment weighting. Cox proportional hazards analysis was performed to identify predictors of local recurrence and major local recurrence. RESULTS: The median follow-up times were 52 and 84 months for the standard-dose and high-dose groups, respectively. The adjusted 3-year local recurrence and major local recurrence rates in the standard-dose and high-dose groups were 33.8 and 9.6% (adjusted hazard ratio, 4.00 [95% confidence interval: 1.64-9.73]; adjusted log-rank p = 0.001) and 12.5 and 4.7% (adjusted hazard ratio, 3.13 [95% confidence interval: 0.91-10.81]; adjusted log-rank p = 0.098), respectively. Cox proportional hazards analysis showed that standard-dose radiotherapy and endoscopic findings of deep submucosal invasion are independently associated with local recurrence and major local recurrence. CONCLUSIONS: High-dose radiotherapy is more beneficial for local tumor control than standard-dose radiotherapy in patients with non-metastatic superficial esophageal squamous cell carcinoma. The use of high-dose radiotherapy may merit consideration for tumors with deep submucosal invasion.

Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy.

BACKGROUND: Biglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear. METHODS: Biglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively. RESULTS: Breast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice. CONCLUSION: Our results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.

Histopathological Characterization of Cases of Spontaneous Fatal Feline Severe Fever with Thrombocytopenia Syndrome, Japan.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease caused by SFTS virus (SFTSV). We report 7 cases of spontaneous fatal SFTS in felines. Necropsies revealed characteristic lesions, including necrotizing lymphadenitis in 5 cases and necrotizing splenitis and SFTSV-positive blastic lymphocytes in all cases. We detected hemorrhagic lesions in the gastrointestinal tract in 6 cases and lungs in 3 cases, suggesting a more severe clinical course of SFTS in felids than in humans. We noted necrotic or ulcerative foci in the gastrointestinal tract in 3 cases, the lung in 2 cases, and the liver in 4 cases. We clarified that blastic lymphocytes are predominant targets of SFTSV and involved in induction of necrotic foci. We also found that thymic epithelial cells were additional targets of SFTSV. These results provide insights for diagnosing feline SFTS during pathological examination and demonstrate the similarity of feline and human SFTS cases.

Minocycline prevents depression-like behavior in streptozotocin-induced diabetic mice.

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia. Diabetic patients are known to have a higher prevalence and a higher risk of depression compared with the general population. The pathogenesis of diabetes-related depression is unclear, and the treatment is not well-established. Therefore, the prevention of diabetes-related depression is important for improving the quality of life of diabetic patients. Minocycline, a second-generation tetracycline antibiotic, has recently gained attention as a new agent for depression. In this study, we investigated the effect of minocycline on diabetes-related depression in a streptozotocin-induced mouse model of diabetes. Eight-week-old male C57BL/6 mice were injected with streptozotocin (200 mg/kg, i.p.). Seven days after injection, the mice received minocycline treatment through drinking water. We compared these mice with vehicle-treated control mice and diabetic mice not receiving minocycline treatment. On day 34, depression-like behavior was investigated using the forced swim test. On the following day, brain samples were collected, and formalin-fixed, paraffin-embedded specimens were prepared for immunohistochemistry. Compared with the control group, the diabetic mice not receiving minocycline treatment showed a prolonged duration of immobility in the forced swim test, the observation being interpreted as a depression-like behavior. Immunohistochemistry revealed an increase in microglia with an activated morphology in the diabetic mice without minocycline treatment. The expression of tumor necrosis factor alpha in microglia was increased. In addition, a decrease in the number of doublecortin-positive immature neurons was found in the hippocampus of diabetic mice. Minocycline treatment of diabetic animals prevented the depression-like behavior and microglial activation; however, minocycline did not reverse impaired hippocampal neurogenesis. These results indicate that minocycline has a preventive effect on diabetes-related depression. Inhibition of microglial activation would be a critical target for the antidepressant mechanism of minocycline. Impaired hippocampal neurogenesis was observed in diabetic mice; however, this may not be involved in the pathogenesis of depression.

Detectability of fiducials' positions for real-time target tracking system equipping with a standard linac for multiple fiducial markers.

PURPOSE: To investigate the detectability of fiducial markers' positions for real-time target tracking system equipping with a standard linac. The hypothesis is that the detectability depends on the type of fiducial marker and the gantry angle of acquired triggered images. METHODS: Three types of ball fiducials and four slim fiducials with lengths of 3 and 5 mm were prepared for this study. Triggered images with three similar fiducials were acquired at every 10° during the conformal arc irradiation to detect the target position. Although only one type of arrangement was prepared for the ball fiducials, a three-type arrangement was prepared for the slim fiducials, such as parallel, orthogonal, and oblique with 45° to the gantry-couch direction. To measure the detectability of the real-time target tracking system for each fiducial and arrangement, detected marker positions were compared with expected marker positions at every angle of acquired triggered images. RESULTS: For the ball-type fiducial, the maximum difference between the detected marker positions and expected marker positions was 0.3 mm in all directions. For the slim fiducial arranged parallel and oblique with 45°, the maximum difference was 0.4 mm in all directions. When each slim fiducial was arranged orthogonal to the gantry-couch direction, the maximum difference was 1.5 mm for the length of 3 mm, and 3.2 mm for the length of 5 mm. CONCLUSIONS: The detectability of fiducial markers' positions for the real-time target tracking system equipping with a standard linac depends on the form and insertion angles of the fiducials.

Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment.

BACKGROUND: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. METHODOLOGY: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. RESULTS: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. CONCLUSION: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

Clinical characteristics of pachydrusen in central serous chorioretinopathy.

PURPOSE: To evaluate the clinical characteristics of pachydrusen in central serous chorioretinopathy (CSC) and investigate the relationship between choroidal circulation and pachydrusen. METHODS: In a retrospective case series of 302 eyes of 151 patients with treatment-naïve CSC, we assessed the incidence of pachydrusen and their features on indocyanine green angiography (ICGA) and optical coherence tomography (OCT). RESULTS: Pachydrusen were observed in 82 of the 302 eyes (27.2%). The patients with pachydrusen were significantly older than those without pachydrusen. In 36 of the 82 eyes with pachydrusen, the choriocapillaris perfusion phase of ICGA was recorded. Pachydrusen were localized within the geographic filling delay of the choriocapillaris in 26 of the 36 eyes (72.2%). In the late phase of ICGA, pachydrusen corresponded to punctate hyperfluorescent spots in 69 of the 82 eyes (84.1%) and localized within sites of choroidal vascular hyperpermeability in 45 eyes (54.9%). En face OCT revealed pachydrusen to be localized over the dilated outer choroidal vessels in 70 of the 82 eyes (85.4%). B-mode OCT showed pachydrusen under the retinal pigment epithelium (RPE) in 72 of the 82 eyes (87.8%). There was no significant difference in central choroidal thickness between eyes with and without pachydrusen. CONCLUSIONS: Pachydrusen in patients with CSC were frequently localized within the choriocapillaris filling delay and over the dilated outer choroidal vessels. Moreover, they were frequently observed under the RPE and corresponded to punctate hyperfluorescent spots on ICGA. These findings suggest that inner choroidal circulation impairment due to dilatation of outer choroidal vessels might induce pachydrusen.

Nippostrongylus brasiliensis infection inhibits hippocampal neurogenesis in mice.

The brain has long been considered a site of "immune privilege"; however, recent evidence indicates the presence of brain-immune interactions in physiological and pathological conditions. Neurogenesis, a process of generating functionally integrated neurons, occurs in the adult brain of mammals. The adult neurogenesis predominantly takes place in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ). Several studies have shown that an immune reaction or alteration could affect adult neurogenesis activity, suggesting a link between the immune system and adult neurogenesis. Helminth infection is one of the activators of Th2 immune response. However, the influence of this type of immune reaction on adult neurogenesis is not well studied. In this study, we evaluated adult neurogenesis in mice infected with the helminth Nippostrongylus brasiliensis (Nb). Immunohistochemically, the number of both doublecortin-positive cells and doublecortin/5-bromodeoxyuridine (BrdU)-double-positive cells was decreased in the SGZ of Nb-infected mice by day 9 after infection. However, the total number of BrdU-positive newborn cells in the SGZ did not change. In no significant alterations were detected in the SVZ of infected mice. In addition, using reverse transcription-quantitative polymerase chain reaction, we observed no significant changes in the expression levels of neurotropic factors important for neurogenesis in the hippocampus. In conclusion, our results indicate that adult neurogenesis in SGZ, but not in SVZ, is inhibited by Nb infection. Th2 immune response might have a suppressive effect on hippocampal neurogenesis.

A phase I/II trial of pemetrexed plus radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

Background Radiotherapy (RT) is an effective treatment for elderly patients with locally advanced non-small-cell lung cancer (NSCLC); however, no clinical trials have investigated combination RT with pemetrexed (PEM) in chemotherapy-naive patients ≥71 years old. We conducted a phase I/II study to evaluate the appropriate PEM dose, efficacy, and safety of PEM plus RT in elderly patients. Methods Patients ≥71 years with performance status (PS) scores of 0-2 who had pathologically confirmed stage IIIA/IIIB NSCLC received PEM (500 mg/m2 on day 1 of a 28-day cycle, 4 courses) and RT (a single 2 Gy daily fraction on 5 consecutive days weekly from day 1; 60 Gy total). The primary endpoint was the objective response rate (ORR); the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results Forty-one patients with a median age of 79 years were enrolled; 31 were men. Eighteen patients had squamous cell carcinoma, 27 had stage IIIA disease, and 38 had PS scores 0-1. The ORR was 80.5%, while the median OS and PFS rates were 24.9 and 6.9 months, respectively. Two treatment-related deaths occurred owing to RT-related pneumonitis and severe infection, respectively. Common hematological AEs were leucopenia and neutropenia; common non-hematological AEs were anorexia and constipation. Three patients developed PEM-induced interstitial lung disease; however, most AEs were RT-related. Conclusions Combination PEM and RT shows promising efficacy but relatively severe RT-related toxicities. Therefore, this treatment should be prescribed to elderly patients with caution. Trial registration UMIN 000005036 .

Development of Age-Related Macular Degeneration (AMD) in the Fellow Eye of Patients with AMD Treated by Treat-and-Extend Intravitreal Therapy with Aflibercept.

PURPOSE: To evaluate the development of neovascular age-related macular degeneration (nAMD) in the fellow eye in patients with unilateral nAMD treated by a treat-and-extend (TAE) regimen with intravitreal aflibercept injections. METHODS: We retrospectively studied 104 patients with treatment-naïve unilateral nAMD. We assessed best-corrected visual acuity (BCVA) and exudative changes in the treated eyes and development of nAMD in the fellow eye for 2 years. RESULTS: The subjects included 46 patients with typical AMD (tAMD), 44 with polypoidal choroidal vasculopathy (PCV), and 14 with retinal angiomatous proliferation (RAP). BCVA was significantly improved after the loading phase in all subtypes. Forty-six patients (44.2%) had no recurrence within 2 years after the loading phase, including 12 (26.1%) with tAMD, 23 (52.2%) with PCV, and 11 (78.6%) with RAP (p < 0.01). Eleven patients (10.6%) developed nAMD in the fellow eye within 2 years, including 4 (8.7%) with tAMD, 0 (0%) with PCV, and 7 (50.0%) with RAP (p < 0.001). CONCLUSIONS: Patients with RAP had significantly more frequent development of nAMD in the fellow eye compared to other subtypes, while they showed significantly less recurrence during the TAE regimen with intravitreal aflibercept injections. Development of nAMD in the fellow eye should be monitored in RAP when the injection interval is extended.

Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance.

Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDHhigh TEC). ALDHhigh TEC have proangiogenic properties compared with ALDHlow TEC. However, the association between ALDHhigh TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor-conditioned medium (tumor CM). The ALDHhigh population increased along with upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVEC. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDHhigh TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDHhigh TEC showed a higher grade of aneuploidy compared with that in ALDHlow TEC. These results suggested that tumor-secreting factor increases ALDHhigh TEC populations that are resistant to 5-FU. Therefore, ALDHhigh TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance.

Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy.

PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naïve polypoidal choroidal vasculopathy (PCV). METHODS: In a retrospective interventional case series of 58 eyes of 58 patients with PCV, we assessed best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and number of injections for 2 years. Polypoidal lesions were also evaluated before treatment and after the loading phase by indocyanine green angiography. RESULTS: BCVA significantly improved after the loading phase and was maintained in the maintenance phase. CMT and CCT significantly reduced after the loading phase and were maintained throughout the follow-up period. The number of injections averaged 7.72 in the first year and 4.67 in the second year. The average number of polypoidal lesions per patient was 2.43 before treatment. In 32 patients (55.2%), polypoidal lesions regressed completely after the loading phase; these patients also needed significantly fewer injections compared to other patients. CCT at baseline was positively correlated with the decreased amount of CCT after 2 years and negatively correlated with the number of injections for 2 years. CONCLUSIONS: Treat-and-extend intravitreal therapy with aflibercept may be effective for improving BCVA and exudative change in eyes with PCV. The regression of polypoidal lesions after the loading phase and thicker choroid at baseline might lead to fewer total number of intravitreal injections of aflibercept.

Two-Year Outcomes of a Treat-and-Extend Regimen Using Intravitreal Aflibercept Injections for Typical Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to evaluate the efficacy of a treat-and-extend (TAE) regimen using intravitreal injection of aflibercept (IVA) for typical age-related macular degeneration (tAMD). METHODS: We retrospectively studied 61 treatment-naïve eyes with tAMD. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), number of injections, and complications during 2 years were evaluated. RESULTS: BCVA significantly improved by on average 0.13 logMAR units, and CMT and CCT significantly decreased after 2 years. The number of injections was on average 13.6. In the second year, eyes with classic choroidal neovascularization (CNV) needed significantly fewer treatments than eyes with occult CNV. Fourteen eyes, which developed subfoveal fibrosis, showed significantly poorer BCVA after 2 years. Subfoveal fibrosis was significantly common in classic CNV. CONCLUSION: A TAE regimen using IVA for tAMD might be effective for improving BCVA and exudative changes. The exudation may be suppressed with fewer treatments in classic CNV compared to occult CNV.

TREAT-AND-EXTEND REGIMEN WITH AFLIBERCEPT FOR RETINAL ANGIOMATOUS PROLIFERATION.

PURPOSE: To evaluate the effects of aflibercept therapy using a treat-and-extend regimen on treatment-naïve retinal angiomatous proliferation (RAP) and development of retinal pigment epithelium (RPE) atrophy. METHODS: We retrospectively studied 17 treated eyes with RAP and 13 untreated fellow eyes. We assessed best-corrected visual acuity (BCVA) in logarithm of the minimal angle of resolution (logMAR) units and recorded the total number of injections for 12 months. Central macular thickness (CMT) and central choroidal thickness (CCT) were assessed by optical coherence tomography (OCT), and RPE atrophy extent in the macular area was assessed by fundus autofluorescence. RESULTS: Average BCVA in eyes with RAP was 0.57 logMAR units (Snellen 20/74 or approximately 56.5 ETDRS letters) before treatment and significantly improved to 0.38 (Snellen 20/48 or approximately 66 ETDRS letters, P < 0.01) after 3 months and 0.32 (Snellen 20/42 or approximately 69 ETDRS letters, P < 0.01) after 12 months. Average CMT was 340 µm before treatment and significantly reduced to 133 µm (P < 0.001) after 3 months and 130 µm (P < 0.001) after 12 months. Average CCT was 147 µm before treatment, 123 µm (P < 0.01) after 3 months, and 131 µm (P < 0.01) after 12 months. Average total number of injections was 7.2. Average area of RPE atrophy enlarged by 1.00 mm in treated eyes compared with 0.34 mm in fellow eyes (P < 0.01). The enlarged area of RPE atrophy was inversely correlated with central choroidal thickness after 12 months (rs = -0.49, P < 0.01) and positively correlated with the number of injections (rs = 0.58, P < 0.01). CONCLUSION: Treat-and-extend intravitreal therapy with aflibercept may be effective for improvement and stabilization of visual acuity and exudative change in eyes with RAP. However, choroidal thinning during the treatment regimen may accelerate enlargement of RPE atrophy.

Mondini dysplasia with recurrent bacterial meningitis caused by three different pathogens.

Mondini dysplasia is rare, but has an important association with recurrent bacterial meningitis. We herein describe the case of a 3-year-old girl with unilateral sensorineural hearing loss who presented with three independent episodes of bacterial meningitis within 8 months. Temporal bone computed tomography indicated the characteristic features of Mondini dysplasia in the right inner ear. This was treated by surgical closure of the inner ear defect via oval window and additional vaccination was administered. Appropriate vaccination might prevent the recurrent bacterial meningitis associated with Mondini dysplasia.