Association between axial length and uveitis.

PURPOSE: Multiple studies have examined the association between myopia and various ocular diseases, but there is no clinical report of the relationship between myopia and uveitis. This study aimed to elucidate the relationship between myopia and uveitis by comparing axial lengths (AL) of uveitis patients with control individuals. METHODS: This study included 1052 eyes (663 patients; 288 males, 375 females; median age 56.0 years) with uveitis referred to Tokyo Medical University Hospital. Controls were 738 eyes with cataract but no other ocular diseases. AL was measured by IOLMaster or conventional A-mode ultrasound system. Uveitis eyes were grouped into various types of non-infectious uveitis, infectious uveitis, and unidentified uveitis. Median AL of each uveitis group was compared with control group using Mann-Whitney U-test, and also compared with adjustment for age and sex using multiple regression analysis. Binary logistic analysis was performed to examine whether AL plays a role in the risk of developing uveitis. RESULTS: Of 1052 eyes, 808 eyes (76.8%) were diagnosed with non-infectious uveitis [sarcoidosis (176 eyes, 16.7%), Vogt-Koyanagi-Harada disease (122 eyes, 11.6%), Behçet's disease (130 eyes, 12.4%), and others (380 eyes, 36.1%)], 146 eyes (13.9%) with infectious uveitis, and 98 eyes (9.3%) with unidentified uveitis. Median AL in all uveitis eyes was significantly shorter than in control eyes (23.73 vs 24.31 mm, p < 0.001 unadjusted), and AL remained significantly shorter in uveitis than in control after age- and sex-adjustment (p < 0.001). Median AL was significantly shorter in non-infectious uveitis (23.72 mm) and in infectious uveitis (23.99 mm) compared to controls (p < 0.001 and < 0.05, respectively), and was significantly shorter in non-infectious uveitis than in infectious uveitis (p < 0.05). Each millimeter decrease in AL was associated with 1.266-fold increase in unadjusted risk [odds ratio (OR), 1.266; 95% confidence interval (CI), 1.196-1.341; p < 0.001) and 1.446-fold in age- and sex-adjusted risk (OR, 1.446; 95% CI, 1.349-1.549; p < 0.001) of developing uveitis. CONCLUSION: Median AL of uveitis eyes with infectious or non-infectious etiologies was significantly shorter than that in control eyes, suggesting an increased risk of developing uveitis in eyes with shorter AL. This feature should be considered when exploring new pathogenetic mechanisms of uveitis. KEY MESSAGES: What is known Shorter axial length may be associated with the pathogenesis of central serous chorioretinopathy and increased risk of early age-related macular degeneration. What is new Here we assessed the relationship between myopia and uveitis by comparing axial lengths of uveitis patients. Median axial length in all uveitis eyes was significantly shorter than in control eyes, and axial length remained significantly shorter in uveitis than in control after age- and sex-adjustment. Each millimeter decrease in axial length was associated with 1.266-fold increase in unadjusted risk and 1.446-fold in age- and sex-adjusted risk of developing uveitis.

Immunophenotypic profiles in chalazion and pyogenic granuloma associated with chalazion.

PURPOSE: To evaluate immunophenotypic profiles of infiltrating cells in surgically excised tissues of chalazion and pyogenic granuloma associated with chalazion. METHODS: Eighty-two surgical specimens from 74 consecutive patients newly diagnosed with chalazion or chalazion-associated pyogenic granuloma at Tokyo Medical University Hospital between 2016 and 2022 were studied. Sixty specimens were chalazion lesions and 22 specimens were pyogenic granuloma lesions (from 15 men and 7 women, mean age 36.6 ± 14.4 years). All patients were immunocompetent Asian Japanese adults. Specimens were analyzed by immunohistochemistry and flow cytometry. Flow cytometry was performed using the following antibodies: CD3, CD4, CD8, CD11b, CD11c, CD16, CD19, CD20, CD23, CD25, CD34, CD44, CD56, CD69, and CD138. RESULTS: In flow cytometric analysis, the proportion of cells expressing the T cell marker CD3 was significantly higher compared with other immune cells expressing specific markers (p < 0.0001), and the proportion of CD4-positive T cells was significantly higher than that of CD8-positive T cells (p < 0.0001), in both chalazion and pyogenic granuloma specimens. The chalazion and pyogenic granuloma lesions shared similar immunophenotypic profile characterized by predominant T cell infiltration, and CD4 T cells dominating over CD8 cells. The pattern of expression of CD4 and CD8 in the specimens was confirmed by immunohistochemistry. CONCLUSION: The present study demonstrates immunophenotypic features of chalazion and chalazion-associated pyogenic granuloma. Although various inflammatory cells are involved in the pathology of chalazion and pyogenic granuloma, a significantly higher proportion of CD4-positive T cells may be closely related to the pathological mechanisms of both lesions.

Comprehensive microRNA analyses using vitreous humor of ocular sarcoidosis.

PURPOSE: MicroRNAs (miRNAs) are non-coding RNAs which have attracted attention as biomarkers in a variety of diseases. However, extensive unbiased analysis of miRNA in vitreous humor of sarcoidosis patients has not been reported. In the present study, we comprehensively analyzed the dysregulated miRNAs in ocular sarcoidosis to search for potential biomarkers. MATERIALS AND METHODS: This study included seven patients diagnosed with ocular sarcoidosis (five definite and two presumed). Five patients with unclassified uveitis and 24 with non-inflammatory diseases served as controls. MicroRNA expression levels in vitreous humor samples were measured by microarray, and differentially expressed miRNAs between sarcoidosis and other diseases were explored. Next, pathway enrichment analysis was performed to evaluate the functions of the dysregulated miRNAs, and machine learning was used to search for candidate biomarkers. RESULTS: A total of 614 upregulated miRNAs and 8 downregulated miRNAs were detected in vitreous humor of patients with ocular sarcoidosis compared with patients with unclassified uveitis and non-inflammatory diseases. Some dysregulated miRNAs were involved in the TGF-ß signaling pathway. Furthermore, we identified miR-764 as the best predictor for ocular sarcoidosis using Boruta selection. CONCLUSIONS: In this study, comprehensive miRNA analysis of vitreous humor samples identified dysregulated miRNAs in ocular sarcoidosis. This study suggests new insights into molecular pathogenetic mechanisms of sarcoidosis and may provide useful information toward developing novel diagnostic biomarkers and therapeutic targets for sarcoidosis.

Step ladder VY advancement flap for lower eyelid reconstruction after resection eyelid malignant tumors.

BACKGROUND: In oculoplastic surgery, reconstruction of a large defect after the removal of a massive malignant lower lid tumor still represents a unique challenge. We will report on this case, including a presentation of the case using step ladder V-Y advancement flap. METHODS: During November 2018 to March 2023, five patients of lower eyelid malignant tumor had wide resection with safety margin and reconstructed using step ladder V-Y advancement flap. The flap was used step ladder V-Y advancement flap. RESULTS: No complications, including ectropion deformity, occurred. This flap does not sacrifice healthy skin as seen with the cheek rotation flap, and the area of dissection is very small and can be performed in a short time. CONCLUSIONS: Step ladder V-Y advancement flap is highly useful in cases that require a reconstruction of a large defect after the removal of a massive malignant lower lid tumor from viewpoints of operating time, ease of procedure, aesthetics, and complications.

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice.

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1-/-) mice. Histopathologic analysis showed that Pdcd1-/- mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1-/- mice. Experiments of lymphocyte transfer from Pdcd1-/- into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1-/- mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells.

Nationwide epidemiological survey of immunoglobulin G4-related disease with malignancy in Japan.

BACKGROUND AND AIM: To clarify the clinicoepidemiological characteristics of immunoglobulin G4 (IgG4)-related disease (IgG4-RD) with malignancy, a nationwide epidemiological survey was conducted. METHODS: Immunoglobulin G4-related disease patients with malignancy who had visited selected hospitals in Japan were surveyed. The study consisted of two stages: the number of IgG4-RD patients with malignancy was estimated by the first questionnaire and their clinicoepidemiological characteristics were assessed by the second questionnaire. RESULTS: The frequencies of autoimmune pancreatitis (AIP), IgG4-related sialadenitis, IgG4-related eye disease, IgG4-related kidney disease, and IgG4-related retroperitoneal fibrosis were 44.7%, 20.8%, 14.0%, 5.16%, and 5.12%, respectively. The overall prevalence of malignant disease in IgG4-RD cases was estimated to be 10 900 per 100 000 cases, which was significantly higher than that of malignant disease in the general population. The prevalence of malignant lymphoma in IgG4-RD cases was the highest and was estimated to be 1985 per 100 000 cases. IgG4-related kidney disease had the highest frequency of malignant disease (17.1%). In data from 200 patients, 61 (30.5%) cases of cancer were found 2 years or more before the IgG4-RD diagnosis, 92 cases (46%) during the 1 year preceding or following IgG4-RD diagnosis, and 62 cases of cancer (31%) 2 or more years following IgG4-RD diagnosis. CONCLUSIONS: The nationwide survey for IgG4-RD with malignancy in Japan showed that IgG4-RD may be related with malignant diseases.

Outcomes after Rivaroxaban Treatment of Extensive Deep Vein Thrombosis.

BACKGROUND: Regression of thrombus in response to treatment with direct oral anticoagulants (DOACs) in patients with extensive deep vein thrombosis (DVT) has not been fully evaluated. This study aimed to determine the therapeutic efficacy of rivaroxaban in the treatment of extensive DVT. METHODS: We retrospectively evaluated 76 patients treated with rivaroxaban among 728 new DVT patients, at our hospital from January 2018 to March 2021. Extensive DVT was defined as thrombus connecting to 2 or more segments of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. Localized DVT was defined as a thrombus confined to 1 segment of the inferior vena cava (IVC), iliac vein, femoral vein, or popliteal vein. We compared the changes in thrombus between the extensive DVT group (36 patients) and the localized DVT group (40 patients). RESULTS: In the localized DVT group, 14 (37%) had total recanalization within 3 weeks after DOAC initiation, and 30 (79%) had total recanalization within 3 months. In the extensive DVT group, only 3 (9%) had total recanalization within 3 weeks after starting DOAC, and even after 3 months, only 5 (15%) had total recanalization. Symptoms (P = 0.01) and extensive DVT (P < 0.01) were significantly associated with the risk for failure of total recanalization. CONCLUSIONS: Rivaroxaban was highly effective for total recanalization of localized DVT but not for symptomatic or extensive DVT. In patients with symptomatic extensive DVT, catheter-based thrombolysis may be considered in selected cases.

Intravitreal ranibizumab improves macular sensitivity in patients with central retinal vein occlusion and macula edema.

BACKGROUND: Patients with central retinal vein occlusion (CRVO) and macular edema often are treated by intravitreal ranibizumab injection (IRI). The role of changes in macular sensitivity in the positive effects of IRI on visual functions is unclear. Therefore, we assessed the relationship between macular sensitivity and improvement of visual functions. METHODS: We included 15 eyes of 15 patients with treatment-naïve CRVO and followed patients for 6 months after pro re nata IRI. IRI was repeated if the central macular thickness was greater than or equal to 300 µm. Microperimetry-3 was used to measure macular sensitivity within the central 1-mm, 3-mm, and 6-mm fields before and monthly for 6 months after IRI. RESULTS: IRI significantly improved mean macular sensitivity over time within the central 1-mm, 3-mm, and 6-mm fields (all P < 0.001). None of the fields showed significant differences in the change of mean macular sensitivity between patients with little improvement in best corrected visual acuity (BCVA; i.e., in patients with a change in logarithm of the minimum angle of resolution [logMAR] BCVA < 0.3) and those with marked improvement in BCVA (change in logMAR BCVA > 0.3). The mean macular sensitivity before IRI showed correlations with the improvement of macular sensitivity in every field. CONCLUSION: These findings suggest that IRI improves macular sensitivity in patients with CRVO and macular edema independent of any improvement in BCVA and that macular sensitivity before treatment is associated with improvement of macular sensitivity after treatment.

Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles.

PURPOSE: Various immune mediators have crucial roles in the pathogenesis of intraocular diseases. Machine learning can be used to automatically select and weigh various predictors to develop models maximizing predictive power. However, these techniques have not yet been applied extensively in studies focused on intraocular diseases. We evaluated whether 5 machine learning algorithms applied to the data of immune-mediator levels in aqueous humor can predict the actual diagnoses of 17 selected intraocular diseases and identified which immune mediators drive the predictive power of a machine learning model. DESIGN: Cross-sectional study. PARTICIPANTS: Five hundred twelve eyes with diagnoses from among 17 intraocular diseases. METHODS: Aqueous humor samples were collected, and the concentrations of 28 immune mediators were determined using a cytometric bead array. Each immune mediator was ranked according to its importance using 5 machine learning algorithms. Stratified k-fold cross-validation was used in evaluation of algorithms with the dataset divided into training and test datasets. MAIN OUTCOME MEASURES: The algorithms were evaluated in terms of precision, recall, accuracy, F-score, area under the receiver operating characteristic curve, area under the precision-recall curve, and mean decrease in Gini index. RESULTS: Among the 5 machine learning models, random forest (RF) yielded the highest classification accuracy in multiclass differentiation of 17 intraocular diseases. The RF prediction models for vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma achieved the highest classification accuracy, precision, and recall. Random forest recognized vitreoretinal lymphoma, acute retinal necrosis, endophthalmitis, rhegmatogenous retinal detachment, and primary open-angle glaucoma with the top 5 F-scores. The 3 highest-ranking relevant immune mediators were interleukin (IL)-10, interferon-γ-inducible protein (IP)-10, and angiogenin for prediction of vitreoretinal lymphoma; monokine induced by interferon γ, interferon γ, and IP-10 for acute retinal necrosis; and IL-6, granulocyte colony-stimulating factor, and IL-8 for endophthalmitis. CONCLUSIONS: Random forest algorithms based on 28 immune mediators in aqueous humor successfully predicted the diagnosis of vitreoretinal lymphoma, acute retinal necrosis, and endophthalmitis. Overall, the findings of the present study contribute to increased knowledge on new biomarkers that potentially can facilitate diagnosis of intraocular diseases in the future.

Long-Term Safety and Efficacy of Adalimumab in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis.

PURPOSE: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. DESIGN: Open-label, multicenter, phase 3 extension study (VISUAL III). PARTICIPANTS: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis). METHODS: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose. MAIN OUTCOME MEASURES: Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids. RESULTS: At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively. CONCLUSIONS: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab.

Continuous measurement of surface electrical potentials from transplanted cardiomyocyte tissue derived from human-induced pluripotent stem cells under physiological conditions in vivo.

Recording the electrical potentials of bioengineered cardiac tissue after transplantation would help to monitor the maturation of the tissue and detect adverse events such as arrhythmia. However, a few studies have reported the measurement of myocardial tissue potentials in vivo under physiological conditions. In this study, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSCM) sheets were stacked and ectopically transplanted into the subcutaneous tissue of rats for culture in vivo. Three months after transplantation, a flexible nanomesh sensor was implanted onto the hiPSCM tissue to record its surface electrical potentials under physiological conditions, i.e., without the need for anesthetic agents that might adversely affect cardiomyocyte function. The nanomesh sensor was able to record electrical potentials in non-sedated, ambulating animals for up to 48 h. When compared with recordings made with conventional needle electrodes in anesthetized animals, the waveforms obtained with the nanomesh sensor showed less dispersion of waveform interval and waveform duration. However, waveform amplitude tended to show greater dispersion for the nanomesh sensor than for the needle electrodes, possibly due to motion artifacts produced by movements of the animal or local tissue changes in response to surgical implantation of the sensor. The implantable nanomesh sensor utilized in this study potentially could be used for long-term monitoring of bioengineered myocardial tissue in vivo under physiological conditions.

Effects of ranibizumab on growth factors and mediators of inflammation in the aqueous humor of patients with diabetic macular edema.

PURPOSE: The study aims to investigate changes in the aqueous humor levels of 8 growth factors and inflammatory mediators after intravitreal ranibizumab injection (IRI) and the relationship between these substances and functional-morphological parameters in patients with diabetic macular edema (DME). METHODS: We recruited 25 patients with DME who were scheduled to receive 2 doses of IRI at monthly intervals. At baseline and 1 month after IRI, we measured aqueous levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, and interferon-gamma inducible protein 10 (IP-10) by the suspension array method. Central macular edema (CMT) or macular volume (MV) was examined by optical coherence tomography before and 1 month after IRI, and the improvement of macular edema was evaluated by calculating the percent change of CMT or MV. RESULTS: Aqueous humor levels of VEGF, PlGF, PDGF-AA, and IP-10 were significantly decreased 1 month after IRI (P < 0.001, P = 0.002, P = 0.002, and P = 0.005, respectively). In addition, the baseline aqueous humor levels of PlGF, MCP-1, and IL-6 were significantly correlated with the improvement in best corrected visual acuity (P = 0.036, P = 0.024, and P = 0.049, respectively). The baseline aqueous humor level of sICAM-1 was significantly negatively correlated with the change in CMT (P = 0.005), and the baseline aqueous humor levels of VEGF and PlGF were significantly correlated with the change in MV (P = 0.020 and P = 0.003, respectively). Furthermore, the percentage reduction in VEGF after IRI was significantly correlated with the change in MV (P = 0.037). CONCLUSIONS: Our findings suggest that the change in aqueous humor levels of VEGF, PlGF, and ICAM-1 in DME may not only be an anatomic response but also a potential therapeutic target. CLINICAL TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry. The registration number is UMIN000030301.

Retinal Blood Flow as a Predictor of Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Central Retinal Vein Occlusion.

INTRODUCTION: To investigate the relationship between retinal blood flow and the presence or absence of macular edema (ME) recurrence after intravitreal ranibizumab injection (IRI) in patients with central retinal vein occlusion (CRVO). METHODS: We reviewed the medical records of 16 eyes with ME associated with CRVO. All eyes had received pro re nata IRI. Repeat IRI was performed if the central macular thickness was ≥300 µm. At 12 months, patients without additional IRI in the past 6 months were assigned to the resolved group, and those with additional IRI, to the recurrence group. We used laser speckle flowgraphy (LSFG) to measure the mean blur rate (MBR) of the optic disc before and after IRI. RESULTS: Ten of the 16 eyes were assigned to the resolved group, and the other 6 eyes to the recurrence group. At several visits in the 12 months after IRI, MBR was significantly higher in the resolved group than in the recurrence group. Percent change of MBR (%Δ MBR) from baseline was significantly higher in the resolved group than in the recurrence group at 1 month (initial %Δ MBR) and 11 and 12 months. Multivariate stepwise analysis showed that the initial %Δ MBR was significantly and negatively correlated with the number of IRIs. DISCUSSION/CONCLUSION: These findings suggest that determining %Δ MBR in LSFG may be a useful way to determine the likelihood of ME recurrence in CRVO patients.

Anti-VEGF Therapy Reduces Inflammation in Diabetic Macular Edema.

PURPOSE: Correlations among the aqueous flare value (an indicator of inflammation), several functional-morphologic parameters, and aqueous humor levels of multiple cytokines or inflammatory factors were investigated in patients with diabetic macular edema (DME) receiving intravitreal rani-bizumab injection (IRI). METHODS: Aqueous humor levels of 12 cytokines, growth factors, or inflammatory factors were measured in 46 DME patients who received IRI. Vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR), and the other cytokines/inflammatory factors were measured by the suspension array method. In addition, aqueous flare values were measured with a laser flare meter, and central macular thickness (CMT) was examined by optical coherence tomography. RESULTS: At 1 month after IRI therapy, the aqueous flare value showed a significant decrease compared with before treatment (baseline). Significant correlations were noted between the aqueous flare value and the aqueous humor levels of 6 factors/cytokines, including sVEGFR-1, placental growth factor, monocyte chemoattractant protein 1, soluble intercellular adhesion molecule-1, interleukin (IL)-6, and interferon-inducible 10-kDa protein (IP-10). There was also a significant correlation between the change in aqueous flare value and improvement in CMT 1 month after IRI. CONCLUSIONS: These findings suggest that IRI reduces subclinical inflammation and that the aqueous flare value is influenced by inflammatory factors/cytokines. In addition, the change in the aqueous flare value may be an indicator of the response of CMT to IRI in patients with DME.

The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD.

IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.

Blockade of costimulatory CD27/CD70 pathway promotes corneal allograft survival.

PURPOSE: To determine whether the CD27/CD70 pathway plays a significant role in corneal allograft rejection by investigating the effect of blocking the CD27/CD70 pathway by anti-CD70 antibody on corneal allograft survival. METHODS: Orthotopic penetrating keratoplasty was performed using C57BL/6 donor grafts and BALB/c recipients. Expression of CD27 and CD70 on rejected cornea was examined by immunohistochemistry. Corneal transplant recipients received intraperitoneal injection of anti-CD70 antibody (FR70) or control rat IgG. Alloreactivity was measured by mixed lymphoid reaction (MLR) in recipients administered control rat IgG and those administered anti-CD70 antibody. Corneal expression of IFN-γ and IL-12 was also examined in both groups. Graft opacity was assessed over an 8-week period and graft survival was evaluated using Kaplan-Meier survival curves. Proportion of CD4+CD44+ memory T cells in lymph nodes was measured by flow cytometry. RESULTS: CD4+CD27+ cells and CD11c+CD70+ cells were present in rejected cornea. Anti-CD70 antibody administration suppressed alloreactivity in corneal allograft recipients, and inhibited IFN-γ expression in recipient cornea (p < 0.05). Anti-CD70 antibody suppressed opacity score of recipient cornea and prolonged corneal allograft survival (p < 0.05). Proportion of CD4+CD44+ memory T cells in recipient lymph nodes was reduced by anti-CD70 antibody treatment. CONCLUSION: The CD27/CD70 pathway plays a significant role in corneal allograft rejection by initiating alloreactive Th1 cells and preserving memory T cells. Anti-CD70 antibody administration prolongs corneal allograft survival indicating the potential therapeutic effect of CD27/CD70 pathway blockade on corneal allograft rejection.

[Assessment for Local Treatment for Elderly Breast Cancer Cases].

The number of elderly breast cancer patients has been increasing recently nevertheless the optimal treatment for the elderly breast cancer patients still remains controversial. In this study, 21 primary breast cancer cases who were equal or older than 85 years old at our hospital were examined their clinical and pathological features. These 21 cases were divided into 2 group; Group A; ten cases who received operations, Group B; eleven cases who did not receive operations. T categories, M categories and clinical stages in Group B were significantly higher than those of Group A. The main causing reason why Group B cases had not received operations was that their primary breast cancer were too advanced to perform operation. Instead of operation, most Group B cases received endocrine therapy or radiotherapy. Group A cases received standard operative procedures including partial or total mastectomy and biopsies or dissection of axillary lymph nodes. Besides, their post- operative courses were good and safe. These results suggest that even for elderly patients, early diagnosis and treatment could improve their prognosis and quality of life. In addition, careful surveillances for elderly breast cancer patients, those who tend to stop attending regular check up to their hospital, should be considered for further assessment for characteristics of elderly breast cancer patients.

Clinical features of anterior uveitis caused by three different herpes viruses.

PURPOSE: To compare the clinical findings in patients with anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). METHODS: We retrospectively analyzed the clinical profiles of HSV-AU (14 patients), VZV sine herpete (ZSH-AU: 21 patients), and CMV-AU (17 patients) diagnosed by the detection of corresponding viral DNA in aqueous humor samples by polymerase chain reaction. Further, five patients with Posner-Schlossman (P-S) syndrome were selected as controls for CMV-AU. RESULTS: Patients with CMV-AU were predominately male or older in age, and all cases were unilateral except for three patients with CMV-AU. Mutton-fat keratic precipitates (KPs) were found mostly in patients with HSV-AU and ZSH-AU. Severities of AU and viral load were the highest in ZSH-AU, followed by HSV-AU and CMV-AU. Iris atrophy was observed in HSV-AU (50%) and ZSH-AU (76%), with typical morphology of round type and sector type, respectively. In patients with CMV-AU, a ring-shaped KP was found in 53% patients, 76% of whom showed a decreased number of corneal endothelial cells. CMV was not detected in the aqueous humor of patients with typical P-S syndrome. CONCLUSION: Clinical findings of HSV-AU and VZV-AU were similar; however, more inflammatory findings were observed in VZV-AU. Iris atrophy morphologically differed in HSV-AU and VZV-AU. Inflammatory findings in CMV-AU were mild, and clinical features of iritis differed from those of the two former groups. A difference in the etiology between CMV-AU and P-S syndrome was observed.

[A Case of Pancreatic Neuroendocrine Carcinoma Presenting Multiple Liver Metastasis as an Initial Manifestation for Which Diagnosis Confirmation Was Difficult].

A 67-year-old woman with a history of esophageal cancer(poorly-differentiated squamous cell carcinoma, pStageⅡ) was diagnosed with 2 liver tumors by regular checkup CT 10 years after her operation. We also observed elevated levels of tumor marker CEA. The tumors were suspected to be metastatic although no primary lesion was identified. We performed partial hepatectomy for diagnostic therapy. The pathological diagnosis was adenocarcinoma suggestive of metastatic tumors but the primary lesion remained unknown. Tumor marker levels were elevated 2 months after the operation and we detected a pancreatic tumor, multiple liver tumors, peritoneal dissemination, and para-aortic lymph node metastasis. Therefore, our clinical diagnosis was multiple metastases with primary pancreatic cancer and chemotherapy was performed. We conducted a thorough review of the diagnostic images and repeated the pathological analysis. Immunobiological staining showed that the tumor cells were positive for neuroendocrine markers such as chromogranin A, CD56, and Ki-67. We eventually diagnosed the liver tumors as metastasis from the pancreatic neuroendocrine carcinoma(Grade 3).