A preliminary evaluation of the diagnostic performance of a smartphone-based machine learning-assisted system for evaluation of clinical activity score in digital images of thyroid-associated orbitopathy.

BACKGROUND: We previously developed a machine learning (ML)-assisted system for predicting the clinical activity score (CAS) in thyroid-associated orbitopathy (TAO) using digital facial images taken by a DSLR camera in a studio setting. In this study, we aimed to apply this system to smartphones and detect active TAO (CAS ≥ 3) using facial images captured by smartphone cameras. We evaluated the performance of our system on various smartphone models and compared it with the performance of ophthalmologists with varying clinical experience. METHODS: We applied the pre-existing ML architecture to classify photos taken with smartphones (Galaxy S21 Ultra, iPhone 12 pro, iPhone 11, iPhone SE 2020, Galaxy M20, and Galaxy A21S). The performance was evaluated with smartphone-captured images from 100 patients with TAO. Three ophthalmology residents, 3 general ophthalmologists with < 5 years of clinical experience, and 3 oculoplastic specialists independently interpreted the same set of images taken under a studio environment and compared their results with those generated by the smartphone-based ML-assisted system. Reference CAS was determined by a consensus of three oculoplastic specialists. RESULTS: Active TAO (CAS ≥3) was identified in 28 patients. Smartphone model used in capturing facial images influenced active TAO detection performance (f1 score 0.59 to 0.72). The smartphone-based system showed 74.5% sensitivity, 84.8% specificity, and f1 score 0.70 on top three smartphones. On images from all six smartphones, average sensitivity, specificity, and f1 score were 71.4%, 81.6%, and 0.66, respectively. Ophthalmology residents' values were 69.1%, 55.1%, and 0.46. General ophthalmologists' values were 61.9%, 79.6%, 0.55. Oculoplastic specialists' values were 73.8%, 90.7%, 0.75. This smartphone-based ML-assisted system predicted CAS within 1 point of reference CAS in 90.7% using facial images from smartphones. CONCLUSIONS: Our smartphone-based ML-assisted system shows reasonable accuracy in detecting active TAO, comparable to oculoplastic specialists and outperforming residents and general ophthalmologists. It may enable reliable self-monitoring for disease activity, but confirmatory research is needed for clinical application. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT05731154.

Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism.

Mitochondrial dysfunction has been implicated in Parkinson's Disease (PD) progression; however, the mitochondrial factors underlying the development of PD symptoms remain unclear. One candidate is CR6-interacting factor1 (CRIF1), which controls translation and membrane insertion of 13 mitochondrial proteins involved in oxidative phosphorylation. Here, we found that CRIF1 mRNA and protein expression were significantly reduced in postmortem brains of elderly PD patients compared to normal controls. To evaluate the effect of Crif1 deficiency, we produced mice lacking the Crif1 gene in dopaminergic neurons (DAT-CRIF1-KO mice). From 5 weeks of age, DAT-CRIF1-KO mice began to show decreased dopamine production with progressive neuronal degeneration in the nigral area. At ~10 weeks of age, they developed PD-like behavioral deficits, including gait abnormalities, rigidity, and resting tremor. L-DOPA, a medication used to treat PD, ameliorated these defects at an early stage, although it was ineffective in older mice. Taken together, the observation that CRIF1 expression is reduced in human PD brains and deletion of CRIF1 in dopaminergic neurons leads to early-onset PD with stepwise PD progression support the conclusion that CRIF1-mediated mitochondrial function is important for the survival of dopaminergic neurons.

Efficacy of selenium supplementation for mild-to-moderate Graves' ophthalmopathy in a selenium-sufficient area (SeGOSS trial): study protocol for a phase III, multicenter, open-label, randomized, controlled intervention trial.

BACKGROUND: The therapeutic effect of selenium has been demonstrated in mild Graves' ophthalmopathy (GO) in a European region where selenium status is suboptimal. However, there is a lack of evidence to support selenium use in selenium-sufficient areas. The aim of this study is to evaluate the therapeutic effect of selenium in mild-to-moderate GO in selenium-sufficient South Korea. METHODS: The SeGOSS trial is a multicenter, prospective, randomized, open-label trial in South Korea. Eighty-four patients aged 19 years or older with mild-to-moderate GO will be randomized to receive either vitamin B complex alone or vitamin B complex with selenium for 6 months with three monthly follow-up visits. The primary outcome is comparison of the improvement in quality of life at 6 months from baseline between the control and selenium groups. The secondary outcomes are intergroup differences in changes in quality of life at 3 months, clinical activity of GO at 3 and 6 months, thyroid autoantibody titers at 3 and 6 months, and the response rate at 3 and 6 months from baseline. Quality of life will be measured by questionnaire for patients with GO, and the clinical activity of GO will be evaluated by the clinical activity score (CAS). A positive response is defined as either changes in the CAS < 0 or the changes in the GO-QOL score ≥ 6. DISCUSSION: The SeGOSS study will evaluate the therapeutic potential of selenium for mild-to-moderate GO in a selenium-sufficient area and provide support in tailoring better treatment for GO. TRIAL REGISTRATION: KCT0004040. Retrospectively registered on 5 June 2019. https://cris.nih.go.kr/cris/search/detailSearch.do/14160 .

Differentiating malignant and benign eyelid lesions using deep learning.

Artificial intelligence as a screening tool for eyelid lesions will be helpful for early diagnosis of eyelid malignancies and proper decision-making. This study aimed to evaluate the performance of a deep learning model in differentiating eyelid lesions using clinical eyelid photographs in comparison with human ophthalmologists. We included 4954 photographs from 928 patients in this retrospective cross-sectional study. Images were classified into three categories: malignant lesion, benign lesion, and no lesion. Two pre-trained convolutional neural network (CNN) models, DenseNet-161 and EfficientNetV2-M architectures, were fine-tuned to classify images into three or two (malignant versus benign) categories. For a ternary classification, the mean diagnostic accuracies of the CNNs were 82.1% and 83.0% using DenseNet-161 and EfficientNetV2-M, respectively, which were inferior to those of the nine clinicians (87.0-89.5%). For the binary classification, the mean accuracies were 87.5% and 92.5% using DenseNet-161 and EfficientNetV2-M models, which was similar to that of the clinicians (85.8-90.0%). The mean AUC of the two CNN models was 0.908 and 0.950, respectively. Gradient-weighted class activation map successfully highlighted the eyelid tumors on clinical photographs. Deep learning models showed a promising performance in discriminating malignant versus benign eyelid lesions on clinical photographs, reaching the level of human observers.

Insulin syringe for anesthesia in ptosis surgery: a randomized, fellow eye-controlled clinical study.

PURPOSE: Unlike ordinary 30-gauge needles, insulin syringe needles are thinner and shorter and have a comparatively blunt tip. Therefore, insulin syringes may reduce injection discomfort, bleeding, and edema by minimizing tissue damage and vascular penetration. This study aimed to evaluate the potential benefits of using insulin syringes for local anesthesia in ptosis surgery. METHODS: This randomized, fellow eye-controlled study included 60 patients (120 eyelids), conducted at a university-based hospital. An insulin syringe was used on one eyelid, and a conventional 30-gauge needle was used on the other. Patients were instructed to score pain in both eyelids using a visual analog scale (VAS) ranging from 0 (no pain) to 10 (unbearable pain). Ten minutes after the injection, two observers scored degrees of hemorrhage and edema in both eyelids on five- and four-pointing grading scales (0-4 and 0-3) for each value, and the average score between the two observers was calculated and compared. RESULTS: The VAS score was 5.17 in the insulin syringe group and 5.35 in the 30-gauge needle group (p = 0.282). Ten minutes after the anesthesia, the median hemorrhage scores were 1.00 and 1.75 (p = 0.010), and the median eyelid edema scores were 1.25 and 2.00 (p = 0.007) in the insulin syringe and 30-gauge needle groups, respectively (Fig. 1). CONCLUSION: Injecting local anesthesia using an insulin syringe significantly reduces hemorrhage and eyelid edema, but not injection pain, before skin incision. Insulin syringes are useful in patients at high risk of bleeding because they can reduce the penetrative tissue damage caused by needle insertion.

ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia.

The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1ß and tumor necrosis factor-α (TNF-α), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation.

Serum microRNA as a potential biomarker for the activity of thyroid eye disease.

The aim of this study is to characterize the microRNA (miRNA) expression signatures in patients with thyroid eye disease (TED) and identify miRNA biomarkers of disease activity. Total RNA was isolated from the sera of patients with TED (n = 10) and healthy controls (HCs, n = 5) using the miRNeasy Serum/Plasma Kit. The NanoString assay was used for the comprehensive analysis of 798 miRNA expression profiles. Analysis of specific miRNA signatures, mRNA target pathway analysis, and network analysis were performed. Patients with TED were divided into two groups according to disease activity: active and inactive TED groups. Differentially expressed circulating miRNAs were identified and tested using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) tests in the validation cohort. Among the 798 miRNAs analyzed, 173 differentially downregulated miRNAs were identified in TED patients compared to those in the HCs. Ten circulating miRNAs were differentially expressed between the active and inactive TED groups and regarded as candidate biomarkers for TED activity (one upregulated miRNA: miR-29c-3p; nine downregulated miRNAs: miR-4286, miR-941, miR-571, miR-129-2-3p, miR-484, miR-192-5p, miR-502-3p, miR-597-5p, and miR-296-3p). In the validation cohort, miR-484 and miR-192-5p showed significantly lower expression in the active TED group than in the inactive TED group. In conclusion, the expression levels of miR-484 and miR-192-5p differed significantly between the active and inactive TED groups, suggesting that these miRNAs could serve as circulating biomarkers of TED activity, however, these findings need to be validated in further studies.

Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.

The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.

Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease.

BACKGROUND/OBJECTIVES: Although it has been reported that thyroid-stimulating immunoglobulin (TSI) is associated with the clinical characteristics of thyroid eye disease (TED), there is a paucity of literature regarding the role of TSI in diagnosing active TED. This study investigated the relationship between the level of TSI and the activity of TED and assessed the cut-off value of TSI discriminating active TED from inactive TED. METHODS: This cross-sectional study included 101 patients with TED. TSI was quantitatively measured with a cell-based bioassay using a chimeric TSH receptor and a cyclic adenosine monophosphate response element-dependent luciferase. The association between TSI and a variety of demographic and clinical features of TED was analysed. Multivariate regression analysis was performed to determine possible independent factors affecting the level of TSI. RESULTS: TSI level was higher in males than in females (p = 0.023) and smokers than in nonsmokers (p = 0.004). TSI level was inversely correlated with the duration of ocular symptoms (r = -0.295, p = 0.003). The level of TSI was also significantly different when compared to the thyroid function (p = 0.003), TED activity (p < 0.001), and TED severity (p = 0.001). Multivariate regression analysis revealed a significant relationship between TED activity and thyroid function jointly and the TSI level. The cut-off level of TSI for predicting active TED was a specimen-to-reference ratio of 406.7 (p < 0.001, area under the curve = 0.847, sensitivity 77.4%, specificity 81.3%). CONCLUSIONS: TSI was a functional biomarker strongly associated with TED activity even after being adjusted by other clinical characteristics. Serum TSI level may help identify patients with active TED in clinics.

Machine learning-assisted system using digital facial images to predict the clinical activity score in thyroid-associated orbitopathy.

Although the clinical activity score (CAS) is a validated scoring system for identifying disease activity of thyroid-associated orbitopathy (TAO), it may produce differing results depending on the evaluator, and an experienced ophthalmologist is required for accurate evaluation. In this study, we developed a machine learning (ML)-assisted system to mimic an expert's CAS assessment using digital facial images and evaluated its accuracy for predicting the CAS and diagnosing active TAO (CAS ≥ 3). An ML-assisted system was designed to assess five CAS components related to inflammatory signs (redness of the eyelids, redness of the conjunctiva, swelling of the eyelids, inflammation of the caruncle and/or plica, and conjunctival edema) in patients' facial images and to predict the CAS by considering two components of subjective symptoms (spontaneous retrobulbar pain and pain on gaze). To train and test the system, 3,060 cropped images from 1020 digital facial images of TAO patients were used. The reference CAS for each image was scored by three ophthalmologists, each with > 15 years of clinical experience. We repeated the experiments for 30 randomly split training and test sets at a ratio of 8:2. The sensitivity and specificity of the ML-assisted system for diagnosing active TAO were 72.7% and 83.2% in the test set constructed from the entire dataset. For the test set constructed from the dataset with consistent results for the three ophthalmologists, the sensitivity and specificity for diagnosing active TAO were 88.1% and 86.9%. In the test sets from the entire dataset and from the dataset with consistent results, 40.0% and 49.9% of the predicted CAS values were the same as the reference CAS, respectively. The system predicted the CAS within 1 point of the reference CAS in 84.6% and 89.0% of cases when tested using the entire dataset and in the dataset with consistent results, respectively. An ML-assisted system estimated the clinical activity of TAO and detect inflammatory active TAO with reasonable accuracy. The accuracy could be improved further by obtaining more data. This ML-assisted system can help evaluate the disease activity consistently as well as accurately and enable the early diagnosis and timely treatment of active TAO.

Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.

A transcriptomic analysis of cerebral microvessels reveals the involvement of Notch1 signaling in endothelial mitochondrial-dysfunction-dependent BBB disruption.

BACKGROUND: Endothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood-brain barrier (BBB) disruption. Previous studies have reported that enhancement of mitochondrial function within ECs may reduce BBB disruption and decrease the severity of acute brain injuries. However, the molecular signaling pathways through which enhanced EC mitochondrial function is enhanced to exert this BBB protective effect have not been fully elucidated. METHODS: To identify signaling pathways involved in linking EC-specific mitochondrial dysfunction and BBB disruption, we first performed RNA sequencing using isolated cerebral vessels from TEKCRIF1 KO mice, a mouse strain that displays EC-specific mitochondrial dysfunction. After identification, we assessed the significance of candidate signaling pathways using an intracerebral hemorrhage (ICH) mouse model. BBB integrity was assessed using an IgG leakage assay, and symptomatic changes were evaluated using behavioral assays. RESULTS: Transcriptome analyses of the TEKCRIF1 KO mouse revealed significant changes in Notch1 signaling, a pathway intimately involved in BBB maintenance. We also observed a decrease in Notch1 signaling and expression of the mitochondrial oxidative phosphorylation (OxPhos) complex in the ICH mouse model, which also exhibits BBB disruption. To further assess the function of Notch1 signaling in relation to BBB disruption, we injected ICH model mice with adropin, a protein that interacts with the Notch1 ligand NB-3 and activates Notch1 signaling. We found that adropin prevented BBB disruption and reduced the extent (area) of the injury compared with that in vehicle controls, in association with alteration of mitochondrial function. CONCLUSION: These results suggest that the Notch1 signaling pathway acts as an upstream regulator of DEGs and can be a target to regulate the changes involved with endothelial mitochondrial dysfunction-dependent BBB disruption. Thus, treatment methods that activate Notch1 may be beneficial in acute brain injuries by protecting BBB integrity.

Repeated ketamine anesthesia during neurodevelopment upregulates hippocampal activity and enhances drug reward in male mice.

Early exposures to anesthetics can cause long-lasting changes in excitatory/inhibitory synaptic transmission (E/I imbalance), an important mechanism for neurodevelopmental disorders. Since E/I imbalance is also involved with addiction, we further investigated possible changes in addiction-related behaviors after multiple ketamine anesthesia in late postnatal mice. Postnatal day (PND) 16 mice received multiple ketamine anesthesia (35 mg kg-1, 5 days), and behavioral changes were evaluated at PND28 and PND56. Although mice exposed to early anesthesia displayed normal behavioral sensitization, we found significant increases in conditioned place preference to both low-dose ketamine (20 mg kg-1) and nicotine (0.5 mg kg-1). By performing transcriptome analysis and whole-cell recordings in the hippocampus, a brain region involved with CPP, we also discovered enhanced neuronal excitability and E/I imbalance in CA1 pyramidal neurons. Interestingly, these changes were not found in female mice. Our results suggest that repeated ketamine anesthesia during neurodevelopment may influence drug reward behavior later in life.

The Incidence and Risk Factors of Medial and Inferior Orbital Wall Fractures in Korea: A Nationwide Cohort Study.

PURPOSE: We aimed to investigate orbital wall fracture incidence and risk factors in the general Korean population. METHOD: The Korea National Health Insurance Service-National Sample Cohort dataset was analyzed to find subjects with an orbital wall fracture between 2011 and 2015 (based on the diagnosis code) and to identify incident cases involving a preceding disease-free period of 8 years. The incidence of orbital wall fracture in the general population was estimated, and the type of orbital wall fracture was categorized. Sociodemographic risk factors were also examined using Cox regression analysis. RESULTS: Among 1,080,309 cohort subjects, 2415 individuals with newly diagnosed orbital wall fractures were identified. The overall incidence of orbital wall fractures was estimated as 46.19 (95% CI: 44.37-48.06) per 100,000 person-years. The incidence was high at 10-29 and 80+ years old and showed a male predominance with an average male-to-female ratio of 3.33. The most common type was isolated inferior orbital wall fracture (59.4%), followed by isolated medial orbital wall fracture (23.7%), combination fracture (15.0%), and naso-orbito-ethmoid fracture (1.5%). Of the fracture patients, 648 subjects (26.8%) underwent orbital wall fracture repair surgeries. Male sex, rural residence, and low income were associated with an increased risk of orbital wall fractures. CONCLUSIONS: The incidence of orbital wall fractures in Korea varied according to age groups and was positively associated with male sex, rural residency, and low economic income. The most common fracture type was an isolated inferior orbital wall fracture.

A longitudinal study of the association between visual impairment and income change using a national health screening cohort.

We evaluated the influence of visual impairment (VI) on income change using the longitudinal database of a Korean National Health Insurance Service cohort. A total of 5292 participants ≥ 40 years old and registered as visually impaired persons were selected at a 1:4 ratio with 45,081 non-VI participants matched for age, sex, and income level. The income level of both the VI and non-VI groups increased over time. In the VI group, the income levels 3, 4 and 5 years were higher than the initial value, while the income levels from 1 through 5 years were increased each year in the non-VI group. The rate of change in income between time and VI were significant. In the subgroup analysis considering age, sex, and severity of VI, the rate of change in income were significant in < 65 years old subgroups. Regarding the severity of VI, a significant interaction was found for the mild-to-moderate VI subgroup. Although both the VI and non-VI groups showed increased income levels over 5 years, the degree of income increase in the VI group was relatively lower than that in the non-VI group. This finding was prominent in the middle-age subgroup. These results strongly suggested that VI induced an income inequality.

Reactive microglia and mitochondrial unfolded protein response following ventriculomegaly and behavior defects in kaolin-induced hydrocephalus.

Ventriculomegaly induced by the abnormal accumulation of cerebrospinal fluid (CSF) leads to hydrocephalus, which is accompanied by neuroinflammation and mitochondrial oxidative stress. The mitochondrial stress activates mitochondrial unfolded protein response (UPRmt), which is essential for mitochondrial protein homeostasis. However, the association of inflammatory response and UPRmt in the pathogenesis of hydrocephalus is still unclear. To assess their relevance in the pathogenesis of hydrocephalus, we established a kaolin-induced hydrocephalus model in 8-week-old male C57BL/6J mice and evaluated it over time. We found that kaolin-injected mice showed prominent ventricular dilation, motor behavior defects at the 3-day, followed by the activation of microglia and UPRmt in the motor cortex at the 5-day. In addition, PARP-1/NF-κB signaling and apoptotic cell death appeared at the 5-day. Taken together, our findings demonstrate that activation of microglia and UPRmt occurs after hydrocephalic ventricular expansion and behavioral abnormalities which could be lead to apoptotic neuronal cell death, providing a new perspective on the pathogenic mechanism of hydrocephalus. [BMB Reports 2022; 55(4): 181-186].

Outcomes of enucleation and porous polyethylene orbital implant insertion in patients with paediatric retinoblastoma: a long-term follow-up study.

BACKGROUND/AIMS: To report the long-term outcomes of enucleation and insertion of porous polyethylene (PP) orbital implant according to the evolving surgical techniques and implant in patients with paediatric retinoblastoma . METHODS: Patients with paediatric retinoblastoma who underwent enucleation and PP implant insertion from December 1998 to December 2014 were retrospectively reviewed and divided into four groups: group A, classic enucleation +PP implant; group B, enucleation +PP implant +anterior closure of the posterior Tenon's (ACPT) capsule; group C, enucleation +PP implant +free orbital fat graft +ACPT and group D, enucleation +smooth surface tunnel PP implant +ACPT. Survival analysis of implant exposure and eyelid malpositions was performed. RESULTS: One hundred and ninety-eight eyes of 196 patients were included. The median follow-up period was 13.0 years (range, 5.0-21.1). A 20 mm implant was inserted for 149 eyes (75.3%). The 10-year exposure-free survival probabilities were 44.6% in group A, 96.4% in group B, 97.4% in group C and 97.7% in group D. ACPT was associated with significant reduction in implant exposure (p<0.001). The most common eyelid malposition was upper eyelid ptosis (24.2%). The eyelid malposition-free survival probability did not differ among the four groups. However, the insertion of a 20 mm implant was associated with significant reduction in upper eyelid ptosis and lower eyelid entropion (p=0.004 and 0.038, respectively). CONCLUSIONS: The long-term postenucleation implant exposure was rare after PP implant insertion and ACPT, even with a 20 mm-diameter implant. A larger implant can be beneficial in long-term prevention of eyelid malposition.

Ultra-low-dose radiation treatment for early-stage ocular adnexal MALT lymphoma.

PURPOSE: To investigate the long-term outcomes of ultra-low-dose (4 Gy) radiation treatment (RT) in patients with early-stage ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: This retrospective case series includes eight patients with ocular adnexal MALT lymphoma who received ultra-low-dose RT at a single tertiary referral center between March 2016 and February 2018. Response to treatment and the time taken to respond were analyzed. RESULTS: Of the eight patients (three men, five women), seven patients had conjunctival lymphoma (T1N0M0), and one patient had orbital lymphoma (T2N0M0). Six patients with T1 disease showed complete response (CR), and the median time to CR was 4.5 months (range 2-5). Partial response was achieved in the remaining two patients (one each with T1 and T2). During the median follow-up period of 44 months (range 30-54), none of the patients had a relapse or needed additional treatment. RT was well-tolerated in all patients with no ocular complications, including cataracts and dry eye. CONCLUSION: This case series suggests that ultra-low-dose RT is effective and well-tolerated in patients with early-stage ocular adnexal MALT lymphoma. Further studies with a larger sample size and long-term follow-up are needed to evaluate the local control rate and disease-free survival precisely.

Head and Neck Cancer Cell Death due to Mitochondrial Damage Induced by Reactive Oxygen Species from Nonthermal Plasma-Activated Media: Based on Transcriptomic Analysis.

Mitochondrial targeted therapy is a next-generation therapeutic approach for cancer that is refractory to conventional treatments. Mitochondrial damage caused by the excessive accumulation of reactive oxygen species (ROS) is a principle of mitochondrial targeted therapy. ROS in nonthermal plasma-activated media (NTPAM) are known to mediate anticancer effects in various cancers including head and neck cancer (HNC). However, the signaling mechanism of HNC cell death via NTPAM-induced ROS has not been fully elucidated. This study evaluated the anticancer effects of NTPAM in HNC and investigated the mechanism using transcriptomic analysis. The viability of HNC cells decreased after NTPAM treatment due to enhanced apoptosis. A human fibroblast cell line and three HNC cell lines were profiled by RNA sequencing. In total, 1 610 differentially expressed genes were identified. Pathway analysis showed that activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were upstream regulators. Mitochondrial damage was induced by NTPAM, which was associated with enhancements of mitochondrial ROS (mtROS) and ATF4/CHOP regulation. These results suggest that NTPAM induces HNC cell death through the upregulation of ATF4/CHOP activity by damaging mitochondria via excessive mtROS accumulation, similar to mitochondrial targeted therapy.