Comparing two mucin secretagogues for the treatment of dry eye disease: a prospective randomized crossover trial.

This study aimed to compare the clinical efficacy and investigate patients' preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p < 0.001 and 0.026, respectively), and corneal (p < 0.001 and 0.001, respectively) and conjunctival (p = 0.017 and 0.042, respectively) staining after 4 weeks of treatment. An increase in Schirmer test scores was observed only after rebamipide treatment (p = 0.007). No significant changes were detected in tear osmolarity, MMP-9, and LLT following both treatments. The patients' preference was slightly greater for diquafosol (46.4%) than rebamipide (36.7%), presumably due to rebamipide's bitter taste. The self-efficacy of both drugs and overall satisfaction scores were comparable. These findings indicate that two mucin secretagogues showed comparable effects in ameliorating symptoms and improving signs (TBUT, corneal and conjunctival staining) in patients with DED.

Adult-onset hypophosphatemic osteomalacia as a cause of widespread musculoskeletal pain: A retrospective case series of single center experience.

BACKGROUND: Osteomalacia (OM) is frequently confused with various musculoskeletal or other rheumatic diseases, especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-specific manifestations. AIM: To facilitate the early diagnosis and etiology-specific treatment of adult-onset hypophosphatemic OM. METHODS: A retrospective review of medical records was performed to screen adult patients who visited a physiatry locomotive medicine clinic (spine and musculoskeletal pain clinic) primarily presenting with widespread musculoskeletal pain at a single tertiary hospital between January 2011 and December 2019. We enrolled patients with hypophosphatemia, high serum bone-specific alkaline phosphatase levels, and at least one imaging finding suggestive of OM. RESULTS: Eight patients with adult-onset hypophosphatemic OM were included. The back was the most common site of pain. Proximal dominant symmetric muscle weakness was observed in more than half of the patients. Bone scintigraphy was the most useful imaging modality for diagnosing OM because radiotracer uptake in OM showed characteristic patterns. Six patients were diagnosed with adefovir (ADV)-induced Fanconi syndrome, and the other two patients were diagnosed with tumor-induced OM and light-chain nephropathy, respectively. After phosphorus and vitamin D supplementation and treatment for the underlying etiologies, improvements in pain, muscle strength, and gait were observed in all patients. CONCLUSION: Mechanical pain characteristics, hypophosphatemia, and distinctive bone scintigraphy patterns are the initial diagnostic indicators of adult-onset hypophosphatemic OM. ADV-induced Fanconi syndrome is the most common etiology of hypophosphatemic OM in hepatitis B virus-endemic countries.

Induction of meibocyte differentiation by three-dimensional, matrigel culture of immortalized human meibomian gland epithelial cells to form acinar organoids.

PURPOSE: Recent studies have shown that two-dimensional (2D) culture of primary rabbit and immortalized human meibomian gland epithelial cells (iHMGEC) do not recapitulate normal meibocyte differentiation and fail to express critical enzymes necessary for synthesis of meibum lipids. The purpose of this study was to test the hypothesis that 3D-spheroid culture of iHMGEC can facilitate meibocyte differentiation and induce the expression of acyl-CoA wax-alcohol acyltransferase 2 (AWAT2), shown to be required for synthesis of meibum wax esters. METHODS: iHMGEC were suspended in matrigel/basement membrane matrix and grown in proliferation media to form distinct cell clusters or spheroids. Cells were then treated with serum-free, differentiation media (advanced DMEM/F12) with and without FGF10 and synthetic agonists for the nuclear lipid receptor, peroxisome proliferator activator receptor gamma (PPARγ). Cells were then evaluated for differentiation markers using western blotting, immunocytochemistry (ICC) and real-time PCR. Control cells were grown in standard 2D culture systems. RESULTS: Under proliferative conditions, 3D culture induced the formation of KRT5+ spheroids that contained a Ki67+/P63+ undifferentiated, basal cell population. When spheroids were switched to differentiation media containing PPARγ agonists, two different organoid populations were detected, a KRT6low population that was AWAT2+/PPARγ+ and a KRT6high population that was AWAT2-/PPARγ-, suggesting that iHMGEC exhibit a dual differentiation potential toward either a ductal or meibocyte organoid phenotype. CONCLUSION: The 3D culturing of iHMGEC can induce the formation of both meibocyte and ductal organoids and may thus serve as a better in vitro model system for studying the regulatory mechanisms controlling meibomian gland function.

Prevalence and risk factors of epiretinal membrane: Data from the Korea National Health and Nutrition Examination Survey VII (2017-2018).

BACKGROUND: To determine the prevalence and risk factors of epiretinal membrane (ERM) utilising spectral-domain optical coherence tomography (SD-OCT). METHODS: We investigated data from the 2017 to 2018 Korea National Health and Nutrition Examination Survey. Individuals aged ≥40 years with readable fundus photographs and SD-OCT results were included. ERM was diagnosed by fundus photography and OCT. The following data was collected: demographics, health interview, health examination, and nutritional survey results. The prevalence of ERM was estimated and risk factors for ERM were analysed. RESULTS: A total of 6807 participants were finally included. Adjusted prevalence of ERM was 7.0% (95% confidence interval, 6.3%-7.8%). Multivariate logistic regression analysis revealed that age ≥ 50 years (p < 0.001 for all age groups), history of cataract surgery (p < 0.001), well-controlled hypertension (p = 0.006), and diabetic retinopathy (p = 0.041) were risk factors for ERM. CONCLUSIONS: The estimated prevalence of ERM was 7.0%, which was higher than that of previous reports using fundus photography only in an East Asian population. Possible risk factors for ERM were older age, history of cataract surgery, hypertension, and diabetic retinopathy.

Lumbosacral plexopathy caused by the perineural spread of pelvic malignancies: clinical aspects and imaging patterns.

BACKGROUND: Perineural spread (PNS) of tumors from pelvic malignancies is a rare phenomenon but constitutes an important differential diagnosis of lumbosacral plexopathy (LSP). Herein, we describe the clinical and imaging features of patients with LSP due to PNS of pelvic malignancies along with a literature review. METHODS: We retrospectively reviewed 9 cases of LSP caused by PNS of pelvic malignancy between January 2006 and August 2021, and all clinical and imaging parameters were recorded in detail. Clinical symptoms and signs of patients were described and listed in the order in which they occurred. The results of imaging test were analyzed to describe specific findings in LSP caused by PNS. RESULTS: This study enrolled nine adult patients (mean age, 50.1 years). Two cases initially presented as LSP and were later diagnosed with pelvic malignancy. Pain in the perianal or inguinal area preceded pain at the extremities in six patients. Neurogenic bladder or bowel symptoms developed in five patients. On the magnetic resonance imaging (MRI), the S1-S2 spinal nerve was most commonly involved, and S1 myotome weakness was more prominent in six patients than the other myotomes. One patient had an intradural extension. 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) showed abnormal signal intensity in six patients. No abnormality in 18F-FDG PET/CT was detected in the nervous structures in one patient. Only four patients survived until the last follow-up visit. CONCLUSIONS: Though rare, physicians should always keep in mind the possibility of LSP due to the PNS in patients with pelvic malignancy. Thorough physical examination and history taking could provide clues for diagnosis. Pelvic MRI and 18F-FDG-PET/CT should be considered for patients with LSP to rule out neoplastic LSP.

Intraneural ganglion cysts originating from the hip joint: A single-center experience.

INTRODUCTION/AIMS: Intraneural ganglion cysts (INGCs) are non-neoplastic mucinous cysts within the epineurium of peripheral nerves. Characteristics of INGCs around the hip joint have not been adequately described. We aimed to describe clinical features, imaging findings, and treatment outcomes in patients with INGCs originating from the hip joint. METHODS: We retrospectively included cystic lesions around the hip joint satisfying the following inclusion criteria over 6 years: (1) multilocular elongated hyperintense cystic mass on T2-weighted imaging; and (2) distribution along the course of the peripheral nerve and its branches on magnetic resonance imaging (MRI). RESULTS: Six patients with an INGC around the hip joint were identified. Parent peripheral nerves were the sciatic nerve (four patients), the superior gluteal nerve (one patient), and the nerve to quadratus femoris (one patient). Buttock, groin, or lower extremity pain/paresthesias were the initial symptoms in all patients. INGCs within the articular branches of the hip joint were identified on MRI. Four patients underwent arthroscopic debridement and capsulotomy. All patients showed generally favorable outcome regardless of treatment. DISCUSSION: Physicians should consider the possibility of INGCs originating from the hip joint as a cause of nontraumatic hip, buttock, or lower extremity pain. This can occur in any nerve innervating the hip joint, and usually it originates in the posterior capsule of the hip joint. Arthroscopic surgery shows promising results; however, more information about the surgical technique and long-term follow-up results are needed.

Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus.

Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.

Brachial Plexus Injury Associated with Median Sternotomy during Cardiac Surgery: Three Cases of C8 Radiculopathy Due to the Fracture of the First Rib.

In cardiac surgery, median sternotomy is often necessary during certain surgical processes and it can cause the rare complication of brachial plexus injury. Retraction of the rib cage during median sternotomy may produce a fracture of the first thoracic rib at the costovertebral junction which might penetrate or irritate the lower root of the brachial plexus. Because the C8 ventral root is located immediately superior to the first thoracic rib, the extraforaminal C8 root is thought to be the key location of brachial plexus injury by the first rib fracture. This report describes three cases of brachial plexus injury after median sternotomy in a single center. In our cases, fracture of the first rib and consequent brachial plexus injury is confirmed with imaging and electrophysiologic studies. The fracture of the first rib is not detected with standard plain images and it is confirmed only with CT or MRI studies. Advanced imaging tools are recommended to assess the first rib fracture when brachial plexus injury is suspected after median sternotomy.

Effectiveness of Transarterial Chemoembolization-First Treatment for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients. PATIENT AND METHODS: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response. RESULTS: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P<0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort. CONCLUSION: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.

The FIB-4 Index Is a Useful Predictor for the Development of Hepatocellular Carcinoma in Patients with Coexisting Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B.

BACKGROUND: The FIB-4 index, a noninvasive tool (FIB-4 index = age × aspartate transaminase (AST)/(platelet count × âˆšalanine aminotransferase (ALT)), is a useful assessment for liver fibrosis. Patients with a high FIB-4 index were reported to have a high risk of developing hepatocellular carcinoma (HCC). This study analyzed the clinical association of the FIB-4 index with HCC development in patients with coexisting nonalcoholic fatty liver disease and chronic hepatitis B (NAFLD-CHB). METHODS: This retrospective study analyzed 237 consecutive patients with NAFLD-CHB between January 2006 and December 2010 at the National Police Hospital in Korea. Patients with HCC at baseline and those diagnosed with HCC within 6 months from baseline were excluded. Propensity score matching analysis (PSM) was adopted to balance the baseline characteristics between patients with low and high FIB-4 index values. The cumulative rates of HCC development were compared between the two groups using the Kaplan-Meier method in the matched population. RESULTS: The median follow-up duration was 13 years (interquartile range, 8.2-15.7). The optimal cutoff for the FIB-4 index of 1.77 was calculated based on the maximum Youden index value, with an AUC of 0.70. Among a total of 237 patients with NAFLD-CHB, HCC developed in 20 patients (8.4%) (14 of the 90 patients with a high FIB-4 index vs. 6 of the 147 patients (4.1%) with a low FIB-4 index; log-rank p = 0.003). Patients with a high FIB-4 index had a significantly and independently higher risk of HCC than those with a low FIB-4 index (adjusted hazard ratio, 4.35; 95%; confidence interval, 1.42-13.24; log-rank test, p = 0.006). CONCLUSION: A high FIB-4 index (≥1.77) might be a useful marker for predicting the development of HCC in patients with NAFLD-CHB.

Focal vasculitic myositis as a primary manifestation of Behçet's disease: a case series of 10 Korean patients in a locomotive medicine clinic.

OBJECTIVES: Muscle involvement in Behçet's disease (BD) is rare, and several cases have been reported in the literature. Therefore, this study aimed to describe the clinical, laboratory and imaging findings in adult patients presenting with BD-associated myositis before the diagnosis of BD. METHODS: We retrospectively screened patients who visited a locomotive medicine clinic presenting with myalgia, local swelling, or tenderness of extremities without an established diagnosis of BD. We enrolled patients whose pain in the extremities was proven to be suggestive of focal vasculitic myositis and who were eventually diagnosed as having BD at the initial visit or during follow-up. We thoroughly reviewed the clinical, histological and imaging findings and treatment outcomes in patients who presented with focal vasculitic myositis as the primary manifestation of BD. RESULTS: Ten adult patients with focal vasculitic myositis as the primary manifestation of BD were enrolled. The lower and upper extremities were affected in eight and two patients, respectively. The affected lower extremities were the calf (n = 6) and thigh muscles (n = 2). The common findings of MRI included high signal intensity of the affected muscles and intermuscular fascia on fat-suppressed images, suggestive of myofascitis and oedematous changes in the subcutaneous layer. The results of skin or muscle biopsy were suggestive of vasculitis. All the patients were pain-free at the short-term follow-up (1-3 weeks) after oral steroid therapy. CONCLUSION: Focal vasculitic myositis can be a primary manifestation of BD warranting medical attention. BD-associated myositis responds well to oral steroid therapy.

Prognostic role of spleen volume measurement using computed tomography in patients with compensated chronic liver disease from hepatitis B viral infection.

OBJECTIVES: To determine the prognostic value of CT-based splenic volume measurement in patients with compensated chronic liver disease (cCLD) from chronic hepatitis B (CHB). METHODS: A total of 584 patients having multiphasic liver CT scans between January and December 2011 were retrospectively reviewed. Spleen volume was measured using a semi-automated three-dimensional volumetric software program. Electronic medical records and national registry data were reviewed to determine the diagnosis of hepatocellular carcinoma (HCC), hepatic decompensation, or death. The cumulative incidence (CI) of the development of decompensation, HCC occurrence, and overall survival (OS) were estimated by the Kaplan-Meier method. The Cox proportional hazard regression model was used to evaluate prognostic factors. The optimal cutoff spleen volume to predict each outcome was obtained using a minimal p value approach method. RESULTS: After a median follow-up of 92 months, 114 patients developed HCC with a 7-year CI of 17.2%. A larger spleen volume was a significant predictor of HCC occurrence (HR = 2.13, p = 0.009). Decompensation occurred in 30 patients with a 7-year CI of 5.0%, and a larger spleen volume was also significantly associated with the development of decompensation (HR = 4.66, p = 0.005). Twenty-three patients died, and their estimated 7-year OS was 96.4%. A larger spleen volume also significantly affected OS (HR = 6.15, p = 0.007). The optimal cutoff spleen volume was set at 532 mL for HCC occurrence, 656.9 mL for the development of decompensation, and 741.1 mL for OS. CONCLUSIONS: A larger spleen volume was significantly associated with HCC occurrence, development of decompensation, and poor OS in patients with cCLD from CHB. KEY POINTS: • Spleen volume could be easily acquired from routine multiphasic liver CT scan using a semi-automated 3D volumetric software program with excellent inter-observer agreement. • A larger spleen volume was significantly associated with a higher rate of hepatocellular carcinoma occurrence, the development of decompensation, and poor overall survival in patients with compensated chronic liver disease from chronic hepatitis B.

Neurolymphomatosis: a single-center experience of neuromuscular manifestations, treatments, and outcomes.

OBJECTIVES: Neurolymphomatosis (NL) is a disease characterized by the infiltration of malignant lymphocytes into the peripheral nervous system. We report clinical features, radiographic findings, modes of treatment, and outcomes of patients with NL. METHODS: We retrospectively investigated patients with NL. We extracted data, including clinical features, magnetic resolution imaging (MRI), 18F-fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scans, cerebrospinal fluid cytology findings, the results of electrodiagnostic studies, as well as patient treatments and outcomes. RESULTS: Ten NL patients were identified. All patients reported pain/paresthesia and weakness in the affected area. The MRI scans were abnormal in eight out of nine patients with an enhancement of the spinal nerve root, plexus, peripheral nerve trunk, and cranial nerve. The FDG PET/CT scans were positive in all patients. Radiculopathy or radiculoplexopathy was the most common electrodiagnostic finding. Neurological improvement was observed in only three patients. The condition of the nine patients who underwent multimodality treatments for cancer eventually deteriorated and the patients died. CONCLUSIONS: NL should be considered in the differential diagnosis of any type of neuropathy in patients with lymphoma. Because it could be confused with other neuropathies in lymphoma and various musculoskeletal diseases, a high index of suspicion and familiarity with clinical manifestation of NL are key. FDG PET/CT was the most sensitive diagnostic imaging modality to detect relevant neural invasion. The root within the spinal neural foramen was the most frequently affected neural structure. Early diagnosis of this rare neurologic manifestation of lymphoma may improve treatment outcomes.

Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma.

BACKGROUND: The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC). AIM: To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway. METHODS: The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with H2O2, which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses. RESULTS: H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo (both P < 0.05). The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response (UPR), including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues (P < 0.05) and were positively correlated with the ATF-6 Levels (Pearson's coefficient = 0.299; P < 0.05). CONCLUSION: This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. The ROS-induced activation of YAP-1 via the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC.

AMPK Activation by 5-Amino-4-Imidazole Carboxamide Riboside-1-ß-D-Ribofuranoside Attenuates Alkali Injury-Induced Corneal Fibrosis.

Purpose: Increased TGF-ß1 synthesis after corneal alkali injury is implicated in corneal fibrosis, as it promotes transdifferentiation of keratocytes into myofibroblasts. The activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) by 5-amino-4-imidazole carboxamide riboside-1-ß-d-ribofuranoside (AICAR) inhibits TGF-ß1-induced fibrosis in other cell types. We investigated the antifibrotic effect of AICAR in corneal fibroblasts after alkali injury. Methods: Mouse models of corneal alkali burn, produced by placing 2-mm-diameter filter paper soaked in 0.1-N NaOH on the right cornea for 30 seconds, were treated with the test drugs 4× daily for 21 days. The central cornea was scanned by optical coherence tomography (OCT). Corneal tissues were obtained and processed for western blotting and immunohistochemistry. For in vitro analysis, primary human corneal fibroblasts were treated directly with TGF-ß1 to induce fibrosis, with or without AICAR pretreatment. Myofibroblast activation and extracellular matrix (ECM) protein synthesis were detected by western blotting, real-time PCR, and collagen gel contraction assay. Signaling proteins were analyzed by western blotting. Results: Alkali injury induced the upregulation of TGF-ß1 expression, which led to increased α-smooth muscle actin (α-SMA) and fibronectin synthesis and myofibroblast differentiation. AMPK activation by AICAR significantly suppressed TGF-ß1 and ECM protein expression. The antifibrotic effect of AICAR was AMPK dependent, as treatment with the AMPK inhibitor Compound C attenuated the antifibrotic response. Conclusions: AMPK activation by AICAR suppresses the myofibroblast differentiation and ECM synthesis that occur after alkali injury in corneal fibroblasts.

Eicosapentaenoic acid (EPA) activates PPARγ signaling leading to cell cycle exit, lipid accumulation, and autophagy in human meibomian gland epithelial cells (hMGEC).

PURPOSE: The purpose of this study was to access the ability of the natural PPAR agonist, eicosapentaenoic acid (EPA), to activate PPAR gamma (γ) signaling leading to meibocyte differentiation in human meibomian gland epithelial cell (hMGEC). METHODS: HMGEC were exposed to EPA, alone and in combination with the specific PPARγ antagonist, T0070907, to selectively block PPARγ signaling. Expression of PPARγ response genes were evaluated by qPCR. Effect on cell cycle was evaluated using Ki-67 labelling and western blots. During differentiation, autophagy was monitored using the Autophagy Tandem Sensor (ATS) and LysoTracker. Lipid accumulation was characterized by Stimulated Raman Scattering microscopy (SRS) and neutral lipid staining in combination with ER-Tracker, LysoTracker, and ATS. Autophagy was also investigated using western blotting. Seahorse XF analysis was performed to monitor mitochondrial function. RESULTS: EPA specifically upregulated expression of genes related to lipid synthesis and induced cell cycle exit through reduced cyclin D1 expression and increased p21 and p27 expression. EPA also induced accumulation of lipid droplets in a time and dose dependent manner (P < 0.05) by specific PPARγ signaling. Lipid analysis identified both de novo synthesis and extracellular transport of lipid to form lipid droplets that were localized to the ER. PPARγ signaling also induced activation of AMPK-ULK1 signaling and autophagy, while inhibition of autophagy induced mitochondrial crisis with no effect on lipid accumulation. CONCLUSIONS: EPA induces meibocyte differentiation through PPARγ activation that is characterized by cell cycle exit, de novo and transported lipid accumulation in the ER, and autophagy.

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment.

BACKGROUND/AIMS: Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients. METHODS: Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias. RESULTS: Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0-10.8) months for regorafenib and 5.9 (95% CI, 3.7-8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30-0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51-1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04). CONCLUSION: After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.

Prognostic impact of concurrent nonalcoholic fatty liver disease in patients with chronic hepatitis B-related hepatocellular carcinoma.

BACKGROUND AND AIM: As the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, patients with both NAFLD and chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) is also frequently found. This study aimed to investigate the clinical impact of concurrent NAFLD on the prognosis of patients with CHB-related HCC. METHODS: Patients with CHB-related HCC who underwent surgical resection were consecutively selected from August 2009 to December 2013. The association between histologically proven concurrent NAFLD and clinical outcomes were analyzed. Propensity score (PS) matching was adapted to adjust for baseline characteristics. We also investigated the presence of nonalcoholic steatohepatitis (NASH) among patients with NAFLD and its association with clinical outcomes. RESULTS: Among 338 CHB-related HCC patients selected, 196 patients (58.0%) were diagnosed with concurrent NAFLD. The median follow-up duration was 74.9 months. The patients with NAFLD tended to have better recurrence-free survival (RFS; log-rank, P = 0.16) and had significantly better overall survival (OS; log-rank, P = 0.004) than those without NAFLD. However, the survival benefit of the concurrent NAFLD was not significant in a multivariable Cox analysis (adjusted hazard ratio, 0.94; 95% confidence interval, 0.51-1.73, P = 0.84) or an analysis after PS matching (log-rank, P = 0.57). Regarding the presence or absence of NASH, no differences in the RFS (log-rank, P = 0.61) and OS (log-rank, P = 0.26) were found. CONCLUSIONS: Concurrent NAFLD was not associated with both RFS and OS in patients with CHB-related HCC after adjusting for baseline characteristics. Moreover, NAFLD patients with NASH did not have significantly different clinical outcomes compared with NAFLD patients without NASH.

Tumor Marker-Based Definition of the Transarterial Chemoembolization-Refractoriness in Intermediate-Stage Hepatocellular Carcinoma: A Multi-Cohort Study.

BACKGROUND: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. METHODS: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). RESULTS: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37-3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54-8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. CONCLUSION: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

Cataract Surgery Practices in the Republic of Korea: A Survey of the Korean Society of Cataract and Refractive Surgery 2018.

PURPOSE: To describe current cataract surgery practice patterns and changing trends among Korean ophthalmologists. METHODS: A survey of members of the Korean Society of Cataract and Refractive Surgery was performed in July 2018. One hundred and two (12.7%) of 801 questionnaires were returned for analysis. The data were analyzed using descriptive statistics and compared with previous surveys. RESULTS: Most of the respondents (75%) had been in practice for 6 or more years and performed an average of 31 cataract surgeries per month. The preferred method for cataract surgery was phacoemulsification (95%); 5% used a femtosecond laser. The use of topical anesthesia markedly increased from 69% (2012) to 80% (2018). The use of optical biometry exceeded that of ultrasound A-scan biometry. A multifocal intraocular lens was used by 76% of the respondents compared with 44% of the respondents in 2012. Topical nonsteroidal anti-inflammatory drugs were used by 70% of the respondents postoperatively. Most (59%) of these anti-inflammatory drugs were prescribed for 4 weeks. CONCLUSIONS: This survey provided a comprehensive update of the present cataract surgery practices in the Republic of Korea. The results emphasized the increasing use of premium intraocular lenses, optical biometry, and topical anesthesia.