How is eyeball growth associated with optic nerve head shape and glaucoma? The Lamina cribrosa/Bruch's membrane opening offset theory.

The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.

Clostridium ventriculi in a cynomolgus monkey with acute gastric dilatation and rupture: A case report.

Acute gastric dilatation (AGD) is one of the most prevalent and life-threatening diseases in nonhuman primates worldwide. However, the etiology of this syndrome has not been determined. Recently, sudden death occurred in a 7-year-old female cynomolgus monkey with a history of fecal microbiota transplantation using diarrheic stools. The monkey had undergone surgery previously. On necropsy, gastric dilatation and rupture demonstrated a tetrad arrangement on histopathologic examination. On 16S rRNA sequencing, a high population of Clostridium ventriculi was identified in the duodenum adjacent to stomach but not in the colon. This paper is the first report of Clostridium ventriculi infection in a cynomolgus macaque with acute gastric dilatation and rupture.

Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Outcomes of laparoscopic radiofrequency ablation versus percutaneous radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. METHODS: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. RESULTS: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. CONCLUSIONS: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.

Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells.

BACKGROUND AND AIMS: The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon-γ (IFN-γ) production in both mice and humans. APPROACH AND RESULTS: Following 2-week injection of carbon tetrachloride (CCl4 ) or 5-week methionine-deficient and choline-deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild-type mice. Consistently, NK cell-specific mGluR5 knockout mice had aggravated CCl4 -induced liver fibrosis with decreased production of IFN-γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti-fibrosis-related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN-γ through the mitogen-activated extracellular signal-regulated kinase/extracellular signal-related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl4 -induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells. CONCLUSIONS: mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis.

Mitochondrial Double-Stranded RNA in Exosome Promotes Interleukin-17 Production Through Toll-Like Receptor 3 in Alcohol-associated Liver Injury.

BACKGROUND AND AIMS: Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD. APPROACH AND RESULTS: Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in γδ T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4+ T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1ß expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of γδ T cells in mice and humans. CONCLUSIONS: EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1ß expression in Kupffer cells triggers IL-17A production in γδ T cells at the early stage that may accelerate IL-17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.

Relationship between Three-Dimensional Magnetic Resonance Imaging Eyeball Shape and Optic Nerve Head Morphology.

PURPOSE: To determine if the 3-dimensional (3D) eyeball shape is associated with the positions of the central retinal vascular trunk (CRVT) and the externally oblique border (EOB) in the optic nerve head (ONH). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Fifty-six subjects (112 eyes) with a diagnosis of glaucoma or glaucoma suspect. METHODS: The eyeball shape on 3D magnetic resonance imaging (MRI) scans was classified according to the dimension of the longest diameter: axial dimension (prolate sphere), group 1; horizontal dimension (horizontally oblate sphere), group 2; and vertical dimension (vertically oblate sphere), group 3. The deviation of the CRVT, as a surrogate of lamina cribrosa (LC) shift, was measured from the center of the Bruch's membrane opening (BMO) demarcated by OCT imaging, with the horizontal midline as 0° and the superior location as a positive value. The angular location of the longest EOB was also measured. MAIN OUTCOME MEASURE: Positions of CRVT and EOB according to the 3D eyeball shape. RESULTS: Among 112 eyes, 54 (48%) had a prolate shape (group 1), 23 (21%) had a horizontally oblate shape (group 2), and 35 (31%) had a vertically oblate shape (group 3). The angular deviation of the CRVT differed among the groups: to the nasal side in group 1, to the temporal side in group 2, and along the vertical meridian in group 3. In cases of asymmetric eyeball shape, the CRVT was deviated toward the undergrown side from the overgrown side, regardless of grouping. The angular location of the longest EOB was in the direction opposite to the CRVT position (P < 0.001). A generalized estimating equation analysis revealed that the temporal location of the CRVT was associated with older age (P = 0.001), nasal location of the longest EOB (P < 0.001), and oblate shape of the eyeball (P < 0.001, group 2; P = 0.007, group 3). CONCLUSIONS: The position of the CRVT and EOB were associated with the 3D eyeball shape. Considering that infant ONH morphology is highly uniform, various modes of eyeball expansion during growth can result in diverse directionalities of offset between the LC and the BMO in adults.

Effectiveness of sorafenib dose modifications on treatment outcome of hepatocellular carcinoma: Analysis in real-life settings.

Controlling adverse events (AEs) through dose reduction can enhance drug adherence and treatment response. Currently, there is no guide for sorafenib dosing. The aim of this study was to evaluate whether sorafenib dosing could affect treatment outcomes. A total of 782 hepatocellular carcinoma (HCC) patients treated with sorafenib were evaluated for sorafenib dosing and its modifications via medical records at baseline and regular follow-up. Study outcomes included progression-free survival (PFS), overall survival (OS), sorafenib duration, cumulative dose, AEs and drug discontinuation. The median patient survival was 7.7 months. Overall, 242 (30.9%) patients underwent dose reduction and 121 (17.5%) discontinued sorafenib due to AEs. In multivariate analysis, dose reduction was identified to be independently predictive of PFS and OS. The 800-to-400 mg/day group provided significantly better PFS than the 800 mg/day-maintained group or the 800-to-600 mg/day group. Likewise, the 800-to-400 mg/day group resulted in a significantly better OS than other dosing. However, dose reduction to 200 mg/day led to significantly worse PFS and OS. Hand-foot skin reaction and drug discontinuation due to AEs were higher in the 800-to-600 mg/day group than the 800-to-400 mg/day group. The 800-to-400 mg/day group had significantly longer treatment duration and higher cumulative dose than the 800 mg/day-maintained group. Sorafenib dose reduction can improve HCC survival and increase patient tolerance and adherence coupled with longer duration and higher cumulative dose. Dose reduction from 800 to 400 mg/day than to 600 mg/day is recommended when clinically warranted. However, dose reduction to 200 mg/day is not recommendable.

Case report: what gives the myopic tilted disc an oval appearance?

BACKGROUND: Myopic tilted disc, observed as an oval disc, has been alleged to be a funduscopic en-face manifestation of excessive optic nerve head (ONH) sloping or tilting. Here, we report the case of a myopic child showing a developing oval disc in fundus photos during axial elongation, but without progressive tilting in spectral-domain optical coherence tomography (SD-OCT) images. CASE PRESENTATION: By merging B-scan SD-OCT images of the ONH and macula, the curvature of the posterior pole, including both the fovea and ONH, was reconstructed and compared before and after 2 years of axial elongation. Despite the marked increase of disc ovality, the posterior polar curvature was rarely changed. The preponderance of optic disc change was induced by the shift of the temporal disc margin in the nasal direction. This shifting alone imitated an increase of tilt angle but one that was still far smaller than the required degree of tilt for ONH-tilt-based disc ovality. To clarify, we calculated the required extent of axial elongation to obtain a substantial degree of ONH tilt when considering the adjacency of the fovea and the ONH. Without a focal increase of posterior polar curvature, which is to say posterior staphyloma, such change is not possible until the axial length increases extraordinarily. CONCLUSION: The most prominent change in the development of myopic tilted disc, which change gives it an oval appearance and imitates a tilt when measured, is actually not a tilt but rather a shift of the temporal disc margin.

Emergence of Transferable mcr-9 Gene-Carrying Colistin-Resistant Salmonella enterica Dessau ST14 Isolated from Retail Chicken Meat in Korea.

Colistin is an important antibiotic currently used to manage infections caused by multidrug-resistant pathogens in both humans and livestock animals. A new mobile colistin-resistance (mcr-9) gene was recently discovered; this discovery highlighted the need for rigorous monitoring of bacterial resistance against colistin. Salmonella is one of the major pathogens responsible for foodborne illnesses; however, there is minimal information regarding the presence of mcr genes in foodborne Salmonella strains. The aim of this study was to investigate the presence of mcr genes among 178 Salmonella strains isolated from chicken meat in Korea. Antimicrobial susceptibility was measured using the broth microdilution method. Bioinformatics characterization of colistin-resistant strains and genetic environment of the mcr-9 gene were analyzed using next-generation sequencing. Transferability of the mcr-9 carrying colistin-resistant Salmonella strain was tested using broth-mating conjugation. Thirteen of the 178 Salmonella isolates showed colistin resistance, but only one strain, Salmonella Dessau ST14 (KUFSE-SAL043) from a traditional chicken market in Korea, carried an mcr family gene, mcr-9. This strain also carried other acquired antimicrobial resistance genes such as blaTEM-1B, qnrS1, and aac(6')-Iaa. Only the IncX1 plasmid replicon type was detected in this strain. In the strain KUFSE-SAL043, the mcr-9 gene was located between two insertion sequences, IS903B and IS26, followed by the downstream regulatory genes qseB-like and qseC-like, which were located between IS1R and ΔIS1R. Conjugation tests revealed that the mcr-9 gene was successfully transferred to Escherichia coli J53 at a mean frequency of 2.03 × 10-7. This is the first report of a transferable mcr-9 gene in Salmonella isolated from chicken meat in Korea, highlighting the possibility of transfer of colistin resistance. Therefore, the wide use of colistin should be reconsidered, and a One Health perspective should be adopted to monitor the antimicrobial resistance of Enterobacteriaceae strains in humans, livestock, and the environment.

Clinical outcomes after the introduction of direct antiviral agents for patients infected with genotype 1b hepatitis C virus depending on the regimens: A multicenter study in Korea.

BACKGROUND: A real-life study is essential outside clinical trials. The aim is to evaluate the clinical outcomes of direct acting agents (DAA) for patients with chronic hepatitis C (CHC) in real practice. METHODS: We analyzed 590 consecutively enrolled patients with CHC-1b who received DAAs since 2015, when DAAs were introduced in Korea. The patients were checked for resistance-associated variants (RAV) against nonstructural protein 5A inhibitors and then daclatasvir/asunaprevir or sofosbuvir based regimens were chosen. RESULTS: The frequency of patients with cirrhosis and prior hepatocellular carcinoma (HCC) was 29.2% and 4.7%, respectively. For the RAV test, 10% were positive and in 3.6% the result was "indeterminate." Overall, 518 patients were treated with a 24-week regimen of daclatasvir/asunaprevir, 72 patients (RAV positive 75%) were treated with 12 weeks regimen of ledipasvir/sofosbuvir or daclatasvir/sofosbuvir. The SVR12 was 94.0% in the daclatasvir/asunaprevir, 98.2% in the ledipasvir/sofosbuvir, and 100% in the daclatasvir/sofosbuvir group. A total of 93.3% of SVR12 in the RAV-"indeterminate" patients was not difference 95.0% in the RAV-negative patients. Up to 1 year, de novo HCC occurrence and recurrence developed in 2.6% and 17.8%, respectively. HCC was more frequent in cirrhotic patients than in noncirrhotic patients (P = 0.000). α Fetoprotein (AFP) level at the end of treatment was a predicting factor for de novo HCC. CONCLUSIONS: Optimizing the choice of DAAs according to RAV test resulted in high SVR among CHC-1b Korean patients. This real practice multicenter cohort study suggests the importance of AFP and HCC surveillance in cirrhotic patients even after successful HCV therapy.

Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. METHODS: We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m2 /body surface area). RESULTS: We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). CONCLUSIONS: These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. LAY SUMMARY: Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria.

Longitudinal Changes of Optic Nerve Head and Peripapillary Structure during Childhood Myopia Progression on OCT: Boramae Myopia Cohort Study Report 1.

PURPOSE: To delineate longitudinal changes in the optic nerve head (ONH) and peripapillary structure during myopia progression in childhood using spectral-domain (SD) OCT and to explore the factors associated with myopic ONH and peripapillary changes. DESIGN: Prospective cohort study. PARTICIPANTS: Twenty-three healthy children with myopia (46 eyes). METHODS: The participants underwent fundus photography, SD OCT, and axial length (AXL) measurements every 6 months for 2 years. Based on the morphologic changes of the ONH and ß-zone parapapillary atrophy (PPA), eyes were classified as group A (ONH unchanged without ß-zone PPA; 11 eyes), group B (ONH changed without ß-zone PPA at baseline; 10 eyes), group C (ONH changed with ß-zone PPA at baseline; 15 eyes), and group D (ONH unchanged with ß-zone PPA; 10 eyes). The configuration of the border tissue (BT) at the temporal margin of the ONH was assessed, and the ONH parameters, including Bruch's membrane opening distance (BMOD), border length (BL), and BT angle (BTA), were measured on horizontal SD OCT scans. MAIN OUTCOME MEASURES: Changes in ONH parameters and associated factors. RESULTS: Group B showed the greatest AXL increase per year (group B > group C > group A = group D; P < 0.001). During the follow-up periods, the BT configuration initially was changed from internally oblique to externally oblique (group B) and was stretched, resulting in optic disc ovality and γ-zone PPA development (group C). In group C, BL was increased significantly nasally and BTA was decreased significantly, whereas BMOD remained stable (P < 0.001, P < 0.001, and P = 0.100, respectively). In the multivariate analysis using the generalized linear mixed-effect model, the changes of BL and BTA were associated with axial elongation (P = 0.028 and P = 0.010, respectively). CONCLUSIONS: Development of myopic optic disc and γ-zone PPA during myopia progression was delineated using SD OCT images. During the ONH and peripapillary changes, the BL was increased nasally and the BTA was decreased, whereas the BMOD remained relatively stable. The association of axial elongation with ONH and peripapillary tissue changes may facilitate understanding of the relationship between myopia and glaucoma.

Positional Change of Optic Nerve Head Vasculature during Axial Elongation as Evidence of Lamina Cribrosa Shifting: Boramae Myopia Cohort Study Report 2.

PURPOSE: To investigate the positional change of central retinal vasculature and vascular trunk to deduce the change in the lamina cribrosa (LC) during axial elongation. DESIGN: Prospective cohort study. PARTICIPANTS: Twenty-three healthy myopic children (46 eyes). METHODS: Participants had undergone a full ophthalmologic examination and axial length measurement every 6 months for 2 years. Using spectral-domain OCT, circle scans centered around the optic disc in the glaucoma progression analysis mode, which enabled capturing of the same positions throughout the entire study period, and enhanced depth imaging of the deep optic nerve head complex were performed. Infrared imaging of the circle scans was used to measure the changes in the angles between the first and final visits. The angle between the major superior and inferior retinal arteries was measured along the circle scan twice: from the center of the circle scan and from the central retinal vascular trunk, respectively. The positional change of the retinal vascular trunk also was measured. MAIN OUTCOME MEASURES: Change in vascular angle and position of vascular trunk with axial elongation and associated factors. RESULTS: The vascular angle measured from the center of the circle scan did not change (P = 0.247), whereas the angle measured from the central retinal arterial trunk decreased with axial elongation (P < 0.001). A generalized estimating equation analysis revealed that the factors associated with angle decrease were axial elongation (P = 0.004) and vascular trunk dragging (P < 0.001). The extent of vascular trunk dragging was associated with axial elongation (P < 0.001) and increased border length with marginal significance (P = 0.053), but the extent of dragging could not be explained fully by their combination. The major directionality of dragging was mostly to the nasal side of the optic disc, with large variations among participants. CONCLUSIONS: During axial elongation, the retinal vasculature at the posterior pole was unchanged, whereas the position of the central vascular trunk was dragged nasally. Because the central retinal vascular trunk is embedded in the LC, its dragging indicates nasal shifting of the LC, which could explain the vulnerability of myopic eyes to glaucomatous optic neuropathy.

Once-daily, prolonged-release tacrolimus vs twice-daily, immediate-release tacrolimus in de novo living-donor liver transplantation: A Phase 4, randomized, open-label, comparative, single-center study.

Randomized, open-label, comparative, single-center, Phase 4, 24-week study comparing pharmacokinetics (PK), safety, and efficacy of once-daily, prolonged-release tacrolimus (PR-T) with twice-daily, immediate-release tacrolimus (IR-T) in adult de novo living-donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR-T or IR-T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration-time curve over 24 hour (AUC0-24 ). Predefined similarity interval for confidence intervals of ratios: 80%-125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24 ), patient/graft survival, biopsy-confirmed acute rejection (BCAR), treatment-emergent adverse events (TEAEs). One-hundred patients were included (PR-T, n = 50; IR-T, n = 50). Compared with IR-T, 40% and 66% higher mean PR-T daily doses resulted in similar AUC0-24 between formulations on Day 6 (PR-T:IR-T ratio of means 96.8%), and numerically higher AUC0-24 with PR-T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0-24 and C24 , and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR-T vs IR-T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR-T was efficacious; no new safety signals were detected.

Totally laparoscopic living donor left hepatectomy for liver transplantation in a child.

BACKGROUND: Minimally invasive surgery has been validated to be a new standard in living donor hepatectomy for adult-to-pediatric transplantation with less morbidity [1]. Laparoscopic donor hepatectomy can reduce the major concerns about pain and morbidity associated with open surgery and a slow return to daily activities of donors [2]. Herein, we present one case of totally laparoscopic living donor left hepatectomy including the middle hepatic vein (MHV). DONOR AND METHOD: A 37-year-old mother volunteered to donate to her 3-year-old son with biliary atresia (PELD score 7). Total donor liver volume was 833 cm3 and left liver, including MHV, was 290 cm3. Graft to recipient body weight ratio was 2.07. Our operative technique has been published previously [2]. The left hepatic artery and portal vein were dissected and encircled with two vessel loops. Pringle's maneuver was used during parenchymal transection. The transection of the liver was performed using an alternating combination of laparoscopic ultrasonic aspirator (CUSA) and THUNDERBEAT™ (Olympus, Japan). The MHV was identified and parenchymal transection was performed right side to it. Several small tributaries from segment V and VIII were identified and divided. Finally, left bile duct was identified and divided after performing intraoperative cholangiography using a mobile C-arm. RESULTS: Totally laparoscopic living donor left hepatectomy was performed successfully without intraoperative complications and transfusion. The operation time was 300 min, the estimated blood loss was less than 125 ml and Graft weight was 314 g. Oral intake was resumed on the first postoperative day (POD). On POD 4, CT scan showed no pathological findings. The patient was discharged on POD 8 without complications. CONCLUSION: The authors conclude that the laparoscopic living donor left hepatectomy is a safe and feasible procedure but should be performed in selected patients with a favorable anatomy.

Long-term results of laparoscopic liver resection for the primary treatment of hepatocellular carcinoma: role of the surgeon in anatomical resection.

BACKGROUND: Liver resection is a potentially curative therapy for hepatocellular carcinoma (HCC). LLR is a newly developed and safe technique associated with shorter hospital stay, less pain, better cosmetic outcomes, and similar complication rates as open surgery; however, data on its long-term outcomes remain scarce. METHODS: We retrospectively examined the clinical and follow-up data of 234 patients who underwent LLR (performed by a single surgeon in all cases) for the primary treatment of HCC between July 2007 and December 2015 at Asan Medical Center. RESULTS: The mean patient age was 55.63 (range 31-76) years; 167 were men. The median follow-up duration was 38 (range 6-116) months. A total of 227 patients (97.0%) had Child-Turcotte-Pugh grade A disease. Of them, 167 (71.4%) underwent anatomical resections and 63 (28.6%) underwent non-anatomical partial hepatectomies. Overall survival rates were 98.3, 91.7, and 87.1%, and recurrence-free survival rates were 82.1, 67.5, and 55.3% at 1, 3, and 5 years, respectively. In Cox regression analysis, anatomical resection was a risk factor for recurrence (univariate analysis: hazard ratio [HR] 0.49; 95% confidence interval [CI] 0.31-0.75; p = 0.001; multivariate analysis: HR 0.59; 95% CI 0.38-0.94; p = 0.025). CONCLUSIONS: LLR is an acceptable primary treatment for patients with HCC with good hepatic function and with an appropriate anatomical structure, and is associated with improved prognosis. LLR can achieve lower recurrence rates through anatomical resection.

Three-Dimensional Analysis of the Correlation Between Soft Tissue and Bone of the Lower Face Using Three-Dimensional Facial Laser Scan.

BACKGROUND: The prime aims of this study were to establish cephalometric linear and angular normative values of the lower face using a three-dimensional (3D) analysis in Korean individuals, and validate whether the linear and angular measurements using 3D laser scanner are comparable with measurements using 3D computed tomography (CT). METHODS: In this study, 40 Korean individuals aged between 18 and 60 years were enrolled. Using 3D CT scan and 3D laser scanner, linear and angular values of the lower face were measured and recorded. Statistical analysis was carried out to verify the concordance and correlation between two 3D imaging modalities. RESULTS: The 40 samples consisted of 11 women with a mean age of 40.8 ±â€Š14.5 years and 29 men with a mean age of 29.7 ±â€Š15.0 years. The results demonstrated the difference between sex and the tendency of asymmetry on both sides. Among different methods of measuring angular values, the gonial angle (GA) between tragion' (Tr')-gonion' (Go')-menton' (Me') from 3D laser scanning and between articulate-gonion-menton from CT scan demonstrated a good concordance and a high correlation. CONCLUSIONS: The GA measured between Tr'-Go'-Me' using a 3D facial laser scan was comparable with values from 3D CT scan. The reference points and the GA, which we assessed here for 3D laser scanning, can be a reliable alternative method evaluating mandibular angles for assessing patients and surgical planning in plastic and orthognathic surgery.

Longterm prognosis of combined hepatocellular carcinoma-cholangiocarcinoma following liver transplantation and resection.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CC) is a rare disease. We investigated the clinicopathological features of cHCC-CC and compared the longterm outcomes following liver transplantation (LT) and hepatic resection (HR). We identified 32 LT patients with cHCC-CC through an institutional database search. The HR control group (n = 100) was selected through propensity score-matching. The incidence of cHCC-CC among all adult LT patients was 1.0%. Mean patient age was 53.4 ± 6.7 years, and 26 patients were male. Thirty patients had hepatitis B virus infection. All patients of cHCC-CC were diagnosed incidentally in the explanted livers. Mean tumor diameter was 2.5 ± 1.3 cm, and 28 patients had single tumors. Tumor stage was stage I in 23 and II in 9. Concurrent hepatocellular carcinoma (HCC) was detected in 12 patients with stage I in 5 and II in 7. Mean tumor diameter was 1.9 ± 1.2 cm, and 5 had single tumors. Tumor recurrence and survival rates were 15.6% and 84.4% at 1 year and 32.2% and 65.8% at 5 years, respectively. Patients with very early stage cHCC-CC (1 or 2 tumors ≤ 2.0 cm) showed 13.3% tumor recurrence and 93.3% patient survival rates at 5 years, which were significantly improved than those with advanced tumors (P = 0.002). Tumor recurrence and survival rates did not differ significantly between the LT and HR control groups (P = 0.22 and P = 0.91, respectively); however, postrecurrence patient survival did (P = 0.016). In conclusion, cHCC-CC is rarely diagnosed following LT, and one-third of such patients have concurrent HCC. The longterm posttransplant prognosis was similar following LT and HR. Very early cHCC-CC resulted in favorable posttransplant prognosis, thus this selection condition can be prudently considered for LT indication. Liver Transplantation 23 330-341 2017 AASLD.

Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure.

Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5'-nucleotidase, Ecto5'NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care.