Publications by authors named "Hitoshi Takagi"

213 Publications

Efficacy of Zinc Acetate Treatment for Patients with Decompensated Liver Cirrhosis Complicated by Hypozincemia.

Biol Trace Elem Res 2021 Apr 29. Epub 2021 Apr 29.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

The aim of this study was to evaluate the efficacy of zinc acetate treatment for patients with decompensated liver cirrhosis complicated by hypozincemia. We retrospectively analyzed 49 patients with decompensated liver cirrhosis complicated by hypozincemia who received zinc acetate treatment from August 2017 to March 2020. The relationships between serum zinc levels and several parameters including the prognosis, sarcopenia, and immunity were evaluated. Serum zinc levels measured at 3 months post-treatment and the incidence of adverse events were also determined. The median age was 69.0 years (IQR:59.5-78.8) and the male to female ratio was 29:20. Twenty-seven patients had a Child-Pugh classification of B and 22 had a Child-Pugh classification of C; the median Child-Pugh score was 9.0 (IQR, 8.0-11.0). The median serum zinc levels measured at 3 months post-treatment (74.7 (IQR, 50.0-101.0) μg/dL) were significantly elevated in comparison to the pre-treatment levels (43.0 (IQR, 34.0-51.0) μg/dL, P < 0.0001). The overall survival of patients with pre-treatment serum zinc levels of ≥60 μg/dL was significantly better than that of those with pre-treatment serum zinc levels of <60 μg/dL (P = 0.013). The survival of patients with zinc levels of ≥70 μg/dL at 3 months post-treatment was significantly better than those with levels of <70 μg/dL (P = 0.013). The serum albumin level, Child-Pugh score, albumin-bilirubin (ALBI) score and model for end-stage liver disease (MELD) score were identified as factors predicting a good response at 3 months post-treatment. There were no significant relations between the pretreatment serum zinc levels and skeletal muscle mass, lymphocyte count, and neutrophil lymphocyte ratio. There were no obvious problematic adverse events in patients who received zinc acetate treatment. The patients with higher basal zinc levels and good responders to zinc acetate treatment had a better prognosis. Zinc acetate was useful and safe for patients with decompensated liver cirrhosis complicated by hypozincemia.
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http://dx.doi.org/10.1007/s12011-021-02675-5DOI Listing
April 2021

Clinical Characteristics and Outcomes in 314 Japanese Patients with Bacterial Endophthalmitis: A Multicenter Cohort Study from J-CREST.

Pathogens 2021 Mar 24;10(4). Epub 2021 Mar 24.

Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya 6638501, Japan.

Bacterial endophthalmitis is an intraocular infection that causes rapid vison loss. Pathogens can infect the intraocular space directly (exogenous endophthalmitis (ExE)) or indirectly (endogenous endophthalmitis (EnE)). To identify predictive factors for the visual prognosis of Japanese patients with bacterial endophthalmitis, we retrospectively examined the bacterial endophthalmitis characteristics of 314 Japanese patients and performed statistics using these clinical data. Older patients, with significantly more severe clinical symptoms, were prevalent in the ExE group compared with the EnE group. However, the final best-corrected visual acuity (BCVA) was not significantly different between the ExE and EnE groups. Bacteria isolated from patients were not associated with age, sex, or presence of eye symptoms. , and were more prevalent in ExE patients than EnE patients and contributed to poor final BCVA. The presence of eye pain, bacterial identification, and poor BCVA at baseline were risk factors for final visual impairment.
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http://dx.doi.org/10.3390/pathogens10040390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063932PMC
March 2021

Changes of F-fluoro-2-deoxyglucose position-emission tomography findings by the eradication of Helicobacter pylori in the stomach.

Helicobacter 2021 Mar 8:e12797. Epub 2021 Mar 8.

Department of Gastroenterology and Hepatology, Kusunoki Hospital, Fujioka, Japan.

Purpose: Helicobacter pylori (HP) infection is reported to increase F-fluoro-2-deoxyglucose (FDG) accumulation in the stomach. The accumulation of FDG by positron-emission tomography (FDG-PET) in the stomach for the voluntary health examinees of cancer checkup was examined before and after the HP eradication.

Subjects And Methods: From March 2013 to October 2015, eighty-one subjects were performed FDG-PET to detect cancer at the health checkup. All of them were also surveyed by esophagogastroduodenoscopy. Subjects were classified as the 33 cases of HP positive (group A), 38 cases of originally negative (group B), and the 10 negative cases by HP eradication therapy (group C). Group A was treated by combination of amoxicillin, clarithromycin, and proton pump inhibitor for a week, and all of them eradicated HP. A part of group A (n = 7) was serially performed FDG-PET one to five years after the treatment and compared the maximum standard uptake value of FDG (SUV) around the fundic gland region.

Results: SUV of group A (3.55 ± 0.69) was significantly higher than those of both group B (2.96 ± 0.72) and group C (2.89 ± 0.51) (p < 0.01, respectively). Groups B and C are almost comparable and showed no significant difference during the course. In group A, HP eradication significantly decreased the SUV to 3.1 ± 0.43 (P < .01). SUV after the eradication was significantly reduced (P < .01) in the mild to moderate atrophy (C1-C3) group according to Kimura and Takemoto classification of chronic gastritis of group A. Although SUV in the advanced atrophy group (O1-O3) tended to decline after the eradication, the change was not significant.

Conclusion: HP-infected stomach showed higher FDG uptake in the fundic gland region and HP eradication decreased the uptake in the mild to moderate atrophic gastritis but not in the severe atrophic gastritis.
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http://dx.doi.org/10.1111/hel.12797DOI Listing
March 2021

Prognosis of late elderly patients with chronic hepatitis C after achieving a sustained viral response by direct-acting antivirals.

JGH Open 2021 Jan 23;5(1):122-127. Epub 2020 Nov 23.

Department of Gastroenterology and Hepatology Gunma University Graduate School of Medicine Maebashi Japan.

Background And Aim: We investigated the prognosis of late elderly patients (≥75 years old) after the achievement of a sustained viral response (SVR) by direct-acting antivirals (DAAs).

Methods: One hundred and four late elderly patients and 251 young patients (≤74 years old) who had achieved an SVR were included. We compared the cumulative hepatocellular carcinoma (HCC) incidence rates and survival rates after DAA administration. Furthermore, the factors associated with HCC incidence and the causes of death after DAA administration were also investigated.

Results: The cumulative HCC incidence rates for 1 and 3 years were 2.9% and 11.7% in the late elderly patients and 2.4% and 5.4% in the young patients, respectively. The cumulative survival rates for 1 and 3 years were 100% and 95.6% in the late elderly patients and 100% and 96.4% in the young patients, respectively, with no significant differences in those rates noted ( = 0.133, = 0.322, respectively). In the late elderly patients, only a history of HCC was a significant factor associated with HCC incidence after DAA administration. Five late elderly patients died after achieving an SVR, and malignant liver tumor was the cause of death in three of those patients.

Conclusions: The prognosis did not differ markedly between late elderly patients and young patients. The factor most strongly influencing the prognosis of late elderly patients was likely liver disease, including HCC. DAAs should be introduced even in late elderly patients who can be expected to have a relative long-term survival.
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http://dx.doi.org/10.1002/jgh3.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812467PMC
January 2021

27-gauge trocar-assisted sutureless intraocular lens fixation.

BMC Ophthalmol 2021 Jan 6;21(1). Epub 2021 Jan 6.

Department of Ophthalmology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.

Backgrounds: However there have been numerous investigations of intrascleral intraocular lens (IOL) fixation techniques, there is room for improvement in terms of simplifying complicated techniques and reducing the high levels of skill required. This study aimed to report a novel technique for sutureless intrascleral fixation of the IOL using retinal forceps with a 27-gauge trocar.

Methods: Nineteen eyes of 18 patients underwent intrascleral fixation of the IOL from July 2018 to September 2019 were enrolled in this study. A 27-gauge trocar formed 3-mm scleral tunnels positioned at 4 and 10 o'clock, 2 mm from the corneal limbus. We used a 3-piece IOL haptic grasped by a 27-gauge retinal forceps and pulled from the 27-gauge trocar. The IOL was fixed by making a flange. Main outcome measures were visual acuity, corneal endothelial cell density, IOL tilt, decentration, predicted error of refraction and complications.

Results: The 19 eyes were followed up for 1 month. The mean pre- and postoperative logMAR uncorrected visual acuity (UCVA) was 1.06 ± 0.63 and 0.40 ± 0.26, respectively (p < 0.01), while the mean pre- and postoperative logMAR best corrected visual acuity (BCVA) was 0.27 ± 0.51 and 0.06 ± 0.15, respectively (p = 0.09). The mean corneal endothelial cell density was 2406 ± 625 to 2004 ± 759 cells/mm at 1 month (p = 0.13). The mean IOL tilt was 3.52 ± 3.00°, and the mean IOL decentration was 0.39 ± 0.39 mm. There was no correlation among IOL tilt, decentration and BCVA (p > 0.05). The mean prediction error of the target refraction was - 0.03 ± 0.93 D. The complications were vitreous hemorrhage (3 eyes), hyphema (1 eye), IOP elevation (1 eye), iris capture of the IOL (1 eye) and hypotony (2 eyes). No IOL dislocation occurred.

Conclusions: IOL intrascleral fixation with a flange achieved good IOL fixation and visual outcome in the scleral tunnels created with the 27-gauge trocar.
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http://dx.doi.org/10.1186/s12886-020-01758-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789339PMC
January 2021

Efficacy and Safety of Intravitreal Aflibercept Injection in Japanese Patients with Neovascular Glaucoma: Outcomes from the VENERA Study.

Adv Ther 2021 02 16;38(2):1106-1115. Epub 2020 Dec 16.

Bayer Consumer Care AG, Basel, Switzerland.

Introduction: Neovascular glaucoma is characterized by neovascularization of the iris and anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may decrease intraocular pressure (IOP) and improve neovascularization. The VENERA study assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma.

Methods: This was a 5-week, single-arm, nonrandomized, open-label, phase 3 study performed at 7 study sites in Japan that enrolled Japanese patients with anterior segment neovascularization and IOP > 25 mmHg who had not undergone (within 30 days prior), nor were imminently scheduled to undergo (within 8 days following) intraocular surgeries, including panretinal photocoagulation (PRP). Patients received background therapy plus 2 mg IVT-AFL at baseline. Background therapy with systemic IOP-lowering drugs was prohibited for 3 days before day 1 and until IOP evaluation at week 1. The primary endpoint was the change in IOP from baseline to week 1 and the secondary endpoint was the proportion of patients with an improvement of ≥ 1 grade of neovascularization of the angle (NVA) from baseline to week 1.

Results: Sixteen patients received treatment (full analysis set); the per-protocol set comprised 15 patients. The mean IOP decreased from 34.1 mmHg at baseline to 25.8 mmHg at week 1 (mean change, -8.3 mmHg [95% confidence interval; CI -12.2 to -4.4; P = 0.0004]). At week 1, 81.3% of patients had an improvement in the grade of neovascularization of the iris (NVI) and 50.0% of patients had an improvement in NVA grade. The proportion of patients with controlled IOP (≤ 21 mmHg) was 43.8% (95% CI 19.8-70.1) at week 1, and increased to 56.3% at week 2 and 86.7% at week 5. The most common ocular treatment-emergent adverse event was eye pain, which occurred in 4 patients (25.0%).

Conclusions: IVT-AFL was associated with statistically significant and clinically meaningful IOP reductions, without concomitant use of systemic IOP-lowering drugs or PRP. The safety profile was consistent with the known safety profile of IVT-AFL. These findings supplement those from the previous VEGA study, and suggest that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma.

Trial Registration: Clinicaltrials.gov identifier NCT03639675.
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http://dx.doi.org/10.1007/s12325-020-01580-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889553PMC
February 2021

Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression.

Mol Biol Rep 2021 Jan 5;48(1):195-202. Epub 2020 Dec 5.

Department of Molecular Neuroscience, St. Marianna University Graduate School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kaswasaki, Kanagawa, 216-8511, Japan.

Excitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.
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http://dx.doi.org/10.1007/s11033-020-06032-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884588PMC
January 2021

Akebia Saponin D prevents axonal loss against TNF-induced optic nerve damage with autophagy modulation.

Mol Biol Rep 2020 Dec 28;47(12):9733-9738. Epub 2020 Nov 28.

Department of Molecular Neuroscience, St. Marianna University Graduate School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.

Akebia Saponin D (ASD), a triterpenoid saponin, was shown to have protective effects in certain neuronal cells. The purpose of the present study was to investigate the possibility of ASD to prevent tumor necrosis factor (TNF)-induced axonal loss and the ASD modulation of the biologic process of autophagy in optic nerves. Rats were given intravitreal administration of TNF, simultaneous administration of 2, 20, or 200 pmol ASD and TNF, or ASD alone. LC3-II and p62 expression, which is a marker of autophagic flux, and phosphorylated p38 (p-p38) expression in optic nerves were examined by immunoblot analysis. Morphometric analysis revealed a significant ameliorated effect of ASD against TNF-induced optic nerve damage. p62 was significantly increased in the optic nerve in TNF-treated eyes, but this increase was totally prevented by ASD. The ASD alone injection showed significant reduction of p62 levels compared with the PBS-treated control eyes. LC3-II was significantly increased by ASD treatment in the TNF-injected eyes. p-p38 was significantly increased in the optic nerve in TNF-treated eyes, but this increase was completely prevented by ASD. The protective effects of ASD may be associated with enhanced autophagy activation and inhibition of p-p38.
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http://dx.doi.org/10.1007/s11033-020-06008-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723935PMC
December 2020

The development of broncho-biliary fistula after treatment for hepatocellular carcinoma: a report of two cases.

Clin J Gastroenterol 2021 Feb 24;14(1):229-237. Epub 2020 Oct 24.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Broncho-biliary fistula (BBF) is a rare but severe disorder defined as abnormal communication between the biliary system and bronchial tree. Cases of BBF have occasionally been reported, but no standard treatment has been established. We report two cases of BBF that developed after the treatment of hepatocellular carcinoma (HCC) and reviewed the relevant literature. Case 1, a man in his early eighties was diagnosed with BBF 4 months after undergoing surgical resection for HCC (diameter, 7 cm; location, segments 4 and 5). Percutaneous drainage and endoscopic nasobiliary drainage (ENBD) improved BBF without recurrence for more than a year. Case 2, a woman in her late sixties was diagnosed with BBF after percutaneous radiofrequency ablation for HCC. Although the BBF was treated with ENBD, bronchial occlusion, and percutaneous transhepatic portal vein embolization, these treatments were unsuccessful and the patient died. Although non-invasive treatments have been developed, refractory BBF still exists. The prediction of BBF and the development of more effective treatments are necessary to improve outcomes.
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http://dx.doi.org/10.1007/s12328-020-01264-8DOI Listing
February 2021

Successfully Treated Case of Cholangiolocellular Carcinoma with a Poor Hepatic Functional Reserve Reporting with Various Imaging Findings.

Intern Med 2021 Mar 14;60(6):873-881. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

Cholangiolocellular carcinoma (CoCC) is a rare primary liver cancer that is difficult diagnose due to a lack of specific imaging findings. We herein report a case of CoCC accompanied by severe alcoholic cirrhosis. Dynamic computed tomography showed a low-density tumor with a faint surrounding enhancement. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging revealed iso-intensity in the hepatobiliary phase and a maximum tumor diameter of 53 mm. F-fluoro-2-deoxyglucose position-emission tomography was moderately positive (maximum standardized uptake value: 4.3). CoCC was diagnosed based on the pathological findings, including immunohistochemistry. We discuss the diagnostic imaging findings and review previous reports.
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http://dx.doi.org/10.2169/internalmedicine.5891-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024949PMC
March 2021

Hepatitis C virus-associated decompensated liver cirrhosis with refractory hepatic encephalopathy successfully treated by balloon-occluded retrograde transvenous obliteration after sofosbuvir/velpatasvir.

Clin J Gastroenterol 2020 Dec 10;13(6):1303-1309. Epub 2020 Sep 10.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Sofosbuvir/velpatasvir (SOF/VEL) is expected to be highly effective, even in patients with decompensated liver cirrhosis. However, portal hypertension can be problematic after achieving a sustained viral response (SVR), especially in patients with hepatic encephalopathy (HE) associated with large portal-systemic shunt. Although balloon-occluded retrograde transvenous obliteration (BRTO) is a useful option, whether BRTO or SOF/VEL therapy should be initially performed in patients with a poor liver function reserve is controversial. We herein report a case of refractory HE caused by decompensated liver cirrhosis due to hepatitis C virus (HCV) classified as Child-Pugh class C that was treated by BRTO after SVR with SOF/VEL. A 64-year-old woman with HCV-associated decompensated cirrhosis developed refractory HE. Dynamic contrast-enhanced computed tomography (CT) revealed large portal-systemic shunt. We treated the patient with 12 weeks of SOF/VEL, and she achieved SVR. Although the serum albumin level, edema, and ascites were improved, intractable HE remained. Her general condition had been improved after SVR, so HE was suspected to have been caused by portal-systemic shunting. We, therefore, treated the patient by BRTO. On dynamic contrast-enhanced CT, partial obstruction of the shunt vessel was confirmed after BRTO. Thereafter, her serum ammonia level rapidly improved, and HE did not recur. Interventional radiology such as BRTO following SOF/VEL therapy may be a useful option even in patients with decompensated HCV-associated cirrhosis accompanied by portal-systemic shunt.
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http://dx.doi.org/10.1007/s12328-020-01229-xDOI Listing
December 2020

Adenocarcinoma with intraductal papillary mucinous neoplasm arising in a duodenal heterotopic pancreas: a case report.

Clin J Gastroenterol 2020 Dec 10;13(6):1373-1382. Epub 2020 Sep 10.

Clinical Department of Pathology, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

A woman in her 70 s was diagnosed with a tumor in her duodenal wall during a routine visit for diabetes. She subsequently underwent subtotal stomach-preserving pancreatoduodenectomy. Histologically, the tumor was present mainly in the duodenal wall, and atypical cystic ducts were seen in the muscularis propria and subserosa. Invasive well-differentiated adenocarcinoma was seen in the duodenal submucosal and mucosal layers. Heterotopic pancreatic tissue was seen within the tumor, and atypical epithelium had proliferated and replaced the cystic ductal epithelium of the heterotopic pancreas. Therefore, adenocarcinoma with intraductal papillary mucinous neoplasm arising in duodenal heterotopic pancreas was the final histopathological diagnosis, which is considered rare.
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http://dx.doi.org/10.1007/s12328-020-01224-2DOI Listing
December 2020

Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.

Mol Neurobiol 2020 Dec 20;57(12):4952-4960. Epub 2020 Aug 20.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan.

Nicotinamide adenine dinucleotide (NAD) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD precursor and known to increase NAD level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic nerve degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and nerve fibers in retina and optic nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.
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http://dx.doi.org/10.1007/s12035-020-02063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541376PMC
December 2020

An autopsy case of primary jejunal pouch cancer which protruded from the abdominal wall 14 years after total gastrectomy for gastric cancer.

Clin J Gastroenterol 2020 Dec 8;13(6):1091-1095. Epub 2020 Jul 8.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Adenocarcinoma which develops in the jejunal pouch has rarely been reported, but most of such cases tend to be a recurrence of primary cancer due to the presence of residual or disseminated cancer cells. Primary jejunal pouch cancer is extremely rare. We experienced an autopsy case of primary jejunal pouch cancer which occurred 14 years after proximal gastrectomy for gastric cancer. A female in her late 60s was admitted because of hypoglycemia with liver dysfunction. She underwent total gastrectomy for fundic cancer and had been reconstructed by jejunal pouch interposition 14 years prior to this presentation. Hypoglycemia recovered by nutritional support. Computed tomography demonstrated severe fatty liver and liver biopsy proved non-alcoholic steatohepatitis, which was supposed to have been induced by malnutrition. Screening esophagogastroduodenoscopy (EGD) revealed no tumorous lesions in the jejunal pouch at this time. However, her anorexia gradually progressed and the symptom of bowel obstruction appeared. EGD performed 5 months after the previous EGD revealed adenocarcinoma which extended from the anastomosis of the interposed jejunum. Then liver metastasis developed and jejunal pouch cancer invaded the abdominal wall and protruded with ulcer formation. Finally, the patient died of malnutrition. An autopsy revealed adenocarcinoma which had developed in the interposed jejunal pouch and protruded through the abdominal wall accompanied with lung and liver metastasis. We herein describe this rare case of primary interposed jejunal pouch cancer and discuss our findings including a review of the pertinent literature.
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http://dx.doi.org/10.1007/s12328-020-01177-6DOI Listing
December 2020

PPARα activation directly upregulates thrombomodulin in the diabetic retina.

Sci Rep 2020 07 2;10(1):10837. Epub 2020 Jul 2.

Department of Ophthalmology, St. Marianna University of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, Japan.

Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.
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http://dx.doi.org/10.1038/s41598-020-67579-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331602PMC
July 2020

Two elder cases of hepatocellular carcinoma adjacent to intrahepatic vessels successfully treated by carbon ion radiotherapy.

Clin J Gastroenterol 2020 Oct 11;13(5):920-926. Epub 2020 Jun 11.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

The treatment for hepatocellular carcinoma (HCC) adjacent to the portal vein and/or bile duct requires considerable caution to avoid the complications, such as hepatic infarction and obstructive jaundice. Carbon ion radiotherapy (CIRT) has been attempted for HCC and has become accepted as a promising modality for minimizing hepatic damage with good local tumor control. We experienced two elder cases of HCC adjacent to intrahepatic vessels successfully treated by CIRT. Case 1, a 75-year-old man, was treated by CIRT for a 2-cm HCC near the porta hepatis adjacent to the right first portal branch. The treatment was sufficiently effective, and no vascular damage was demonstrated after CIRT. The liver function transiently deteriorated after CIRT, but recovered quickly. Alpha-fetoprotein transiently increased after the treatment and decreased thereafter. Tumor stain persisted for 3 months after CIRT, so a liver tumor biopsy was performed. However, no viable carcinoma cells were detected. There was no local recurrence or complications for 17 months. Case 2, 76-year-old male HCC patient, showed dilation of the peripheral bile duct in the left lobe, suggesting tumor invasion to the duct. The tumor was hypovascular and was found to be well-differentiated HCC by a tumor biopsy. He was treated with CIRT, because he had a history of cerebral infarction and was being administered an antiplatelet agent daily. He achieved complete remission, and no adverse events were observed after the treatment for 3 years.
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http://dx.doi.org/10.1007/s12328-020-01151-2DOI Listing
October 2020

A Resected Case of Follicular Cholangitis That Was Positive on F-fluorodeoxyglucose-positron Emission Tomography.

Intern Med 2020 Sep 23;59(17):2123-2128. Epub 2020 May 23.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

We experienced a case of follicular cholangitis that was positive on fluorodeoxyglucose-positron emission tomography (F-FDG-PET). A 70-year-old man was admitted for jaundice. Endoscopic retrograde cholangiography showed stenosis of the middle to upper choledocus. F-FDG-PET depicted a localized hot spot at the stenotic lesion (maximum standardized uptake value = 8.2). Although no malignant findings were found in the cytology or on a bile duct biopsy, malignancy could not be excluded, so surgical treatment was performed. Follicular cholangitis is a new, rare disease that causes severe biliary stricture. Only 11 cases of follicular cholangitis have been reported, including the present case.
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http://dx.doi.org/10.2169/internalmedicine.4611-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516323PMC
September 2020

Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention .

Br J Ophthalmol 2020 12 13;104(12):1755-1761. Epub 2020 Mar 13.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Background/aims: To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO).

Methods: Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment.

Results: Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term.

Conclusion: For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785163PMC
December 2020

Axonal protection by a small molecule SIRT1 activator, SRT2104, with alteration of autophagy in TNF-induced optic nerve degeneration.

Jpn J Ophthalmol 2020 May 10;64(3):298-303. Epub 2020 Mar 10.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan.

Purpose: To examine the effects of SRT2104, an SIRT1 activator, in optic nerve degeneration induced by TNF and to investigate whether it affects the autophagic status after induction of axonal degeneration.

Study Design: Experimental.

Methods: Adult male Wistar rats received intravitreal injection of TNF alone, concomitant injection of SRT2104 and TNF, or injection of SRT2104 alone. The autophagic status in the optic nerve was evaluated to examine p62 and LC3-II expression by immunoblot analysis. The effect of SRT2104 on TNF-induced axon loss was determined by counting the number of axons.

Results: Intravitreal injection of SRT2104 showed a modest protective tendency in the 2-pmol-treated groups against TNF-induced axon loss, although the tendency was not significant on quantitative analysis. However, significant protective effects were found in the 20- or 200-pmol-treated groups. Injection of SRT2104 alone significantly decreased the p62 levels and increased the LC3-II levels as compared with the basal levels. Similarly, concomitant injection of SRT2104 and TNF significantly decreased the p62 levels and increased the LC3-II levels as compared with the TNF-treated group. Upregulation of SIRT1 expression was observed in the optic nerve after SRT2104 treatment.

Conclusion: The SIRT1 activator SRT2104 exerts axonal protection in TNF-induced optic nerve degeneration. This effect may be associated with upregulated autophagic status in the optic nerve.
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http://dx.doi.org/10.1007/s10384-020-00731-6DOI Listing
May 2020

Successful treatment with glecaprevir/pibrentasvir for chronic hepatitis C complicated by primary biliary cholangitis.

Clin J Gastroenterol 2020 Oct 17;13(5):896-901. Epub 2020 Feb 17.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Background: Cases of autoimmune liver diseases complicated with hepatitis C (HCV) infection have occasionally been reported. However, the efficacy and safety of direct acting antivirals for chronic hepatitis C (CHC) complicated with autoimmune liver diseases remain unclear.

Case Report: A 74-year-old woman was referred to our hospital for an acute exacerbation of liver dysfunction. She had been diagnosed with CHC 10 years previously. Laboratory data showed elevated immunoglobulin G (IgG), and she was positive for antinuclear antibody (ANA), anti-mitochondrial M2 antibody, and HCV-RNA (genotype 2a). Liver biopsy revealed significant infiltration of lymphocytes and plasma cells in the portal triad, moderate interface hepatitis with mild bridging fibrosis, and chronic non-suppurative destructive cholangitis. She was diagnosed with chronic active hepatitis and primary biliary cholangitis (PBC). Combination therapy with glecaprevir/pibrentasvir (GLE/PIB) rapidly improved her serum transaminase and HCV-RNA levels. A sustained viral response was achieved 24 weeks after GLE/PIB. No adverse events were observed, and her IgG and ANA levels were normalized 6 months after GLE/PIB. The second liver biopsy performed 10 months after GLE/PIB demonstrated the remarkable improvement of active hepatitis. However, the findings suggesting PBC were remained and the AMA-M2 titer was decreased but positive at that time.

Conclusion: GLE/PIB is an effective and tolerated choice for the treatment in cases of CHC complicated by PBC.
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http://dx.doi.org/10.1007/s12328-020-01103-wDOI Listing
October 2020

Effect of axial length and age on the visual outcome of patients with idiopathic epiretinal membrane after pars plana vitrectomy.

Sci Rep 2019 12 13;9(1):19056. Epub 2019 Dec 13.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

We evaluated predictive factors for visual outcomes in patients with idiopathic epiretinal membrane (iERM) after pars plana vitrectomy (PPV). Clinical records for 114 eyes (114 patients, mean age: 70.6 years) with iERM treated by PPV between March 2012 and March 2018 were retrospectively reviewed. Overall, the mean postoperative best-corrected visual acuity (BCVA) and central retinal thickness measured by optical coherence tomography improved as early as 1 month after surgery, and further improved until 3 months (P < 0.01). Multiple linear regression analyses adjusted for the preoperative BCVA showed that older age (B, 0.010; 95% confidence interval, 0.003 to 0.016; P = 0.003) and a shorter axial length (AL; B, -0.059; 95% confidence interval, -0.099 to -0.019; P = 0.005) predicted worse postoperative BCVA. The Mann-Whitney U test showed that the postoperative BCVA was worse in eyes with AL < 23.6 mm than in eyes with AL ≥ 23.6 mm (P = 0.037), and in patients aged ≥69 years than in patients aged <69 years (P = 0.024). The findings may help in evaluating surgical indications for each patient to obtain satisfactory outcomes, irrespective of the preoperative BCVA.
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http://dx.doi.org/10.1038/s41598-019-55544-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911110PMC
December 2019

Spatial-sweep steady-state pattern electroretinography can detect subtle differences in visual function among healthy adults.

Sci Rep 2019 12 2;9(1):18119. Epub 2019 Dec 2.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

We aimed to establish a highly sensitive method for measuring visual function using spatial-sweep steady-state pattern electroretinography (swpPERG). Overall, 35 eyes of 35 healthy adults (18 men; mean age, 32.3 years) were examined using swpPERG, and the data were recorded using spatial-patterned and contrast-reversed stimuli of size 1 (thickest) to 6. Data were converted into frequency-domain using a Fourier transform and expressed by signal-to-noise ratio (SNR). The number of participants who showed SNR ≥ 1 was significantly lesser at stimulus sizes 5 and 6 compared with those at greater stimulus sizes. Among the data with SNR ≥ 1, SNRs were negatively correlated with age at stimulus size 5 (r = -0.500, P = 0.029), and positively correlated with macular volume evaluated by optical coherence tomography (OCT) within a 6-mm circle diameter from the fovea of the retinal nerve fibre layer at size 4 (r = 0.409, P = 0.025) and of the ganglion cell layer at size 5 (r = 0.567, P = 0.011). We found that SNRs of swpPERG, recorded using the EvokeDx system, were correlated with age and macular morphology in participants without diagnosed eye diseases. The system detected subtle differences in retinal function, which may help in early disease diagnosis and visual evaluation in neuroprotective interventions in the future.
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http://dx.doi.org/10.1038/s41598-019-54606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889279PMC
December 2019

Real-world management of treatment-naïve diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study.

Br J Ophthalmol 2020 09 29;104(9):1209-1215. Epub 2019 Nov 29.

Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan.

Background/aims: To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME).

Methods: Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C).

Results: The mean 2-year improvement of BCVA was -0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was -0.09±0.39, -0.02±0.40 and -0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively.

Conclusion: Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577088PMC
September 2020

Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure.

Hepatol Res 2020 Mar 19;50(3):303-312. Epub 2019 Dec 19.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Aim: In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations.

Methods: We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines.

Results: The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed.

Conclusions: Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.
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http://dx.doi.org/10.1111/hepr.13462DOI Listing
March 2020

Fairly rare small-diameter hepatocellular carcinoma with right adrenal gland metastasis having an inferior vena cava tumor thrombus: a case report.

Surg Case Rep 2019 Nov 6;5(1):170. Epub 2019 Nov 6.

Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Background: Hepatocellular carcinoma (HCC) may lead to extrahepatic metastasis (EHM). Most patients with EHM had either intrahepatic stage III or IVA tumor at the site of metastases. Herein, we present the case of a fairly rare 1.5-cm small-diameter HCC with right adrenal gland tumor having an inferior vena cava (IVC) tumor thrombus.

Case Presentation: A 75-year-old man had a 1.5-cm hepatocellular carcinoma (HCC) in segment 8 of the liver and a 3.0-cm right adrenal gland tumor with inferior vena cava (IVC) tumor thrombus. He underwent partial hepatectomy, right adrenalectomy, and IVC tumor thrombectomy. Tumor resection was successful, but the tumor progressed rapidly, and the patient died 8 months after the operation. Immunohistochemical staining revealed that both HCC cells and adrenal tumor cells were positive for HCC markers Glypican-3 and alpha-fetoprotein. In terms of adrenal carcinoma markers vimentin and Melan-A, vimentin was negative in the HCC and adrenal tumor, and Melan-A was negative in the HCC. In adrenal tumor, slight positivity of Melan-A was observed, but the intensity of staining was clearly weak compared with that in normal adrenal glands. CD133, one of the stem cell markers, was positive in both HCC and adrenal tumor cells. Next-generation amplicon sequencing analyses were performed using DNA derived from the HCC, adrenal tumor, and normal liver tissue. After exome data analyses for representative HCC-related genes as TERT, CTNNB1, TP53, and ARID2, TP53 mutation (exon3: c.G351 T: p.R117S) was found in both HCC cells and adrenal tumor cells. Conversely, no significant mutations in other genes were observed. These pathological findings and sequencing results showed that the adrenal tumor might be an adrenal metastasis of HCC in spite of small primary tumor size.

Conclusions: This case suggests that the right adrenal tumor was a metastasis of HCC. Immunohistochemical staining and gene mutation analyses using NGS are very useful in differentiating the tumor origin.
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http://dx.doi.org/10.1186/s40792-019-0705-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834821PMC
November 2019

Eltrombopag enables initiation and completion of pegylated interferon/ribavirin therapy in Japanese HCV-infected patients with chronic liver disease and thrombocytopenia.

Exp Ther Med 2019 Jul 24;18(1):596-604. Epub 2019 May 24.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

To investigate the efficacy of eltrombopag for the treatment of thrombocytopenia in patients with chronic hepatitis C, a phase II, single-arm, open-label study with a 9-week pre-antiviral phase was conducted, followed by a 48-week antiviral phase and a 24-week follow-up phase. The proportion of patients who achieved a platelet count threshold, the proportion of patients who maintained a platelet count >50,000/µl, sustained virological response (SVR) rates and safety parameters were evaluated. Of the 45 enrolled patients (median age, 59 years; median platelet count, 63,000/µl; 98% with Child-Pugh class A), 43 (96%) achieved the platelet count threshold during the pre-antiviral phase. A total of 13 patients (29%) experienced ≥1 adverse event (AE), of which headache and vomiting were the most common, and 41 patients (mostly receiving eltrombopag 12.5 mg or 25 mg) entered the antiviral phase, of which 36 (88%) maintained the platelet count threshold; no patient platelet count decreased below 25,000/µl. Nine patients (22%) achieved an SVR at the 24-week follow-up. Grade ≥3 AEs occurred in 25 patients (61%). A total of 8 serious AEs occurred in five patients (12%). No mortality, thromboembolic events (TEEs), or cataract progression were reported. Eltrombopag increased the platelet count in chronic hepatitis C virus-infected patients with cirrhosis and thrombocytopenia and enabled them to initiate and complete interferon-based antiviral therapy (NCT01636778; first submitted: July 05, 2012).
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http://dx.doi.org/10.3892/etm.2019.7616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566053PMC
July 2019

Axonal Protection by Tacrolimus with Inhibition of NFATc1 in TNF-Induced Optic Nerve Degeneration.

Neurochem Res 2019 Jul 13;44(7):1726-1735. Epub 2019 May 13.

Department of Ophthalmology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Kanagawa, Japan.

Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
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http://dx.doi.org/10.1007/s11064-019-02804-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555779PMC
July 2019

Impact of the Prognostic Nutritional Index on the Survival of Japanese Patients with Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Retrospective Study.

Intern Med 2019 Jul 28;58(13):1835-1844. Epub 2019 Mar 28.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan.

Objective The purpose of this multicenter retrospective study was to investigate the impact of the prognostic nutritional index (PNI) on the survival of Japanese patients with hepatocellular carcinoma (HCC) treated with sorafenib. Methods A total of 178 HCC patients from May 2009 to December 2015 at our affiliated hospitals was included in this study. The PNI was calculated as follows: 10×serum albumin (g/dL) +0.005×total lymphocyte count (per mm). The patients were divided into two groups according to the cut-off value of the PNI and as calculated by a receiver operating characteristic curve analysis. Results The optimum cut-off value of the PNI was set at 46.8. We defined the 33 patients with a PNI≥46.8 as the PNI-high group and the 145 patients with a PNI<46.8 as the PNI-low group. The response rate was 20.0% in the PNI-high group and 8.1% in the PNI-low group, without any statistically significance (p=0.09). The duration of sorafenib therapy and the overall survival in the PNI-high group were significantly better than those in the PNI-low group. The PNI-high group was thus found to be a predictive factor associated with the duration of sorafenib therapy [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.39-0.87, p=0.008] and overall survival (HR 0.62; 95% CI 0.39-0.99, p=0.046) in a multivariate analysis. Conclusion The PNI is a simple and useful marker for predicting the survival of patients with HCC treated with sorafenib.
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http://dx.doi.org/10.2169/internalmedicine.1594-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663544PMC
July 2019

Adenosquamous Carcinoma of the Choledochus.

Case Rep Gastroenterol 2018 Sep-Dec;12(3):773-779. Epub 2019 Jan 4.

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan.

The patient was an 86-year-old man who was admitted with obstructive jaundice. Computed tomography revealed a tumor in the hilar choledochus with peripheral hepatic duct dilatation. Endoscopic cholangiography (ERC) demonstrated the defect in the choledochus. Brushing cytology during ERC showed Orange-G-philic keratinized atypical cells, which led to a diagnosis of squamous cell carcinoma. Chemotherapy with tegafur-gimeracil-oteracil potassium was ineffective and was discontinued due to adverse effects. The patient died 5 months after the diagnosis and autopsy revealed tubular adenocarcinoma of the hilar bile duct with squamous cell carcinoma component. Progression of the disease might influence the distribution of adenosquamous carcinoma. The clinicopathological sequence of adenosquamous carcinoma of the choledochus was documented.
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http://dx.doi.org/10.1159/000495936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341349PMC
January 2019

β-Hydroxy-β-methyl Butyrate/L-Arginine/L-Glutamine Supplementation for Preventing Hand-Foot Skin Reaction in Sorafenib for Advanced Hepatocellular Carcinoma.

In Vivo 2019 Jan-Feb;33(1):155-161

Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan.

Background/aim: Sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a notorious side-effect of this therapy. This study evaluated prophylactic benefits of an oral nutritional supplement (ONS) on sorafenib-associated HFSR in advanced HCC.

Patients And Methods: This was a prospective, single-center, open-label trial arm using combined ONS and sorafenib in patients with unresectable HCC from August 2014 to February 2018. Control patients received sorafenib without ONS from 2011 to 2014. From September 2014, prophylactic ONS containing β-hydroxy-β-methylbutyrate (HMB), L-arginine, and L-glutamine was given. Sorafenib dosage was 400 mg/day for both groups.

Results: Each group comprised 22 men and three women. Age, sex, Child-Pugh score, and clinical stage excluding IV-B did not significantly differ between the groups. HFSR occurred after 2 weeks: 15/25 patients in the control group (60%; HFSR grade 1: 6, grade 2: 7, grade 3: 2) vs. 8/25 in the ONS group (32%; HFSR grade 1: 4, grade 2: 4, grade 3: 0; p=0.047, Pearson's Chi-square test).

Conclusion: Prophylactic HMB, L-arginine and L-glutamine supplementation effectively prevented sorafenib-associated HFSR in patients with advanced HCC.
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http://dx.doi.org/10.21873/invivo.11452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364076PMC
April 2019