Factors Related to Liver Stiffness in Patients with Hepatitis C During Direct-acting Antiviral Agent Treatment

Background and Aim：The purpose of this study was to observe the changes over time in liver stiffness measured by shear wave elastography（SWE）in hepatitis C patients during direct-acting antiviral agent（DAA）treatment and evaluate the factors affecting the liver stiffness.Methods：The subjects were 206 consecutive patients diagnosed with hepatitis C in the Dokkyo Medical University Saitama Medical Center treated with DAAs. SWE was performed to measure the propagation velocity of shear waves（Vs）before starting treatment（baseline）, at the end of treatment（EOT）, and 12 weeks after EOT（follow-up 12）. The change in Vs（ΔVs）was calculated for the difference between baseline and follow-up 12. Clinical parameters were obtained on the same day as SWE. Multiple regression analysis was used to identify factors related to ΔVs.Results：Data from 149 patients were used；all 149 patients achieved sustained virological response. Mean Vs decreased significantly, from 1.58±0.92 m/s at baseline to 1.46±0.27 m/s at EOT（P＝0.00045）. Mean Vs at follow-up 12 was 1.42±0.28 m/s, significantly lower than at EOT（P＝0.00002）. The mean ΔVs was 0.147±0.164 m/s. On multiple regression analysis, prothrombin time％（PT％）and the change in alanine aminotransferase（ΔALT）from baseline were significantly related to ΔVs. Baseline ALT and the FIB4-index tended to affect ΔVs.Conclusions：In hepatitis C patients, Vs measured by SWE improved with 12 weeks of DAA therapyand continued to improve to follow-up 12. Baseline PT％ and ΔALT contributed significantly to theimprovement of Vs during DAA treatment, and the FIB-4 index also had a great effect

Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells

Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell–derived VEGFR2+ mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)–BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A–induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras−/− mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2+ progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2+ progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6–9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras–Erk signaling to direct endothelial specification of VEGFR2+ vascular progenitor cells

Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.We thank Kaori Yoshida, Keiko Uchiyama, Satomi Kawai, Naomi Hatanaka, Yoko Sawaguchi, Runa Washio, Takako Ichihashi, Nanako Koike, Keiko Uchiyama, Masaaki Nameta (Niigata University), Kaori Igarashi, Kaori Saitoh, Keiko Endo, Hiroko Maki, Ayano Ueno, Maki Ohishi, Sanae Yamanaka, Noriko Kagata (Keio University) for their excellent technical assistance, C. Ronald Kahn (Joslin Diabetes Center and Harvard Medical School) for providing the BAT cell line, Evan Rosen (Harvard Medical School) for providing us Ucp-Cre mice, Kosuke Morikawa (Kyoto University), Tomitake Tsukihara (University of Hyogo) and Shinya Yoshikawa (University of Hyogo) for their professional opinions and suggestions. Tis work was supported by a Grant-in-Aid for Scientifc Research (A) (20H00533) from MEXT, AMED under Grant Numbers JP20ek0210114, and AMED-CREST under Grant Number JP20gm1110012, and Moonshot Research and Development Program (21zf0127003s0201), MEXT Supported Program for the Strategic Research Foundation at Private Universities Japan, Private University Research Branding Project, and Leading Initiative for Excellent Young Researchers, and grants from the Takeda Medical Research Foundation, the Vehicle Racing Commemorative Foundation, Ono Medical Research Foundation, and the Suzuken Memorial Foundation (to T.M.). Support was also provided by a Grants-in-Aid for Young Scientists (Start-up) (26893080), and grants from the Uehara Memorial Foundation, Kowa Life Science Foundation, Manpei Suzuki Diabetes Foundation, SENSHIN Medical Research Foundation, ONO Medical Research Foundation, Tsukada Grant for Niigata University Medical Research, Te Nakajima Foundation, SUZUKEN memorial foundation, HOKUTO Corporation, Mochida Memorial Foundation for Medical & Pharmaceutical Research, Grants-in-Aid for Encouragement of Young Scientists (A) (16H06244), Daiichi Sankyo Foundation of Life Science, AMED Project for Elucidating and Controlling Mechanisms of Aging and Longevity under Grant Number JP17gm5010002, JP18gm5010002, JP19gm5010002, JP20gm5010002, JP21gm5010002, Astellas Foundation for Research on Metabolic Disorders, Research grant from Naito Foundation, Te Japan Geriatrics Society (to I.S.); by a Grant-in-Aid for Scientifc Research (C) (19K08974), Yujin Memorial Grant, Sakakibara Memorial Research Grant from Te Japan Research Promotion Society for Cardiovascular Diseases, TERUMO Life Science Foundation, Kanae Foundation (to Y.Y.), JST ERATO (JPMJER1902), AMED-CREST (JP20gm1010009), the Takeda Science Foundation, the Food Science Institute Foundation (to S.F.), and by a grant from Bourbon (to T.M., I.S. and Y.Y.).S

C 型肝炎患者に対するインターフェロン療法後の肝発癌についての検討

目的：C型慢性肝炎患者に対するインターフェロン(IFN)療法後の肝発癌について検討した．方法：C型慢性肝炎に対してIFN療法が施行された180例を対象とした．非発癌群と発癌群の間で，治療前の背景因子と半年後のウイルス学的著効(SVR24)の有無，治療後のALT，AFPについて比較した．また，それぞれの因子別に発癌曲線を作成して発癌率を比較した．結果：IFN治療によるSVR24の達成率は68.9％(124/180)であり，36.3ヶ月の観察期間で全体の発癌率は2.3％(5/180)であった．発癌群では非発癌群に比べ，高齢者，男性，SVR24非達成例，ALT高値例が多い傾向にあった．治療後のALT高値，AFP高値例は発癌が多かったが，特にAFPでは統計学的な有意差を認めた．結論：IFN治療前の線維化進展例と高齢者，男性，治療後ALT高値，AFP高値は肝発癌率が高い傾向にある．特に治療後AFP高値は肝発癌予測因子になる

粘液性嚢胞腺腫の悪性化との鑑別に苦慮した膵未分化癌の1例

症例は70歳代の女性．7年前に膵尾部単純性嚢胞と診断され，経過観察中であった．4ヶ月持続する発熱と心窩部痛の精査を目的として入院した．入院時のCTでは多発肝腫瘍を認め，嚢胞内には結節病変を，嚢胞周囲には出血・感染を示唆する所見を認めた．以上より，嚢胞性病変が癌化して転移・浸潤をきたし，嚢胞周囲に膿瘍を形成したものと考えて対症的に治療したが，第15病日に死亡した．剖検所見から嚢胞の癌化は否定され，嚢胞に近接して発生した膵未分化癌と，肝転移，肺転移等の多臓器転移，腹膜播種と診断された

A Case of Hemangiosarcoma of the Liver which led to a Diagnosis with Hemoptysis

Angiosarcoma is a vascular endothelium-derived malignant tumor that arises in blood vessel walls, accounting for only 2.3% of soft tissue sarcomas in adults. Primary hepatic angiosarcoma(PHA)is rare, comprising< 5% of all angiosarcomas. We report a case of PHA in a 61-year-old man evaluated by another clinic around our hospital for a chief complaint of hemoptysis in May 2012. Chest computed tomography(CT) showed abnormal shadows in bilateral lung fields, so he was referred to Department of Respiratory Medicine at our hospital in late July. However, no definitive diagnosis was not made, even after bronchoscopy. In mid-August, he presented to the outpatient clinic of the respiratory department with a chief complaint of right-sided abdominal pain. Abdominal CT showed a liver lesion, and he was urgently admitted to our department. Initial physical examination was unremarkable except for palpable liver in the right hypochondrium. Tumor markers for liver and biliary cancers were all within normal limits, and negative results were obtained for hepatitis B and C virus. CT, ultrasonography, and(MRI)identified a large lesion replacing the right hepatic lobe and medial segment of the left hepatic lobe. Hemangioma or hepatic angiosarcoma was suspected, accompanied by intraperitoneal rupture. Transcatheter arterial embolization was attempted, but had to be discontinued, and the patient died from hemorrhagic shock due to tumor rupture after onset of abdominal pain. The PHA which assumes hemoptysis primary symptom is extremely rare, and by reports for the past ten years searched using PubMed, this is the second report in the world

ドッキョウ イカ ダイガク コシガヤ ビョウイン ニオケル, フクブ チョウ オンパ ケンサ ニヨル タンノウ リュウキセイ ビョウヘン ノ ケントウ

腹部超音波検査が施行された3572 例を対象として胆嚢隆起性病変の検討を行った.胆嚢隆起性病変は3572例中791例( 22.1%) に認められ,重複検査例を除いた773例の平均年齢は59.6±13.6歳であり,男性370 例,女性403 例であった.胆嚢隆起性病変の最大径の平均は4.7±5.8 mm で,単発が256 例 (33.1%),多発が517例( 66.9%) であった.773例中,10 mm 以上の病変を有する症例は44 例( 5.6%) であった.これら44例の最終診断は,胆嚢良性ポリープ19例( 43.2%),胆嚢腺筋症2 例( 4.6%),胆泥貯留2 例( 4.6%),胆嚢結石2例( 4.6%) 切除可能胆嚢癌6例( 13.6%),切除不能胆嚢癌6 例( 13.6%),その他の癌2 例( 4.6%),不明5例( 11.3%) であり,胆嚢癌の半数が切除不能であった.今後,超音波検査を用いて切除可能な胆嚢癌をより多く拾い上げるためには,人間ドック等による,より幅広いスクリーニングが必要であると考えられた.The present study investigated the presence and characteristicsof elevated gallbladder lesions in 3572 patients whounderwent abdominal ultrasonography in our hospital betweenApril 2011 and March 2012. Elevated gallbladder lesionswere present in 791 patients (22.1 %). After excludingpatients who underwent repeat examination, 44 of theremaining 773 patients (5.6 %) had lesions &#8805; 10 mm. Finaldiagnoses in these 44 patients were as follows:benign gallbladderpolyp, n=19 (43.2 %);gallbladder adenomyosis,n=2 (4.6 %);biliary sludge accumulation, n=2 (4.6 %);gallbladder stone, n=2( 4.6%);resectable gallbladder cancer,n=6( 13.6%);non-resectable gallbladder cancer, n=6(13.6%);other cancers, n=2( 4.6%);and unknown, n=5(11.3 %). Wider screening during routine medical examinationssuch as annual health checks is required to enable increasedidentification of gallbladder cancer at an early stagewhen resection is still possible

キュウセイ スイエン オ ケイキ ニ シンダン サレタ タンノウガン ノ 1レイ

80 歳,女性.急性膵炎の診断で入院した際の腹部CT と超音波検査で,胆嚢に3.6 cm 大の腫瘍を認めた.MRCP で膵・胆管合流異常症の合併は否定された.膵炎軽快後に胆嚢腫瘍の診断で腹腔鏡下胆嚢摘出術が施行された.病理診断は胆嚢癌であり,腫瘍表面は脆弱性で一部に脱落と考えられる所見を認めた.本症例は,腫瘍片が総胆管へと脱落することによって惹起された急性膵炎によって診断された稀な胆嚢癌と思われた.An 80-year-old woman was admitted to the emergencydepartment of our hospital complaining of upper abdominalpain. Acute pancreatitis was diagnosed based on increasedserum levels of amylase and lipase. Computed tomographyand abdominal ultrasonography showed a gallbladder tumor3.6 cm in diameter. Pancreaticobiliary maljunction wasexcluded based on Magnetic Resonance cholangiopancreatography.The patient underwent laparoscopic cholecystectomyafter improvement of pancreatitis, and the tumorwas diagnosed as gallbladder cancer. On pathology, the tumorsurface was fragile and defluxion of the tumor was observed.We speculated that the acute pancreatitis wascaused by a small piece of tumor breaking off and passinginto the common bile duct

ショハツ カンサイボウ ガン ノ ビョウイン ト ヨゴ キテイ インシ ニ カン スル リンショウ テキ ケントウ

目的:初発肝細胞癌の病因と予後規定因子について検討し,2000年の我々の獨協医科大学病院症例を対象とした報告と比較することを目的とした.方法:初発肝細胞癌102例を対象とした.病因はB型肝炎 (HBV),C型肝炎 (HCV),NBNC,アルコールの4つに分類した.Kaplan-Meier法を用いて生存率を求め,Coxの比例ハザードモデルを用いて予後因子の検討を行った.得られた結果を2000年の報告と比較した.結果:病因はHBV 12.8%,HCV 60.7%,NBNC 15.7%,アルコール10.8%であり,HCVは減少し,NBNCとアルコールは増加傾向にあった.治療例の生存率は1年87.5%,2年78.0%,3年71.5%であり,近年の診断と治療の進歩による予後改善が確認された.腫瘍ステージがIII以上であること,およびPIVKA-II 40 mAU/ml以上の2つが独立した予後規定因子であった.結論:肝細胞癌の病因ではHCVが減少し,NBNCとアルコールが増加していた.腫瘍ステージ,PIVKA-IIが独立した生命予後規定因子であった.Purpose:The purpose of this study was to investigate the causes of initial hepatocellular carcinoma and the factors determining prognosis, and to compare the findings with those of our year 2000 report.Method:Subjects comprised 102 patients with initial hepatocellular carcinoma. Causes were divided into four categories: hepatitis B virus (HBV);hepatitis C virus (HCV);non-B, non-C hepatitis (NBNC);and alcohol. Survival rates were obtained using the Kaplan-Meier method and prognostic factors were investigated using Cox\u27s proportional hazards model. The results were compared with the findings of the year 2000 report.Results:The cause was HBV in 12.8 % of cases, HCV in 60.7%, NBNC in 15.7%, and alcohol in 10.8%. Frequency of HCV was decreased and frequencies of NBNC and alcohol showed increasing tendencies. The survival rate of treated patients was 87.5 % at 1 year, 78.0 % at 2 years, and 71.5 % at 3 years. Improved prognosis was confirmed with diagnosis in recent years and treatment advances. Two factors were independently associated with poor prognosis:tumor stage III or IV; and PIVKA-II level>40 mAU/ml.Conclusion:HCV decreased and NBNC and alcohol increased as causes of hepatocellular carcinoma. Factors independently associated with life prognosis were tumor stage and PIVKA-II level