119 results on '"Tada F"'
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2. Incidence and risk factors of esophagogastric varices bleeding in cirrhotic patients with advanced hepatocellular carcinoma treated with lenvatinib
- Author
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Iavarone, M., primary, Alimenti, E., additional, Tada, T., additional, Shimose, S., additional, Suda, G., additional, Yoo, C., additional, Soldà, C., additional, Piscaglia, F., additional, Casadei-Gardini, A., additional, Marra, F., additional, Vivaldi, C., additional, Conti, F., additional, Schirripa, M., additional, Iwamoto, H., additional, Sho, T., additional, Lee, So Heun, additional, Rizzato, M.D., additional, Tonnini, M., additional, Rimini, M., additional, Campani, C., additional, Masi, G., additional, Foschi, F., additional, Bruccoleri, M., additional, Kawaguchi, T., additional, Kumada, T., additional, Hiraoka, A., additional, Atsukawa, M., additional, Fukunishi, S., additional, Ishikawa, T., additional, Tajiri, K., additional, Ochi, H., additional, Yasuda, S., additional, Toyoda, H., additional, Hatanaka, T., additional, Kakizaki, S., additional, Kawata, K., additional, Tada, F., additional, Ohama, H., additional, Itokawa, N., additional, Okubo, T., additional, Arai, T., additional, Imai, M., additional, Naganuma, A., additional, Tosetti, G., additional, and Lampertico, P., additional
- Published
- 2023
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3. Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA
- Author
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McGuire D, Alexander J, Johansen O, Perkovic V, Rosenstock J, Cooper M, Wanner C, Kahn S, Toto R, Zinman B, Baanstra D, Pfarr E, Schnaidt S, Meinicke T, George J, von Eynatten M, Marx N, Aizenberg D, Fiorella A, Edgardo N, Belen C, Alonso P, Walter M, Maia K, Guillermo S, Leandro B, Constanza R, Alejandra N, Melina C, Ariel I, Rodrigo C, Alvarez C, Jorge M, Gabriel C, German S, Bartolacci I, Bolobanich G, Tale T, Meritano M, Echeverria M, Gerrini S, Alvarez M, Torrijos N, Berli M, Coggiola J, Castaneda G, Rode R, Milessi R, Roude A, Bono J, Caresani J, Arias V, Westberg J, Allende G, Liberman A, Bordonava A, Almagro S, Gerbaudo C, Schiavi L, Budassi N, Cecilia M, Buncuga M, Carlos S, Osvaldo T, Mercedes S, Calella P, Agustina V, Aljandro M, Alberto D, Fiorella M, Cantero M, Cariganano M, Anadon P, Cartasegna L, Gabriela M, Fernanda A, Alberto R, Chacon C, Jazmin F, Colombo H, Coni E, Mattausch S, Thomsenhall K, della Torre M, Morandini M, Berra F, Margarita H, Commendatore V, Tedesco J, Bolzan P, Cuneo C, Narcisa G, Caputi V, Pablo S, Sandra G, Pacora F, Tinari M, Jure H, Parody M, Toranzo A, Frechtel G, Yohena S, Lovecchio S, Muller C, Martin S, Olivera C, Breyaui M, Bianchi G, Garcia C, Luciana V, Florencia F, Ruben G, Gelersztein E, Rey G, Sanchez C, Fornasari L, Di Pierro L, Giacomi G, Miguel S, Laura T, Gonzalo C, Ramon C, Glenny J, Koretzky M, Porto A, Tiberio O, Ellenberg A, Saurral R, Igarzabal C, Vilamajo O, Matkovich J, de Lapertosa S, Villagra M, Cuzziol G, de la Cruz M, Pinchetti R, Mierez M, Lopez C, Gorosito V, Gabito A, Kleiban A, Grosembacher L, Adrian P, Paula R, Javier G, Kraft F, Andres F, Krynski F, Nicolas P, Marcelo F, Alfredo F, de la Fuente R, Natalia C, Luquez H, Recuero Y, Becchetti N, Ruiz M, Costantino M, Vazquez G, Guzman C, Pelatia P, Maffei L, Sassone S, Yantorno M, Prado G, Khron B, Maldonado N, Gustavo L, Veronica V, Marino J, Elizabeth A, Alejandra C, Oscar R, Azize G, Gallardo M, Escudero M, Vargas E, Ramos H, Lucero C, Najenson M, Crocci I, Chiesa A, Nardone L, Dominguez S, Zanini A, Manghi F, Grossman M, Giudice G, Romeo A, Piskorz D, Miguel C, Susana D, Noeli U, Rosa S, Martin V, Soledad A, Virginia M, Lorena G, Prado A, Veronica L, Eduardo H, Adolfo P, Florencia W, Rista L, Scolari C, Rojas N, Bertolio V, Zarandon R, Jair S, Orlando C, Sanabria H, Ignacio D, Viviana C, Marina R, Sarjanovich R, Scaro G, Huerta C, Mana M, Gutierrez M, Dain A, Gavicola R, Sessa H, Sacripanti J, Felman R, Vilarino P, Sicer M, Lagrutta M, Sala J, Casabella T, Cecilia H, Carlos B, Vines G, Javier R, Vico M, Lanchiotti P, Martella C, Torres L, Villarino A, Molina M, Martinez J, Farias C, Bertola S, Rojas M, Guzman P, Nisi J, Martinez D, Barrionuevo M, Vita N, Lopez A, Vottero E, Giuliano M, Paron L, Vogel D, Mele P, Imposti H, Dominguez A, Zaidman C, Fernando G, Beck M, Beltrame P, Chemello D, Junior R, Abreu A, Fernandes V, Saboia J, Rodrigues L, Carvalho M, Gurgel M, Gadelha D, Ramos C, Borba V, Golbert M, Pitthan M, Golbert L, Valentini R, Canani L, Gross J, Valenti A, Sartori C, Dutra O, Azevedo E, Azevedo A, Vaz R, Vaz H, da Costa F, da Costa L, Panarotto D, Lain F, Camazzola F, Dellomea B, Rech R, Pizzato P, Nunes C, Jaeger C, Silveira D, Wagner L, Machado L, Rea R, de Bem A, Alves J, Jonasson T, Malucelli F, Betti R, Lerario A, Lisboa H, Bem J, Tres G, Tavares C, Nardi A, Pozzatto M, Backes L, Reolao J, Scariot E, Ziguer E, Baldissera D, Griz L, Antunes D, Victor F, Freire K, Barros A, Costi B, Sa M, Carneiro A, Felicio J, Felicio K, Penha P, Ferreira J, Melo F, Alves A, Souza A, Costa L, Pinheiro D, Turatti L, Augusto G, Leanca C, Santomauro A, Forti A, Sena R, Marinho A, Facanha C, de Souza K, de Souza A, de Queiroz W, Leite S, Vieira S, Gubert L, Olsen A, Piazzetta G, Fuck A, Ferreira M, Fortes J, Brandao T, Alves F, Radice E, dos Santos J, de Almeida R, Franco D, Saporito W, Eliaschewitz F, de Siqueira K, Bona R, Genestreti P, de Castro D, Visconti G, Sampaio C, Palhares F, Konigsfeld H, Alves E, Feder C, Leao B, Saraiva J, Rodovalho S, Costa M, Pires N, Figueiredo E, Werner G, Garcia J, de Paiva I, Quirino B, Botelho R, da Silva R, Navarro A, Lourenco C, Pereira A, Arantes F, Boner D, Saad J, Falchetto E, Washizu E, Mandil A, Pimenta N, Tofani F, Fonseca T, Teixeira L, Maia L, Lemos M, Mouco O, Nakazone M, Weiand L, Bohn J, Hissa M, Araripe F, Carvalho F, Cancado G, Wang R, Chacra A, Fusaro A, de Mendonca E, Cercato C, Halpern A, Alves B, Braile M, Sestito R, Mustafa E, Ferreira V, Sbardellini B, de Almeida P, Guimaraes F, Piedade M, Bienert I, Braga J, Daher R, Hirakawa T, Terra E, Farias E, Figueiredo M, Lima L, Moraes K, Avelino I, Flato U, Plavnik F, Portes E, Moreira M, Vendramini M, Veloso R, Padilha M, Rodrigues A, Adam R, Santos S, Sayeg N, Guerrero D, Madeira M, Siqueira J, Pinheiro R, Villacorta A, Mellazi A, Braga T, Kaiser S, Paolino B, Lefterov I, Marinchev A, Angelova S, Klyuchkova N, Lybomirova Z, Kerekovski Y, Kuneva T, Penkova D, Levterov G, Videnova E, Georgieva P, Shinkov A, Borissova A, Vlahov J, Dakovska-Dekova L, Lucheva M, Luchev P, Temelkova M, Borisova K, Tsenov S, Andreeva V, Margaritov V, Arasheva G, Lozanov L, Borisov R, Gorcheva D, Henein S, Whatley S, Boutros M, Kalyniuk N, Berlingieri J, Nisker W, Hoag G, Hepburn D, Harvey M, Manjoo P, Yale J, Sherman M, Tsoukas M, Rehman W, Mason M, Santerre M, De Kock J, Barkhuizen F, Rooke C, Gill C, Kooy J, Burgoyne G, de Kock J, Degen G, Hockman L, Invik R, Roberts P, Ward K, Alasaad H, Susan A, Davies V, Gupta N, Milhalidis J, Grossman L, Agawal N, Yared Z, Rwaheed, Nouhad S, Nahla A, Khandwala H, Warwick A, Wadehra D, Manan A, Vecchiarelli J, Aslam N, Ferrao A, St-Maurice F, Collette R, Davey B, Nawaz S, Coutu B, Costi P, Greiss I, Mansour F, Raymond J, St-Phard W, Nadra I, Della Siega A, Barahona L, Klinke P, Contractor H, Fryer M, Chandra N, Conti B, Telzer L, Sorensen S, Lounsbury N, Martin E, Mitchell L, Pelzer E, Nelson S, Jones M, Cox J, Luco G, Trhoughton T, Labonte R, Chouinard G, Frechette A, Rheaume M, Cusson J, Faucher J, Dery V, Kelly A, Miranda B, Al-Kayssi N, Malette P, Rheault P, Fredette P, Dumas R, Palardy J, Belanger A, Boucher P, Doyon B, Charbonneau J, Bailey G, Odendaal M, Stephan K, Badenhorst J, Knight D, Thurgood A, Johnston M, Cooper-Rosen E, Jagger R, Green M, Weisnagel S, Gangloff A, Bergeron J, Pesant Y, Chevalier P, Woo V, Hurd C, Ruckert G, Lira J, Navarro G, Venegas M, Gonzalez P, Montecinos H, Vidal G, Fernandez M, Varas J, Fernandez C, Aguilar J, Marin R, Kindel C, Yovaniniz P, Gherman O, Aravena M, Carvajal J, Macias E, Corrado P, Lazcano M, Garrido B, Charme G, Carrasco J, Vignolo P, Saavedra S, Gajardo V, Saavedra C, Santamaria D, del Castillo B, Balda I, Zurvarra V, Fu G, Jiang D, Huang H, Wang M, Song J, Lu W, Lin Y, Lu Z, Shi Y, Zhong M, Zhao X, Chen D, Zhang G, He Y, Shi P, Chu K, Gao Q, Deng W, Zhang J, Zhang Y, Chen H, Liu E, Xie Y, Lin R, Tan W, Yuan Z, Wang Y, Ren J, Yu H, Luo M, Ma W, Shi W, Xu H, Xu M, Liu G, Dong Y, Bai B, Guo R, Liu X, Gao Y, Li S, Xu X, Liu P, Dong X, Wang S, Fu F, Jiang Q, Meng C, Yin X, Lu Y, Cui Y, Su G, Miao W, Wei F, Zhao Q, Li Z, Gao X, Lozno H, Prada W, Figueroa W, Ordonez A, Quintero E, Vallejo G, Contreras C, Escobar J, Alvaran J, Ortiz L, Marin M, Montoya C, Mendoza J, Manjarres J, Navarro B, Martinez G, Bonfanti A, Perci X, de la Hoz L, Arroyo J, Rendon C, Lopez J, Escobar N, Franco J, Lozano M, Zapata C, Ibarra L, Barrero A, Sarmiento A, Lozada H, Olitte M, Florez L, Munoz C, Quintero G, Correa G, Ruiz S, Dorado A, Causa A, Palma E, Morales A, Arteaga J, Beltran J, Granados M, Rubio A, Dada F, Bueno W, Rivera R, Corredor K, Romero V, Accini F, Palmera J, Ruiz G, Ortega M, Sanchez A, Lora Y, Cano J, Duque S, Thiriez S, Castano M, Giraldo P, Boljkovac Z, Grcic I, Balen M, Zukanovic S, Jeric M, Dvorscak D, Car S, Knezevic A, Herceg D, Franov B, Miskovic V, Bakula M, Hadak A, Superba M, Rubes J, Gornik I, Hamzic J, Ballek L, Sedlackova L, Hejlova J, Galatikova D, Huskova A, Zak P, Flekac M, Mraz M, Potuznik P, Palova S, Novak P, Okenka L, Matuska J, Rohac F, Vondrak K, Reichert P, Shamasna A, Skopek J, Lejskova M, Jiruska M, Lang P, Podoubsky R, Svobodova J, Cifkova R, Jozifova M, Krajcoviechova A, Wolfhart P, Sulc P, Silhova E, Cechakova M, Machova V, Balkova J, Peterka M, Votocek S, Prosecky R, Valis M, Barton P, Tomek J, Pumprla J, Axmannova M, Vitaskova R, Sincl F, Horanska P, Richter B, Malicherova E, Roderova E, Jenickova P, Winkelmann B, Finger C, Klausmann G, Milek K, Schwabe M, Weiss N, Mahlmann A, Werth S, Schmidt C, Schoell I, London M, Steidl E, Orban K, Taeschner H, Bonigut S, Schiefke I, Schwittay A, Kornmann O, Eich A, Franke S, Kis J, Szobota E, Danos P, Beke E, Grosz A, Csecsei G, Ferenczy J, Filo A, Ferencz I, Mihaly E, Baranyi T, Revesz K, Schlezak J, Harcsa E, Dombroczki Z, Kocsis I, Juhasz E, Literati-Nagy B, Kulcsar E, Bezzeg K, Kemeny V, Peterfai E, Buday B, Keltai K, Balo T, Somogyi A, Nagy G, Oroszlan T, Bagosi Z, Bujtor Z, Tabak A, Ferencz V, Domjan B, Tanczer T, Palinkas A, Karolyi H, Kovacs K, Csaszar I, Palhegyi E, Engelhalter G, Horthy R, Vanko E, Szabo G, Sipos G, Szigyarto M, Sebo N, Paragh G, Zsiros N, Szentimrei R, Pal D, Kobling T, Szanto I, Varadi Z, Bajnok L, Szujo S, Nemes O, Bajnok A, Mezosi E, Bodis B, Marton Z, Konyves L, Farago M, Kiss G, Kiss O, Nagy E, Takacs R, Nyitray S, Abraham G, Fehertemplomi K, Deak L, Dezso E, Karneili E, Deeb D, Zloczower M, Mahmid R, Zolotov S, Hochberg I, Elias M, Goldstein L, Poletaev V, Rock W, Koren O, Saliba W, Wolf F, Adawi F, Nimer A, Mosenzon O, Raz I, Potekhin M, Cahn A, Yulian T, Zvulunov E, Israel H, Shpitz D, Bar-Or I, Chananashvili L, Irena L, Dessau H, Halabe A, Vishlitzky V, Nabriski D, Baraf L, Itelman M, Schiff E, Willner N, Fireman-Klein E, Svistunov V, Dotan Y, Pavlichev O, Saig L, Bashkin A, Kuyantseva E, Gershkov S, Nodelman M, Arbel Y, Bogomolny N, Leshem-Rubinow E, Rofe M, Chorin E, Havkuk O, Wainstein J, Feldman D, Fujino Y, Kitamura H, Toriumi Y, Ishiguro H, Naganuma T, Shu S, Suzuki K, Hirota Y, Hayashi T, Hozawa K, Fukui T, Abe Y, Yamauchi K, Maruyama M, Matsumura S, Kozuma R, Nagai Y, Kihara Y, Maeda H, Nakanishi K, Iitsuka T, Hatori M, Shinozaki Y, Akiyama D, Kawabe M, Takei M, Sato A, Kawai Y, Kitajima K, Ide M, Sato N, Morisaki H, Nakashima K, Takayanagi H, Watanabe H, Iwahashi N, Tsujimoto M, Hibuse K, Hata T, Ueno K, Tatsuma H, Wakida Y, Ito T, Mizuno R, Fujita H, Konishi N, Kanehira T, Watanabe R, Miyaoka H, Okada T, Yamamoto M, Okita S, Murakami H, Todo Y, Umeoka F, Hori K, Shiraishi K, Tada F, Shimizu T, Tamai J, Sasaki C, Okuzima Y, Yasuda M, Iwaita Y, Tanaka K, Rha S, Na J, Cho D, Cho Y, Hwang E, Choi T, Won K, Kim H, Kim S, Oh D, Lee J, Choi H, Chung H, Park H, Suh Y, Kim Y, Kim N, Kim K, An J, Kim J, Park K, Kwak S, Kim M, Hwangbo Y, Lee D, Hong A, Kim L, Oh C, Moon S, Jung C, Jin J, Hyun B, Yang Y, Kong S, Yoon K, Yang H, Hong T, Oh J, Park J, Lee H, Choi J, Ahn J, Han S, Park W, Jo S, Suh S, An W, Park M, Lee S, Kim D, Jin H, Seo J, Chung C, Lim J, Huh J, Park I, Yu S, Sim N, Khan S, Albakari N, Sivaraman J, Manaf K, Maharuddin I, Nagendram S, Ali N, Abdul Latiff N, Othman N, Sarip S, Chew E, Mohamed S, Aziz N, Hui K, Lin L, Velaiutham S, Khir A, Lee L, Manikam S, Chooi K, Chang M, Ooi C, Anthony J, Seganathirajah M, Ng O, Ismail N, Cheah C, Ramanathan G, Mui N, Wen F, Choo T, Bin Ruhani A, Jamaludin S, Abidin S, Nor F, Abu Hassan M, Hanari N, Ahmad N, Suan M, Zainul N, Ali S, Sridhar G, Han C, Chin A, Vin L, Kadir K, Zain A, Hussain N, Pusparajah P, Lozano F, Gomez A, Zaccari E, Vigil A, Preciado C, de Leon M, Parra M, Cervantes A, Aguirre E, Orozco E, Gonzalez S, Elizondo R, Flores E, Guerrero M, Flores F, Sanchez J, Perez F, Rodriguez J, Martinez L, Marquez D, Gutierrez B, Flores M, Real M, Campos P, Garcia P, Rios M, Romero E, Perez Z, Tarabay C, Munoz L, Farias J, Gonzalez J, Palestino N, Sanchez L, Carrillo G, Ordonez N, Pech C, Andrade M, Euan J, Ortegon M, Garcia S, Orozco J, Vazquez H, Herrera R, Perez E, Arango A, Ibarra M, Gonzales L, Esperano J, Quintana L, Salazar I, Ruiz L, Barron C, Ballesteros C, Cervera L, Hercilla E, Gomez H, Mesa J, Herrera P, Rodriguez M, Ochoa R, Mora E, Charles C, Silva R, Mijangos J, Diaz C, Zavala C, Baron P, Bernal A, Martinez F, Tlapale M, Ramirez E, Basila A, Munguia R, Tello M, Martinez M, Mulder H, van der Graaff P, Nawaz A, Keller I, Schoofs M, Smak-Gregoor P, Al-Windy N, Bulut S, de Jong J, Maas A, Schaardenburgh P, Imholz B, Heijster J, Hoogenberg K, Smit C, Kooy A, Huvers F, Landewe-Cleuren S, Kars M, van Moorsel D, Wolffenbuttel B, Lutgens H, Schutte E, Gansevoort R, Idzerda N, Westerink J, Weijmans M, Berg J, van Kleef M, Slob M, Jaspers N, Hovens M, Monajemi H, Kobielusz-Gembala I, Zmuda W, Adamczyk M, Konieczny M, Strzelecka-Sosik A, Nowacka E, Krzyzagorska E, Sekulska M, CzajkowskaKaczmarek E, Kaczmarek B, Opawska K, Dabrowska M, Kus W, Wrzesien-Kus A, Piotrowski G, Hotlos L, Ocicka-Kozakiewicz A, Jurowiecki J, Stasinska T, Karczewicz-Janowska J, Jaruga J, ZytkiewiczJaruga D, Krupinska E, Pupek-Musialik D, Bogdanski P, Szulinska M, Skrypnik D, Skokowska E, Bojarska-Los M, Giermkowska-Samek M, Pirog M, Wojnowski L, Jelinska A, Gradzka M, Danyluk A, Lysek R, Sliwinska T, Podrazka-Szczepaniak A, Barney M, Tomczyk A, Necki M, Malicka J, Dudzinska M, KiszczakBochynska E, Markiewicz A, Galbas K, Paciorkowski A, Mazur S, Mazur M, Chmielowski A, Swiatek A, Sobocka B, Wis J, Jozefowska M, Kaczmarek M, Timler M, Cieplucha Z, Lazuka L, Lazuka N, Wittek A, Spyra J, Jasiel-Wojculewicz H, Stefanski A, Wierucki L, Hanczuk A, Misiura M, Szmygel K, Kolcowa O, Orlowska-Kunikowska E, Rutkowski M, Ignaszewska-Wyrzykowska A, Popenda G, Maciejewska J, Mostowy A, WojteckaGrabka M, Grazyna M, Wieslaw K, Barbara K, Kramarczuk E, Wojciech C, Jaroslaw H, Ewa B, Karas P, Agnieszka S, Hanna C, Justyna S, Piotr K, Wozniak I, Mateusz W, Katarzyna W, Jacek F, Andrzej J, Cymerman K, Gmytrasiewicz M, Zambrzycki J, Krysiak-Kowaluk H, Klodawska K, Klszczewski Z, Zieleniewski J, Opadczuk P, Urbanska K, Faran-Grabowska K, Szczepanik T, Siegel A, Kleczek A, Kincel K, Nowak D, Slowik-Gomulka L, Watemborska-Matuszyk G, Lampart J, Strozik-Krecichwost A, Dziewit T, Broncel M, Wojcik-Odyniec J, Jakubczyk E, Wierzbicka K, Witowicz A, Jedrych B, Korczyk P, Socik-Pojawa M, Monteiro P, Monteiro S, Mendes P, Soares F, Mendes S, Leite L, Vicente J, Santos M, Ferreira A, Alves P, Rosario F, Garrao A, Duarte L, Rogado C, Duarte R, Laginha T, Matos P, Raposo J, Mariz J, Teixeira J, Capela C, Leitao A, Cardiga R, Alface M, Augusto S, Basto L, Cunha A, Rei D, Dantas J, Verdasca I, Andrade L, Silva A, Suarez M, Dias V, Silva J, Pereira N, Goncalves M, Goncalves A, Silveira A, Sampaio A, Dias A, Diogo M, Vilaca C, Cif A, Calin T, Elena S, Crisan C, Adina S, Ramona S, Anghel V, Simona C, Turcu L, Mihaela V, Cosma D, Cristina H, Marius-Calin H, Negrisanu G, Andreea-Andrada M, Maria-Mihaela V, Camelia T, Oana P, Monia A, Onaca A, Mircea O, Mot A, Stolea V, Elena N, Barbonta D, Cristian B, Oana S, Popescu A, Madalina M, Coman A, Anca C, Constantinescu S, Mircea C, Diaconu-Sotropa M, Ene D, Pintilei E, Mihai G, Delia R, Toarba I, Simona H, Negru D, Flaminzeanu F, Iulian C, Maria-Cristina C, Doros R, Cleo S, Sorin B, Demian L, Mihai S, Raul B, Ioana A, Nicolau A, Cosmin P, Isabela G, Elena C, Ileana T, Valuyskikh E, Miroshnichenko E, Klementyeva N, Zelman O, Chumakova G, Vigel A, Leonova N, Pergaeva Y, Stefanovskaya O, Pushkareva S, Antoshkina L, Zheleznova N, Iveitsman, Barbarash O, Zvereva T, Zhuravleva E, Zavyrylina I, Usoltceva E, Savostyanova Y, Kupriyanova T, Krivoshapova K, Kondyukova N, Inozemceva A, Argunova Y, Tsyba L, Belenky D, Mariich O, Terekhova A, Tsygankova O, Kuznetsova E, Nagibovich G, Ivchenko Y, Dobronravov V, Dobronravov A, Bush M, Trofimenko I, Vishnevsky A, Zikov V, Kositsyn D, Palzman Z, Spiridonova T, Rodina N, Polozhentsev S, Mamedova L, Panov A, Abesadze I, Alugishvili M, Ivashkin V, Drapkina O, Korneeva O, Zyatenkova E, Glinkina I, Poluboyarinova I, Gurova O, Raykhman A, Vertkin A, Rodykova I, Shamaeva K, Petrovskaya T, Uzueva E, Milovanov Y, Milovanova S, Milovanova L, Markina M, Dobrosmyslov I, Markov V, Afanasiev S, Babich E, Belokopytova N, Demyanov S, Maximov A, Maximov I, Rebrova T, Shtatolkina M, Masin A, Demko A, Chuyko O, Pronina A, Charf G, Akatova E, Urlaeva I, Nikolin O, Khovaeva Y, Ermachkova L, Burdina E, Shvalb P, Suchkov I, Pshennikov A, Gryaznov S, Rymar O, Dolinskaya Y, Bahareva Y, Mustafina S, Sherbakova L, Ovsyannikova A, Bolshakova O, Polunicheva E, Dora S, Agafyina A, Yashina A, Vasilieva I, Yakhontova P, Selivanova S, Kargapoltseva O, Shilina N, Bayramova G, Sorokin I, Astamirova K, Kuchuk P, Koniushenko D, Malykh N, Dvorkin M, Krovelets T, Konovalova K, Seeber M, van Niekerk F, Siebert H, Steenkamp W, Wiid S, Noeth M, Siebert R, Breedt J, Bouwer J, Kapp C, Venter T, Rayner B, Trinder Y, Rheeder P, 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Satyavolu S, Dev D, Yalamanchili H, Sumeyye C, Fernandes H, Chaleff F, Jancko M, Trenche S, Kaplan W, Wilcox S, Goisse M, Rua M, Black J, Chapman K, Suh D, Yan L, Song D, Chanara S, Houchin V, McKeinness A, Sotolongo R, Gutierrez K, Miranda-Palma B, Solano M, Jain M, Needell J, Banerjee A, Jarratt M, Hantel S, Lees K, Welty F, Freedman S, Parhofer K, Birkeland K, McGill J, Tijssen J, Clemmensen P, Pehrson S, Grande P, Januzzi J, Wood M, Petrie M, Sairanen T, Tatlisumak T, Soinne L, Kase C, Turan T, Mann J, Agarwal R, Fogarty D, Navaneethan S, Srinivas T, Forsmark C, Frossard J, Gelrud A, Mayerle J, Lee R, Heist R, Sullivan R, Buchbinder E, Chodak G, Edelman M, Thompson V, Coles A, and CARMELINA Investigators
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cardiovascular disease ,type 2 diabetes mellitus ,heart failure ,chronic kidney diseases - Abstract
Background: Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and/or kidney disease. Methods: Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction > or 50%. Results: CARMELINA enrolled 6979 participants (mean age, 65.9 years; estimated glomerular filtration rate, mL/min per 1.73m(2); hemoglobin A1c, 8.0%; 62.9% men; diabetes mellitus duration, 14.8 years), including 1873 (26.8%) with a history of HF at baseline. Median follow-up was 2.2 years. Linagliptin versus placebo did not affect the incidence of hHF (209/3494 [6.0%] versus 226/3485 [6.5%], respectively; hazard ratio [HR], 0.90; 95% CI, 0.74-1.08), the composite of cardiovascular death/hHF (HR, 0.94; 95% CI, 0.82-1.08), or risk for recurrent hHF events (326 versus 359 events, respectively; rate ratio, 0.94; 95% CI, 0.75-1.20). There was no heterogeneity of linagliptin effects on hHF by history of HF at baseline, baseline estimated glomerular filtration rate or urine albumin-creatinine ratio, or prerandomization left ventricular ejection fraction. Conclusions: In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01897532.
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- 2019
4. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk The CARMELINA Randomized Clinical Trial
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Levterov G, Videnova E, Georgieva P, Shinkov A, Borissova A, Vlahov J, Dakovska-Dekova L, Lucheva M, Luchev P, Temelkova M, Borisova K, Tsenov S, Andreeva V, Margaritov V, Arasheva G, Lozanov L, Borisov R, Gorcheva D, Henein S, Whatley S, Boutros M, Kalyniuk N, Berlingieri J, Nisker W, Hoag G, Hepburn D, Harvey M, Manjoo P, Yale J, Sherman M, Tsoukas M, Rehman W, Mason M, Santerre M, De Kock J, Barkhuizen F, Rooke C, Gill C, Kooy J, Burgoyne G, de Kock J, Degen G, Hockman L, Invik R, Roberts P, Ward K, Alasaad H, Susan A, Davies V, Gupta N, Milhalidis J, Grossman L, Agawal N, Yared Z, Rwaheed, Nouhad S, Nahla A, Khandwala H, Warwick A, Wadehra D, Manan A, Vecchiarelli J, Aslam N, Ferrao A, St-Maurice F, Collette R, Davey B, Nawaz S, Coutu B, Costi P, Greiss I, Mansour F, Raymond J, St-Phard W, Nadra I, Della Siega A, Barahona L, Klinke P, Contractor H, Fryer M, Chandra N, Conti B, Telzer L, Sorensen S, Lounsbury N, Martin E, Mitchell L, Pelzer E, Nelson S, Jones M, Cox J, Luco G, 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W, Xu H, Xu M, Liu G, Dong Y, Bai B, Guo R, Liu X, Gao Y, Li S, Xu X, Liu P, Dong X, Wang S, Fu F, Jiang Q, Meng C, Yin X, Lu Y, Cui Y, Su G, Miao W, Wei F, Zhao Q, Li Z, Gao X, Lozno H, Prada W, Figueroa W, Ordonez A, Quintero E, Vallejo G, Contreras C, Escobar J, Alvaran J, Ortiz L, Marin M, Montoya C, Mendoza J, Manjarres J, Navarro B, Martinez G, Bonfanti A, Perci X, de la Hoz L, Arroyo J, Rendon C, Lopez J, Escobar N, Franco J, Lozano M, Zapata C, Ibarra L, Barrero A, Sarmiento A, Lozada H, Olitte M, Florez L, Munoz C, Quintero G, Correa G, Ruiz S, Dorado A, Causa A, Palma E, Morales A, Arteaga J, Beltran J, Granados M, Rubio A, Dada F, Bueno W, Rivera R, Corredor K, Romero V, Accini F, Palmera J, Ruiz G, Ortega M, Sanchez A, Lora Y, Cano J, Duque S, Thiriez S, Castano M, Giraldo P, Boljkovac Z, Grcic I, Balen M, Zukanovic S, Jeric M, Dvorscak D, Car S, Knezevic A, Herceg D, Franov B, Miskovic V, Bakula M, Hadak A, Superba M, Rubes J, Gornik I, Hamzic J, Ballek L, Sedlackova L, Hejlova J, Galatikova D, Huskova A, Zak P, Flekac M, Mraz M, Potuznik P, Palova S, Novak P, Okenka L, Matuska J, Rohac F, Vondrak K, Reichert P, Shamasna A, Skopek J, Lejskova M, Jiruska M, Lang P, Podoubsky R, Svobodova J, Cifkova R, Jozifova M, Krajcoviechova A, Wolfhart P, Sulc P, Silhova E, Cechakova M, Machova V, Balkova J, Peterka M, Votocek S, Prosecky R, Valis M, Barton P, Tomek J, Pumprla J, Axmannova M, Vitaskova R, Sincl F, Horanska P, Richter B, Malicherova E, Roderova E, Jenickova P, Winkelmann B, Finger C, Klausmann G, Milek K, Schwabe M, Weiss N, Mahlmann A, Werth S, Schmidt C, Schoell I, London M, Steidl E, Orban K, Taeschner H, Bonigut S, Schiefke I, Schwittay A, Kornmann O, Eich A, Franke S, Kis J, Szobota E, Danos P, Beke E, Grosz A, Csecsei G, Ferenczy J, Filo A, Ferencz I, Mihaly E, Baranyi T, Revesz K, Schlezak J, Harcsa E, Dombroczki Z, Kocsis I, Juhasz E, Literati-Nagy B, Kulcsar E, Bezzeg K, Kemeny V, Peterfai E, Buday B, Keltai K, Balo T, Somogyi A, Nagy G, Oroszlan T, Bagosi Z, Bujtor Z, Tabak A, Ferencz V, Domjan B, Tanczer T, Palinkas A, Karolyi H, Kovacs K, Csaszar I, Palhegyi E, Engelhalter G, Horthy R, Vanko E, Szabo G, Sipos G, Szigyarto M, Sebo N, Paragh G, Zsiros N, Szentimrei R, Pal D, Kobling T, Szanto I, Varadi Z, Bajnok L, Szujo S, Nemes O, Bajnok A, Mezosi E, Bodis B, Marton Z, Konyves L, Farago M, Kiss G, Kiss O, Nagy E, Takacs R, Nyitray S, Abraham G, Fehertemplomi K, Deak L, Dezso E, Karneili E, Deeb D, Zloczower M, Mahmid R, Zolotov S, Hochberg I, Elias M, Goldstein L, Poletaev V, Rock W, Koren O, Saliba W, Wolf F, Adawi F, Nimer A, Mosenzon O, Raz I, Potekhin M, Cahn A, Yulian T, Zvulunov E, Israel H, Shpitz D, Bar-Or I, Chananashvili L, Irena L, Dessau H, Halabe A, Vishlitzky V, Nabriski D, Baraf L, Itelman M, Schiff E, Willner N, Fireman-Klein E, Svistunov V, Dotan Y, Pavlichev O, Saig L, Bashkin A, Kuyantseva E, Gershkov S, Nodelman M, Arbel Y, Bogomolny N, Leshem-Rubinow E, Rofe M, Chorin E, Havkuk O, Wainstein J, Feldman D, Fujino Y, Kitamura H, Toriumi Y, Ishiguro H, Naganuma T, Shu S, Suzuki K, Hirota Y, Hayashi T, Hozawa K, Fukui T, Abe Y, Yamauchi K, Maruyama M, Matsumura S, Kozuma R, Nagai Y, Kihara Y, Maeda H, Nakanishi K, Iitsuka T, Hatori M, Shinozaki Y, Akiyama D, Kawabe M, Takei M, Sato A, Kawai Y, Kitajima K, Ide M, Sato N, Morisaki H, Nakashima K, Takayanagi H, Watanabe H, Iwahashi N, Tsujimoto M, Hibuse K, Hata T, Ueno K, Tatsuma H, Wakida Y, Ito T, Mizuno R, Fujita H, Konishi N, Kanehira T, Watanabe R, Miyaoka H, Okada T, Yamamoto M, Okita S, Murakami H, Todo Y, Umeoka F, Hori K, Shiraishi K, Tada F, Shimizu T, Tamai J, Sasaki C, Okuzima Y, Yasuda M, Iwaita Y, Tanaka K, Rha S, Na J, Cho D, Cho Y, Hwang E, Choi T, Won K, Kim H, Kim S, Oh D, Lee J, Choi H, Chung H, Park H, Suh Y, Kim Y, Kim N, Kim K, An J, Kim J, Park K, Kwak S, Kim M, Hwangbo Y, Lee D, Hong A, Kim L, Oh C, Moon S, Jung C, Jin J, Hyun B, Yang Y, Kong S, Yoon K, Yang H, Hong T, Oh J, Park J, Lee H, Choi J, Ahn J, Han S, Park W, Jo S, Suh S, An W, Park M, Lee S, Kim D, Jin H, Seo J, Chung C, Lim J, Huh J, Park I, Yu S, Sim N, Khan S, Albakari N, Sivaraman J, Manaf K, Maharuddin I, Nagendram S, Ali N, Abdul Latiff N, Othman N, Sarip S, Chew E, Mohamed S, Aziz N, Hui K, Lin L, Velaiutham S, Khir A, Lee L, Manikam S, Chooi K, Chang M, Ooi C, Anthony J, Seganathirajah M, Ng O, Ismail N, Cheah C, Ramanathan G, Mui N, Wen F, Choo T, Bin Ruhani A, Jamaludin S, Abidin S, Nor F, Abu Hassan M, Hanari N, Ahmad N, Suan M, Zainul N, Ali S, Sridhar G, Han C, Chin A, Vin L, Kadir K, Zain A, Hussain N, Pusparajah P, Lozano F, Gomez A, Zaccari E, Vigil A, Preciado C, de Leon M, Parra M, Cervantes A, Aguirre E, Orozco E, Gonzalez S, Elizondo R, Flores E, Guerrero M, Flores F, Sanchez J, Perez F, Rodriguez J, Martinez L, Marquez D, Gutierrez B, Flores M, Real M, Campos P, Garcia P, Rios M, Romero E, Perez Z, Tarabay C, Munoz L, Farias J, Gonzalez J, Palestino N, Sanchez L, Carrillo G, Ordonez N, Pech C, Andrade M, Euan J, Ortegon M, Garcia S, Orozco J, Vazquez H, Herrera R, Perez E, Arango A, Ibarra M, Gonzales L, Esperano J, Quintana L, Salazar I, Ruiz L, Barron C, Ballesteros C, Cervera L, Hercilla E, Gomez H, Mesa J, Herrera P, Rodriguez M, Ochoa R, Mora E, Charles C, Silva R, Mijangos J, Diaz C, Zavala C, Baron P, Bernal A, Martinez F, Tlapale M, Ramirez E, Basila A, Munguia R, Tello M, Martinez M, Mulder H, van der Graaff P, Nawaz A, Keller I, Schoofs M, Smak-Gregoor P, Al-Windy N, Bulut S, de Jong J, Maas A, Schaardenburgh P, Imholz B, Heijster J, Hoogenberg K, Smit C, Kooy A, Huvers F, Landewe-Cleuren S, Kars M, van Moorsel D, Wolffenbuttel B, Lutgens H, Schutte E, Gansevoort R, Idzerda N, Westerink J, Weijmans M, Berg J, van Kleef M, Slob M, Jaspers N, Hovens M, Monajemi H, Kobielusz-Gembala I, Zmuda W, Adamczyk M, Konieczny M, Strzelecka-Sosik A, Nowacka E, Krzyzagorska E, Sekulska M, CzajkowskaKaczmarek E, Kaczmarek B, Opawska K, Dabrowska M, Kus W, Wrzesien-Kus A, Piotrowski G, Hotlos L, Ocicka-Kozakiewicz A, Jurowiecki J, Stasinska T, Karczewicz-Janowska J, Jaruga J, ZytkiewiczJaruga D, Krupinska E, Pupek-Musialik D, Bogdanski P, Szulinska M, Skrypnik D, Skokowska E, Bojarska-Los M, Giermkowska-Samek M, Pirog M, Wojnowski L, Jelinska A, Gradzka M, Danyluk A, Lysek R, Sliwinska T, Podrazka-Szczepaniak A, Barney M, Tomczyk A, Necki M, Malicka J, Dudzinska M, KiszczakBochynska E, Markiewicz A, Galbas K, Paciorkowski A, Mazur S, Mazur M, Chmielowski A, Swiatek A, Sobocka B, Wis J, Jozefowska M, Kaczmarek M, Timler M, Cieplucha Z, Lazuka L, Lazuka N, Wittek A, Spyra J, Jasiel-Wojculewicz H, Stefanski A, Wierucki L, Hanczuk A, Misiura M, Szmygel K, Kolcowa O, Orlowska-Kunikowska E, Rutkowski M, Ignaszewska-Wyrzykowska A, Popenda G, Maciejewska J, Mostowy A, WojteckaGrabka M, Grazyna M, Wieslaw K, Barbara K, Kramarczuk E, Wojciech C, Jaroslaw H, Ewa B, Karas P, Agnieszka S, Hanna C, Justyna S, Piotr K, Wozniak I, Mateusz W, Katarzyna W, Jacek F, Andrzej J, Cymerman K, Gmytrasiewicz M, Zambrzycki J, Krysiak-Kowaluk H, Klodawska K, Klszczewski Z, Zieleniewski J, Opadczuk P, Urbanska K, Faran-Grabowska K, Szczepanik T, Siegel A, Kleczek A, Kincel K, Nowak D, Slowik-Gomulka L, Watemborska-Matuszyk G, Lampart J, Strozik-Krecichwost A, Dziewit T, Broncel M, Wojcik-Odyniec J, Jakubczyk E, Wierzbicka K, Witowicz A, Jedrych B, Korczyk P, Socik-Pojawa M, Monteiro P, Monteiro S, Mendes P, Soares F, Mendes S, Leite L, Vicente J, Santos M, Ferreira A, Alves P, Rosario F, Garrao A, Duarte L, Rogado C, Duarte R, Laginha T, Matos P, Raposo J, Mariz J, Teixeira J, Capela C, Leitao A, Cardiga R, Alface M, Augusto S, Basto L, Cunha A, Rei D, Dantas J, Verdasca I, Andrade L, Silva A, Suarez M, Dias V, Silva J, Pereira N, Goncalves M, Goncalves A, Silveira A, Sampaio A, Dias A, Diogo M, Vilaca C, Cif A, Calin T, Elena S, Crisan C, Adina S, Ramona S, Anghel V, Simona C, Turcu L, Mihaela V, Cosma D, Cristina H, Marius-Calin H, Negrisanu G, Andreea-Andrada M, Maria-Mihaela V, Camelia T, Oana P, Monia A, Onaca A, Mircea O, Mot A, Stolea V, Elena N, Barbonta D, Cristian B, Oana S, Popescu A, Madalina M, Coman A, Anca C, Constantinescu S, Mircea C, Diaconu-Sotropa M, Ene D, Pintilei E, Mihai G, Delia R, Toarba I, Simona H, Negru D, Flaminzeanu F, Iulian C, Maria-Cristina C, Doros R, Cleo S, Sorin B, Demian L, Mihai S, Raul B, Ioana A, Nicolau A, Cosmin P, Isabela G, Elena C, Ileana T, Valuyskikh E, Miroshnichenko E, Klementyeva N, Zelman O, Chumakova G, Vigel A, Leonova N, Pergaeva Y, Stefanovskaya O, Pushkareva S, Antoshkina L, Zheleznova N, Iveitsman, Barbarash O, Zvereva T, Zhuravleva E, Zavyrylina I, Usoltceva E, Savostyanova Y, Kupriyanova T, Krivoshapova K, Kondyukova N, Inozemceva A, Argunova Y, Tsyba L, Belenky D, Mariich O, Terekhova A, Tsygankova O, Kuznetsova E, Nagibovich G, Ivchenko Y, Dobronravov V, Dobronravov A, Bush M, Trofimenko I, Vishnevsky A, Zikov V, Kositsyn D, Palzman Z, Spiridonova T, Rodina N, Polozhentsev S, Mamedova L, Panov A, Abesadze I, Alugishvili M, Ivashkin V, Drapkina O, Korneeva O, Zyatenkova E, Glinkina I, Poluboyarinova I, Gurova O, Raykhman A, Vertkin A, Rodykova I, Shamaeva K, Petrovskaya T, Uzueva E, Milovanov Y, Milovanova S, Milovanova L, Markina M, Dobrosmyslov I, Markov V, Afanasiev S, Babich E, Belokopytova N, Demyanov S, Maximov A, Maximov I, Rebrova T, Shtatolkina M, Masin A, Demko A, Chuyko O, Pronina A, Charf G, Akatova E, Urlaeva I, Nikolin O, Khovaeva Y, Ermachkova L, Burdina E, Shvalb P, Suchkov I, Pshennikov A, Gryaznov S, Rymar O, Dolinskaya Y, Bahareva Y, Mustafina S, Sherbakova L, Ovsyannikova A, Bolshakova O, Polunicheva E, Dora S, Agafyina A, Yashina A, Vasilieva I, Yakhontova P, Selivanova S, Kargapoltseva O, Shilina N, Bayramova G, Sorokin I, Astamirova K, Kuchuk P, Koniushenko D, Malykh N, Dvorkin M, Krovelets T, Konovalova K, Seeber M, van Niekerk F, Siebert H, Steenkamp W, Wiid S, Noeth M, Siebert R, Breedt J, Bouwer J, Kapp C, Venter T, Rayner B, Trinder Y, Rheeder P, Delport E, Mathijs S, Soma P, van Zyl D, Strydom M, Marais A, Badat A, Hansa S, Fourie D, Walton T, Engelbrecht J, Jansen J, Roos J, du Toit S, Lehloenya K, van Zyl L, van Zyl F, Naude M, Mookadam M, van der Merwe A, Trokis J, Lombard L, Coetzee K, Ismail S, Bruning H, Latiff G, Yasmin O, Pillay T, Mohamed Z, Dawood S, Stapelberg A, Abrahams P, Jurgens J, van Heerden P, Swart E, Botha C, Meeding J, Hemus A, Oosthuysen W, Visagie G, Fourie N, Hutton P, van der Merwe N, Chelin N, Everton T, Duki M, Ghila N, Joshi M, Hira M, Madueno F, Martinez B, Sebastian N, Mercadal L, Isbert S, Gonzalez I, Asencio J, Figueras M, Rivas M, Garcia H, Fusalba A, Geat D, Cambra G, Sastre J, Castro F, Mas A, Portillo C, Serrano I, Hernandez S, Fajardo F, Juan C, Ferrer J, Peralta F, Padin C, Mauricio D, Madorell B, San Miguel F, Pedrol N, Trescoli C, Montanana C, Gonzalo M, Capellan J, Estrella A, Martinez C, Montesinos I, Loscos A, Coronado J, Perez J, Castillo B, Alonso C, Quesada V, Teruel J, Perez S, Lama M, del Rio E, Zlova T, Ponomarenko K, Karpenko O, Bezuglova S, Mitskevych L, Kizim S, Nevolina I, Katerenchuk V, Liudmyla B, Ivan K, Rudyk I, Olena M, Anna I, Ganna B, Topchii I, Semenovykh P, Yulia Y, Mykhalchyshyn G, Kirienko D, Kobiliak N, Bodnar, Mykhalchyshyn, Pertseva N, Olena G, Tomashkevych H, Korpachev V, Prybyla O, Kovalchuk A, Kushnarova N, Zinych O, Tseluyko V, Andriy Z, Olga R, Mankovskyy B, Zherdova N, Lykhoshapko O, Logoida P, Godlevska O, Olena V, Olga C, Gyrina O, Alifer O, Dozhuk K, Pekhenko V, Gorobets N, Korneichuk A, Makarenko E, Martynyuk L, Martynuyk O, Stanislavchuk M, Larysa P, Natalia S, Botsyurko V, Kostitska I, Dzeman O, Ablitsov Y, Ivaseiko S, Konovart O, Sandurska S, Vendzilovych Y, Samoylov O, Iryna C, Rozhkivska L, Ulyanchenko I, Kateryna V, Orlenko V, Ivaskina K, Tronko M, Tronko K, Pashkovska N, Stankova N, Vynnychenko L, Bolotnikova N, Demokhova N, Reshotko D, Popova A, Dr Bogdana, Tetiana S, Svitlana D, Oksana R, Vlasenko M, Litvinova S, Semenyuk I, Fishchuk O, Mostovoy Y, Tkachenko T, Ovcharuk M, Rasputina L, Vakaliuk I, Tymochko N, Drapchak I, Petrovska L, Lai W, Yen H, Voon W, Lin T, Cheng K, Chiu C, Chu C, Hsu P, Chiang C, Li Y, Kuo C, Lin S, Chao T, Yu W, Sung S, Wang K, Lu T, Shih K, Wu C, Chiang F, Hwang J, Tsai C, Juang J, Jeng J, Tang S, Lai C, Cheng C, Hsieh I, Hsieh M, Chen C, Lee C, Pai P, Ko P, Wang T, Chen T, Wu H, Chang S, Chen K, Hsieh L, Chou C, Jiang J, Lee M, Huang J, Chen J, Chiu K, Tsai L, Chen P, Saxena M, Collier D, Vaidya B, Harman S, Ramell M, Davies M, Chatterjee S, Meakin L, Quinn M, Bain S, Mallipedhi A, Min T, Bashir J, Blagden M, Ali J, McCrimmon R, Brennan G, Malcolm E, McDonald D, Pearson E, Illsley G, Darzy K, Winocour P, Hanif W, Cockwell P, Charlton M, Thekkepat S, Howat I, Devers M, Patrick J, Wyatt N, Smith C, Singh B, Nicholas J, Gillani S, Green F, Bell E, Boyle J, MacKin S, Livingstone R, Arif A, Syed M, Hammoud J, Sparks J, Anderson M, Tumey R, Condit J, Reddy M, Abalos-Galito M, Rebecca J, Barker T, Seaton B, Campbell E, Kompanik H, Jayson L, Huffman C, Bialow M, McDonnell G, McCaffrey J, Manis C, DeLuca E, Levins J, Bartlett M, Anorga K, Franco M, Gentry P, Hodge D, Pohil R, Rschultz, Leggett R, Blair L, Gisler J, Niegos F, Osburn M, Parma K, Schendel S, Stines L, Winnie M, Wu P, Canales J, Yu J, Cornett G, Beavins J, Hyde D, Zapinski D, Johnson T, Levinson D, Ahmed A, Kenny B, Kuehl A, Bates C, Jantzi C, Ananthula P, Shafer J, Louthan J, Bays A, Stapleton A, Staton P, Strum D, Taylor P, Smith A, Rapp R, Bao S, Randolph C, MacGillivray B, Schuster R, Harden T, Barnella C, Dunnam T, Whiles R, Bolick C, Brockmyre A, Plucker S, Marshall C, Poteet C, Morin D, Tavel E, Averill N, McFann A, Purcell D, Dixon T, Corey E, Goss J, Drescher R, Irfan M, Naeem M, Egelhof R, Mehta P, Koehler T, Walia J, Fernandez J, Bedel G, Preet R, Bhuchar S, Ahmed F, Onyema D, Benchabbat A, Kohanbash L, Miller P, Lalinde M, Carrithers E, Patterson R, Raube-Miceli A, Martinez A, Harris B, Levy R, Siev E, Berlin H, DiMattia M, Sugimoto D, Dugas J, Benson M, Stegemoller R, Schmoll M, Kinnaman S, O'Connor T, Powel T, Rudolph L, Lewiecki M, Best E, Chavez J, Garcia M, Cohen R, Colman D, Ocampo M, Heaney L, Rappley G, Quezada I, Santos V, Nikfarjam A, Reyes M, Rodriguez R, Josephs L, Hernandez R, Flores P, Espinoza L, Mejia W, Pedraza Z, Castaneda R, Laguerre J, Cook R, Patel R, Werner H, Blank R, Small S, Andersen J, Holmes D, Farmer M, Wiener V, Pharr W, Bray B, Beekman J, Anderson A, Andrawis N, Gabra N, Moche T, Marty S, Galvez O, Reyes R, Garcia R, Lerma G, Pliquin B, Mayfield R, Durham N, Phillips R, Baran A, Kondo N, Dempsey S, Kufs W, Laddis T, Zimmer K, Van Depol M, Dweck L, Kestler M, Werner N, Ashraf M, Quick A, Schallert G, Sligh T, Trueba P, Batista J, Martinez T, Moya J, Amarales V, Santos E, Torres P, Diaz T, Diaz J, Hodish I, Else T, Buras E, Moratis A, Valika S, Rahman A, Malalis W, Box E, Box P, Kerwood B, Nagaeva J, Metz C, Hinnant J, Griswell D, Philbeck A, Dukkipati R, Shaarawy R, Patak R, Kaye W, Steinsapir J, Horowitz B, Denenberg M, Reynolds C, Jenkinsdr M, Adlakha A, Hicklin H, Peelman J, Lerman S, Lamkin S, Smith S, Gould G, Cheung D, Stephen Z, Leigh T, Norwood P, Chelsea F, Trejo R, Neolms K, Bache R, Dinnerstein A, Sachson R, Aronoff S, Mendez A, Brooks S, Jones L, Dorfman S, Schill J, Leuck, Miklius A, Maw K, Hahn J, Gamarra L, Buynak R, Smith M, Ames J, Volom P, Anderson R, Desouza C, Shivaswamy V, Lefebvre G, Schweppe L, Berenguer R, Nelson R, Mas L, Gonzalez N, Palacio J, Bartkowiak A, Dilling J, Jordan T, Geishauser J, Jordan R, Arias E, Griffin C, Fisher M, Bryant C, Schnitz W, Kipgen W, Kasper J, Lopez R, Wright E, Thomas J, Weinstein D, Emerick G, Mendelson R, Aqua K, Lafaille J, Seco G, Garcia G, Cubillas M, de Souza J, Schneider A, Tjaden J, Goswami G, Schubart U, Kishore P, Bravo W, Guerrero J, Bertoli-Avella M, Reyes C, Dominguez M, Ramos S, Columbie A, Ares-Romero P, Hechavarria J, Villaverde M, Doyle N, Sherrod T, Krishnaswamy K, Aamir S, Giddaluri P, Guevara S, Kazmi P, Thomas P, Popeil L, Albright D, Pimentel S, Mould E, Cox M, Alderson T, Conrow J, Sandberg J, Raam S, Suresh B, Lafave J, Lorenz T, Johnston J, Fereidouni S, Mahadevan A, West R, Nelson A, Scott K, Ansari S, Khan B, Rastogi A, Saumell F, Gonzalez G, Torres E, Elias R, Hart T, Lozano J, Gudavilla G, Savin V, Khan A, Wiegmann T, Goel A, Gomes M, Fernandez-Gonzalez M, Gustavo F, Ivan C, Chiong R, Llerena S, Jimenez M, Oram D, George D, Lewis J, Kiefer J, Dollman A, Edje L, Pastor F, Kandath D, Lorch D, Graves A, Powell R, Hooker T, Shah S, Gomez N, Miranda F, Rosales J, Bayona I, Gomez Y, Guedes R, Rodriguez Y, Wahlen J, Jonathan W, Spencer H, Michael W, Kumar U, Govindariju K, Ordonez S, Aguirre H, Sulur P, Agarwal N, Peters L, Kaviani B, Fomenko O, Firek A, Loreen W, Ronald F, Olha F, Parrillo J, Janovitz R, Hutchinson R, Delgado E, Ashley A, Robinson S, Barbel-Johnson K, Timothy L, William C, Al-Karadsheh A, Hooper L, Suarez J, Perez D, Guerrero V, Tung D, Loo C, Sodolak K, Michaelis C, Jackson R, Covington D, Wise J, Tran T, Messina T, Torres D, Falcone J, Barettella M, Patel K, Ribo A, Mattews T, Amendolare D, McGeehan J, Corder C, Black C, Hearne S, Bounds C, Cinderella J, Etherton J, Kiem S, Treuth M, Burke B, Tivikaran V, Howard S, Miller C, Neff H, Giullian J, Mcrae J, Surratt D, Phillips J, Kretchmar J, Valdes M, Cruz J, Navarro E, Zewail A, Tai-Chi-Kwo, Stevens J, Diane S, Kim T, Gregory L, Neal S, William S, Sangrigoli R, Gejer E, Stoller S, Jeffrey D, Colar S, Kenneth W, Farris N, Mooney S, Jamal A, Nitin B, Syed R, Andrew Y, Christopher W, Abid R, Claudio G, Mojtaba M, Amna R, Michael B, Vincent T, Cherlin R, Ashton R, Pudi K, Julian W, Stephen K, Ronald A, Frias J, Kelly S, Hsia S, Clemens P, Cara H, Farley B, Raible L, Oliveros O, Hafeez H, Pecci P, Bagga-Malhotra S, Reza R, Jamal M, Mulgado M, Guevara A, Vela M, Ochoa H, Melliza T, Pena G, Awua-Larbi S, Shafi M, Alausa T, Polster S, Earl J, McNeill R, Farrington C, Carr K, Nabat M, Matthew S, Yvette E, Handelsman Y, Delkhah S, Ismail Y, Janna C, Akhtar A, Neiman A, Blumenthal S, Colleen V, Schmidt D, Ashraf E, Bhargava A, Khoo T, Langel C, Theuma P, Wright D, Fitzgerald K, Hitchcock J, Capasso-Gulve E, Wolff E, Umpierrez G, Priyathama V, Francisco P, Dawn S, Quraishi A, Kahn B, Ferro F, Hertz B, Phelps J, Campbell A, Downing J, Pangtay D, Pangatay S, Villagran-Solis K, Haseeb M, Rettig K, Kwan R, Cox R, Slimak V, So A, Schmedtje J, Chang A, Douglas Z, McGarity W, Jestel J, Kanade P, Julie J, Asher R, Canaan Y, Perez A, Alonso I, Cutchin R, Koser A, Adeola Y, Brito S, Stocks J, Frandsen B, Weigelt M, Stehouwer E, Ince C, Stephen P, Shadi B, Jeffrey C, Thethi T, Carpio G, McDuffie R, Moreau C, Stell C, Katalenich B, McKendall-Lewis C, Htun W, Conroy K, Lovre D, Galagan R, Olmeda C, Sihota A, Barton A, Beasley R, Nankivel P, Aberle M, Machin I, Porras J, Rodriguez D, Albornoz A, Haidar A, Lopez-Santini R, Rivero G, Robins G, Colyar L, Hutchins C, Sturm D, Hart K, Phillips T, Montgomery C, Albrecht W, Fehlis K, Overman D, Box M, Villarreal-Martinez D, David-Svatek D, Ajani D, Shaikh Z, Wheeler K, Brown M, Ghosh C, Bandukwala I, Kleber S, Madden J, Bishara M, Perry K, Paoli-Bruno J, Abreu E, Espiritu R, Zmeili O, Christensen T, Grubb S, Beloff S, Caugh A, van Dijk C, Yalavarthy R, DeGraauw J, Fabian S, Gillum D, Corrigan G, Singh H, Jensen K, DeMore S, Montague T, Zieve F, Levy J, Fredrickson S, Tarkington P, Chapla P, Salacata A, Walls U, Iyer R, Nguyen K, Lettman J, Appleman B, Safavie F, Scaliem L, Eder F, Maklad S, Schlaen B, Molstead J, Hartwell J, Hubish D, Little R, Rando K, Kelly R, Drury M, Young P, Wininger S, Harman A, Daza R, Robbin S, Sanchez M, Rivera I, Garcia-Estrada M, Iglesias N, Dobs A, Andrade A, Falkowski S, Parrott T, Koon A, Wood T, Burkett E, Chavous K, Gupta A, Estes C, Loud D, Rhodes S, Chen M, Bromley L, Palma R, Kattan D, Kirk U, Tatu H, Stamatin R, Lupea S, Frasie M, Colfer H, Kane L, Teklinski A, Gadowski G, Levanovich P, Saba F, Confident L, Hossain S, Steinberg B, Philippe B, Choroenthkongtrakal S, Boccalano F, Anand R, Syam V, Manohar A, Suresh P, Madhusudhan P, Patel P, Cambier P, Klonaris J, Cheng W, Fisher S, Schelle M, Reese L, McLean S, Poock J, Hoens J, Rosie A, Welshons R, Dean J, Kuhlman P, Luke R, Lohrbauer L, Cunningham M, Buday P, Lehmann M, Chrzanowski K, Fletcher A, Hargrove J, Harris F, Debs-Perez G, Maiquez A, Cordoves L, Georgescu M, Tayoun H, Munoz F, Ortiz D, Munoz G, Hamzeh I, Misra A, Zhang L, Forgosh L, Loria K, Roncari C, Hommerding J, Morris G, Lebron C, Blake K, LaVenture K, Lange C, Levinson L, Baungarten T, Edevante S, Shawley S, Moyer H, Elliott K, Iachini K, Rajan R, Davis C, Shattuck A, Simon W, Lakin G, Secrist N, Buth D, Steere D, Talbot K, Singh N, Mascolo R, Sloan S, Kmetzo J, Brown J, Carter L, Lawrence M, Arauz-Pacheco C, Lender D, Kozlow W, Cavanaugh L, Wilson J, Gujja P, Akhter F, Khan M, Mohammed A, Satyavolu S, Dev D, Yalamanchili H, Sumeyye C, Fernandes H, Chaleff F, Jancko M, Trenche S, Kaplan W, Wilcox S, Goisse M, Rua M, Black J, Chapman K, Suh D, Yan L, Song D, Chanara S, Houchin V, McKeinness A, Sotolongo R, Gutierrez K, Miranda-Palma B, Solano M, Jain M, Needell J, Banerjee A, Jarratt M, Hantel S, Lees K, Welty F, Freedman S, Parhofer K, Birkeland K, McGill J, Tijssen J, Clemmensen P, Pehrson S, Grande P, Januzzi J, Wood M, Petrie M, Sairanen T, Tatlisumak T, Soinne L, Kase C, Turan T, Mann J, Agarwal R, Fogarty D, Navaneethan S, Srinivas T, Forsmark C, Frossard J, Gelrud A, Mayerle J, Lee R, Heist R, Sullivan R, Buchbinder E, Chodak G, Edelman M, Thompson V, Coles A, and CARMELINA Investigators
- Abstract
IMPORTANCE Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. OBJECTIVE To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A(1c) of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] > 200mg/g), and high renal risk (reduced eGFR and micro-or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. INTERVENTIONS Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. MAIN OUTCOMES AND MEASURES Primary outcomewas time to first occurrence of the composite of CV death, nonfatalmyocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. RESULTS Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73m2; 80.1% with UACR > 30mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI,-0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P
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- 2019
5. Description of Ovariectomy Protocol in Mice
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Vanessa R, Souza, Eduardo, Mendes, Mateus, Casaro, Ana Tada F B, Antiorio, Fernando A, Oliveira, and Caroline M, Ferreira
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Disease Models, Animal ,Mice ,Ovariectomy ,Ovary ,Animals ,Humans ,Estrogens ,Female ,Menopause - Abstract
Estrogen and ovarian function decline are relevant characteristics of menopause period. Numerous physiological, metabolic and immunological alterations in the female body occur in the menopause period and some of these changes remain uncertain. The animal model that mimics menopause phase is an important approach to better comprehend the biological process involved in this period of women life. Ovariectomy is a procedure where ovaries are surgically excised and have been a valuable tool for understanding estrogen deficiency through animal experiments. Despite the diversity of ovariectomy protocols, the aim of this chapter is to provide a comprehensive guideline in performing ovariectomy in mice. Furthermore, isoflurane anesthesia system, postoperative care and surgery success evaluation will be described. We highlight that all procedures must be carried out by a qualified and trained professional, respecting ethical and safety principles.
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- 2018
6. Antiemetic efficacy of combined aprepitant and dexamethasone in patients at high-risk of postoperative nausea and vomiting from epidural fentanyl analgesia
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Hiroaki Kawano, Matsumoto T, Hamaguchi E, Manabe S, Nakagawa M, Yamada A, Fujimoto M, and Tada F
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Morpholines ,Middle Aged ,Dexamethasone ,Analgesia, Epidural ,Analgesics, Opioid ,Fentanyl ,Osteoarthritis ,Postoperative Nausea and Vomiting ,Antiemetics ,Humans ,Female ,Knee ,Aprepitant ,Aged - Abstract
Postoperative opioid analgesia increases the incidence of postoperative nausea and vomiting (PONV). We investigated whether a combination of the neurokinin-1 antagonist aprepitant and dexamethasone decreases PONV incidence compared with dexamethasone alone in high-risk patients receiving continuous epidural fentanyl.Sixty nonsmoking female patients scheduled for elective knee osteoarthritis surgery were randomly allocated to receive oral aprepitant 80 mg (aprepitant+dexamethasone group, N.=30) 2 h before anesthesia induction or no oral aprepitant (dexamethasone group, N.=30). All patients received intravenous dexamethasone 8 mg immediately before anesthesia induction. Anesthesia was maintained with remifentanil and sevoflurane. Continuous infusion of epidural analgesia, including fentanyl, was provided during and after surgery. We assessed complete response (no PONV and no rescue antiemetic use), incidence of nausea and vomiting, nausea severity scale, vomiting frequency, rescue antiemetic use, and postoperative pain at 2 and 24 h after surgery.The cumulative incidence of vomiting at 24 h was 3% in the aprepitant+dexamethasone group and 27% in the dexamethasone group (P=0.011). The incidence and frequency of vomiting in the late postoperative period was also significantly lower in the aprepitant+dexamethasone group than in the dexamethasone group. However, there were no significant group differences in the proportion of patients who experienced a complete response, the incidence and severity of nausea, and rescue antiemetic use at 24 h.The combination of aprepitant and dexamethasone was more effective in preventing postoperative vomiting compared with dexamethasone alone in patients at high-risk of PONV from continuous epidural fentanyl analgesia.
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- 2014
7. Calculation of NMR chemical shifts. IV. Hydronium and hydroxyl ions.
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Fukui, H., Miura, K., and Tada, F.
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- 1983
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8. P547 LOCAL RECURRENCE IN THE TUMOR BLOOD DRAINAGE AREA AFTER RADIOFREQUENCY ABLATION
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Hirooka, M., primary, Ochi, H., additional, Koizumi, Y., additional, Hiraoka, A., additional, Tada, F., additional, Miyake, T., additional, Tokumoto, Y., additional, Abe, M., additional, and Hiasa, Y., additional
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- 2014
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9. P802 PORTAL HYPERTENSION DUE TO OUTFLOW BLOCK IN NON-CIRRHOTIC PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE
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Koizumi, Y., primary, Hirooka, M., additional, Ochi, H., additional, Tada, F., additional, Miyake, T., additional, Tokumoto, Y., additional, Hiraoka, A., additional, Abe, M., additional, Matsuura, B., additional, and Hiasa, Y., additional
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- 2014
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10. Ipragliflozin ameliorates liver damage in non-alcoholic fatty liver disease
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Miyake Teruki, Yoshida Sakiko, Furukawa Shinya, Sakai Takenori, Tada Fujimasa, Senba Hidenori, Yamamoto Shin, Koizumi Yohei, Yoshida Osamu, Hirooka Masashi, Kumagi Teru, Niiya Tetsuju, Miyaoka Hiroaki, Masanori Abe, Matsuura Bunzo, and Hiasa Yoichi
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selective sodium-glucose cotransporter-2 inhibitor ,ipragliflozin ,type 2 diabetes mellitus ,non-alcoholic steatohepatitis ,non-alcoholic fatty liver disease ,Medicine - Abstract
There are few effective medications for non-alcoholic steatohepatitis (NASH). We investigated the efficacy of ipragliflozin (selective sodium-glucose cotransporter-2 inhibitor [SGLT2I]) for the treatment of patients with type 2 diabetes mellitus (T2DM) complicated by non-alcoholic fatty liver disease (NAFLD).
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- 2018
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11. EFFECTS OF DILTIAZEM ON VENTRICULO-ARTERIAL COUPLING IN HUMANS
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Oshita, S, primary, Kaieda, R, additional, Funatsu, N, additional, Kitahata, H, additional, Tada, F, additional, and Kinoshita, Y, additional
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- 1998
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12. A540 NOREPINEPHRINE POTENTIATES, BUT LOWERING TEMPERATURE OF THE SUPERFUSATE ATTENUATES ISCHEMIA-INDUCED INCREASES IN CYTOSOLIC CALCIUM CONCENTRATIONS
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Oshita, S., primary, Park, Y.-C., additional, Kitahata, H., additional, Kimura, H., additional, and Tada, F., additional
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- 1997
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13. Design And Synthesis Of Array Structured Telecommunication Processing Applications.
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Meyer, W., Seawright, A., and Tada, F.
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- 1997
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14. The analysis of relay control systems with coloured noise inputs.
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AKIZUKI, K. and TADA, F.
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- 1977
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15. Computation of the index of pollution caused by heavy metals in river sediment
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Nishida, H., primary, Miyai, M., additional, Tada, F., additional, and Suzuki, S., additional
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- 1982
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16. ChemInform Abstract: ISOQUINOLINES PART 1, PREPARATION AND STEREOCHEMISTRY OF 9,10-EPOXY-1-(P-METHOXYBENZYL)-2-METHYLDECAHYDROISOQUINOLINES
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ONDA, M., primary, SUGAMA, Y., additional, YOKOYAMA, H., additional, and TADA, F., additional
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- 1974
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17. Fault Scarp by Reverse Faulting
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Tada, F., primary
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- 1930
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18. Sand dunes along the middle course of Tone river
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Tada, F., primary
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- 1947
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19. A study of regional differences in flood-types : an example of applied geography
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Tada, F., primary and Oya, M., additional
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- 1971
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20. Abrasion Terraces of the South Sea Islands
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Tada, F., primary
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- 1926
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21. On the Topography of Chino Mongolian Frontier Regions
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Tada, F., primary
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- 1925
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22. Significance of Longitudinal Profiles of the River Kitsu and its Tributaries on the Migrations of their River Courses
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Tada, F., primary
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- 1929
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23. Sand dunes formed by Wind Erosion
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Tada, F., primary
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- 1948
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24. Applied Geography
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Tada, F., primary and Nakano, T., additional
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- 1953
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25. Morphology of Ensyûnada Coast near Yokosuka
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Tada, F., primary
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- 1943
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26. Design And Synthesis Of Array Structured Telecommunication Processing Applications
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Meyer, W., primary, Seawright, A., additional, and Tada, F., additional
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27. Predictive factors and survival outcome of conversion therapy for unresectable hepatocellular carcinoma patients receiving atezolizumab and bevacizumab: Comparative analysis of conversion, partial response and complete response patients.
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Hatanaka T, Kakizaki S, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Toyoda H, Ogawa C, Nishikawa H, Nishimura T, Kawata K, Kosaka H, Naganuma A, Yata Y, Ohama H, Kuroda H, Matono T, Aoki T, Kanayama Y, Tanaka K, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Nakamura S, Enomoto H, Kaibori M, Hiasa Y, Kudo M, and Kumada T
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Prognosis, Adult, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular mortality, Liver Neoplasms drug therapy, Liver Neoplasms mortality, Bevacizumab therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use
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Aim: This study aims to investigate the predictive factors for conversion therapy in patients with unresectable hepatocellular carcinoma (uHCC) and to evaluate the prognosis of conversion cases by comparing them with partial response (PR) and complete response (CR) cases., Methods: In this retrospective multicentre study, we included a total of 946 uHCC patients treated with atezolizumab and bevacizumab (Atez/Bev) from September 2020 to September 2023., Results: Out of the patients, 43 (4.5%) received conversion therapy following Atez/Bev treatment. The overall response rate was 65.1% and 23.7% in the conversion and non-conversion group, respectively, with a statistical significance (p < 0.001). Multivariate analyses identified that BCLC stage B or an earlier stage (p = 0.045), absence of macrovascular invasion and extrahepatic spread (p = 0.045), and a low value of neutrophil to lymphocyte ratio (p = 0.04) were significantly favourable predictive factors associated with conversion therapy. The conversion group showed significantly better survival compared to the non-conversion group (p < 0.001). In the landmark analysis at 6, 12 and 18 months, the conversion group exhibited better survival compared to PR patients in the non-conversion group (p = 0.04, 0.01 and 0.03, respectively) and there were no significant differences in the overall survival (OS) between the conversion group and patients who achieved a CR (p = 0.7, 1.0 and 0.3, respectively)., Conclusions: Patients with low tumour burden and low value of NLR were more likely to undergo conversion therapy. The OS of patients undergoing conversion therapy showed better survival compared to those achieving PR and was comparable to those with CR patients. Conversion therapy could be considered if feasible., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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28. Brief intervention for chronic liver disease patients with alcohol use disorder in a hepatology outpatient unit: Effects and limitations.
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Hara N, Hiraoka A, Nakai M, Shiraki M, Namisaki T, Miyaaki H, Hisanaga T, Takahashi H, Ohama H, Tada F, Sakamoto N, Nakao K, Takami T, Eguchi Y, and Yoshiji H
- Abstract
Aim: It is not uncommon to encounter outpatients in the hepatology department with harmful alcohol habits. When treating such chronic liver disease (CLD) patients, an adequate intervention method for harm reduction of alcohol use, such as brief intervention (BI) or BI and nalmefene, should be considered. This study aimed to elucidate the clinical effectiveness of BI for CLD patients affected by harmful alcohol use., Methods: From June 2021 to 2023, 123 Japanese CLD outpatients (hepatitis B virus : hepatitis C virus : alcoholic liver disease : others = 32:18:42:31) with an Alcohol Use Disorders Identification Test (AUDIT) score of ≥8 at the initial interview and a repeat interview with AUDIT 9 months later were enrolled. Clinical features related to patient behavior following the initial AUDIT interview were retrospectively evaluated, and compared between patients without and with BI treatment., Results: For the non-BI and BI groups, baseline AUDIT score (median 10 [interquartile range (IQR) 9-13] vs. 12 [IQR 10-17], p = 0.016) and relative change in AUDIT score (median 0 [IQR -3 to 2] vs. -3 [IQR -7 to 0], p < 0.01) showed significant differences, whereas there was no significant difference between the groups for AUDIT score at the time of the second interview (p = 0.156). Following BI, significant improvements were observed for items 1, 2, 3, 4, 5, 8, and 10 of AUDIT (each p < 0.05)., Conclusion: Patients with an alcohol use disorder as well as those with alcohol dependency who received BI showed a significant decline in AUDIT score, although the score of the follow-up AUDIT indicated continued alcohol use disorder. In addition to BI, medication with nalmefene should be considered, based on individual factors., (© 2024 Japan Society of Hepatology.)
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- 2024
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29. Lenvatinib versus Sorafenib Second-Line Therapy in Patients with Hepatocellular Carcinoma Progressed to Atezolizumab plus Bevacizumab: A Retrospective Real-World Study.
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Persano M, Casadei-Gardini A, Tada T, Suda G, Shimose S, Kudo M, Rossari F, Yoo C, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Bergamo F, Amadeo E, Vitiello F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Iavarone MA, Cabibbo G, Montes M, Foschi FG, Vivaldi C, Soldà C, Sho T, Niizeki T, Nishida N, Steup C, Bruccoleri M, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Hiraoka A, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Mascia L, Foti S, Camera S, Piscaglia F, Scartozzi M, Cascinu S, and Rimini M
- Abstract
Introduction: The most frequently used first-line treatment in patients with advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab. Upon progression after this treatment, the standard of care in many countries is sorafenib, due to the lack of reimbursement for other drugs. Several randomized trials are currently underway to clarify the best second-line therapy in patients with HCC. This real-world study aimed to compare outcomes reached by lenvatinib and sorafenib second-line therapy in this setting., Methods: The overall cohort included 891 patients with HCC from 5 countries treated with atezolizumab plus bevacizumab in first-line setting between October 2018 and April 2022. At the data cut-off (May 2022), 41.5% of patients were continuing a first-line treatment, 5.5% were lost at follow-up, and 53.0% of patients had progressive disease after first-line therapy. 51.5% of patients with progressive disease received a second-line treatment, while 48.5% did not receive any subsequent therapy. Between patients receiving second-line treatment, 11.1% of patients underwent transarterial chemoembolization, 21.0% received sorafenib, 35.4% underwent lenvatinib, and 32.5% were treated with other drugs., Results: Lenvatinib second-line subgroup achieved a median overall survival (mOS) of 18.9 months, significative longer (p = 0.01; hazard ratio [HR]: 2.24) compared to sorafenib subgroup that reached a mOS of 14.3 months. The multivariate analysis highlighted albumin-bilirubin 1 grade (p < 0.01; HR: 5.23) and lenvatinib second-line therapy (p = 0.01; HR: 2.18) as positive prognostic factors for OS. The forest plot highlighted a positive trend in terms of OS in favor of patients treated with lenvatinib second-line regardless of baseline characteristics before first-line therapy., Conclusion: These results suggest that, in patients with HCC progressed to first-line atezolizumab plus bevacizumab, lenvatinib second-line therapy is associated to an improved survival compared to sorafenib., (© 2024 S. Karger AG, Basel.)
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- 2024
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30. Correction: Clinical features of patients with hepatocellular carcinoma treated with radiofrequency ablation therapy: developing a simple score to determine the need for immune-adjuvant therapy.
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Tada F, Hiraoka A, Nakatani K, Matsuoka K, Fukumoto M, Matsuda T, Yanagihara E, Saneto H, Murakami T, Onishi K, Izumoto H, Kitahata S, Kanemitsu-Okada K, Kawamura T, Kuroda T, Hanaoka J, Watanabe J, Ohtani H, Yoshida O, Hirooka M, Miyata H, Tsubouchi E, Abe M, Matsuura B, Ninomiya T, and Hiasa Y
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- 2024
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31. Development of a Scoring System for Predicting the Difficulty of Bile Duct Cannulation and Selecting the Appropriate Cannulation Method.
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Kuroda T, Miyata H, Kanemitsu-Okada K, Yanagihara E, Saneto H, Murakami T, Izumoto H, Onishi K, Kitahata S, Kawamura T, Iwasaki R, Tada F, Tsubouchi E, Hiraoka A, and Ninomiya T
- Abstract
Background: Selective biliary cannulation in endoscopic retrograde cholangiopancreatography can be challenging due to factors like papillary morphology. Various patterns indicate cannulation difficulty, but the combinations causing difficulty and the optimal cannulation method for each scenario are unclear., Aims: This study aimed to identify cannulation difficulty patterns and develop a predictive scoring system for selecting the appropriate cannulation method., Methods: We retrospectively compared 776 patients with naïve papilla, dividing them into conventional contrast cannulation (N = 510) and salvage technique (N = 266) groups. The salvage group included patients using pancreatic duct guidewire placement and/or wire-guided cannulation due to difficulties with the contrast method. Papillary morphology (Haraldsson's classification), periampullary diverticulum (PAD), and scope operability were analyzed using multiple regression to identify risk factors for cannulation difficulties. Factors were scored based on hazard ratios to access combinations causing difficulties., Results: The salvage group had more older patients and higher frequencies of type 2 (small), type 3 (protruding or pendulous), type 4 (creased or ridged) papillae, PAD, and poor scope operability. Significant risk factors in the multivariate analysis included type 2 [odds ratio (OR) 6.88], type 3 (OR 7.74), type 4 (OR 4.06) papillae, PAD (OR 2.26), and poor scope operability (OR 4.03). Pattern recognition scores were significantly higher in the salvage group (1.31 vs. 3.43, P < 0.0001)., Conclusions: Type 2-4 papillae, PAD, and poor scope operability are significant risk factors for cannulation difficulty. Pattern recognition scores based on these factors can predict cannulation difficulty and aid in selecting between conventional and salvage methods., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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32. Factors Affecting an Increase in Spleen Volume and Association of Spleen Volume Variation with the Clinical Outcomes of Atezolizumab and Bevacizumab Treatment for Hepatocellular Carcinoma: A Retrospective Analysis.
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Hatanaka T, Saito N, Kakizaki S, Hiraoka A, Tada T, Kariyama K, Tani J, Takaguchi K, Itobayashi E, Ishikawa T, Toyoda H, Kawata K, Naganuma A, Yata Y, Ohama H, Matono T, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Nakamura S, and Kumada T
- Abstract
Introduction: Gastrointestinal varices rupture is considered to be prone to occur during atezolizumab and bevacizumab (Atez/Bev) treatment. This study aimed to investigate predictive factors affecting the increase in spleen volume (SpV) and the association of SpV variation with the clinical outcomes of Atez/Bev., Methods: A total of 164 HCC patients were included in this retrospective multicenter study. We measured SpV based on CT scans obtained before treatment and at evaluations. We used the inverse probability of treatment weight to address the imbalance between patient characteristics., Results: The median pretreatment SpV was 184 (130-257) cm3 and the median SpV variation was 27 (9-60) cm3. An increase in the SpV was observed in 140 patients (85.4%). Age <74 years (p = 0.03), mALBI grade 2b or 3 (p = 0.03), and pretreatment SpV ≥184 cm3 (p < 0.001) were significantly associated with increased SpV. There were no significant differences in progression-free survival (PFS) or overall survival (OS) between patients with SpV variation <25 cm3 and those with SpV variation ≥25 cm3 in the crude (p = 0.3 and 0.7) and IPTW-weighted cohorts (p = 0.08 and 0.8, respectively). Regarding pretreatment SpV, there were no significant differences in PFS or OS between patients with and without pretreatment spleen enlargement in the crude (both p = 0.3) and IPTW-weighted cohort (p = 0.6 and 0.3, respectively)., Conclusion: Caution is warranted to detect the aggravation of portal hypertension when administering Atez/Bev to young patients or patients with an impaired liver function or pretreatment spleen enlargement. The impact of spleen modulation by Atez/Bev appears to be limited on clinical efficacy., (© 2024 S. Karger AG, Basel.)
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- 2024
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33. Changes in characteristics of gastroenterology center inpatients in Japan because of rapidly aging society.
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Fukunishi Y, Hiraoka A, Tada F, Fukumoto M, Matsuda T, Matsuoka K, Nakatani K, Yanagihara E, Saneto H, Izumoto H, Murakami T, Onishi K, Kitahata S, Kanemitsu-Okada K, Kawamura T, Kuroda T, Miyata H, Tsubouchi E, Hanaoka J, Watanabe J, Ohtani H, Yoshida O, Hirooka M, Abe M, Matsuura B, Ninomiya T, and Hiasa Y
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- Humans, Japan epidemiology, Aged, Retrospective Studies, Male, Female, Aged, 80 and over, Middle Aged, Aging, Liver Diseases epidemiology, Liver Diseases therapy, Liver Diseases diagnosis, Biliary Tract Diseases epidemiology, Biliary Tract Diseases therapy, Gastrointestinal Diseases epidemiology, Gastrointestinal Diseases therapy, Gastrointestinal Diseases diagnosis, Hospitalization statistics & numerical data, Time Factors, Age Factors, Adult, Pancreatic Diseases epidemiology, Pancreatic Diseases therapy, Inpatients statistics & numerical data, Gastroenterology statistics & numerical data, Gastroenterology trends
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Background and Aim: Rapidly aging societies have become a major issue worldwide including Japan. This study aimed to elucidate relative changes in the characteristics of inpatients in Japan related to this issue., Methods: A total of 23 835 Japanese inpatients treated from 2010 to 2021 were enrolled (2010-2013, period I; 2014-2017, period II; 2018-2021, period III). Changes in clinical features were retrospectively analyzed based on ICD-10 diagnosis data., Results: The percentage of patients aged over 75 years increased over time (period I, 38.0%; II, 39.5%, III, 41.4%). Emergency admissions comprised 27.5% of all in period I, which increased to 43.2% in period II and again to 44.5% in period III (P < 0.001). In period I, gastrointestinal disease, liver disease, pancreatic-biliary disease, and other disease types were noted in 47.4%, 29.5%, 19.2%, and 3.9%, respectively, while those values were 44.0%, 18.0%, 33.9%, and 4.1%, respectively, in period III (P < 0.001). The frequency of liver disease decreased by approximately 0.6-fold from periods I to III, while that of biliary-pancreatic disease increased by approximately 1.8-fold during that time. Both percentage and actual numbers of patients with biliary-pancreatic disease increased during the examined periods. Analysis of changes in the proportion of organs affected by malignancy during periods I, II, and III showed a marked increase in cases of biliary-pancreatic malignancy (11.6%, 19.5%, 26.6%, respectively) (P < 0.001)., Conclusion: In association with the rapidly aging Japanese society, there has been an increasing frequency of biliary-pancreatic disease cases requiring hospitalization for treatment in the west Japan region of Shikoku., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
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- 2024
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34. Outcomes of patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab in real-world clinical practice who met or did not meet the inclusion criteria for the phase 3 IMbrave150 trial.
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Tada T, Kumada T, Hiraoka A, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Nishikawa H, Tsuji K, Ishikawa T, Tajiri K, Koshiyama Y, Toyoda H, Ogawa C, Hatanaka T, Kakizaki S, Kawata K, Ohama H, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Nishimura T, Imai M, Kosaka H, Naganuma A, Matono T, Aoki T, Kuroda H, Yata Y, Koizumi Y, Nakamura S, Enomoto H, Kaibori M, Hiasa Y, and Kudo M
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- Humans, Male, Female, Middle Aged, Aged, Treatment Outcome, Progression-Free Survival, Adult, Liver Neoplasms drug therapy, Liver Neoplasms mortality, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular mortality, Bevacizumab therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use
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Background: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC)., Aims: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real-world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial., Methods: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non-IMbrave150 group)., Results: Median progression-free survival (PFS) in the IMbrave150 and non-IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non-B, non-C HCC aetiology (hazard ratio [HR], 1.173), α-fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin-bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non-Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α-fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a., Conclusions: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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35. Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents.
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Ohama H, Hiraoka A, Tada T, Kariyama K, Itobayashi E, Tsuji K, Ishikawa T, Toyoda H, Hatanaka T, Kakizaki S, Naganuma A, Tada F, Tanaka H, Nakamura S, Nouso K, Tanaka K, and Kumada T
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- Aged, Female, Humans, Male, Middle Aged, Age Factors, East Asian People, Hepacivirus, Japan, Prognosis, Retrospective Studies, Survival Rate, Treatment Outcome, Antiviral Agents therapeutic use, Carcinoma, Hepatocellular virology, Carcinoma, Hepatocellular mortality, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic complications, Liver Neoplasms virology, Liver Neoplasms mortality, Sustained Virologic Response
- Abstract
Background and Aim: Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development., Methods: A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n = 1169) and post-DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed., Results: Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 10
4 /μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P < 0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P < 0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P = 1.0)., Conclusion: The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)- Published
- 2024
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36. Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab.
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Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Rossari F, Yoo C, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Bergamo F, Amadeo E, Vitiello F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Iavarone MA, Cabibbo G, Montes M, Foschi FG, Vivaldi C, Soldà C, Sho T, Niizeki T, Nishida N, Steup C, Bruccoleri M, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Hiraoka A, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Foti S, Camera S, Piscaglia F, Scartozzi M, Cascinu S, and Casadei-Gardini A
- Subjects
- Humans, Male, Female, Retrospective Studies, Aged, Middle Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Aged, 80 and over, Adult, Prognosis, Bevacizumab therapeutic use, Bevacizumab pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized adverse effects, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular pathology
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Background: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors., Objective: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting., Patients and Methods: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea)., Results: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival., Conclusions: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab., (© 2024. The Author(s).)
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- 2024
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37. Clinical features of patients with hepatocellular carcinoma treated with radiofrequency ablation therapy: developing a simple score to determine the need for immune-adjuvant therapy.
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Tada F, Hiraoka A, Nakatani K, Matsuoka K, Fukumoto M, Matsuda T, Yanagihara E, Saneto H, Murakami T, Onishi K, Izumoto H, Kitahata S, Kanemitsu-Okada K, Kawamura T, Kuroda T, Hanaoka J, Watanabe J, Ohtani H, Yoshida O, Hirooka M, Miyata H, Tsubouchi E, Abe M, Matsuura B, Ninomiya T, and Hiasa Y
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- Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Chemotherapy, Adjuvant, Risk Factors, Aged, 80 and over, Carcinoma, Hepatocellular therapy, Carcinoma, Hepatocellular surgery, Carcinoma, Hepatocellular pathology, Liver Neoplasms therapy, Liver Neoplasms pathology, Liver Neoplasms surgery, Neoplasm Recurrence, Local, Radiofrequency Ablation
- Abstract
Background/aim: Unresectable recurrence after curative treatments for hepatocellular carcinoma (HCC) is a life-limited event. Although the IMbrave050 trial (IM050) showed a favorable reduction in recurrence with adjuvant immune-combination chemotherapy, inclusion criteria of the radiofrequency ablation (RFA) group were lower risk than that of the resection group. This study aimed to elucidate the clinical features of patients treated with RFA, which really need adjuvant-chemotherapy., Methods: From 2000 to 2022, 528 patients with Child-Pugh A and HCC within the Milan criteria (MC), who met the IM050 criteria for RFA and undergone resection or RFA, were enrolled (71 years, HCV:HBV:HBV/HCV:alcohol:others = 337:44:5:53:89, multi-tumor = 138, RFA:resection = 309:219). Unresectable recurrence was defined as beyond the MC. Risk factors for recurrence beyond the MC were retrospectively evaluated., Results: Multivariate Cox-hazard analysis showed HCV-positive (HR 1.49), AFP-L3 > 10% (HR 1.75), and DCP > 100 mAU/mL (HR1.80) as significant prognostic factors for recurrence beyond the MC (each P < 0.05). Summing of positive factors (1 point for each) was used for scoring (AD-ON score), which showed increased positive rates for micro-hepatic vein invasion (score 0:1:2:3 = 0%:1.1%:6.6%:15.8%), micro-portal vein invasion (0:1:2:3 = 2.0%:12.1%:14.1%:31.6%), and poor differentiation (0:1:2:3 = 6.0%:6.7%:15.3%:15.8%) in the resection group associated with a greater score (each P < 0.01). In patients treated with RFA, those with greater AD-ON scores showed shorter time to recurrence beyond the MC, recurrence-free time, and overall survival (score 0:1:2:3 = no-estimation:97:66:23 months, 35:27:20:12 months, and 91:82:67:52 months, respectively, each P < 0.05)., Conclusion: HCC patients treated by RFA and with a high AD-ON score (≧2) should be considered for aggressive adjuvant-chemotherapy to prolong the period of recurrence beyond the MC., (© 2024. Japanese Society of Gastroenterology.)
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- 2024
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38. mADRES predicts hepatocellular carcinoma development in patients with hepatitis C virus who achieved sustained virological response.
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Tada T, Kumada T, Hiraoka A, Kariyama K, Yasuda S, Tada F, Ohama H, Nouso K, Matono T, Nakamura S, and Toyoda H
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- Humans, Male, Female, Middle Aged, Aged, Proportional Hazards Models, Predictive Value of Tests, Sex Factors, Carcinoma, Hepatocellular virology, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular epidemiology, Liver Neoplasms virology, Liver Neoplasms etiology, Liver Neoplasms epidemiology, Sustained Virologic Response, alpha-Fetoproteins analysis, alpha-Fetoproteins metabolism, Antiviral Agents therapeutic use, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic complications
- Abstract
Background and Aim: The study aims to develop a novel predictive model including the fibrosis (FIB)-3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct-acting antiviral (DAA) therapy., Methods: This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB-4 index was replaced by the FIB-3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score., Results: In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48-3.01), FIB-3 index (HR, 1.36; 95% CI, 1.28-1.45), and α-fetoprotein (HR, 1.05; 95% CI, 1.03-1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02-4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80-22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17-47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759)., Conclusion: The mADRES score is useful for predicting HCC development after SVR., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)
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- 2024
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39. C-reactive Protein-to-Albumin Ratio: A Useful Predictor for Biliary Fistula After Hepatectomy.
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Utsunomiya T, Watanabe J, Tokuda K, Ueno Y, Hanaoka J, Yagi S, Tada F, Hiraoka A, Ninomiya T, and Ohtani H
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Introduction Postoperative bile leakage (POBL) has emerged as a complication following hepatectomy. POBL is associated with an elevated risk of liver failure and surgical death. This study aimed to examine risk factors for POBL in primary hepatocellular carcinoma (HCC) patients. Methods A total of 296 patients who had surgical resection for a preoperative diagnosis of primary HCC from January 2013 to December 2022 at Ehime Prefectural Central Hospital were included in this study. The patients were categorized into two groups based on the presence of POBL. The preoperative, operative, and histopathological findings were analyzed between the two groups. Risk factors were determined using multivariable analysis. Results Regarding preoperative findings, statistically significant differences were observed in white blood cell count, platelet count, C-reactive protein (CRP) level, and CRP-to-Albumin ratio (CAR) between the two groups (p = 0.023, p = 0.025, p = 0.011, and p = 0.012, respectively). As for intraoperative variables, only operation time (p = 0.017) was statistically correlated with the risk of POBL. Regarding pathological variables, there were no statistically significant differences between the two groups. The optimal cut-off value of CAR, as determined by ROC curve analysis, was 0.053. This value had a sensitivity of 80.0% and a specificity of 72.8%. Multivariate logistic regression analysis indicated that CAR ≥ 0.053 (p = 0.030) and operation time ≥ 308 min (p = 0.023) were independent potential markers for POBL after hepatectomy. Conclusion A high CAR level can be an effective predictor for POBL following hepatectomy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Utsunomiya et al.)
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- 2024
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40. Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.
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Rimini M, Stefanini B, Tada T, Suda G, Shimose S, Kudo M, Finkelmeier F, Yoo C, Presa J, Amadeo E, Genovesi V, De Grandis MC, Iavarone M, Marra F, Foschi F, Tamburini E, Rossari F, Vitiello F, Bartalini L, Soldà C, Tovoli F, Vivaldi C, Lonardi S, Silletta M, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Himmelsbach V, Montes M, Hiraoka A, Sho T, Niizeki T, Nishida N, Steup C, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Persano M, Camera S, Foti S, Aldrighetti L, Cascinu S, Casadei-Gardini A, and Piscaglia F
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- Humans, Bevacizumab therapeutic use, Body Mass Index, Overweight, Prognosis, Thinness, Antibodies, Monoclonal, Humanized therapeutic use, Carcinoma, Hepatocellular, Liver Neoplasms, Phenylurea Compounds therapeutic use, Quinolines therapeutic use
- Abstract
Introduction: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment., Methods and Material: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests., Results: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis., Conclusion: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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41. Disease Etiology Impact on Outcomes of Hepatocellular Carcinoma Patients Treated with Atezolizumab plus Bevacizumab: A Real-World, Multicenter Study.
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Rossari F, Tada T, Suda G, Shimose S, Kudo M, Yoo C, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Bergamo F, Amadeo E, Vitiello F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Iavarone M, Cabibbo G, Montes M, Foschi FG, Vivaldi C, Soldà C, Sho T, Niizeki T, Nishida N, Steup C, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Hiraoka A, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Persano M, Foti S, Camera S, Stefanini B, Scartozzi M, Cascinu S, Casadei-Gardini A, and Rimini M
- Abstract
Introduction: The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients., Methods: We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies., Results: Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups., Conclusion: Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice., Competing Interests: Andrea Casadei-Gardini has received grants and personal fees from MSD, Eisai, Bayer and is an advisor for MSD, Eisai, Bayer, Bristol-Myers Squibb, AstraZeneca and GSK. Atsushi Hiraoka received lecture’s fees from Chugai, Lilly, AstraZeneca. Fabian Finkelmeier has received travel support from Ipsen, and speaker’s fees from AbbVie, MSD, Ipsen, Eisai and Fresenius. Gianluca Masi is an advisor for Roche, MSD, Eisai. Giuseppe Cabibbo is a consultant for Roche, AstraZeneca, Eisai, MSD. Hidenori Toyoda has received grants and personal fees from Gilead, AbbVie, Eisai, Fujifilm, Teruma, Kowa, Takeda. Ho Yeong Lim is an advisor for Roche, Eisai, AstraZeneca, Bayer. Hong Jae Chon has advisory role for Roche, Eisai, Bayer, ONO, MDS, BMS, Sanofi, Servier, AstraZeneca, Silajen, Menarini, GreenCross Cell; received speaker’s fee and research grants from Roche, Eisai, Bayer, BMS, Sanofi, Dong-A ST, BORYUNG, Inno.N, Hanmi, YUHAN. Josè Presa is an advisor for Gilead, AbbVie, Roche, AstraZeneca, Giszi, Advaus. Mario Scartozzi received grants and personal fees from MSD, Merck, Servier, Novartis, AstraZeneca. Masatoshi Kudo received lecture’s fees from Chugai Pharmaceutical, Eisai, Eli Lilly Japan, Takeda Pharmaceutical; is an advisor for F. Hoffmann-La Roche, AstraZeneca, Chugai Pharmaceutical, Eisai; and received grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, GE Healthcare Japan Corporation, Eisai, AbbVie, EA Pharma. Massimo Iavarone received grants and personal fees from MSD, Gilead, AstraZeneca, Bayer, Roche, Ipsen, Eisai. Takeshi Hatanaka received lecture’s fees from Eisai. The other coauthors have no conflict of interest to disclose., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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42. Comparative analysis of the therapeutic outcomes of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma patients aged 80 years and older: Multicenter study.
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Hatanaka T, Kakizaki S, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Yokohama K, Nishikawa H, Nishimura T, Shimada N, Kawata K, Kosaka H, Naganuma A, Yata Y, Ohama H, Kuroda H, Aoki T, Tanaka K, Tanaka T, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Kudo M, and Kumada T
- Abstract
Aim: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older., Methods: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed., Results: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression-free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group., Conclusions: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients., (© 2023 Japan Society of Hepatology.)
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- 2024
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43. Renal Cell Carcinoma and Hepatocellular Carcinoma in a Patient with Wilson's Disease.
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Kitahata S, Michitaka K, Kinebuchi M, Matsuura A, Hiraoka A, Ohama H, Yanagihara E, Saneto H, Izumoto H, Kawamura T, Kuroda T, Tada F, Miyata H, Ninomiya T, and Hiasa Y
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- Male, Humans, Adult, Copper, Carcinoma, Hepatocellular diagnosis, Hepatolenticular Degeneration complications, Hepatolenticular Degeneration diagnosis, Carcinoma, Renal Cell complications, Liver Neoplasms diagnosis, Kidney Neoplasms complications
- Abstract
No reports of renal cancer in patients with Wilson's disease (WD) exist. We herein report a 37-year-old Japanese man diagnosed with WD who had been treated with d-penicillamine 9 years prior. Hepatocellular carcinoma had been diagnosed at 36 years old and treated with radiofrequency ablation therapy. One year later, renal cancer and recurrent hepatocellular carcinoma had developed. The hepatocellular carcinoma was treated after renal cancer surgical resection of a clear-cell-type renal cell carcinoma, with iron, rather than copper, deposited on the renal cancer cells. This patient harbored a novel mutation, p. Leu1395Terfs in ATP7B.
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- 2024
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44. Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma.
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Ohama H, Hiraoka A, Tada T, Hirooka M, Kariyama K, Hatanaka T, Tani J, Takaguchi K, Atsukawa M, Itobayashi E, Nishimura T, Tsuji K, Tajiri K, Ishikawa T, Yasuda S, Toyoda H, Fukunishi S, Ogawa C, Kakizaki S, Shimada N, Naganuma A, Kawata K, Kosaka H, Kuroda H, Matono T, Yata Y, Ochi H, Tada F, Nouso K, Morishita A, Itokawa N, Okubo T, Arai T, Tsutsui A, Nagano T, Yokohama K, Nishikawa H, Imai M, Koizumi Y, Nakamura S, Iijima H, Kaibori M, Hiasa Y, and Kumada T
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- Male, Humans, Aged, Bevacizumab, Prognosis, Retrospective Studies, alpha-Fetoproteins, Carcinoma, Hepatocellular diagnosis, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Antibodies, Monoclonal, Humanized
- Abstract
Aims: The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment., Methods: A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c-index) and Akaike information criterion (AIC) results., Results: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring system. For IMABALI-De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS., Conclusion: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)
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- 2024
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45. α-FAtE: A new predictive score of response to atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.
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Rossari F, Tada T, Suda G, Shimose S, Kudo M, Yoo C, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Bergamo F, Amadeo E, Vitiello F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Iavarone M, Cabibbo G, Montes M, Foschi FG, Vivaldi C, Soldà C, Sho T, Niizeki T, Nishida N, Steup C, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Hiraoka A, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Persano M, Burgio V, Piscaglia F, Scartozzi M, Cascinu S, Casadei-Gardini A, and Rimini M
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- Humans, Bevacizumab therapeutic use, Prospective Studies, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Phenylurea Compounds, Quinolines, Antibodies, Monoclonal, Humanized
- Abstract
Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/μL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB., (© 2023 UICC.)
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- 2024
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46. Comparison of prognostic impact of atezolizumab plus bevacizumab versus lenvatinib in patients with intermediate-stage hepatocellular carcinoma.
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Tada T, Kumada T, Hiraoka A, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Kosaka H, Naganuma A, Matono T, Aoki T, Kuroda H, Yata Y, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, and Kudo M
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- Humans, Prognosis, Bevacizumab therapeutic use, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Antineoplastic Agents therapeutic use
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Background & Aims: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy., Methods: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included., Results: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044)., Conclusions: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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47. Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.
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Camera S, Rimini M, Rossari F, Tada T, Suda G, Shimose S, Kudo M, Yoo C, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Bergamo F, Salani F, Marseglia M, Amadeo E, Vitiello F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Iavarone M, Cabibbo G, Montes M, Foschi FG, Vivaldi C, Lonardi S, Sho T, Niizeki T, Nishida N, Steup C, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Nishimura T, Hatanaka T, Kakizaki S, Shimada N, Kawata K, Hiraoka A, Tada F, Ohama H, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Imai M, Kosaka H, Naganuma A, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Persano M, Foti S, Piscaglia F, Scartozzi M, Cascinu S, and Casadei-Gardini A
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- Humans, Aged, 80 and over, Phenylurea Compounds adverse effects, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy, Quinolines pharmacology, Quinolines therapeutic use
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Background: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing., Objective: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC., Patients and Methods: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years)., Results: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115)., Conclusions: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2024
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48. Simple Scoring System for Esophagogastric Varices Prediction in Hepatocellular Carcinoma Patients without Liver Stiffness Evaluation.
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Hiraoka A, Tada F, Ohama H, Fukumoto M, Matsuoka K, Matsuda T, Nakatani K, Yanagihara E, Saneto H, Izumoto H, Murakami T, Onishi K, Kitahata S, Kanemitsu-Okada K, Kawamura T, Kuroda T, Miyata H, Tsubouchi E, Hirooka M, Abe M, Matsuura B, Ninomiya T, and Hiasa Y
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- Humans, Retrospective Studies, Liver Cirrhosis, Carcinoma, Hepatocellular diagnostic imaging, Carcinoma, Hepatocellular therapy, Liver Neoplasms diagnostic imaging, Liver Neoplasms therapy, Esophageal and Gastric Varices diagnostic imaging, Esophageal and Gastric Varices etiology, Varicose Veins
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Introduction: For predicting esophagogastric varices (EGVs), the Virtual Baveno VII Consensus Workshop has proposed a combination of liver stiffness determination and platelet count measurement using a FibroScan®. However, FibroScan® is not available at all institutions. The present study aimed to develop a simple method to predict development of EGV using only general blood examination results., Materials and Methods: A total of 1,090 hepatocellular carcinoma patients were enrolled, after excluding 956 with major portal vein tumor thrombus (Vp3/Vp4) or without upper gastrointestinal endoscopy examination results available. Those with EGV (≥ grade F2) or a history of treatment for the condition were defined as positive for significant EGV, and then clinical factors were retrospectively evaluated to determine indicators of occurrence., Results: Logistic multivariate analysis showed platelet count (≤12 × 104/μL) (odds ratio [OR] 3.79, p < 0.001), mALBI grade 2a (OR 1.52, p = 0.036), and mALBI 2b or 3 (OR 3.46, p < 0.001) as significant predictive factors. Based on the OR values, platelet count (≤12 × 104/μL) and mALBI grade 2b/3 were each assigned 2 points and mALBI 2a was given 1 point, with the result termed recommendation for EGV screening (REGS) score. Significant EGV occurrence was noted in 2.9% (9/311) of the patients with a REGS score 0, 11.0% (13/118) with a score 1, 19.3% (53/274) with a score 2, 29.5% (39/132) with a score 3, and 38.0% (97/255) with a score 4 (p < 0.001)., Conclusion: The findings indicate that REGS score can provide useful predictive information for development of significant EGV without the need for special equipment such as a FibroScan®., (© 2023 S. Karger AG, Basel.)
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- 2024
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49. Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach.
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Hatanaka T, Kakizaki S, Hiraoka A, Tada T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Fukunishi S, Tsuji K, Ishikawa T, Tajiri K, Ochi H, Yasuda S, Toyoda H, Ogawa C, Yokohama K, Nishikawa H, Nishimura T, Shimada N, Kawata K, Kosaka H, Naganuma A, Yata Y, Ohama H, Kuroda H, Tanaka K, Tanaka T, Tada F, Nouso K, Morishita A, Tsutsui A, Nagano T, Itokawa N, Okubo T, Arai T, Imai M, Koizumi Y, Nakamura S, Kaibori M, Iijima H, Hiasa Y, Kudo M, and Kumada T
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- Humans, Bevacizumab adverse effects, Retrospective Studies, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy
- Abstract
Aim: This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma., Methods: We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity-score-matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed-effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow-up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups., Results: Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were -2.41 ± 0.40 and -2.44 ± 0.42 at baseline, and -2.17 ± 0.56 and -2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN-treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev., Conclusions: Using a nonlinear mixed-effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN-treated patients with BCLC advanced stage or those receiving the full dose of LEN., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
50. Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era.
- Author
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Nakamura Y, Hirooka M, Hiraoka A, Koizumi Y, Yano R, Morita M, Okazaki Y, Imai Y, Ohama H, Hirooka K, Watanabe T, Tada F, Yoshida O, Tokumoto Y, Abe M, and Hiasa Y
- Abstract
Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009-2013, n = 86; period 2: 2014-2018, n = 132; period 3: 2019-2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1-3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin-bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.
- Published
- 2023
- Full Text
- View/download PDF
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