Poor outcomes after gastric Endoscopic Submucosal Dissection: a systematic review and meta-analysis on predictive factors

2018/2019 Gonçalo Viei a Figuei ôa Gomes Poo ou comes a e gas ic Endoscopic Submucosal Dissec ion: a sys ema ic e iew and me a-analysis on p edic i e ac o s Resul ados des a o á eis após disseção endoscópica da submucosa gás ica: e isão sis emá ica e me a-análise ma ço, 2019 Mes ado In eg ado em Medicina Á ea: Gas en e ologia Tipologia: Disse ação T abalho e e uado sob a O ien ação de: D . Diogo Miguel Pe ei a Libânio Mon ei o E sob a Coo ien ação de: P o esso Dou o Má io Jo ge Dinis Ribei o T abalho o ganizado de aco do com as no mas da e is a: Diges i e Endoscopy Gonçalo Viei a Figuei ôa Gomes Poo ou comes a e gas ic Endoscopic Submucosal Dissec ion: a sys ema ic e iew and me a-analysis on p edic i e ac o s Resul ados des a o á eis após disseção endoscópica da submucosa gás ica: e isão sis emá ica e me a-análise ma ço, 2019 Poo ou comes a e gas ic Endoscopic Submucosal Dissec ion: a sys ema ic e iew and me a-analysis on p edic i e ac o s Gonçalo Figuei ôa1, Ped o Pimen el-Nunes MD PhD1,2, Má io Dinis-Ribei o MD PhD1,2, Diogo Libânio MD1,2 1 MEDCIDS – Depa amen o de Medicina da Comunidade, In o mação e Decisão em Saúde, Po o, Po ugal 2 Gas oen e ology Depa men , Ins i u o Po uguês de Oncologia do Po o, Po o, Po ugal Co esponding au ho : Gonçalo Figuei ôa Depa amen o de Medicina da Comunidade, In o mação e Decisão em Saúde (MEDCIDS) Faculdade de Medicina da Uni e sidade do Po o Rua Dou o Plácido da Cos a 4200-450 Po o, Po ugal Phone: +351 969 925 733 E-mail: g. iguei [email protected] ABSTRACT BACKGROUND AND AIMs: Endoscopic submucosal dissec ion (ESD) is now es ablished as he i s op ion o manage ea ly gas ic neoplasms bu i s e icacy may a y acco ding o di e se ac o s. We aimed o sys ema ically iden i y a iables p edic i e o poo ou comes o gas ic ESD. METHODS: Th ee online da abases (MEDLINE, ISI Web o Knowledge and Scopus) we e sea ched (las sea ch on June 2018) o poo ou comes o gas ic ESD (deep submucosal in asion, piecemeal/incomple e esec ion, non-cu a i e esec ion, local ecu ence and me ach onous lesions). RESULTS: One hund ed and ou een s udies we e included e e ing o 55.986 ESDs. Undi e en ia ed his ology and uppe loca ion ( s lowe ) we e ound o be associa ed o submucosal in asion (OR=2.42 [95%CI 1.62-3.61] and OR=3.20 [1.04-9.86], espec i ely) and deep submucosal in asion (OR=2.98 [2.02-4.39] and OR=2.35 [1.45-3.81], espec i ely). Lesion size >30mm and ulce a ion we e associa ed wi h piecemeal esec ion (OR=2.78 [1.17-6.60] and OR=2.76 [1.23, 6.20]). Lesion size >30mm, ulce a ion, uppe loca ion and ib osis we e isk ac o s o incomple e esec ion (OR=3.83 [2.68-5.49], OR=4.06 [1.62-10.16], OR=3.71 [2.49- 5.54] and OR=4.46 [1.66-11.96]), espec i ely). A non-cu a i e esec ion was mo e o en obse ed o lesions wi h uppe loca ion (OR=1.49 [1.24-1.79]), dep essed mo phology (OR=1.49 [1.04-2.12]) and hose ou side s anda d c i e ia (OR=3.56 [2.31-5.48]). Olde age was signi ican ly linked wi h local ecu ence a es (OR=3.08 [1.13-5.02]) and me ach onous lesions (OR=3.00 [1.77-4.22]). CONCLUSIONS: Se e al isk ac o s in luence poo e icacy ou comes o gas ic ESD ha may be used o in o m bo h pa ien s and heal h p o ide s abou he expec ed e icacy. Key wo ds: Endoscopic submucosal dissec ion, gas ic cance , ou comes, isk ac o s. In oduc ion Ea ly gas ic neoplasms wi h null o minimal isk o lymph node me as asis (LNM) can be e ec i ely ea ed by gas ic endoscopic submucosal dissec ion (ESD). Endoscopic esec ion (by Endoscopic Mucosal Resec ion o ESD) is ecommended as he s anda d ea men o di e en ia ed adenoca cinoma <2cm clinically diagnosed as in amucosal (T1a); lesions wi h low isk o LNM bu ou side hese c i e ia can also be ea ed wi h ESD as an al e na i e o su ge y, al hough i is s ill conside ed as an in es iga ional ea men in Japanese guidelines[1]. Recen Eu opean guidelines ecommend endoscopic esec ion as he i s line ea men o gas ic supe icial neoplas ic lesions wi h e y low isk o LNM, being ESD ecommended as he ea men o choice[2]. Since he in oduc ion o ESD, se e al s udies e alua ed i s e icacy and sa e y in he ea men o ea ly gas ic neoplasms [3-6]. A e e icacy and sa e y is p o en and a echnology becomes accep ed and widely pe o med, esea ch should aim o p edic and op imize ou comes, in o de o imp o e pa ien selec ion o he echnique and also o imp o e pa ien in o ma ion abou expec ed ou comes [7-9]. ESD achie es en-bloc/R0 esec ions in mo e han 90% o he cases [10]. Lesions sui able o endoscopic ea men a e selec ed based on he endoscopic e alua ion wi h ch omoendoscopy (endoscopic ul asound does no imp o e p edic ion o submucosal in asion and he e o e is no ou inely ecommended) [2]. Howe e , ESD is no cu a i e in nea ly 20% o he cases because his opa hological e alua ion shows p e iously unsuspec ed submucosal in asion o lympho ascula in asion (among o he c i e ia)[11]. Thus, e alua ion o isk ac o s o submucosal in asion is impo an in o de o imp o e pa ien selec ion o ESD. Since en-bloc esec ion and R0 esec ion a e equisi es o cu a i e esec ion, i is also impo an o analyze isk ac o s o piecemeal and R1 ha could possibly help in he selec ion o p ocedu al modi ica ions o pe haps e e al o expe cen e s [12-14]. ESD is associa ed wi h low local ecu ence a es (1-3%) bu wi h a high isk o me ach onous lesions on long- e m ollow-up which makes endoscopic su eillance necessa y [11, 15, 16]. Se e al s udies also assessed isk ac o s o hese long- e m ou comes, al hough esul s a e o en con o e sial. The iden i ica ion o isk ac o s o ecu ence and me ach onous could he e o e in luence su eillance schedule. In summa y, se e al pa ien - and lesion-speci ic ac o s ha e been ound o in luence bo h sho - and long- e m ou comes, bu he e is no consensus ega ding which ac o s a e ac ually signi ican . The aim o his s udy was o assess isk ac o s (clinical o endoscopic a iables, a ailable a he p e- esec ion s age) o poo e icacy ou comes o gas ic ESD, bo h sho - e m (submucosal in asion, piecemeal and incomple e esec ion, non-cu a i e esec ion) and long- e m (local ecu ence and me ach onous lesions). Me hods a) S udy selec ion A sys ema ic e iew o he li e a u e was conduc ed in h ee elec onic da abases (MEDLINE h ough Pubmed), ISI Web o Knowledge and Scopus om incep ion un il 26 h June 2018. The ollowing sea ch que y wi hou language es ic ion was used in Pubmed: ([gas ic OR s omach] AND [“endoscopic submucosal dissec ion” OR “ESD”]) AND (non-cu a i e OR “non cu a i e” OR “submucosal in asion” OR “ ea men ailu e” OR “p ocedu e ailu e” OR “ ecu ence”), wi h he sea ch que y o o he da abases being adap ed om his que y. The e e ences o included s udies and e ie ed a icles we e uploaded o Co idence online pla o m (www.co idence.o g) ha was used o a icles selec ion. Bo h i le and abs ac sc eening ( o exclusion o i ele an a icles) and ull ex sc eening we e made by wo independen in es iga o s (GF, DL), being con lic s sol ed by consensus. The ollowing inclusion Discussion This sys ema ic e iew and me a-analysis is, o ou knowledge, he i s ha e alua ed p e- esec ion isk ac o s o poo ou comes o gas ic ESD (deep submucosal in asion, non-cu a i e esec ion, piecemeal/incomple e esec ion, local ecu ence and me ach onous lesions). ESD is gaining wo ldwide accep ance as he i s line ea men o gas ic supe icial neoplasms, al hough i is unsuccess ul in nea ly 20% o he cases [11]. Iden i ica ion o p e- esec ion isk ac o s o poo e e icacy ou comes o gas ic ESD is hus impo an in o de o e ine pa ien selec ion o his echnique and also o be e in o m pa ien s abou he success p obabili y o endoscopic ea men , gi en ha su gical esec ion can also be conside ed when he isk o poo ou comes is signi ican . We p e iously e alua ed isk ac o s which po en ially in luenced sa e y o esec ion, bu da a was con o e sial ega ding he p edic o s o poo e ec i eness o gas ic ESD [7] [8] [3] [4]. We ound ha an undi e en ia ed his ology is a signi ican isk ac o o submucosal in asion and deep submucosal in asion, which is p obably explained by he p edominan ly in il a i e g ow h pa e n o undi e en ia ed lesions [21]. Conce ning loca ion, p oximal lesions seem o ha e a highe p opensi y o ha bo ing submucosal in asion. While he biological explana ion emains unknown, possibly uppe lesions a e mo e p one o be missed a endoscopy and a e de ec ed la e . G ea e lesion size and ulce a ion we e associa ed wi h incomple e/piecemeal esec ion, likely gi en o echnical p ocedu al di icul ies. Fu he mo e, an uppe loca ion also inc eases he isk o IR which is p obably ela ed wi h he mo e challenging dissec ion in e o lexed posi ion. A highe deg ee o ib osis was also iden i ied as being associa ed wi h highe IR a es, and can also di icul esec ion gi en ha he iden i ica ion o he esec ion ield may be impai ed. Expanded Endoscopic Indica ion was ound o be associa ed wi h PR/IR, which is in line wi h a p e ious me a-analysis[22]. Finally, an undi e en ia ed his ology was associa ed wi h IR, which is p obably ela ed wi h di icul ies in iden i ying lesion ma gins e en using ch omoendoscopy and also wi h deepe in il a ion which may di icul achie ing a ee e ical ma gin. Lesions cha ac e is ics, namely g ea e size, uppe loca ion, dep essed mo phology and ulce a ion we e signi ican ly associa ed wi h non-cu a i e esec ion. Fu he mo e, EGCs ou side s anda d c i e ia we e also ound o be associa ed wi h NCR, which suppo s he impo ance o his classi ica ion. An age o e 75 yea s, con as ing wi h o he cu -o s also e alua ed, was iden i ied as a signi ican isk ac o , which is p obably ela ed o he p e e ence o minimally in asi e ea men like ESD in olde pa ien s e en when he p obabili y o NCR is highe . Age is consis en ly epo ed as a isk ac o o LR and ML and was ound o be a signi ican isk ac o in ou s udy. This inding can ha e implica ions in su eillance schedule, gi en ha acco ding o his da a i is di icul o de ine an age cu -o when esec ion is no longe o bene i (con as ing wi h colo ec al cance and pos -polypec omy su eillance). O he signi ican isk ac o s, such as an uppe loca ion, an undi e en ia ed his ology and BEC lesions we e linked o he occu ence o LR. We acknowledge ha incomple e esec ion is also he mos impo an isk ac o o LR; howe e , he aim o his sys ema ic e iew was o iden i y p e- esec ion a iables associa ed wi h his ou come, and so he signi icance o incomple e esec ion on LR was no e alua ed in his s udy al hough i was e alua ed in a p e ious me a-analysis by ou g oup [23]. On he o he hand, ML was signi ican ly associa ed wi h he p esence o mul iple lesions, mos likely due o he p esence o a ield de ec and mic osa elli e ins abili y [24]. In summa y, a p oximal loca ion is a isk ac o o SI, DSI, IR, LR and NCR. Undi e en ia ed his ology is a isk ac o o SI, DSI, IR, and LR, ulce a ion o PR, IR and NCR, Expanded Endoscopic Indica ion o PR and IR and Expanded Endoscopic C i e ia o NCR and LR. Finally, age is a isk ac o o NCR, LR and ML and g ea e lesion size o PR, IR and NCR. The p ima y limi a ion ha we acknowledge in ou s udy is he occasional sca ci y o s udies o some isk ac o s. As such, some o he conclusions he e d awn may be unde powe ed, gi en ha i hinde s he de ec ion o possible in e ac ions and con ounding be ween isk ac o s. Ne e heless, we conside ha ou esul s a e aluable and a e a s ep o wa d in enabling endoscopis s in be e selec ing pa ien s ha should be submi ed ESD. In conclusion, his s udy iden i ies a se o p e- esec ion isk ac o s which signi ican ly in luence se e al poo e icacy ou comes, bo h sho - and long- e m, ela ed o he esec ion o gas ic EGCs using ESD. We belie e ha he conclusions he e d awn can be use ul in guiding gas oen e ologis s when selec ing pa ien s ha should unde go ESD and be e de ining he p ognosis o such esec ion. Figu e 1 – Flowcha o included s udies. Figu e 2 – Fo es plo o Piecemeal esec ion a e acco ding o he p esence/absence o ulce a ion. Figu e 3 – Fo es plo o Incomple e esec ion a e acco ding o size (20mm as cu -o ). Figu e 4 – Fo es plo o Non-cu a i e esec ion a e acco ding o localiza ion (uppe s lowe ). Tables Table 1 – Gene al cha ac e is ics o included s udies. Pe iod n1 (n2) Ou come(s) e alua ed Risk ac o s e alua ed Quali y MA P ospec i e s udies Japan Hi a a K, 2013 [25] 2008-2010 65 (65) ML Mul iple 8 Yes Semba S, 2008 [26] - 73 ( - ) ML Single (Claudin exp ession) 8 No Hasuo T, 2007 [27] 2000-2004 110 (110) ML Single (Mic osa elli e Ins abili y S a us) 7 No Yagi K, 2014 [28] 2010-2013 - (197) SI Mul iple 7 Yes Takenaka R, 2008 [29] 2001-2005 275 (306) PR, IR, LR Mul iple 7 Yes China Shi H, 2017 [30] 2013-2014 32 (32) LR Single (Mic oRNA-499 s3746444 A/G polymo phism) 7 No Yu K, 2017 [31] 2013-2014 45 (45) LR Single (miR-34b s4938723 Polymo phism) 8 No Li H, 2012 [32] 2009-2011 146 (164) DSI Single (ME-NBI image ype) 7 No Xue H, 2016 [33] 2013-2015 230 ( - ) LR Single (CD44 exp ession) 6 No Fu QY, 2016 [34] 2009-2015 242 (242) SI, DSI Single (La e al Ma gin Posi i i y) 8 No Ko ea Ok KS, 2016 [35] 2012-2014 160 (160) SI Mul iple 7 No Choi IJ, 2016 [18] 2010-2011 712 (737) SI, NCR Mul iple 9 Yes Eu ope P obs A, 2017 [36] 2005-2016 179 (191) SI, DSI, PR, IR, NCR Single (Endocopic C i e ia) 9 No Re ospec i e s udies Japan Nagami Y, 2014 [37] 2007-2011 43 (43) SI, PR, IR, NCR Single (His ology) 8 No Omae, 2013 [38] 2004-2010 44 (44) SI, NCR Mul iple 7 Yes Nishide N, 2012 [39] 2002-2009 59 (62) PR, IR Mul iple 7 Yes Yonezawa J, 2006 [40] 2004-2005 60 (60) PR, NCR, LR Single (R-scope ESD) 8 No Ojima T, 2016 [41] 2002-2013 85 (85) LR Mul iple 7 No Oka S, 2014 [42] 2002-2011 97 (97) SI, DSI, IR, NCR Single (His ology) 8 No Kanemis u T, 2014 [43] 2006-2011 - (105) SI Mul iple 8 No Komo i K, 2016 [44] 2002-2012 107 (124) PR, IR Single (Age) 9 Yes Hi asaki S, 2007 [45] 2002-2006 112 (112) SI, PR, IR Single (Size) 8 Yes Naka a B, 2016 [46] 2007-2016 123 (140) PR, NCR Single (Endocopic Indica ion) 8 Yes Yamada T, 2014 [47] 2007-2012 132 (143) SI Single (Submucosal and lympho ascula in asions) 8 No Sugimo o T, 2015 [48] 2000-2009 155 ( - ) ML Mul iple 8 Yes Ho iguchi N, 2016 [49] 2007-2015 164 (182) SI, DSI Single (Helicobac e pylo i E adica ion) 8 Yes Kakushima N, 2007 [50] 2000-2004 165 (184) IR Single (Age) 7 Yes Sanomu a Y, 2012 [51] 1994-2009 173 (173) DSI, PR, IR Mul iple 8 No Nakamo o S, 2009 [52] 1999-2007 177 (202) PR, IR Single (Size) 7 No Oka S, 2006 [53] 2002-2004 185 (195) PR, IR, LR Mul iple 7 Yes Imagawa A, 2006 [54] 2002-2005 185 (196) PR, IR Mul iple 7 Yes Ka sube T, 2015 [55] 2003-2013 231 ( - ) SI, DSI, PR, NCR Mul iple 8 Yes Go o O, 2009 [56] 2000-2007 231 (276) SI, PR, IR Single (Submucosal In asion) 8 Yes Ho iuchi Y, 2018 [57] 2005-2017 264 (268) NCR Mul iple 8 Yes Takenaka R, 2006 [58] 2001-2005 269 (-) LR Mul iple 6 No Oda I, 2006 [59] 2001 - (303) PR, NCR Mul iple 7 Yes Yoshida M, 2016 [60] 2009-2014 307 (334) PR, IR Single (Lea ning Cu e Phases) 6 No Boda T, 2014 [61] 2002-2010 357 (357) ML Mul iple 8 No Oha a Y, 2016 [62] 2008-2012 363 (398) NCR Mul iple 8 Yes Sugimo o T, 2012 [63] 2006-2010 418 (485) PR Mul iple 9 Yes Kosaka T, 2014 [64] 2002-2007 438 ( - ) PR, NCR, LR, ML Mul iple 8 Yes Ohni a K, 2009 [65] 2003-2008 468 (495) SI, PR, NCR Mul iple 8 Yes Toyokawa T, 2011 [66] 2003-2009 514 (586) PR, NCR Sinlge (Age) 9 Yes Ojima T, 2016 [67] 2002-2013 532 (583) SI, PR, IR Single (Remnan ) 8 Yes Go o, 2013 [68] 2006-2011 533 (605) SI, DSI, IR, NCR Mul iple 8 Yes Isomo o H, 2009 [69] 2001-2007 551 (589) SI, PR, NCR, LR, ML Mul iple 8 Yes Yamaguchi N, 2009 [70] 2001-2007 551 (589) SI, DSI, PR, IR, NCR Single (Endoscopic C i e ia) 8 No Isomo o H, 2010 [71] 2001-2007 661 (713) SI, DSI, PR, IR, NCR Single (Age) 8 Yes Nagahama T, 2017 [72] 2006-2012 704 (863) DSI Mul iple 7 Yes Hi asawa K, 2011 [73] 2000-2010 784 (961) PR, IR, NCR Mul iple 8 No Ho eya S, 2011 [74] 2003-2009 818 (977) SI, DSI, IR, NCR Mul iple 7 Yes Numa a N, 2015 [75] 2005-2011 890 (1053) IR Mul iple 7 Yes Higashimaya M, 2013 [76] 2005-2011 891 (1027) IR Mul iple 8 Yes Oda I, 2005 [77] 2000-2003 945 (1033) PR, IR, NCR Mul iple 7 Yes Toyokawa T, 2012 [20] 2003-2010 967 (1123) SI, NCR Mul iple 9 Yes Maeha a Y, 2017 [78] 2003-2014 1053 ( - ) SI, ML Single (Helicobac e pylo i E adica ion) 8 Yes Nakamu a K, 2015 [79] 2002-2011 1161 (1332) SI, PR, IR Single (Endocopic C i e ia) 8 No Ho eya S, 2013 [80] 2005-2010 1224 (1463) IR, NCR Single (Loca ion) 8 No Abe S, 2015 [81] 1999-2006 1526 ( - ) ML Mul iple 9 Yes Kakushima N, 2011 [82] 2002-2008 - (1578) SI Single (La e al Ma gin Posi i i y) 7 No Suzuki H, 2016 [83] 1999-2008 2268 (2268) IR Single (La e al Ma gin Posi i i y) 8 No Ho iuchi Y, 2018 [84] 2005-2016 2551 (2585) NCR Mul iple 8 Yes China Chen ZS, 2017 [85] 2014-2015 80 (90) SI Single (Mul iple Lesions) 8 No Li SJ, 2015 [86] 2011-2013 116 (116) SI, DSI, NCR Mul iple 8 Yes Yan Zhang MM, 2014 [87] 2010-2013 171 (187) SI, PR, NCR, LR Single (Age) 8 Yes Wen J, 2014 [88] 2006-2013 316 (319) SI, DSI, IR Mul iple 8 Yes Ko ea Lee JY, 2010 [89] 2004-2008 43 (43) PR, IR, NCR Single (Loca ion) 7 No Pa k JC, 2011 [90] 2002-2010 47 (47) SI, PR, IR, NCR Single (Loca ion) 8 No Kim TK, 2015 [91] 2005-2012 55 (55) LR Single (La e al Ma gin Posi i i y) 7 No Jeon HK, 2018 [92] 2005-2014 66 (66) SI, PR, IR, NCR Mul iple 7 Yes Kim YY, 2013 [93] 2003-2010 74 (74) PR, IR, NCR, LR Single (Endoscopic C i e ia) 8 No Choi MH, 2013 [94] 2002-2012 81 (82) SI, PR, IR, NCR, LR, ML Single (His ology) 8 No Gong EJ, 2016 [95] 2004-2011 88 (88) PR, IR, NCR Single (Loca ion) 7 Yes Choe WH, 2018 [96] 2006-2013 90 ( - ) SI, DSI, PR, IR, LR, ML Single (Li e Ci hosis) 9 Yes Choi JH, 2012 [97] 2004-2010 92 ( - ) SI, DSI, PR, IR Single (Li e Ci hosis) 8 Yes Bae JH, 2015 [98] 2007-2013 110 (110) PR, IR, LR Single (Loca ion) 7 No Myung YS, 2017 [99] 2005-2014 136 ( - ) SI, PR, IR Single (P o on Pump Inhibi o ) 8 No Jang J, 2014 [100] 2010-2012 141 (141) LR Single (Endoscopic Healing Type) 7 No Kim DY, 2014 [101] 2004-2007 142 ( - ) LR, ML Single (Endocopic C i e ia) 8 Yes Han JP, 2016 [102] 2001-2012 152 (152) LR Mul iple 8 No Jeong JY, 2012 [103] 2006-2011 167 (161) SI, PR Single (Submucosal Fib osis) 7 No Kim H, 2017 [104] - 176 ( - ) ML Single (Helicobac e pylo i In ec ion) 8 Yes Chung CS, 2017 [105] 2008-2013 185 ( - ) SI, ML Mul iple 8 Yes Jang JS, 2009 [106] 2004-2007 198 (198) PR, IR Single (Size) 7 Yes Goh PG, 2011 [107] 2005-2009 210 (210) SI, DSI, PR, IR, LR Mul iple 8 Yes Kang MS, 2015 [108] 2002-2008 280 (309) PR, IR, LR Single (Endocopic C i e ia) 7 Yes Kwon YH, 2014 [109] 2007-2010 283 ( - ) ML Mul iple 8 Yes Han JP, 2013 [110] 2001-2008 304 (335) PR, IR, NCR Mul iple 7 No Kim BJ, 2010 [111] 2003-2006 337 (337) SI, PR, IR, LR, ML Single (Cha lson Como bidi y Scale) 7 No Han JP, 2015 [112] 2002-2009 395 (430) PR, IR, LR, ML Single (His ology) 7 Yes Lee JY, 2016 [113] 2003-2010 401 (415) LR Mul iple 7 Yes Kang HY, 2010 [114] 2005-2008 - (456) SI, IR Single (His ology) 8 Yes Choi MK, 2013 [115] 2006-2010 515 (522) SI, PR, NCR, LR, ML Single (Endocopic Indica ion) 8 Yes Ryu DG, 2017 [116] 2009-2015 532 (557) PR, IR Single (His ology) 8 Yes Sohn SH, 2017 [117] 2005-2014 599 (611) DSI, PR, IR Single (Endocopic Indica ion) 8 Yes Kim JM, 2016 [118] 2010-2011 712 (737) SI, DSI Mul iple 8 Yes Kim JS, 2017 [119] 2009-2015 729 ( - ) PR, NCR, LR Mul iple 8 Yes Kim YI, 2016 [120] 2004-2011 756 (765) PR, IR, NCR Single (Endocopic Indica ion) 9 Yes Lee H, 2011 [121] 2003-2010 780 (806) PR, IR, LR, ML Single (Endoscopic C i e ia) 8 Yes Ahn JY, 2011 [122] 2005-2009 - (833) PR, IR, LR, ML Single (Endoscopic C i e ia) 8 Yes Pa k CH, 2013 [123] 2005-2011 916 (931) PR, IR, NCR, LR, ML Mul iple 8 Yes Jung S, 2015 [124] 2007-2011 1041 (-) SI, PR, ML Mul iple 9 Yes Shin KY, 2015 [125] 2003-2010 1105 (1105) SI, DSI, PR, IR, NCR Single (Endoscopic C i e ia) 8 No Yang HJ, 2017 [126] 2005-2014 1115 ( - ) ML Single (H pylo i e adica ion) 8 No Kang D, 2017 [127] 2010-2016 1181 ( - ) SI, PR, IR, NCR Single (BMI) 7 Yes Yang HJ, 2018 [128] 2005-2014 1237 ( - ) LR, ML Single (Age) 8 Yes Hahn KY, 2016 [129] 2007-2014 1347 ( - ) LR Mul iple 9 Yes Min BH, 2015 [130] 2003-2011 1497 (1539) SI, ML Mul iple 8 Yes Kim EH, 2016 [131] 2007-2013 1639 ( - ) NCR Mul iple 9 Yes Joh DH, 2015 [132] 2008-2011 1823 (1929) PR, IR, NCR Single (Mul iple Lesions) 9 No Taiwan Hsieh Y, 2015 [133] 2004-2009 65 (69) NCR, LR, ML Mul iple 7 No Eu ope Sea a Cos a R, 2018 [134] 2012-2017 105 (114) SI, PR, IR, NCR, LR, ML Single (Endoscopic C i e ia) 8 Yes Libânio D, 2016 [19] 2005-2014 164 (194) NCR Mul iple 8 Yes Libânio D, 2017 [9] 2005-2015 - (245) NCR Mul iple 9 Yes n1 – numbe o pa ien s included in he s udy; n2 – numbe o lesions included in he s udy; MA – Included in he me a-analysis (s udies ha epo ed isk ac o s no e alua ed in o he s udies o ha no p o ided da a allowing calcula ion o odds a io we e no included in me a-analysis); ME-NBI – Na ow Band Imaging Magni ica ion Endoscopy. Table 2 – Submucosal In asion and Deep Submucosal In asion ela ed ac o s. Ou come Risk ac o s Submucosal In asion Signi ican ly associa ed S udies (n) E ec Es ima e I2 Loca ion Ve ical (MxL) 3 2.11 [1.41, 3.16] 0% Loca ion Ve ical (UxL) 3 3.20 [1.04, 9.86] 64% His ology 4 2.42 [1.62, 3.61] 0% Single ac o s signi ican ly associa ed VEC pa e n [43], submucosal ib osis [103], des uc i e mic o su ace pa e n [35], ulce a ion [74] and me ach onous lesions [34]. No signi ican ly associa ed S udies (n) E ec Es ima e I2 Lesion size (20mm) 2 1.50 [0.28, 8.14] 71% Loca ion Ve ical (UxM) 3 1.17 [0.36, 3.80] 76% Mo phology 3 1.05 [0.60, 1.84] 50% HP e adica ion 2 1.35 [0.85, 2.16] 0% Single ac o s no signi ican ly associa ed Gas ec omy [67], PPIs adminis a ion [99], ci hosis [97], cha lson como bidi y scale (a leas one isk ac o ) [111], BMI [127] and mul iple lesions [85]. Deep Submucosal In asion Signi ican ly associa ed S udies (n) E ec Es ima e I2 Loca ion Ve ical (UxM) 3 2.11 [1.18, 3.79] 52% Loca ion Ve ical (UxL) 3 2.35 [1.45,3.81] 42% His ology 3 2.98 [2.02, 4.39] 0% Single ac o s signi ican ly associa ed Size o e 30mm [118], me ach onous lesions [34] and pa e n C wi h ME-NBI (no su ace pa e n and spa se mic o essels ma kedly dis o ed, isola ed, he e ogeneous o wi h a ascula a eas) [32]. No signi ican ly associa ed S udies (n) E ec Es ima e I2 Loca ion Ve ical (MxL) 3 1.12 [0.81, 1.56] 0% Ulce a ion 3 1.42 [0.98, 2.06] 31% Single ac o s no signi ican ly associa ed Age [69], sex [74], size o e 20mm [72], loca ion [118], mo phology [118] and HP e adica ion [49]. n – numbe o s udies; I2 – he e ogenei y; M – middle hi d; L – lowe hi d; U – uppe hi d; VEC Pa e n – Vessels wi hin epi helial ci cle pa e n; HP e adica ion – Helicobac e pylo i e adica ion; PPIs – P o on- pump inhibi o s; BMI – Body Mass Index; ME-NBI – Magni ica ion Endoscopy (Na ow Band Imaging). Table 3 – Piecemeal Resec ion and Incomple e Resec ion ela ed ac o s. Ou come Risk ac o s Piecemeal Resec ion Signi ican ly associa ed S udies (n) E ec Es ima e I2 Lesion size >20mm 5 3.20 [2.07, 4.95] 24% Lesion size >30mm 2 2.78 [1.17, 6.60] 0% Endoscopic Indica ion (AI x EI) 7 2.25 [1.44, 3.53] 0% Endoscopic Indica ion (AI x BEI) 2 4.64 [1.68, 12.82] 0% Ulce a ion 6 2.76 [1.23, 6.20] 44% Single ac o s signi ican ly associa ed Deg ee o ib osis [103] No signi ican ly associa ed S udies (n) E ec Es ima e I2 Age 3 1.37 [0.49, 3.79] 69% Loca ion Ve ical (UxM) 3 1.57 [0.51, 4.80] 57% Loca ion Ve ical (UxL) 3 3.57 [0.31, 41.12] 82% Loca ion Ve ical (MxL) 3 2.35 [0.74, 7.43] 59% Endoscopic Indica ion (EI x BEI) 2 1.53 [0.53, 4.37] 0% His ology 2 1.60 [0.73, 3.53] 0% Gas ec omy 2 2.04 [0.01, 411.2] 91% Ci hosis 2 2.58 [0.70, 9.56] 0% Single ac o s no signi ican ly associa ed Mo phology [59], age o e 70 yea s [63], age o e 80 yea s [44], sex [63], mul iple lesions [132], me ach onous lesions [132], PPIs adminis a ion [99], Cha lson como bidi y scale >=1[111], R-scope ESD [40], lea ning cu e [60] and BMI [127]. Incomple e Resec ion Signi ican ly associa ed S udies (n) E ec Es ima e I2 Lesion size >20mm 7 3.64 [2.24, 5.91] 63% Lesion size >30mm 4 3.83 [2.68, 5.49] 0% Loca ion Ve ical (UxM) 5 1.62 [1.14, 2.31] 0% Loca ion Ve ical (UxL) 5 3.71 [2.49, 5.54] 0% Loca ion Ve ical (MxL) 5 2.28 [1.58, 3.28] 0% Endoscopic Indica ion (AI x EI) 3 3.86 [1.23, 12.08] 77% Ulce a ion 6 4.06 [1.62, 10.16] 83% Dep h o In asion (MxSM) 3 27.89 [3.57, 218.0] 91% Dep h o In asion (M/SM1xSM2) 2 14.99 [2.84, 79.25] 56% His ology 5 6.67 [3.42, 12.99] 66% Deg ee o Fib osis 2 4.46 [1.66, 11.96] 69% Single ac o s signi ican ly associa ed Size [58], umo loca ion [58], Endoscopic Indica ion [117] and age (mean) [88]. No signi ican ly associa ed S udies (n) E ec Es ima e I2 Age 4 1.04 [0.54, 1.98] 55% Sex 2 0.96 [0.55, 1.68] 34% Mo phology 2 0.90 [0.47, 1.75] 0% Gas ec omy 2 0.37 [0.07, 2.15] 87% Ci hosis 2 3.66 [0.64, 20.74] 0% Single ac o s no signi ican ly associa ed Sex [83], age >65 yea s [83], age >80 yea s [44], size [88], loca ion (sho axis) [68], loca ion EGJ [80], PPI adminis a ion [99], Cha lson como bidi y scale >=1 [111], lea ning cu e phase [60], BMI [127], mul iple lesions [132] and local ecu ence [29]. n – numbe o s udies; I2 – he e ogenei y; AI – Absolu e Indica ion; EI – Expanded Indica ion; BEI – Beyond- Expanded Indica ion; U – uppe hi d; M – middle hi d; L – lowe hi d; PPIs – P o on-pump inhibi o s; ESD – Endoscopic Submucosal Dissec ion; BMI – Body Mass Index; M – Mucosa; SM – submucosa; SM1 – lesions in ading less han 500 μm om he submucosa in dep h; SM2 – lesions in ading 500 μm o mo e om he submucosa in dep h; EGJ –Esophagogas ic junc ion. Re e ences 1. 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Eu J Gas oen e ol Hepa ol. 2010;22(3):311-7. 72. Nagahama T, Yao K, Imamu a K, e al. Diagnos ic pe o mance o con en ional endoscopy in he iden i ica ion o submucosal in asion by ea ly gas ic cance : he "non- ex ension sign" as a simple diagnos ic ma ke . Gas ic Cance . 2017;20(2):304-13. 73. Hi asawa K, Kokawa A, Oka H, e al. Risk assessmen cha o cu abili y o ea ly gas ic cance wi h endoscopic submucosal dissec ion. Gas oin es Endosc. 2011;74(6):1268-75. 74. Ho eya S, Yamashi a S, Kikuchi D, e al. Endoscopic submucosal dissec ion o submucosal in asi e gas ic cance and cu abili y c i e ia. Dig Endosc. 2011;23(1):30-6. 75. Numa a N, Oka S, Tanaka S, e al. Risk ac o s and managemen o posi i e ho izon al ma gin in ea ly gas ic cance esec ed by en bloc endoscopic submucosal dissec ion. Gas ic Cance . 2015;18(2):332-8. 76. Higashimaya M, Oka S, Tanaka S, e al. Ou come o endoscopic submucosal dissec ion o gas ic neoplasm in ela ionship o endoscopic classi ica ion o submucosal ib osis. Gas ic Cance . 2013;16(3):404-10. 77. Oda I, Go oda T, Hamanaka H, e al. Endoscopic submucosal dissec ion o ea ly gas ic cance : Technical easibili y, ope a ion ime and complica ions om a la ge consecu i e se ies. Dig Endosc. 2005;17(1):54-8. 78. Maeha a Y, Nakamu a S, Esaki M, e al. Cha ac e is ics o P ima y and Me ach onous Gas ic Cance s Disco e ed a e Helicobac e pylo i E adica ion: A Mul icen e P opensi y Sco e-Ma ched S udy. Gu Li e . 2017;11(5):628-34. 79. Nakamu a K, Honda K, Akahoshi K, e al. Sui abili y o he expanded indica ion c i e ia o he ea men o ea ly gas ic cance by endoscopic submucosal dissec ion: Japanese mul icen e la ge-scale e ospec i e analysis o sho - and long- e m ou comes. Scand J Gas oen e ol. 2015;50(4):413-22. 80. Ho eya S, Ma sui A, Iizuka T, e al. Compa ison o he clinicopa hological cha ac e is ics and esul s o endoscopic submucosal dissec ion o esophagogas ic junc ion and non- junc ional cance s. Diges ion. 2013;87(1):29-33. 81. Abe S, Oda I, Suzuki H, e al. Long- e m su eillance and ea men ou comes o me ach onous gas ic cance occu ing a e cu a i e endoscopic submucosal dissec ion. Endoscopy. 2015;47(12):1113-8. 82. Kakushima N, Ono H, Tanaka M, e al. Fac o s ela ed o la e al ma gin posi i i y o cance in gas ic specimens o endoscopic submucosal dissec ion. Dig Endosc. 2011;23(3):227- 32. 83. Suzuki H, Oda I, Sekiguchi M, e al. Fac o s associa ed wi h incomple e gas ic endoscopic submucosal dissec ion due o misdiagnosis. Endosc In Open. 2016;4(7):E788-93. 84. Ho iuchi Y, Fujisaki J, Yamamo o N, e al. Undi e en ia ed- ype componen mixed wi h di e en ia ed- ype ea ly gas ic cance is a signi ican isk ac o o endoscopic non-cu a i e esec ion. Dig Endosc. 2018. 85. Chen ZS, Jin XF, Wu HL, e al. Simul aneous endoscopic submucosal dissec ion o mul iple ea ly gas ic cance s in a low olume cen e . Medicine (Bal imo e). 2017;96(36):e7745. 86. Li SJ, Wang J, Li ZY, e al. [Applica ion o endoscopic submucosal dissec ion in ea men o ea ly gas ic cance ]. Beijing Da Xue Xue Bao Yi Xue Ban. 2015;47(6):945-51. 87. Zhang Y, Huang L, Li L, e al. Endoscopic submucosal dissec ion o ea ly gas ic neoplasms in elde ly pa ien s. J Lapa oendosc Ad Su g Tech A. 2014;24(6):391-8. 88. Wen J, Linghu EQ, Yang YS, e al. Associa ed isk ac o analysis o posi i e esec ion ma gins a e endoscopic submucosal dissec ion in ea ly-s age gas ic cance . J BUON. 2014;20(2):421-7. 89. Lee JY, Choi IJ, Cho SJ, e al. Endoscopic submucosal dissec ion o me ach onous umo in he emnan s omach a e dis al gas ec omy. Su g Endosc. 2010;24(6):1360-6. 90. Pa k JC, Kim JH, Youn YH, e al. How o manage pylo ic umou s ha a e di icul o esec comple ely wi h endoscopic esec ion: compa ison o he e o lexion s. o wa d iew echnique. Dig Li e Dis. 2011;43(12):958-64. 91. Kim TK, Kim GH, Pa k DY, e al. Risk ac o s o local ecu ence in pa ien s wi h posi i e la e al esec ion ma gins a e endoscopic submucosal dissec ion o ea ly gas ic cance . Su g Endosc. 2015;29(10):2891-8. All manusc ip s should be w i en so ha hey a e in elligible o he p o essional eade who is no a specialis in he pa icula ield. They should be w i en in a clea , concise, di ec s yle. Whe e con ibu ions a e judged as accep able o publica ion on he basis o con en , he Edi o and he Publishe ese e he igh o modi y manusc ip s o elimina e ambigui y and epe i ion and imp o e communica ion be ween au ho and eade . Au ho ship should be inalized du ing he submission p ocess. Please ensu e ha all au ho s a e lis ed and in he co ec o de , because changes a e no pe missible once he accep ed manusc ip goes in o p oduc ion. 4. AUTHORSHIP Diges i e Endoscopy ollows he ecommenda ions o mula ed by he In e na ional Commi ee o Medical Jou nal Edi o s ega ding c i e ia o au ho ship (h p://www.icmje.o g/ ecommenda ions/b owse/ oles-and- esponsibili ies/de ining- he- ole-o -au ho s-and-con ibu o s.h ml). Acco dingly, each pe son lis ed as an au ho o coau ho o a submi ed manusc ip mus mee all ou c i e ia. An au ho o coau ho shall ha e: 1) Subs an ial con ibu ions o he concep ion o design o he wo k, o acquisi ion, analysis o in e p e a ion o da a o he wo k; 2) D a ing he wo k o e ising i c i ically o impo an in ellec ual con en ; 3) Final app o al o he e sion o be published; 4) Ag eemen o be accoun able o all aspec s o he wo k in ensu ing ha ques ions ela ed o he accu acy o in eg i y o any pa o he wo k a e app op ia ely in es iga ed and esol ed. Mee ing hese c i e ia should p o ide each au ho wi h su icien knowledge o and pa icipa ion in he wo k ha he o she can accep public esponsibili y o he epo . Pe son who does no mee he abo e 4 c i e ia should be men ioned in he acknowledgmen sec ion. The co esponding au ho mus submi an Au ho ship con i ma ion o m (wi h COI s a emen om all au ho s) and mus gua an ee ha all au ho s lis ed in he manusc ip mee hese c i e ia and ha all au ho s a e awa e o he submission and abou he au ho ship. I he e is a se ious b each o au ho ship, he ma e will be in es iga ed acco ding o he COPE guideline and ep imand and punishmen will be conside ed acco ding o he se iousness o he ma e . Please use his o m o con i m he au ho ship o all au ho s. 5. DISCLOSURE Con lic o In e es s: All au ho s should decla e, acco ding o he s anda d o each coun y, any employmen , leade ship ole o ad iso y ole wi h a company, s ockowne ship and op ion, pa en oyal ies and licensing ees, hono a ia, ecei ed ees o p omo ional ma e ials, inancial suppo and g an s, de ices dona ed om he indus y and o he po en ial ela ionships ha may pose con lic o in e es s as “In e es s” be ween he Acknowledgmen s and Re e ences sec ions. The co esponding au ho should collec all au ho s COI disclosu e and mus comple e a con lic o in e es s disclosu e o m as pa o he ini ial manusc ip submission p ocess. The co esponding au ho is esponsible o ob aining all he ele an in o ma ion om all au ho s o he manusc ip . Please isi he e o consul he de ails o he la es disclosu e guidelines acco ding o he s anda ds o he In e na ional Commi ee o Medical Jou nal Edi o s (ICMJE).I a ailu e o accu a e epo abou COI disclosu e is suspec ed, he ma e will be esol ed ollowing he p ocedu e de ailed in COPE guidelines. Please disclose all Con lic o In e es s o all au ho s using his o ma . 6. ETHICAL CONSIDERATIONS Au ho s mus s a e ha he p o ocol o he esea ch p ojec has been app o ed by a sui ably cons i u ed E hics Commi ee o he ins i u ion wi hin which he wo k was unde aken and ha i con o ms o he p o isions o he Decla a ion o Helsinki (as e ised in Fo aleza, B azil, Oc obe 2013), a ailable a : h ps://www.wma.ne /wha -we- do/medical-e hics/decla a ion-o -helsinki/. In gene al, submission o a case epo should be accompanied by he w i en consen o he subjec (o pa en /gua dian) be o e publica ion; his is pa icula ly impo an whe e pho og aphs a e o be used o in cases whe e he unique na u e o he inciden epo ed makes i possible o he pa ien o be iden i ied. While he Edi o s ecognize ha i migh no always be possible o app op ia e o seek such consen , he onus will be on he au ho s o demons a e ha his excep ion applies in hei case. Any expe imen s in ol ing animals mus be demons a ed o be e hically accep able and whe e ele an con o m o na ional guidelines o animal usage in esea ch. Diges i e Endoscopy e ains he igh o ejec any manusc ip on he basis o une hical conduc o ei he human o animal s udies. Da a Sha ing and Da a Accessibili y The jou nal encou ages au ho s o sha e he da a and o he a e ac s suppo ing he esul s in he pape by a chi ing i in an app op ia e public eposi o y. Au ho s should include a da a accessibili y s a emen , including a link o he eposi o y hey ha e used, in o de ha his s a emen can be published alongside hei pape . 7. REGISTRY OF RESEARCH STUDIES INVOLVING HUMAN SUBJECTS As shown in he Decla a ion o Helsinki (Fo aleza, B azil, Oc obe 2013), e e y esea ch s udy in ol ing human subjec s mus be egis e ed in a publicly accessible da abase be o e ec ui men o he i s subjec . Thus any esea ch p ojec ha assigns human subjec s o in e en ion o compa ison g oups o s udy he cause-and-e ec ela ionship be ween a medical in e en ion and a heal h ou come mus be egis e ed. The abo e policy applies o e e y esea ch s udy which began wi h en ollmen o pa ien s a e No embe 1s 2013 (I au ho s a e conside ing submi ing a non- egis e ed p ospec i ely designed esea ch s udy, please explain he eason why i has no been egis e ed. Regis a ion o e ospec i e s udies is no equi ed, bu mus ha e o icial app o al om an app op ia e e hical commi ee a submission o he s udy). Resea ch s udies men ioned abo e should be egis e ed in one o he egis ies app o ed by ICMJE. Regis ies ha cu en ly mee all necessa y c i e ia include: (1) he egis y sponso ed by he Uni ed S a es Na ional Lib a y o Medicine (h p://www.clinical ials.go ); (2) he In e na ional S anda d Randomized Con olled T ial Numbe Regis y (h p://www.con olled- ials.com/); (3) he Aus alian New Zealand Clinical T ials Regis y (h p://www.anzc .o g.au/); (4) he Chinese Clinical T ials Regis y (h p://www.chic .o g/); and (5) he Clinical T ials Regis y – India (h p://www.c i.nic.in/); (6) Uni e si y Hospi al Medical In o ma ion Ne wo k (UMIN) (h p://www.umin.ac.jp/c /). 8. RANDOMIZED CONTROLLED TRIALS Randomized con olled ials should ollow he guidelines o he CONSORT S a emen . The CONSORT S a emen will also be used as he c i e ia o pee e iew o andomized con olled ial pape s: h p://www.conso -s a emen .o g/. Please upload he Conso 2010 Checklis wi h you main ex when you submi RCT manusc ip s. 9. MANUSCRIPT CATEGORIES AND REQUIREMENTS (i) ORIGINAL ARTICLES Wo d Limi : 3000 wo ds including abs ac bu excluding e e ences, ables and igu es. Au ho s: Maximum o 29 au ho s. In case you ha e 30 au ho s o mo e, please con ac Edi o ial O ice a diges i [email protected] .jp / [email protected] .jp p io o submission. Abs ac : 250 wo ds maximum, s uc u ed (subheade s): Objec i es, Me hods, Resul s, Conclusions. Re e ences: No limi . Figu es/Tables: No limi . Suppo ing In o ma ion: Video, addi ional da a, ables and audio a e accep able as suppo ing in o ma ion. Desc ip ion: Full-leng h epo s o cu en esea ch in ei he basic o clinical science. A ange ex as ollows: In oduc ion, Me hods, Resul s, Discussion, Acknowledgmen , Con lic o In e es s, Re e ences, and when ele an , Supplemen a y Ma e ial. (ii) REVIEW ARTICLES Wo d Limi : 3500 wo ds including abs ac bu excluding e e ences, ables and igu es. Au ho s: Maximum o 29 au ho s. In case you ha e 30 au ho s o mo e, please con ac Edi o ial O ice a diges i [email protected] .jp / [email protected] .jp p io o submission. Abs ac : 250 wo ds maximum, s uc u ed o uns uc u ed. Re e ences: No limi . Figu es/Tables: No limi . Suppo ing In o ma ion: Video, addi ional da a, ables and audio a e accep able as suppo ing in o ma ion. Desc ip ion: Re iews a e comp ehensi e analyses o speci ic opics wi h an inclusi e e e ence lis , o hey may be sys ema ic e iews. Al hough na a i e e iew a icles a e accep ed, sys ema ic e iews would be p e e able o publica ion. Some o hem will be submi ed upon in i a ion by he Edi o . Bo h solici ed and unsolici ed e iew a icles will unde go pee e iew p io o accep ance. (iii) CASE REPORTS Only cases o excep ional in e es and no el y a e conside ed. Fo manusc ip s ha do no quali y, Edi o s may ask au ho s o sho en manusc ip s and ew i e as Le e s, Techniques and Images. Wo d Limi : 1500 wo ds including abs ac bu excluding e e ences, ables and igu es. Abs ac : Sho , uns uc u ed (no use o subheade s). Maximum o 250 wo ds. Re e ences: Up o 10 in o al. Figu es/Tables: Up o ou in o al. Suppo ing In o ma ion: Video, addi ional da a, ables and audio a e accep able as suppo ing in o ma ion. Desc ip ion: New obse a ions o diseases, clinical indings o no el/unique ea men ou comes ele an o p ac i ione s in Endoscopy. A ange ex as ollows: Abs ac ; In oduc ion; Case Repo ; Discussion; Acknowledgmen ; Con lic o In e es s; Re e ences. (i ) HOW I DO IT Wo d Limi : 3000 wo ds including abs ac bu excluding e e ences, ables and igu es. Abs ac : 250 wo ds, uns uc u ed (no use o subheade s). Re e ences: Up o 20 in o al. Figu es/Tables: Up o i e in o al. Suppo ing In o ma ion: Video, addi ional da a, ables and audio a e accep able as suppo ing in o ma ion. Desc ip ion: How I Do I con ains use ul clinical imp o emen s o diagnosis and ea men . I mus be based on empi ical obse a ion and i should include discussions abou me hods and esul s wi h e e ences. A ange ex as ollows: Abs ac ; In oduc ion; P ocedu e o Technique; Discussion. ( ) LETTERS, TECHNIQUES AND IMAGES Wo d Limi : 300 wo ds. Au ho s: Maximum o h ee au ho s. Abs ac : No abs ac . Re e ences: Up o i e. Figu es/Tables/Images: Up o wo. Size o one igu e should no exceed 80 mm ho izon al x 80 mm e ical. Composi e pho os can be accep ed wi hin his size egula ion when necessa y. Suppo ing In o ma ion: Addi ional da a, igu es and ables a e accep able as suppo ing in o ma ion. Videos should be submi ed o he ca ego y “DEN VIDEO ARTICLES.” Desc ip ion: Le e s may be submi ed o he Edi o on any opic o discussion; clinical obse a ions, as well as le e s commen ing on pape s published in ecen issues. Manusc ip s o me ly published as New Ins umen s and Techniques, Endoscopic Images o In e es , and Clinical T ial No es a e now published unde his manusc ip ca ego y. ( i)DEN VIDEO ARTICLES [ONLINE ONLY] B ie Explana ion (no s uc u ed, in one pa ag aph): Up o 300 wo ds. Au ho s: Maximum o h ee au ho s. Abs ac : No abs ac . Re e ences: Up o i e. Figu es/Tables/Images: Up o wo (se o pho og aphs will be coun ed as one igu e) Videos: Each Video clip will be online ee o access. The o al leng h o he ideo should no be longe han 10 minu es, and he leng h o one ideo s eam should be limi ed o 5 minu es. All ideo o ma s a e accep ed, bu au ho s should bea in mind ha m4 o mp4 a e some imes no compa ible o play/ download in In e ne Explo e o Ch ome and only compa ible o Fi e ox. All na a ion and/ o sub i les should be in English. The ideo should be edi ed ha he eade can unde s and and accompanied by a s uc u ed na a ion and/ o sub i le. All ideos submi ed mus be o he highes quali y possible. You may be ad ised o e ise you ideo i i s quali y is below ou s anda ds. The ma e ials a e published as hey a e supplied and a e no checked o copyedi ed in any way. Use he Video A icle Templa e o p epa e he ideo. A ideo ile should be named s a ing wi h a leas he i s 20 cha ac e s o he manusc ip i le. I you ha e p oblem in uploading you ideo because he size o he ideo is oo big, please con ac [email protected] .jp / diges i [email protected] .jp abou submission o he ideo. Desc ip ion: DEN Video A icles a e a icles wi h a ideo and a b ie explana ion accompanying he submi ed ideo. The ideo mus show inno a i e echniques o clinically impo an use o endoscopy wi h b ie and concise explana ion o he echniques/ clinical impo an poin s in he ex . A publica ion cha ge: 300 USD pe one a icle is cha ged o au ho s commencing om submissions ecei ed a e 1 May 2018. An au ho will be eques ed o send he comple ed page cha ge o mwi hin 3 days when a manusc ip is accep ed o publica ion. ( ii) EDITORIALS [BY INVITATION OF EDITORS] Wo d Limi : 1600 wo ds. Abs ac : No abs ac . Re e ences: Up o 10 in o al. Desc ip ion: P oposals o Edi o ials may be submi ed; howe e , in his case, au ho s should only send an ou line o he p oposed pape o ini ial conside a ion. 10. PREPARATION OF THE MANUSCRIPT Au ho Se ices P io o submission, we encou age you o b owse he ‘Au ho Resou ces’ sec ion o he Wiley ‘Au ho Se ices’ websi e: h p://au ho se ices.wiley.com/bau ho /de aul .asp. This si e includes use ul in o ma ion co e ing such opics as copy igh ma e s, e hics and elec onic a wo k guidelines. P e-accep ance English-language edi ing Au ho s o whom English is a second language may choose o ha e hei manusc ip p o essionally edi ed be o e submission o imp o e he English. Visi ou si e o lea n abou he op ions. All se ices a e paid o and a anged by he au ho . Please no e using he Wiley English Language Edi ing Se ice does no gua an ee ha you pape will be accep ed by his jou nal. Op imizing You A icle o Sea ch Engines Many s uden s and esea che s looking o in o ma ion online will use sea ch engines such as Google, Yahoo o simila . By op imizing you a icle o sea ch engines, you will inc ease he chance o someone inding i . This in u n will make i mo e likely o be iewed and/o ci ed in ano he wo k. We ha e compiled hese guidelines o enable you o maximize he web- iendliness o he mos public pa o you a icle. S yle Manusc ip s Submi ed o Biomedical Jou nals: W i ing and Edi ing o Biomedical Publica ions’ as p esen ed a : h p://www.ICMJE.o g/. Spelling: The jou nal uses US spelling and au ho s should he e o e ollow he la es edi ion o he Me iam–Webs e ’s Collegia e Dic iona y. Uni s: All measu emen s mus be gi en in SI o SI-de i ed uni s. S a is ics and measu emen s should always be gi en in nume als; ha is, 10 mm. Con using ma hema ical no a ion, and pa icula ly subsc ip s and supe sc ip s, should be a oided. Fo mo e in o ma ion abou SI uni s, please go o he Bu eau In e na ional des Poids e Mesu es (BIPM) websi e a : h p://www.bipm. /. Abb e ia ions and Ac onyms: S anda d abb e ia ions may be used and should be de ined in he abs ac and on i s men ion in he ex . In gene al, howe e , abb e ia ions should be used spa ingly and only whe e hey ease he eade ’s ask by educing epe i ion o long, echnical e ms. Ini ially use he wo d in ull, ollowed by he abb e ia ion in pa en heses. The ea e , use he abb e ia ion. T ade Names: D ugs should be e e ed o by hei gene ic names. I p op ie a y d ugs ha e been used in he s udy, e e o hese by hei gene ic name, men ioning he p op ie a y name, and he name and loca ion o he manu ac u e , in pa en heses. 11. STRUCTURE OF MANUSCRIPTS The leng h o manusc ip s mus adhe e o he speci ica ions unde he sec ion Manusc ip Ca ego ies. Manusc ip s should be p esen ed in he ollowing o de : (i) i le page; (ii) abs ac and key wo ds; (iii) ex ; (i ) acknowledgmen s; ( ) con lic s o in e es ; ( i) e e ences; ( ii) suppo ing in o ma ion; ( iii) igu e legends; (ix) ables (each able comple e wi h i le and oo no es); and (x) igu es. Foo no es o he ex a e no allowed and any such ma e ial should be inco po a ed in o he ex as pa en he ical ma e . TITLE PAGE The i le page should con ain: (i) he i le o he pape ; (ii) he ull names o he au ho s; and (iii) he add esses o he ins i u ions a which he wo k was ca ied ou oge he wi h (i ) he name, he ull pos al and email add ess, plus acsimile and elephone numbe s, o he au ho o whom co espondence abou he manusc ip should be sen . The p esen add ess o any au ho , i di e en om ha whe e he wo k was ca ied ou , should be supplied in a oo no e. In keeping wi h he la es guidelines o he In e na ional Commi ee o Medical Jou nal Edi o s, each au ho 's con ibu ion o he pape is o be quan i ied. The i le should be sho , in o ma i e and con ain he majo key wo ds. A sho unning i le (less han 40 cha ac e s including spaces) should also be p o ided. The unning i le is he sho i le in he uppe igh -hand co ne o he a icle o help acili a e a icle sea ch. ABSTRACT AND KEYWORDS The leng h o abs ac s mus adhe e o he speci ica ions unde he sec ion Manusc ip Ca ego ies. Please no e ha he equi emen s di e be ween manusc ip ypes. The abs ac should no con ain abb e ia ions o e e ences. Fi e key wo ds, o he pu poses o indexing, should be supplied below he abs ac , in alphabe ical o de , and should be aken om hose ecommended by he US Na ional Lib a y o Medicine’s Medical Subjec Headings (MeSH) B owse lis a : h p://www.nlm.nih.go /mesh/meshhome.h ml. TEXT Please no e ha he equi emen s di e be ween manusc ip ypes. Please e e o he sec ion Manusc ip Ca ego ies o indi idual equi emen s. ACKNOWLEDGMENTS The con ibu ion o colleagues o ins i u ions should be acknowledged. Thanks o anonymous e iewe s a e no app op ia e. CONFLICT OF INTERESTS Au ho s a e equi ed o disclose any con lic o in e es s. The s a emen should be he same as on he Au ho Submission Requi emen Fo m. The absence o any in e es o disclose mus also be s a ed. REFERENCES The Vancou e sys em o e e encing should be used. In he ex , e e ences should be ci ed using supe sc ip A abic nume als in he o de in which hey appea . I ci ed only in ables o igu e legends, numbe hem acco ding o he i s iden i ica ion o he able o igu e in he ex . In he e e ences lis , he e e ences should be numbe ed and lis ed in o de o appea ance in he ex . Ci e he names o all au ho s when he e a e six o ewe ; when se en o mo e au ho s, lis he i s h ee ollowed by e al. Re e ence o unpublished da a and pe sonal communica ions should no appea in he e e ences lis bu should be ci ed in he ex only (e.g. Smi h A, 2000, unpubl. da a). All ci a ions men ioned in he ex , ables o igu es mus be lis ed in he e e ences lis . Names o jou nals should be abb e ia ed in he s yle used in Index Medicus. Au ho s a e esponsible o he accu acy o all e e ences. S anda d Jou nal A icle: 1 Oda I, Go oda T, Hamanaka H e al. Endoscopic submucosal dissec ion o ea ly gas ic cance : Technical easibili y, ope a ion ime and complica ions om a la ge consecu i e se ies. Dig. Endosc.2004; 17: 54–8. S anda d Jou nal A icle using DOI: a icles published online in ad ance wi hou olume, issue, o page numbe . The DOI will emain alid and allow an a icle o be acked e en a e i s alloca ion o an issue. (Mo e in o ma ion abou DOIs: h p://www.doi.o g/ aq.h ml): 2 Noda Y, Fuji a N, Kobayashi G e al. P ospec i e andomized con olled s udy compa ing cell block me hod and con en ional smea me hod o panc ea ic juice cy ology. Dig. Endosc. Published online: 13 Jul 2011; DOI:10.1111/j.1443-1661.2011.01180.x Book: 3 Yamada T. P inciples o Clinical Gas oen e ology. Blackwell Publishing, Bos on, 2008. Chap e in an Edi ed Book: 4 Ginsbe g GG. Endoscopic equipmen . In: Co on PB (ed). Ad anced Diges i e Endoscopy: P ac ice and Sa e y. Blackwell Publishing, Bos on, 2008; 43–76. Ci a ion o a web page: 5 AMA. helping doc o s help pa ien s [In e ne ]. Chicago: Ame ican Medical Associa ion; c1995-2007 [ci ed 2007 Feb 22]. A ailable om: h p://www.ama-assn.o g/. Ci a ion o a web page wi h au ho s: 6 D'Alessand o DM, D'Alessand o MP. Vi ual Pedia ic Hospi al™: a digi al lib a y o pedia ic in o ma ion [In e ne ]. [Iowa Ci y (IA)]: Donna M. D'Alessand o; c1992-2007 [ e ised 2006 Jul 20; ci ed 2007 Feb 20]. A ailable om: h p://www. i ualpedia ichospi al.o g/. TABLES Tables should be sel -con ained and complemen , bu no duplica e, in o ma ion con ained in he ex . Numbe ables consecu i ely in he ex in A abic nume als. Type ables on a sepa a e page wi h he legend abo e. Legends should be concise bu comp ehensi e – he able, legend and oo no es mus be unde s andable wi hou e e ence o he ex . Ve ical lines should no be used o sepa a e columns. Column headings should be b ie , wi h uni s o measu emen in pa en heses; all abb e ia ions mus be de ined in oo no es. Foo no e symbols: � , ‡, §, ¶, should be used (in ha o de ) and *, **, *** should be ese ed o P- alues. S a is ical measu es such as SD o SEM should be iden i ied in he headings. I ables ha e been ep oduced om ano he sou ce, a le e om he copy igh holde (usually he Publishe ) s a ing au ho iza ion o ep oduce he ma e ial mus be a ached o he co e ing le e . FIGURES All illus a ions (line d awings and pho og aphs) a e classi ied as igu es. Figu es should be ci ed in consecu i e o de in he ex . Figu es should be sized o i wi hin he column (80.5 mm), in e media e (112 mm) o he ull ex wid h (168 mm). Magni ica ions should be indica ed using a scale ba on he illus a ion. Line igu es should be sha p, black and whi e g aphs o diag ams, d awn p o essionally o wi h a compu e g aphics package. Le e ing mus be included and should be sized o be no la ge han he jou nal ex . Magni ica ions should be indica ed using a scale ba on he illus a ion. I igu es ha e been ep oduced om ano he sou ce, a le e om he copy igh holde (usually he Publishe ) s a ing au ho iza ion o ep oduce he ma e ial mus be a ached o he Au ho Submission Requi emen Fo m and also explici ly explained on he co e ing le e . Line Figu es: Mus be sha p, black and whi e g aphs o diag ams, d awn p o essionally o wi h a compu e g aphics package. Tex Sizing in Figu es: Le e ing mus be included and should be sized o be no la ge han he jou nal ex o 8 poin s (should be eadable a e educ ion – a oid la ge ype o hick lines.) Line Wid h: Be ween 0.5 and 1 poin . Figu e Legends Type igu e legends on a sepa a e page. Legends should be concise bu comp ehensi e – he igu e and i s legend mus be unde s andable wi hou e e ence o he ex . Include de ini ions o any symbols used and de ine/explain all abb e ia ions and uni s o measu emen . Mo e help on p epa a ion o illus a ions can be ound a : h p://au ho se ices.wiley.com/bau ho /illus a ion.asp EQUATIONS Equa ions should be numbe ed sequen ially wi h A abic nume als; hese should be anged igh in pa en heses. All a iables should appea in i alics. Use he simples possible o m o all ma hema ical symbols. dx/d = c(x − x3/3 y z) (1) DY/DT = −(X BY − A)/C (2) 12. SUPPORTING INFORMATION Suppo ing In o ma ion is p o ided by he au ho s o suppo he con en o an a icle bu i is no in eg al o ha a icle. Suppo ing In o ma ion is hos ed ia a link on Wiley Online Lib a y, bu does no appea in he p in e sion o he a icle. Suppo ing In o ma ion mus be submi ed oge he wi h he a icle o pee e iew; i should no be added a a la e s age. I can be in he o m o ables, igu es, appendices, audio and ideo oo age. Re e ence o Suppo ing In o ma ion in he main body o he a icle is allowed. Howe e , i should be no ed ha excessi e e e ence o a piece o Suppo ing In o ma ion may indica e ha i would be be e sui ed as a p ope e e ence o a ully included igu e/ able. The ma e ials a e published as hey a e supplied and a e no checked o ypese in any way. All Suppo ing In o ma ion iles should come wi h a legend, lis ed a he end o he main a icle. Each igu e and able ile should no be la ge han 5 MB, al hough ideo iles may be la ge . I you ha e p oblem in uploading you ideo because he size o he ideo is oo big, please con ac [email protected] .jp / diges i [email protected] .jp abou submission o he ideo. All ideos submi ed mus be o he highes quali y possible. P io o submission, please check he guidelines a : h p://au ho se ices.wiley.com/bau ho /suppma .asp. 13. SUBMISSION REQUIREMENTS Manusc ip s mus be submi ed online a : h p://mc.manusc ip cen al.com/den/. Au ho s mus supply an email add ess as all co espondence will be by email. Two iles should be supplied: he co e ing le e and he manusc ip (in Wo d o ich ex o ma (. )). The co e ing le e should be uploaded as a ile no o e iew. COVERING LETTER Pape s a e accep ed o publica ion in he jou nal on he unde s anding ha he con en has no been published o submi ed o publica ion elsewhe e. This mus be s a ed in he co e ing le e . The co e ing le e mus con ain an acknowledgmen ha all he au ho s ha e con ibu ed signi ican ly, and ha all au ho s a e in ag eemen wi h he con en o he manusc ip . In keeping wi h he la es guidelines o he In e na ional Commi ee o Medical Jou nal Edi o s, each au ho ’s con ibu ion o he pape is o be quan i ied. I ables o igu es ha e been ep oduced om ano he sou ce, a le e om he copy igh holde (usually he Publishe s a ing au ho iza ion o ep oduce he ma e ial) mus be a ached o he co e ing le e . 14. NO PUBLICATION FEES Up o ou colo illus a ions, i judged ele an and o good quali y, will be published ee o cha ge. A cha ge o A$550/US$265/¥32,000 o he i h and subsequen colo igu es will be cha ged o he au ho . Composi e colo pho og aphs made up o smalle pic u es will no be accep ed. Fo DEN Video A icles, a publica ion cha ge o 300 USD is cha ged o au ho s commencing om submissions ecei ed a e 1 May 2018. A o m eques ing paymen will be a ailable o download wi h you PDF p oo . 15. PUBLICATION PROCESS AFTER ACCEPTANCE Accep ed pape s will be passed o Wiley’s p oduc ion eam o publica ion. The au ho iden i ied as he o mal co esponding au ho o he pape will ecei e an email p omp ing hem o login in o Wiley’s Au ho Se ices, whe e ia he Wiley Au ho Licensing Se ice (WALS) hey will be asked o comple e an elec onic license ag eemen on behal o all au ho s on he pape . Mo e de ails on he copy igh and licensing op ions o he jou nal appea below. Wiley’s Au ho Se ices Au ho Se ices enables au ho s o ack hei a icle h ough he p oduc ion p ocess o publica ion online and in p in . Au ho s can check he s a us o hei a icles online and choose o ecei e au oma ed e-mails a key s ages o p oduc ion. The co esponding au ho will ecei e a unique link ha enables hem o egis e and ha e hei a icle au oma ically added o he sys em. Please ensu e ha a comple e e-mail add ess is p o ided when submi ing he manusc ip . Visi h p://www.au ho se ices.wiley.com/ o mo e de ails on online p oduc ion acking and o a weal h o esou ces including FAQs and ips on a icle p epa a ion, submission and mo e. Accep ed A icles The jou nal o e s Wiley’s Accep ed A icles se ice o all manusc ip s. This se ice ensu es ha accep ed ‘in p ess’ manusc ip s a e published online e y soon a e accep ance, p io o copy-edi ing o ypese ing. Accep ed A icles a e published online a ew days a e inal accep ance, appea in PDF o ma only, a e gi en a Digi al Objec Iden i ie (DOI), which allows hem o be ci ed and acked, and a e indexed by PubMed. A e p in publica ion, he DOI emains alid and can con inue o be used o ci e and access he a icle. The Accep ed A icles se ice has been designed o ensu e he ea lies possible ci cula ion o esea ch pape s a e accep ance. Gi en ha copy igh licensing is a condi ion o publica ion, au ho s a e equi ed o comple e a copy igh license be o e manusc ip s can be p ocessed as an Accep ed A icle. Accep ed a icles will be indexed by PubMed; he e o e he submi ing au ho mus ca e ully check he names and a ilia ions o all au ho s p o ided in he co e page o he manusc ip , as i will no be possible o al e hese once a pape is made a ailable online in Accep ed A icle o ma . Subsequen ly he inal copyedi ed and p oo ed a icles will appea in an issue on Wiley Online Lib a y; he link o he a icle in PubMed will au oma ically be upda ed. P oo s Once he pape has been ypese he co esponding au ho will ecei e an e-mail ale con aining ins uc ions on how o p o ide p oo co ec ions o he a icle. I is he e o e essen ial ha a wo king e-mail add ess is p o ided o he co esponding au ho . P oo s should be co ec ed ca e ully; esponsibili y o de ec ing e o s lies wi h he au ho . Ea ly View The jou nal o e s apid speed o publica ion ia Wiley’s Ea ly View se ice. Ea ly View a icles a e comple e ull- ex a icles published online in ad ance o hei publica ion in a p in ed issue. Ea ly View a icles a e comple e and inal. They ha e been ully e iewed, e ised and edi ed o publica ion, and he au ho s' inal co ec ions ha e been inco po a ed. Because hey a e in inal o m, no changes can be made a e online publica ion. Ea ly View a icles a e gi en a Digi al Objec Iden i ie (DOI), which allows he a icle o be ci ed and acked be o e alloca ion o an issue. A e p in publica ion, he DOI emains alid and can con inue o be used o ci e and access he a icle. Mo e in o ma ion abou DOIs can be ound a h p://www.doi.o g/ aq.h ml. 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Au ho s o OnlineOpen a icles a e pe mi ed o pos he inal, published PDF o hei a icle on hei pe sonal websi e, and in an ins i u ional eposi o y o o he ee public se e immedia ely a e publica ion. All OnlineOpen a icles a e ea ed in he same way as any o he a icle. They go h ough he jou nal's s anda d pee - e iew p ocess and will be accep ed o ejec ed based on hei own me i . OnlineOpen licenses. Au ho s choosing OnlineOpen e ain copy igh in hei a icle and ha e a choice o publishing unde he ollowing C ea i e Commons License e ms: C ea i e Commons A ibu ion License (CC BY); C ea i e Commons A ibu ion Non-Comme cial License (CC BY NC); C ea i e Commons A ibu ion Non-Comme cial-NoDe i s License (CC BY NC ND). To p e iew he e ms and condi ions o hese open access ag eemen s please isi he Copy igh Te ms and Condi ions FAQs. Funde Open Access and Sel -A chi ing Compliance: Please click he e o mo e in o ma ion on Wiley’s compliance wi h speci ic Funde Open Access and Sel A chi ing Policies, and click he e o mo e de ailed in o ma ion speci ically abou Sel -A chi ing de ini ions and policies. 17. EDITORIAL OFFICE ADDRESS Edi o ial O ice Diges i e Endoscopy Shin-ochanomizu U ban T ini y Bldg. 4F, 3-2-1 Kandasu ugadai, Chiyoda-ku, Tokyo 101-0062, Japan Email: diges i [email protected] .jp, [email protected] .jp Tel: 81-3-3525-4670 Fax: 81-3-3525-4677 Au ho Guidelines upda ed 28 Feb ua y 2019 Ag adecimen os Em p imei o luga , um especial ag adecimen o ao Dou o Diogo Libânio pela o ien ação e apoio incondicional, pelo exemplo de igo cien í ico e pela o al disponibilidade e a quem ag adeço, ainda, a con iança deposi ada em mim e nas minhas capacidades. Ao P o esso Dou o Má io Dinis Ribei o po me e dado a opo unidade de ealiza es e p oje o com a sua equipa e ainda pela ines imá el ajuda na concep ualização e e isão do abalho. Ao P o esso Dou o Ped o Pimen el Nunes o con ibu o indispensá el à conc e ização e inalização des a ese. Finalmen e, um especial ag adecimen o à minha amília, amigos e colegas que acompanha am es a jo nada e cujo apoio me oi imp escindí el.