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

2018/2019 Gonçalo Vieira Figueirôa Gomes Poor outcomes after gastric Endoscopic Submucosal Dissection: a systematic review and meta-analysis on predictive factors Resultados desfavoráveis após disseção endoscópica da submucosa gástrica: revisão sistemática e meta-análise março, 2019 Mestrado Integrado em Medicina Área: Gastrenterologia Tipologia: Dissertação Trabalho efetuado sob a Orientação de: Dr. Diogo Miguel Pereira Libânio Monteiro E sob a Coorientação de: Professor Doutor Mário Jorge Dinis Ribeiro Trabalho organizado de acordo com as normas da revista: Digestive Endoscopy Gonçalo Vieira Figueirôa Gomes Poor outcomes after gastric Endoscopic Submucosal Dissection: a systematic review and meta-analysis on predictive factors Resultados desfavoráveis após disseção endoscópica da submucosa gástrica: revisão sistemática e meta-análise março, 2019 Poor outcomes after gastric Endoscopic Submucosal Dissection: a systematic review and meta-analysis on predictive factors Gonçalo Figueirôa1, Pedro Pimentel-Nunes MD PhD1,2, Mário Dinis-Ribeiro MD PhD1,2, Diogo Libânio MD1,2 1 MEDCIDS – Departamento de Medicina da Comunidade, Informação e Decisão em Saúde, Porto, Portugal 2 Gastroenterology Department, Instituto Português de Oncologia do Porto, Porto, Portugal Corresponding author: Gonçalo Figueirôa Departamento de Medicina da Comunidade, Informação e Decisão em Saúde (MEDCIDS) Faculdade de Medicina da Universidade do Porto Rua Doutor Plácido da Costa 4200-450 Porto, Portugal Phone: +351 969 925 733 E-mail: [email protected] ABSTRACT BACKGROUND AND AIMs: Endoscopic submucosal dissection (ESD) is now established as the first option to manage early gastric neoplasms but its efficacy may vary according to diverse factors. We aimed to systematically identify variables predictive of poor outcomes of gastric ESD. METHODS: Three online databases (MEDLINE, ISI Web of Knowledge and Scopus) were searched (last search on June 2018) for poor outcomes of gastric ESD (deep submucosal invasion, piecemeal/incomplete resection, non-curative resection, local recurrence and metachronous lesions). RESULTS: One hundred and fourteen studies were included referring to 55.986 ESDs. Undifferentiated histology and upper location (vs lower) were found to be associated to submucosal invasion (OR=2.42 [95%CI 1.62-3.61] and OR=3.20 [1.04-9.86], respectively) and deep submucosal invasion (OR=2.98 [2.02-4.39] and OR=2.35 [1.45-3.81], respectively). Lesion size >30mm and ulceration were associated with piecemeal resection (OR=2.78 [1.17-6.60] and OR=2.76 [1.23, 6.20]). Lesion size >30mm, ulceration, upper location and fibrosis were risk factors for incomplete resection (OR=3.83 [2.68-5.49], OR=4.06 [1.62-10.16], OR=3.71 [2.495.54] and OR=4.46 [1.66-11.96]), respectively). A non-curative resection was more often observed for lesions with upper location (OR=1.49 [1.24-1.79]), depressed morphology (OR=1.49 [1.04-2.12]) and those outside standard criteria (OR=3.56 [2.31-5.48]). Older age was significantly linked with local recurrence rates (OR=3.08 [1.13-5.02]) and metachronous lesions (OR=3.00 [1.77-4.22]). CONCLUSIONS: Several risk factors influence poor efficacy outcomes of gastric ESD that may be used to inform both patients and health providers about the expected efficacy. Key words: Endoscopic submucosal dissection, gastric cancer, outcomes, risk factors. Introduction Early gastric neoplasms with null or minimal risk of lymph node metastasis (LNM) can be effectively treated by gastric endoscopic submucosal dissection (ESD). Endoscopic resection (by Endoscopic Mucosal Resection or ESD) is recommended as the standard treatment for differentiated adenocarcinoma <2cm clinically diagnosed as intramucosal (T1a); lesions with low risk of LNM but outside these criteria can also be treated with ESD as an alternative to surgery, although it is still considered as an investigational treatment in Japanese guidelines[1]. Recent European guidelines recommend endoscopic resection as the first line treatment for gastric superficial neoplastic lesions with very low risk of LNM, being ESD recommended as the treatment of choice[2]. Since the introduction of ESD, several studies evaluated its efficacy and safety in the treatment of early gastric neoplasms [3-6]. After efficacy and safety is proven and a technology becomes accepted and widely performed, research should aim to predict and optimize outcomes, in order to improve patient selection for the technique and also to improve patient information about expected outcomes [7-9]. ESD achieves en-bloc/R0 resections in more than 90% of the cases [10]. Lesions suitable for endoscopic treatment are selected based on the endoscopic evaluation with chromoendoscopy (endoscopic ultrasound does not improve prediction of submucosal invasion and therefore is not routinely recommended) [2]. However, ESD is not curative in nearly 20% of the cases because histopathological evaluation shows previously unsuspected submucosal invasion or lymphovascular invasion (among other criteria)[11]. Thus, evaluation of risk factors for submucosal invasion is important in order to improve patient selection for ESD. Since en-bloc resection and R0 resection are requisites for curative resection, it is also important to analyze risk factors for piecemeal and R1 that could possibly help in the selection of procedural modifications or perhaps referral for expert centers [12-14]. ESD is associated with low local recurrence rates (1-3%) but with a high risk of metachronous lesions on long-term follow-up which makes endoscopic surveillance necessary [11, 15, 16]. Several studies also assessed risk factors for these long-term outcomes, although results are often controversial. The identification of risk factors for recurrence and metachronous could therefore influence surveillance schedule. In summary, several patientand lesion-specific factors have been found to influence both shortand long-term outcomes, but there is no consensus regarding which factors are actually significant. The aim of this study was to assess risk factors (clinical or endoscopic variables, available at the pre-resection stage) for poor efficacy outcomes of gastric ESD, both short-term (submucosal invasion, piecemeal and incomplete resection, non-curative resection) and long-term (local recurrence and metachronous lesions). Methods a) Study selection A systematic review of the literature was conducted in three electronic databases (MEDLINE through Pubmed), ISI Web of Knowledge and Scopus from inception until 26th June 2018. The following search query without language restriction was used in Pubmed: ([gastric OR stomach] AND [“endoscopic submucosal dissection” OR “ESD”]) AND (non-curative OR “non curative” OR “submucosal invasion” OR “treatment failure” OR “procedure failure” OR “recurrence”), with the search query for other databases being adapted from this query. The references of included studies and retrieved articles were uploaded to Covidence online platform (www.covidence.org) that was used for articles selection. Both title and abstract screening (for exclusion of irrelevant articles) and full text screening were made by two independent investigators (GF, DL), being conflicts solved by consensus. The following inclusion Discussion This systematic review and meta-analysis is, to our knowledge, the first that evaluated preresection risk factors for poor outcomes of gastric ESD (deep submucosal invasion, non-curative resection, piecemeal/incomplete resection, local recurrence and metachronous lesions). ESD is gaining worldwide acceptance as the first line treatment for gastric superficial neoplasms, although it is unsuccessful in nearly 20% of the cases [11]. Identification of pre-resection risk factors for poorer efficacy outcomes of gastric ESD is thus important in order to refine patient selection for this technique and also to better inform patients about the success probability of endoscopic treatment, given that surgical resection can also be considered when the risk of poor outcomes is significant. We previously evaluated risk factors which potentially influenced safety of resection, but data was controversial regarding the predictors of poor effectiveness of gastric ESD [7] [8] [3] [4]. We found that an undifferentiated histology is a significant risk factor for submucosal invasion and deep submucosal invasion, which is probably explained by the predominantly infiltrative growth pattern of undifferentiated lesions [21]. Concerning location, proximal lesions seem to have a higher propensity of harboring submucosal invasion. While the biological explanation remains unknown, possibly upper lesions are more prone to be missed at endoscopy and are detected later. Greater lesion size and ulceration were associated with incomplete/piecemeal resection, likely given to technical procedural difficulties. Furthermore, an upper location also increases the risk of IR which is probably related with the more challenging dissection in retroflexed position. A higher degree of fibrosis was also identified as being associated with higher IR rates, and can also difficult resection given that the identification of the resection field may be impaired. Expanded Endoscopic Indication was found to be associated with PR/IR, which is in line with a previous meta-analysis[22]. Finally, an undifferentiated histology was associated with IR, which is probably related with difficulties in identifying lesion margins even using chromoendoscopy and also with deeper infiltration which may difficult achieving a free vertical margin. Lesions characteristics, namely greater size, upper location, depressed morphology and ulceration were significantly associated with non-curative resection. Furthermore, EGCs outside standard criteria were also found to be associated with NCR, which supports the importance of this classification. An age over 75 years, contrasting with other cut-offs also evaluated, was identified as a significant risk factor, which is probably related to the preference of minimally invasive treatment like ESD in older patients even when the probability of NCR is higher. Age is consistently reported as a risk factor for LR and ML and was found to be a significant risk factor in our study. This finding can have implications in surveillance schedule, given that according to this data it is difficult to define an age cut-off when resection is no longer of benefit (contrasting with colorectal cancer and post-polypectomy surveillance). Other significant risk factors, such as an upper location, an undifferentiated histology and BEC lesions were linked to the occurrence of LR. We acknowledge that incomplete resection is also the most important risk factor for LR; however, the aim of this systematic review was to identify pre-resection variables associated with this outcome, and so the significance of incomplete resection on LR was not evaluated in this study although it was evaluated in a previous meta-analysis by our group [23]. On the other hand, ML was significantly associated with the presence of multiple lesions, most likely due to the presence of a field defect and microsatellite instability [24]. In summary, a proximal location is a risk factor for SI, DSI, IR, LR and NCR. Undifferentiated histology is a risk factor for SI, DSI, IR, and LR, ulceration for PR, IR and NCR, Expanded Endoscopic Indication for PR and IR and Expanded Endoscopic Criteria for NCR and LR. Finally, age is a risk factor for NCR, LR and ML and greater lesion size for PR, IR and NCR. The primary limitation that we acknowledge in our study is the occasional scarcity of studies for some risk factors. As such, some of the conclusions here drawn may be underpowered, given that it hinders the detection of possible interactions and confounding between risk factors. Nevertheless, we consider that our results are valuable and are a step forward in enabling endoscopists in better selecting patients that should be submitted ESD. In conclusion, this study identifies a set of pre-resection risk factors which significantly influence several poor efficacy outcomes, both shortand long-term, related to the resection of gastric EGCs using ESD. We believe that the conclusions here drawn can be useful in guiding gastroenterologists when selecting patients that should undergo ESD and better defining the prognosis of such resection. Figure 1 – Flowchart of included studies. Figure 2 – Forrest plot of Piecemeal resection rate according to the presence/absence of ulceration. Figure 3 – Forrest plot of Incomplete resection rate according to size (20mm as cut-off). Figure 4 – Forrest plot of Non-curative resection rate according to localization (upper vs lower). Tables Table 1 – General characteristics of included studies. Period n1 (n2) Outcome(s) evaluated Risk factors evaluated Quality MA Prospective studies Japan Hirata K, 2013 [25] 2008-2010 65 (65) ML Multiple 8 Yes Semba S, 2008 [26] - 73 ( - ) ML Single (Claudin expression) 8 No Hasuo T, 2007 [27] 2000-2004 110 (110) ML Single (Microsatellite Instability Status) 7 No Yagi K, 2014 [28] 2010-2013 - (197) SI Multiple 7 Yes Takenaka R, 2008 [29] 2001-2005 275 (306) PR, IR, LR Multiple 7 Yes China Shi H, 2017 [30] 2013-2014 32 (32) LR Single (MicroRNA-499 rs3746444 A/G polymorphism) 7 No Yu K, 2017 [31] 2013-2014 45 (45) LR Single (miR-34b rs4938723 Polymorphism) 8 No Li H, 2012 [32] 2009-2011 146 (164) DSI Single (ME-NBI image type) 7 No Xue H, 2016 [33] 2013-2015 230 ( - ) LR Single (CD44 expression) 6 No Fu QY, 2016 [34] 2009-2015 242 (242) SI, DSI Single (Lateral Margin Positivity) 8 No Korea Ok KS, 2016 [35] 2012-2014 160 (160) SI Multiple 7 No Choi IJ, 2016 [18] 2010-2011 712 (737) SI, NCR Multiple 9 Yes Europe Probst A, 2017 [36] 2005-2016 179 (191) SI, DSI, PR, IR, NCR Single (Endocopic Criteria) 9 No Retrospective studies Japan Nagami Y, 2014 [37] 2007-2011 43 (43) SI, PR, IR, NCR Single (Histology) 8 No Omae, 2013 [38] 2004-2010 44 (44) SI, NCR Multiple 7 Yes Nishide N, 2012 [39] 2002-2009 59 (62) PR, IR Multiple 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 Multiple 7 No Oka S, 2014 [42] 2002-2011 97 (97) SI, DSI, IR, NCR Single (Histology) 8 No Kanemistu T, 2014 [43] 2006-2011 - (105) SI Multiple 8 No Komori K, 2016 [44] 2002-2012 107 (124) PR, IR Single (Age) 9 Yes Hirasaki S, 2007 [45] 2002-2006 112 (112) SI, PR, IR Single (Size) 8 Yes Nakata B, 2016 [46] 2007-2016 123 (140) PR, NCR Single (Endocopic Indication) 8 Yes Yamada T, 2014 [47] 2007-2012 132 (143) SI Single (Submucosal and lymphovascular invasions) 8 No Sugimoto T, 2015 [48] 2000-2009 155 ( - ) ML Multiple 8 Yes Horiguchi N, 2016 [49] 2007-2015 164 (182) SI, DSI Single (Helicobacter pylori Eradication) 8 Yes Kakushima N, 2007 [50] 2000-2004 165 (184) IR Single (Age) 7 Yes Sanomura Y, 2012 [51] 1994-2009 173 (173) DSI, PR, IR Multiple 8 No Nakamoto S, 2009 [52] 1999-2007 177 (202) PR, IR Single (Size) 7 No Oka S, 2006 [53] 2002-2004 185 (195) PR, IR, LR Multiple 7 Yes Imagawa A, 2006 [54] 2002-2005 185 (196) PR, IR Multiple 7 Yes Katsube T, 2015 [55] 2003-2013 231 ( - ) SI, DSI, PR, NCR Multiple 8 Yes Goto O, 2009 [56] 2000-2007 231 (276) SI, PR, IR Single (Submucosal Invasion) 8 Yes Horiuchi Y, 2018 [57] 2005-2017 264 (268) NCR Multiple 8 Yes Takenaka R, 2006 [58] 2001-2005 269 (-) LR Multiple 6 No Oda I, 2006 [59] 2001 - (303) PR, NCR Multiple 7 Yes Yoshida M, 2016 [60] 2009-2014 307 (334) PR, IR Single (Learning Curve Phases) 6 No Boda T, 2014 [61] 2002-2010 357 (357) ML Multiple 8 No Ohara Y, 2016 [62] 2008-2012 363 (398) NCR Multiple 8 Yes Sugimoto T, 2012 [63] 2006-2010 418 (485) PR Multiple 9 Yes Kosaka T, 2014 [64] 2002-2007 438 ( - ) PR, NCR, LR, ML Multiple 8 Yes Ohnita K, 2009 [65] 2003-2008 468 (495) SI, PR, NCR Multiple 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 (Remnant) 8 Yes Goto, 2013 [68] 2006-2011 533 (605) SI, DSI, IR, NCR Multiple 8 Yes Isomoto H, 2009 [69] 2001-2007 551 (589) SI, PR, NCR, LR, ML Multiple 8 Yes Yamaguchi N, 2009 [70] 2001-2007 551 (589) SI, DSI, PR, IR, NCR Single (Endoscopic Criteria) 8 No Isomoto 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 Multiple 7 Yes Hirasawa K, 2011 [73] 2000-2010 784 (961) PR, IR, NCR Multiple 8 No Hoteya S, 2011 [74] 2003-2009 818 (977) SI, DSI, IR, NCR Multiple 7 Yes Numata N, 2015 [75] 2005-2011 890 (1053) IR Multiple 7 Yes Higashimaya M, 2013 [76] 2005-2011 891 (1027) IR Multiple 8 Yes Oda I, 2005 [77] 2000-2003 945 (1033) PR, IR, NCR Multiple 7 Yes Toyokawa T, 2012 [20] 2003-2010 967 (1123) SI, NCR Multiple 9 Yes Maehata Y, 2017 [78] 2003-2014 1053 ( - ) SI, ML Single (Helicobacter pylori Eradication) 8 Yes Nakamura K, 2015 [79] 2002-2011 1161 (1332) SI, PR, IR Single (Endocopic Criteria) 8 No Hoteya S, 2013 [80] 2005-2010 1224 (1463) IR, NCR Single (Location) 8 No Abe S, 2015 [81] 1999-2006 1526 ( - ) ML Multiple 9 Yes Kakushima N, 2011 [82] 2002-2008 - (1578) SI Single (Lateral Margin Positivity) 7 No Suzuki H, 2016 [83] 1999-2008 2268 (2268) IR Single (Lateral Margin Positivity) 8 No Horiuchi Y, 2018 [84] 2005-2016 2551 (2585) NCR Multiple 8 Yes China Chen ZS, 2017 [85] 2014-2015 80 (90) SI Single (Multiple Lesions) 8 No Li SJ, 2015 [86] 2011-2013 116 (116) SI, DSI, NCR Multiple 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 Multiple 8 Yes Korea Lee JY, 2010 [89] 2004-2008 43 (43) PR, IR, NCR Single (Location) 7 No Park JC, 2011 [90] 2002-2010 47 (47) SI, PR, IR, NCR Single (Location) 8 No Kim TK, 2015 [91] 2005-2012 55 (55) LR Single (Lateral Margin Positivity) 7 No Jeon HK, 2018 [92] 2005-2014 66 (66) SI, PR, IR, NCR Multiple 7 Yes Kim YY, 2013 [93] 2003-2010 74 (74) PR, IR, NCR, LR Single (Endoscopic Criteria) 8 No Choi MH, 2013 [94] 2002-2012 81 (82) SI, PR, IR, NCR, LR, ML Single (Histology) 8 No Gong EJ, 2016 [95] 2004-2011 88 (88) PR, IR, NCR Single (Location) 7 Yes Choe WH, 2018 [96] 2006-2013 90 ( - ) SI, DSI, PR, IR, LR, ML Single (Liver Cirrhosis) 9 Yes Choi JH, 2012 [97] 2004-2010 92 ( - ) SI, DSI, PR, IR Single (Liver Cirrhosis) 8 Yes Bae JH, 2015 [98] 2007-2013 110 (110) PR, IR, LR Single (Location) 7 No Myung YS, 2017 [99] 2005-2014 136 ( - ) SI, PR, IR Single (Proton Pump Inhibitor) 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 Criteria) 8 Yes Han JP, 2016 [102] 2001-2012 152 (152) LR Multiple 8 No Jeong JY, 2012 [103] 2006-2011 167 (161) SI, PR Single (Submucosal Fibrosis) 7 No Kim H, 2017 [104] - 176 ( - ) ML Single (Helicobacter pylori Infection) 8 Yes Chung CS, 2017 [105] 2008-2013 185 ( - ) SI, ML Multiple 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 Multiple 8 Yes Kang MS, 2015 [108] 2002-2008 280 (309) PR, IR, LR Single (Endocopic Criteria) 7 Yes Kwon YH, 2014 [109] 2007-2010 283 ( - ) ML Multiple 8 Yes Han JP, 2013 [110] 2001-2008 304 (335) PR, IR, NCR Multiple 7 No Kim BJ, 2010 [111] 2003-2006 337 (337) SI, PR, IR, LR, ML Single (Charlson Comorbidity Scale) 7 No Han JP, 2015 [112] 2002-2009 395 (430) PR, IR, LR, ML Single (Histology) 7 Yes Lee JY, 2016 [113] 2003-2010 401 (415) LR Multiple 7 Yes Kang HY, 2010 [114] 2005-2008 - (456) SI, IR Single (Histology) 8 Yes Choi MK, 2013 [115] 2006-2010 515 (522) SI, PR, NCR, LR, ML Single (Endocopic Indication) 8 Yes Ryu DG, 2017 [116] 2009-2015 532 (557) PR, IR Single (Histology) 8 Yes Sohn SH, 2017 [117] 2005-2014 599 (611) DSI, PR, IR Single (Endocopic Indication) 8 Yes Kim JM, 2016 [118] 2010-2011 712 (737) SI, DSI Multiple 8 Yes Kim JS, 2017 [119] 2009-2015 729 ( - ) PR, NCR, LR Multiple 8 Yes Kim YI, 2016 [120] 2004-2011 756 (765) PR, IR, NCR Single (Endocopic Indication) 9 Yes Lee H, 2011 [121] 2003-2010 780 (806) PR, IR, LR, ML Single (Endoscopic Criteria) 8 Yes Ahn JY, 2011 [122] 2005-2009 - (833) PR, IR, LR, ML Single (Endoscopic Criteria) 8 Yes Park CH, 2013 [123] 2005-2011 916 (931) PR, IR, NCR, LR, ML Multiple 8 Yes Jung S, 2015 [124] 2007-2011 1041 (-) SI, PR, ML Multiple 9 Yes Shin KY, 2015 [125] 2003-2010 1105 (1105) SI, DSI, PR, IR, NCR Single (Endoscopic Criteria) 8 No Yang HJ, 2017 [126] 2005-2014 1115 ( - ) ML Single (H pylori eradication) 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 Multiple 9 Yes Min BH, 2015 [130] 2003-2011 1497 (1539) SI, ML Multiple 8 Yes Kim EH, 2016 [131] 2007-2013 1639 ( - ) NCR Multiple 9 Yes Joh DH, 2015 [132] 2008-2011 1823 (1929) PR, IR, NCR Single (Multiple Lesions) 9 No Taiwan Hsieh Y, 2015 [133] 2004-2009 65 (69) NCR, LR, ML Multiple 7 No Europe Seara Costa R, 2018 [134] 2012-2017 105 (114) SI, PR, IR, NCR, LR, ML Single (Endoscopic Criteria) 8 Yes Libânio D, 2016 [19] 2005-2014 164 (194) NCR Multiple 8 Yes Libânio D, 2017 [9] 2005-2015 - (245) NCR Multiple 9 Yes n1 – number of patients included in the study; n2 – number of lesions included in the study; MA – Included in the meta-analysis (studies that reported risk factors not evaluated in other studies or that not provided data allowing calculation of odds ratio were not included in meta-analysis); ME-NBI – Narrow Band Imaging Magnification Endoscopy. Table 2 – Submucosal Invasion and Deep Submucosal Invasion related factors. Outcome Risk factors Submucosal Invasion Significantly associated Studies (n) Effect Estimate I2 Location Vertical (MxL) 3 2.11 [1.41, 3.16] 0% Location Vertical (UxL) 3 3.20 [1.04, 9.86] 64% Histology 4 2.42 [1.62, 3.61] 0% Single factors significantly associated VEC pattern [43], submucosal fibrosis [103], destructive micro surface pattern [35], ulceration [74] and metachronous lesions [34]. Not significantly associated Studies (n) Effect Estimate I2 Lesion size (20mm) 2 1.50 [0.28, 8.14] 71% Location Vertical (UxM) 3 1.17 [0.36, 3.80] 76% Morphology 3 1.05 [0.60, 1.84] 50% HP erradication 2 1.35 [0.85, 2.16] 0% Single factors not significantly associated Gastrectomy [67], PPIs administration [99], cirrhosis [97], charlson comorbidity scale (at least one risk factor) [111], BMI [127] and multiple lesions [85]. Deep Submucosal Invasion Significantly associated Studies (n) Effect Estimate I2 Location Vertical (UxM) 3 2.11 [1.18, 3.79] 52% Location Vertical (UxL) 3 2.35 [1.45,3.81] 42% Histology 3 2.98 [2.02, 4.39] 0% Single factors significantly associated Size over 30mm [118], metachronous lesions [34] and pattern C with ME-NBI (no surface pattern and sparse microvessels markedly distorted, isolated, heterogeneous or with avascular areas) [32]. Not significantly associated Studies (n) Effect Estimate I2 Location Vertical (MxL) 3 1.12 [0.81, 1.56] 0% Ulceration 3 1.42 [0.98, 2.06] 31% Single factors not significantly associated Age [69], sex [74], size over 20mm [72], location [118], morphology [118] and HP eradication [49]. n – number of studies; I2 – heterogeneity; M – middle third; L – lower third; U – upper third; VEC Pattern – Vessels within epithelial circle pattern; HP eradication – Helicobacter pylori eradication; PPIs – Protonpump inhibitors; BMI – Body Mass Index; ME-NBI – Magnification Endoscopy (Narrow Band Imaging). Table 3 – Piecemeal Resection and Incomplete Resection related factors. Outcome Risk factors Piecemeal Resection Significantly associated Studies (n) Effect Estimate I2 Lesion size >20mm 5 3.20 [2.07, 4.95] 24% Lesion size >30mm 2 2.78 [1.17, 6.60] 0% Endoscopic Indication (AI x EI) 7 2.25 [1.44, 3.53] 0% Endoscopic Indication (AI x BEI) 2 4.64 [1.68, 12.82] 0% Ulceration 6 2.76 [1.23, 6.20] 44% Single factors significantly associated Degree of fibrosis [103] Not significantly associated Studies (n) Effect Estimate I2 Age 3 1.37 [0.49, 3.79] 69% Location Vertical (UxM) 3 1.57 [0.51, 4.80] 57% Location Vertical (UxL) 3 3.57 [0.31, 41.12] 82% Location Vertical (MxL) 3 2.35 [0.74, 7.43] 59% Endoscopic Indication (EI x BEI) 2 1.53 [0.53, 4.37] 0% Histology 2 1.60 [0.73, 3.53] 0% Gastrectomy 2 2.04 [0.01, 411.2] 91% Cirrhosis 2 2.58 [0.70, 9.56] 0% Single factors not significantly associated Morphology [59], age over 70 years [63], age over 80 years [44], sex [63], multiple lesions [132], metachronous lesions [132], PPIs administration [99], Charlson comorbidity scale >=1[111], R-scope ESD [40], learning curve [60] and BMI [127]. Incomplete Resection Significantly associated Studies (n) Effect Estimate I2 Lesion size >20mm 7 3.64 [2.24, 5.91] 63% Lesion size >30mm 4 3.83 [2.68, 5.49] 0% Location Vertical (UxM) 5 1.62 [1.14, 2.31] 0% Location Vertical (UxL) 5 3.71 [2.49, 5.54] 0% Location Vertical (MxL) 5 2.28 [1.58, 3.28] 0% Endoscopic Indication (AI x EI) 3 3.86 [1.23, 12.08] 77% Ulceration 6 4.06 [1.62, 10.16] 83% Depth of Invasion (MxSM) 3 27.89 [3.57, 218.0] 91% Depth of Invasion (M/SM1xSM2) 2 14.99 [2.84, 79.25] 56% Histology 5 6.67 [3.42, 12.99] 66% Degree of Fibrosis 2 4.46 [1.66, 11.96] 69% Single factors significantly associated Size [58], tumor location [58], Endoscopic Indication [117] and age (mean) [88]. Not significantly associated Studies (n) Effect Estimate I2 Age 4 1.04 [0.54, 1.98] 55% Sex 2 0.96 [0.55, 1.68] 34% Morphology 2 0.90 [0.47, 1.75] 0% Gastrectomy 2 0.37 [0.07, 2.15] 87% Cirrhosis 2 3.66 [0.64, 20.74] 0% Single factors not significantly associated Sex [83], age >65 years [83], age >80 years [44], size [88], location (short axis) [68], location EGJ [80], PPI administration [99], Charlson comorbidity scale >=1 [111], learning curve phase [60], BMI [127], multiple lesions [132] and local recurrence [29]. n – number of studies; I2 – heterogeneity; AI – Absolute Indication; EI – Expanded Indication; BEI – BeyondExpanded Indication; U – upper third; M – middle third; L – lower third; PPIs – Proton-pump inhibitors; ESD – Endoscopic Submucosal Dissection; BMI – Body Mass Index; M – Mucosa; SM – submucosa; SM1 – lesions invading less than 500 μm from the submucosa in depth; SM2 – lesions invading 500 μm or more from the submucosa in depth; EGJ –Esophagogastric junction. 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Description: DEN Video Articles are articles with a video and a brief explanation accompanying the submitted video. The video must show innovative techniques or clinically important use of endoscopy with brief and concise explanation of the techniques/ clinical important points in the text. A publication charge: 300 USD per one article is charged to authors commencing from submissions received after 1 May 2018. An author will be requested to send the completed page charge formwithin 3 days when a manuscript is accepted for publication. (vii) EDITORIALS [BY INVITATION OF EDITORS] Word Limit: 1600 words. Abstract: No abstract. References: Up to 10 in total. Description: Proposals for Editorials may be submitted; however, in this case, authors should only send an outline of the proposed paper for initial consideration. 10. PREPARATION OF THE MANUSCRIPT Author Services Prior to submission, we encourage you to browse the ‘Author Resources’ section of the Wiley ‘Author Services’ website: http://authorservices.wiley.com/bauthor/default.asp. This site includes useful information covering such topics as copyright matters, ethics and electronic artwork guidelines. Pre-acceptance English-language editing Authors for whom English is a second language may choose to have their manuscript professionally edited before submission to improve the English. Visit our site to learn about the options. All services are paid for and arranged by the author. Please note using the Wiley English Language Editing Service does not guarantee that your paper will be accepted by this journal. Optimizing Your Article for Search Engines Many students and researchers looking for information online will use search engines such as Google, Yahoo or similar. By optimizing your article for search engines, you will increase the chance of someone finding it. This in turn will make it more likely to be viewed and/or cited in another work. We have compiled these guidelines to enable you to maximize the web-friendliness of the most public part of your article. Style Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publications’ as presented at: http://www.ICMJE.org/. Spelling: The journal uses US spelling and authors should therefore follow the latest edition of the Merriam–Webster’s Collegiate Dictionary. Units: All measurements must be given in SI or SI-derived units. Statistics and measurements should always be given in numerals; that is, 10 mm. Confusing mathematical notation, and particularly subscripts and superscripts, should be avoided. For more information about SI units, please go to the Bureau International des Poids et Mesures (BIPM) website at: http://www.bipm.fr/. Abbreviations and Acronyms: Standard abbreviations may be used and should be defined in the abstract and on first mention in the text. In general, however, abbreviations should be used sparingly and only where they ease the reader’s task by reducing repetition of long, technical terms. Initially use the word in full, followed by the abbreviation in parentheses. Thereafter, use the abbreviation. Trade Names: Drugs should be referred to by their generic names. If proprietary drugs have been used in the study, refer to these by their generic name, mentioning the proprietary name, and the name and location of the manufacturer, in parentheses. 11. STRUCTURE OF MANUSCRIPTS The length of manuscripts must adhere to the specifications under the section Manuscript Categories. Manuscripts should be presented in the following order: (i) title page; (ii) abstract and key words; (iii) text; (iv) acknowledgments; (v) conflicts of interest; (vi) references; (vii) supporting information; (viii) figure legends; (ix) tables (each table complete with title and footnotes); and (x) figures. Footnotes to the text are not allowed and any such material should be incorporated into the text as parenthetical matter. TITLE PAGE The title page should contain: (i) the title of the paper; (ii) the full names of the authors; and (iii) the addresses of the institutions at which the work was carried out together with (iv) the name, the full postal and email address, plus facsimile and telephone numbers, of the author to whom correspondence about the manuscript should be sent. The present address of any author, if different from that where the work was carried out, should be supplied in a footnote. In keeping with the latest guidelines of the International Committee of Medical Journal Editors, each author's contribution to the paper is to be quantified. The title should be short, informative and contain the major key words. A short running title (less than 40 characters including spaces) should also be provided. The running title is the short title in the upper right-hand corner of the article to help facilitate article search. ABSTRACT AND KEYWORDS The length of abstracts must adhere to the specifications under the section Manuscript Categories. Please note that the requirements differ between manuscript types. The abstract should not contain abbreviations or references. Five key words, for the purposes of indexing, should be supplied below the abstract, in alphabetical order, and should be taken from those recommended by the US National Library of Medicine’s Medical Subject Headings (MeSH) Browser list at: http://www.nlm.nih.gov/mesh/meshhome.html. TEXT Please note that the requirements differ between manuscript types. Please refer to the section Manuscript Categories for individual requirements. ACKNOWLEDGMENTS The contribution of colleagues or institutions should be acknowledged. Thanks to anonymous reviewers are not appropriate. CONFLICT OF INTERESTS Authors are required to disclose any conflict of interests. The statement should be the same as on the Author Submission Requirement Form. The absence of any interest to disclose must also be stated. REFERENCES The Vancouver system of referencing should be used. In the text, references should be cited using superscript Arabic numerals in the order in which they appear. If cited only in tables or figure legends, number them according to the first identification of the table or figure in the text. In the references list, the references should be numbered and listed in order of appearance in the text. Cite the names of all authors when there are six or fewer; when seven or more authors, list the first three followed by et al. Reference to unpublished data and personal communications should not appear in the references list but should be cited in the text only (e.g. Smith A, 2000, unpubl. data). All citations mentioned in the text, tables or figures must be listed in the references list. Names of journals should be abbreviated in the style used in Index Medicus. Authors are responsible for the accuracy of all references. Standard Journal Article: 1 Oda I, Gotoda T, Hamanaka H et al. Endoscopic submucosal dissection for early gastric cancer: Technical feasibility, operation time and complications from a large consecutive series. Dig. Endosc.2004; 17: 54–8. Standard Journal Article using DOI: articles published online in advance without volume, issue, or page number. The DOI will remain valid and allow an article to be tracked even after its allocation to an issue. (More information about DOIs: http://www.doi.org/faq.html): 2 Noda Y, Fujita N, Kobayashi G et al. Prospective randomized controlled study comparing cell block method and conventional smear method for pancreatic juice cytology. Dig. Endosc. Published online: 13 Jul 2011; DOI:10.1111/j.1443-1661.2011.01180.x Book: 3 Yamada T. Principles of Clinical Gastroenterology. Blackwell Publishing, Boston, 2008. Chapter in an Edited Book: 4 Ginsberg GG. Endoscopic equipment. In: Cotton PB (ed). Advanced Digestive Endoscopy: Practice and Safety. Blackwell Publishing, Boston, 2008; 43–76. Citation to a web page: 5 AMA. helping doctors help patients [Internet]. Chicago: American Medical Association; c1995-2007 [cited 2007 Feb 22]. Available from: http://www.ama-assn.org/. Citation to a web page with authors: 6 D'Alessandro DM, D'Alessandro MP. Virtual Pediatric Hospital™: a digital library of pediatric information [Internet]. [Iowa City (IA)]: Donna M. D'Alessandro; c1992-2007 [revised 2006 Jul 20; cited 2007 Feb 20]. Available from: http://www.virtualpediatrichospital.org/. TABLES Tables should be self-contained and complement, but not duplicate, information contained in the text. Number tables consecutively in the text in Arabic numerals. Type tables on a separate page with the legend above. Legends should be concise but comprehensive – the table, legend and footnotes must be understandable without reference to the text. Vertical lines should not be used to separate columns. Column headings should be brief, with units of measurement in parentheses; all abbreviations must be defined in footnotes. Footnote symbols: � , ‡, §, ¶, should be used (in that order) and *, **, *** should be reserved for Pvalues. Statistical measures such as SD or SEM should be identified in the headings. If tables have been reproduced from another source, a letter from the copyright holder (usually the Publisher) stating authorization to reproduce the material must be attached to the covering letter. FIGURES All illustrations (line drawings and photographs) are classified as figures. Figures should be cited in consecutive order in the text. Figures should be sized to fit within the column (80.5 mm), intermediate (112 mm) or the full text width (168 mm). Magnifications should be indicated using a scale bar on the illustration. Line figures should be sharp, black and white graphs or diagrams, drawn professionally or with a computer graphics package. Lettering must be included and should be sized to be no larger than the journal text. Magnifications should be indicated using a scale bar on the illustration. If figures have been reproduced from another source, a letter from the copyright holder (usually the Publisher) stating authorization to reproduce the material must be attached to the Author Submission Requirement Form and also explicitly explained on the covering letter. Line Figures: Must be sharp, black and white graphs or diagrams, drawn professionally or with a computer graphics package. Text Sizing in Figures: Lettering must be included and should be sized to be no larger than the journal text or 8 points (should be readable after reduction – avoid large type or thick lines.) Line Width: Between 0.5 and 1 point. Figure Legends Type figure legends on a separate page. Legends should be concise but comprehensive – the figure and its legend must be understandable without reference to the text. Include definitions of any symbols used and define/explain all abbreviations and units of measurement. More help on preparation of illustrations can be found at: http://authorservices.wiley.com/bauthor/illustration.asp EQUATIONS Equations should be numbered sequentially with Arabic numerals; these should be ranged right in parentheses. All variables should appear in italics. Use the simplest possible form for all mathematical symbols. dx/dt = c(x − x3/3 y z) (1) DY/DT = −(X BY − A)/C (2) 12. SUPPORTING INFORMATION Supporting Information is provided by the authors to support the content of an article but it is not integral to that article. Supporting Information is hosted via a link on Wiley Online Library, but does not appear in the print version of the article. Supporting Information must be submitted together with the article for peer review; it should not be added at a later stage. It can be in the form of tables, figures, appendices, audio and video footage. Reference to Supporting Information in the main body of the article is allowed. However, it should be noted that excessive reference to a piece of Supporting Information may indicate that it would be better suited as a proper reference or a fully included figure/table. The materials are published as they are supplied and are not checked or typeset in any way. All Supporting Information files should come with a legend, listed at the end of the main article. Each figure and table file should not be larger than 5 MB, although video files may be larger. If you have problem in uploading your video because the size of the video is too big, please contact [email protected] / [email protected] about submission of the video. All videos submitted must be of the highest quality possible. Prior to submission, please check the guidelines at: http://authorservices.wiley.com/bauthor/suppmat.asp. 13. SUBMISSION REQUIREMENTS Manuscripts must be submitted online at: http://mc.manuscriptcentral.com/den/. Authors must supply an email address as all correspondence will be by email. Two files should be supplied: the covering letter and the manuscript (in Word or rich text format (.rtf)). The covering letter should be uploaded as a file not for review. COVERING LETTER Papers are accepted for publication in the journal on the understanding that the content has not been published or submitted for publication elsewhere. This must be stated in the covering letter. The covering letter must contain an acknowledgment that all the authors have contributed significantly, and that all authors are in agreement with the content of the manuscript. In keeping with the latest guidelines of the International Committee of Medical Journal Editors, each author’s contribution to the paper is to be quantified. If tables or figures have been reproduced from another source, a letter from the copyright holder (usually the Publisher stating authorization to reproduce the material) must be attached to the covering letter. 14. NO PUBLICATION FEES Up to four color illustrations, if judged relevant and of good quality, will be published free of charge. A charge of A$550/US$265/¥32,000 of the fifth and subsequent color figures will be charged to the author. Composite color photographs made up of smaller pictures will not be accepted. For DEN Video Articles, a publication charge of 300 USD is charged to authors commencing from submissions received after 1 May 2018. A form requesting payment will be available for download with your PDF proof. 15. PUBLICATION PROCESS AFTER ACCEPTANCE Accepted papers will be passed to Wiley’s production team for publication. The author identified as the formal corresponding author for the paper will receive an email prompting them to login into Wiley’s Author Services, where via the Wiley Author Licensing Service (WALS) they will be asked to complete an electronic license agreement on behalf of all authors on the paper. More details on the copyright and licensing options for the journal appear below. Wiley’s Author Services Author Services enables authors to track their article through the production process to publication online and in print. Authors can check the status of their articles online and choose to receive automated e-mails at key stages of production. The corresponding author will receive a unique link that enables them to register and have their article automatically added to the system. Please ensure that a complete e-mail address is provided when submitting the manuscript. Visit http://www.authorservices.wiley.com/ for more details on online production tracking and for a wealth of resources including FAQs and tips on article preparation, submission and more. Accepted Articles The journal offers Wiley’s Accepted Articles service for all manuscripts. This service ensures that accepted ‘in press’ manuscripts are published online very soon after acceptance, prior to copy-editing or typesetting. Accepted Articles are published online a few days after final acceptance, appear in PDF format only, are given a Digital Object Identifier (DOI), which allows them to be cited and tracked, and are indexed by PubMed. After print publication, the DOI remains valid and can continue to be used to cite and access the article. The Accepted Articles service has been designed to ensure the earliest possible circulation of research papers after acceptance. Given that copyright licensing is a condition of publication, authors are required to complete a copyright license before manuscripts can be processed as an Accepted Article. Accepted articles will be indexed by PubMed; therefore the submitting author must carefully check the names and affiliations of all authors provided in the cover page of the manuscript, as it will not be possible to alter these once a paper is made available online in Accepted Article format. Subsequently the final copyedited and proofed articles will appear in an issue on Wiley Online Library; the link to the article in PubMed will automatically be updated. Proofs Once the paper has been typeset the corresponding author will receive an e-mail alert containing instructions on how to provide proof corrections to the article. It is therefore essential that a working e-mail address is provided for the corresponding author. Proofs should be corrected carefully; responsibility for detecting errors lies with the author. Early View The journal offers rapid speed to publication via Wiley’s Early View service. Early View articles are complete full-text articles published online in advance of their publication in a printed issue. Early View articles are complete and final. They have been fully reviewed, revised and edited for publication, and the authors' final corrections have been incorporated. Because they are in final form, no changes can be made after online publication. Early View articles are given a Digital Object Identifier (DOI), which allows the article to be cited and tracked before allocation to an issue. After print publication, the DOI remains valid and can continue to be used to cite and access the article. More information about DOIs can be found at http://www.doi.org/faq.html. Offprints A PDF reprint of the article will be supplied free of charge to the corresponding author. Additional printed offprints may be ordered online for a fee. Please click on the following link and fill in the necessary details and ensure that you type information in all of the required fields: http://www.sheridan.com/wiley/eoc. Author Marketing Toolkit The Wiley Author Marketing Toolkit provides authors with support on how to use social media, publicity, conferences, multimedia, email and the web to promote their article. 16. COPYRIGHT, LICENSING AND ONLINE OPEN Accepted papers will be passed to Wiley’s production team for publication. The author identified as the formal corresponding author for the paper will receive an email prompting them to login into Wiley’s Author Services, where via the Wiley Author Licensing Service (WALS) they will be asked to complete an electronic license agreement on behalf of all authors on the paper. Authors may choose to publish under the terms of the journal’s standard copyright transfer agreement (CTA), or under open access terms made available via Wiley OnlineOpen. Standard Copyright Transfer Agreement: FAQs about the terms and conditions of the standard CTA in place for the journal, including standard terms regarding archiving of the accepted version of the paper, are available at: Copyright Terms and Conditions FAQs. Note that in signing the journal’s license agreement authors agree that consent to reproduce figures from another source has been obtained. OnlineOpen – Wiley’s Open Access Option: OnlineOpen is available to authors of articles who wish to make their article freely available to all on Wiley Online Library under a Creative Commons license. With OnlineOpen, the author, the author's funding agency, or the author's institution pays a fee to ensure that the article is made open access. Authors of OnlineOpen articles are permitted to post the final, published PDF of their article on their personal website, and in an institutional repository or other free public server immediately after publication. All OnlineOpen articles are treated in the same way as any other article. They go through the journal's standard peer-review process and will be accepted or rejected based on their own merit. OnlineOpen licenses. Authors choosing OnlineOpen retain copyright in their article and have a choice of publishing under the following Creative Commons License terms: Creative Commons Attribution License (CC BY); Creative Commons Attribution Non-Commercial License (CC BY NC); Creative Commons Attribution Non-Commercial-NoDerivs License (CC BY NC ND). To preview the terms and conditions of these open access agreements please visit the Copyright Terms and Conditions FAQs. Funder Open Access and Self-Archiving Compliance: Please click here for more information on Wiley’s compliance with specific Funder Open Access and Self Archiving Policies, and click here for more detailed information specifically about Self-Archiving definitions and policies. 17. EDITORIAL OFFICE ADDRESS Editorial Office Digestive Endoscopy Shin-ochanomizu Urban Trinity Bldg. 4F, 3-2-1 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan Email: [email protected], [email protected] Tel: 81-3-3525-4670 Fax: 81-3-3525-4677 Author Guidelines updated 28 February 2019 Agradecimentos Em primeiro lugar, um especial agradecimento ao Doutor Diogo Libânio pela orientação e apoio incondicional, pelo exemplo de rigor científico e pela total disponibilidade e a quem agradeço, ainda, a confiança depositada em mim e nas minhas capacidades. Ao Professor Doutor Mário Dinis Ribeiro por me ter dado a oportunidade de realizar este projeto com a sua equipa e ainda pela inestimável ajuda na conceptualização e revisão do trabalho. Ao Professor Doutor Pedro Pimentel Nunes o contributo indispensável à concretização e finalização desta tese. Finalmente, um especial agradecimento à minha família, amigos e colegas que acompanharam esta jornada e cujo apoio me foi imprescindível.