Endoscopic resection (ER) is becoming increasingly established ALIMENTARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11: ALIMENTARY TRACT Efficacy, Safety, and Long-term Results of Endoscopic Treatment for Early Stage Adenocarcinoma of the Esophagus With Low-risk sm1 Invasion HENDRIK MANNER,* OLIVER PECH, YVONNE HELDMANN,* ANDREA MAY,* JUERGEN POHL,* ANGELIKA BEHRENS,* LIEBWIN GOSSNER, MANFRED STOLTE, MICHAEL VIETH, and CHRISTIAN ELL* *Department of Internal Medicine II, HSK Hospital (Teaching Hospital of the University Medicine of Mainz), Wiesbaden; Department of Gastroenterology and Interventional Endoscopy, St John of God Hospital, Regensburg; Department of Internal Medicine II, Karlsruhe Hospital, Karlsruhe; Institute of Pathology, Kulmbach Hospital, Kulmbach; and Institute of Pathology, Bayreuth Hospital, Bayreuth, Germany This article has an accompanying continuing medical education activity on page e45. Learning Objectives At the end of this activity, the successful learner will be able to identify lesions that are candidates for endoscopic treatment with a curative intent, and to differentiate between lesions that are candidates for a curative endoscopic treatment approach and lesions that are not. BACKGROUND & AIMS: METHODS: RESULTS: CONCLUSIONS: Patients with early-stage mucosal (T1a) esophageal adenocarcinoma (EAC) are increasingly treated by endoscopic resection. EACs limited to the upper third of the submucosa (pt1b sm1) could also be treated by endoscopy. We assessed the efficacy, safety, and long-term effects of endoscopic therapy for these patients. We analyzed data from 66 patients with sm1 low-risk lesions (macroscopically polypoid or flat, with a histologic pattern of sm1 invasion, good-to-moderate differentiation [G1/2], and no invasion into lymph vessels or veins) treated by endoscopic therapy at the HSK Hospital Wiesbaden from 1996 through The efficacy of endoscopic therapy was assessed on the basis of rates of complete endoluminal remission (CER), metachronous neoplasia, lymph node events, and long-term remission (LTR). Safety was assessed on the basis of rate of complications. Remissions were assessed in 61 of the 66 patients; 53 of the 61 achieved CER (87%). Of patients with small focal neoplasias <2 cm, 97% achieved CER (for those with tumors >2 cm, 77%; P.026). Metachronous neoplasias were observed in 10 of 53 patients (19%; 9 of the 10 underwent repeat endoscopic resection). One patient developed a lymph node metastasis (1.9%). Fifty-one patients achieved LTR (84%); 90% of those with focal lesions <2 cm achieved LTR after a mean follow-up period of months (range, months). No tumor-associated deaths were observed, and the estimated 5-year survival rate was 84%. The rate of major complications from endoscopic resection was 1.5%, and no patients died. Endoscopic therapy appears to be a good alternative to esophagectomy for patients with pt1b sm1 EAC, on the basis of macroscopic and histologic analyses. The risk of developing lymph node metastases after endoscopic resection for sm1 EAC is lower than the risk of surgery. Keywords: Esophageal Cancer; Neoplasia; Barrett s Esophagus; Endoscopic Resection; Treatment. Endoscopic resection (ER) is becoming increasingly established as the treatment of choice in patients with mucosal (pt1a) early esophageal adenocarcinoma (EAC), because it offers an organ-preserving approach and is effective and safe By contrast, the previous gold standard, esophageal resection with lymph node (LN) dissection, is associated with a relevant morbidity rate of 20% 50%. In addition, there is a significant risk of mortality, with rates of 2% 5% even in centers with large numbers of cases The basis for the curative endoscopic approach in tumors limited to the mucosa is that the risk of LN metastasis is extremely low, with reported rates of 0% 1%. 12,15 18 By contrast, a relevant rate of LN metastasis of 50% has been reported for neoplasias that have invaded the submucosa (pt1b) However, if the rate of LN metastasis is set in Abbreviations used in this paper: APC, argon plasma coagulation; CER, complete endoluminal remission; EAC, esophageal adenocarcinoma; ER, endoscopic resection; ET, endoscopic therapy; EUS, endoscopic ultrasonography; FU, follow-up; LN, lymph node; LR, low-risk; LTR, long-term remission; MN, metachronous neoplasia by the AGA Institute /$

2 June 2013 ENDOSCOPIC THERAPY IN sm1 ESOPHAGEAL ADENOCARCINOMA 631 relation to the tumor s depth of invasion into the submucosa by dividing it into 3 equally thick layers (sm1 sm3), a different picture emerges. Retrospective surgical series have reported an LN metastasis risk of 0% 20% in the presence of incipient submucosal invasion (pt1b sm1) ,20 26 Two retrospective reviews of surgically resected material already suggested in 2004 that there might be a particularly favorable pattern with a very low risk (LR) of LN metastasis among sm1 lesions. 15,16 Our own research group took up this hypothesis and defined LR lesions as being those that were macroscopically polypoid or flat (types I/II) and with histologic findings of initial submucosal invasion (sm1), as well as good-to-moderate tumor differentiation (G1 2) and no tumor invasion into lymphatic vessels (L0 situation) or blood vessels (V0 situation). A limit to the size of the tumor was not included in the definition. 27 An initial pilot series including 21 patients with LR lesions and a follow-up (FU) period of more than 5 years confirmed that very good long-term results, with no tumor-associated deaths, can be achieved with ER. 27 A subsequent case series including 12 patients, published by the Amsterdam group, provided further support for the low-risk pt1b hypothesis. 28 The present study, which includes the patients from our pilot series, investigated efficacy, safety, and long-term results of endoscopic therapy (ET) in the largest number of patients to date who had LR sm1 EACs. Methods Patients From September 1996 December 2010, a total of 1718 patients with suspected EAC were referred to our department. The patients were included in the department s prospective early carcinoma database. In 123 of these patients (104 men, 85%; 19 women, 15%; mean age, years), there was a suspected diagnosis (endoscopic ultrasonography [EUS]), or a diagnosis histologically confirmed at ER or from the surgical specimen, of EAC with incipient submucosal invasion (pt1b sm1) (Figure 1). Sixty-six of these 123 patients met the criteria for LR pt1b EAC and received primary ET. Diagnostic Procedure High-resolution video endoscopes (Fujifilm Europe Inc, Düsseldorf, Germany) were used for esophagogastroduodenoscopy. In addition, chromoendoscopy with methylene blue staining (0.5% solution) was carried out at the start of the study period and later with contrast enhancement by using acetic acid (1.5% solution). Targeted biopsies were taken from areas that were suspicious of neoplasia. The neoplasias were divided into small lesions of up to 2 cm in diameter or larger lesions. In addition, 4-quadrant biopsies were taken in the complete Barrett s segment at intervals of 1 2 cm. 29 The histologic assessment of the biopsies was carried out by 2 experienced pathologists on the basis of the World Health Organization classification. 30 The definition of depth of infiltration was based on the Japanese criteria and Stolte et al 31 and Vieth and Stolte. 32 The depth of neoplasia infiltration and the regional LN status were evaluated by using EUS (Pentax, Europe Ltd, Hamburg; Fujifilm Europe Ltd, Düsseldorf; both Germany). LNs larger than 10 mm with a hypoechoic or rounded appearance on ultrasound promptly underwent EUS-guided puncture if the primary tumor would not have been transversed by the needle, Figure 1. Flow chart for patients with suspected EAC of the esophagus treated from 1996 to or the patient was referred for esophageal resection. In addition, all of the patients underwent computed tomography of the chest with an epigastric section and abdominal ultrasound to exclude metastases or a second neoplasia. Endoscopic Therapy After staging had been completed, initial ER was carried out. This was diagnostic on the one hand (with stratification of the patients to either the LR or high-risk groups) and also therapeutic, if all the LR were met. The suck-and-cut technique was used as the standard method in ER. 2 The ER specimens were stretched on cork and embedded in formalin. Concomitant treatment with a proton pump inhibitor was administered on the day of the ER intravenously at a dosage of 2 40 mg (pantoprazole, omeprazole, or esomeprazole). Thereafter, the proton pump inhibitor was administered for an additional 2 weeks at a dosage of 2 40 mg, or longer if there was a large wound area. ET was completed by using ablative procedures in the area of the residual Barrett s segment after ER and achievement of complete endoluminal remission (CER) from neoplasia. Argon plasma coagulation (APC), radiofrequency ablation, and photodynamic therapy were used. Ablation of non-neoplastic Barrett s mucosa was not yet standardized in the period The aim of thermal ablation was to reduce the rate of

3 632 MANNER ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 metachronous lesions and recurrences in the residual Barrett s segment. Processing of the Endoscopic Specimens After fixation of the endoscopic specimens in formalin, they were cut into strips 1.0- to 1.5-mm wide, dehydrated, degreased, and embedded in paraffin. Four stepped sections 3 4 m thick were then obtained from each block, deparaffinized, and stained with hematoxylin-eosin. Assessment was carried out by 2 pathologists experienced in the diagnosis of early carcinoma. Size, depth of invasion, differentiation, and the presence of lymphatic or blood vessel invasion by the tumor were noted. It was also checked that the basal and lateral resection margins of the specimens were free of tumor. Submucosal carcinomas were classified pragmatically by measuring the relative depth of invasion, with the submucosa being divided into 3 equally thick layers (sm1 3), and the histologic tumor characteristics (G, L, and V status) were assessed. Follow-up After Endoscopic Therapy A strict FU protocol was used for all patients. Check-up esophagogastroduodenoscopies with chromoendoscopy, targeted biopsies, and 4-quadrant biopsies from the residual Barrett s segment were carried out at 3-month intervals during the first year after ER. FU examinations were then carried out at 6-month intervals for a period of 4 years and thereafter at annual intervals. EUS checkups were also carried out every 3 months during the first year of FU and at 6-month intervals for an additional 4 years. Abdominal ultrasound FU was carried out at 6-month intervals during the first 2 years and thereafter annually. Complete Endoluminal Remission CER was regarded as having been achieved if there were R0 basal and R0 lateral status and the first FU examination showed no signs of high-grade intraepithelial neoplasia or carcinoma. Patients with R1 lateral pattern who were free of tumor at the 2 following examinations were also regarded as having achieved CER. A distinction was made in assessing CER between patients with small focal lesions up to 2 cm in diameter and those with larger, bifocal, or multifocal lesions. Metachronous Neoplasias and Treatment Failures If metachronous neoplasia (MN) was noted at a FU examination, repeat ET was usually carried out after the patient had been provided with appropriate information. If it was not possible to carry this out with curative intent for technical reasons eg, when scarring made it impossible to suck the tissue in adequately, because of an advanced infiltration depth (eg, sm3 invasion), or because of other histologic characteristics (eg, L1 status) then the patient was referred for esophageal resection with LN dissection or for palliative treatment if a surgical procedure was not possible. Long-term Remission Long-term remission (LTR) was achieved if the patients reached CER primarily, any MN had received curative ET, and Table 1. Overview of Patients With LR sm1 EAC (n 66) Who Underwent ET Mean age (y) (range, 44 81) BE type LSBE 29 (43.9%) SSBE 37 (56.1%) Mean BE length (cm) (range, 1 17) Sex Male 58 (87.9%) Female 8 (12.1%) Size of hiatal hernia Large 9 (13.9%) Medium 29 (43.9%) Small 28 (42.4%) Gross tumor type I 12 (18.2%) IIa 16 (24.2%) IIb 4 (6.1%) IIc 6 (9.1%) IIa c 21 (31.8%) I II 7 (10.6%) Macroscopic tumor size (cm) 2 36 (54.5%) 2 30 (45.5%) Focality Focal 49 (74.2%) Bifocal 3 (4.5%) Multifocal 14 (21.2%) Tumor differentiation G1 19 (28.8%) G2 47 (71.2%) BE, Barrett s esophagus; LSBE, long-segment Barrett s esophagus; SSBE, short-segment Barrett s esophagus. if no extraesophageal signs of tumor involving metastasis were diagnosed during FU. Statistical Analysis All of the data collected were entered into a newly established database (SPSS 16.0; SPSS, Inc, Chicago, IL). The efficacy of ER was assessed by using the rate of CERs and LTRs achieved with ET, the frequency of MN, and the diagnosis of LN metastases during FU. The safety of ER was assessed on the basis of the complications observed. Hemoglobin-relevant bleeding and perforation were regarded as major complications, and bleeding not affecting the hemoglobin level and esophageal stenoses were regarded as minor complications. The data were analyzed descriptively by using absolute and relative frequencies, means, ranges, minimum and maximum values, and standard deviation. Means for numeric variables were compared by using the t test for unpaired samples or the Mann Whitney test. The distribution of categorical variables was compared by using an exact Fisher test. In addition, Kaplan Meier survival analysis was carried out. Data were collected and analyzed in accordance with the Helsinki Declaration. The study was conducted in accordance with the criteria of good clinical practice and was based on previous approval for a study of local ET for early malignancies in the upper gastrointestinal tract. The approval was received from the Ethics Committee of the General Medical Council of the state of Hesse, Germany (no ).

4 June 2013 ENDOSCOPIC THERAPY IN sm1 ESOPHAGEAL ADENOCARCINOMA 633 Table 2. Overview of Patients in Whom CER Was Not Achieved Patient ER sessions (n) Treatment duration (mo) Reason for not achieving CER Final treatment and outcome Lesion not completely resectable by piecemeal ER (failure of suction) Histologically R1 basal status in last ER specimen Histologically R1 basal status in last ER specimen Histologically R1 basal status in last ER specimen Histologically L1 status in last ER specimen (high risk) Lesion not completely resectable at basal margin Lesion not completely resectable by piecemeal ER (failure of suction) Synchronous CCC at progressive stage histologically R1 basal status in last ER specimen ATER; 0/20 LN positive; no FU endoscopy performed after surgery ATER; 0/29 LN positive; FU after surgery 26 mo ATER; 0/15 LN positive; FU after surgery 6 mo Palliative APC treatment because of cardiovascular comorbidity Surgery recommended, but finally chemoradiotherapy performed near hometown ATER; 0/12 LN positive; FU after surgery 55 mo Surgery planned, but patient died of heart attack before surgery Partial liver resection ATER extended LN dissection; 10 of 75 LNs positive because of synchronous CCC; finally palliative chemotherapy and death caused by CCC ATER, abdominothoracic esophageal resection; CCC, cholangiocellular carcinoma. Results Complete Endoluminal Remission The characteristics of the overall group of 66 patients are shown in Table 1. CER was evaluated in 61 of 66 patients included. One patient was still receiving ET at the time of analysis (1.5%). Four patients were lost to FU (6.1%). Fifty-three of 61 patients (86.9%) achieved CER. A mean of ERs were needed to reach CER (range, 1 4). The mean treatment period was months (1 23 months). CER was not achieved in 8 patients (13.1%; Table 2). CER was achieved in 97% of patients with small focal lesions (up to 2 cm; 30 of 31 patients). The CER rate in patients with larger, bifocal, or multifocal lesions was 77% (23 of 30 patients; P.026). In the intention-to-treat analysis for all 66 patients undergoing ET, the CER rate was 80% (53 of 66). After ER, thermal ablation of the residual Barrett s segment was carried out for prophylaxis of metachronous lesions in 42 of 53 patients (79.2%). The mean number of ablation sessions was (range, 1 7). One patient (1 of 66, 1.5%) developed a major complication, with an occult perforation after ER, which was treated conservatively. Minor complications consisted of esophageal stenoses after ER and supplementary thermal ablation in a total of 8 patients (12.1%). All of the stenoses were successfully treated with bougie dilation. A mean of dilation sessions (range, 1 5) were required. No relevant bleeding (with a fall in hemoglobin 2 g/dl or a need for transfusion) was observed after ER. Metachronous Neoplasias and Lymph Node Metastases MNs were observed in 10 of the 53 patients who had achieved CER (18.9%). The neoplasia was on the margin of the ER site in 6 patients, whereas in 4 patients it was in another location in the Barrett s segment. The mean period from achieving CER to the diagnosis of MN was months (6 60 months). Six of 10 patients with MN had received partial APC ablation of the residual Barrett s mucosa. Nine of 10 patients were again treated endoscopically by using ER (n 7), ER and APC (n 1), or APC (n 1). One patient was found to have a deeply invasive recurrent lesion (sm3) 9 months after ET. Surgery was therefore indicated in principle. However, because of concomitant cardiovascular diseases, palliative APC was carried out. The patient afterward remained in CER for an FU period of 6 months at the time of writing. EUS-guided LN puncture was carried out during the subsequent course in a total of 3 of the 53 patients (5.7%). An LN metastasis was found in 1 of these patients (1 of 53, 1.9%), with a histologically positive LN finding on the cardia 11 months after CER had been achieved. This patient was a 52-year-old man with a long-segment Barrett s esophagus and a small-type IIa lesion at initial presentation. The initial staging protocol did not show any abnormalities. After 1 ER, CER was achieved, and 2 APC sessions were carried out for complete Barrett s ablation. After diagnosis of LN metastasis by EUS, the patient underwent esophageal resection with perioperative chemotherapy. At the time of writing, the patient was in good health and without signs of local or distant recurrence (postoperative FU 9 months). Long-term Remission Fifty-one of the 61 patients (83.6%) in whom remission was assessed achieved LTR after a mean FU of months (8 120 months). In patients with small focal lesions, the LTR rate was 90.3% (28 of 31 patients), whereas in those with larger, bifocal, or multifocal lesions, it was 76.7% (23 of 30 patients; P.182). Eight of the 10 patients who did not achieve LTR did not become free of tumor during the primary ER or had histologic findings on the basis of which surgery was indicated after primary ER. One other patient developed an endoscopically unresectable recurrent tumor during the subsequent course, and another patient developed an LN metastasis in the area of the cardia. In the intention-to-treat analysis including all 66

5 634 MANNER ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Figure 2. Kaplan Meier survival curve for patients in whom remission status was evaluated; censored if last FU examination carried out. Cum, cumulative. patients in whom curative ET was carried out, the LTR rate was 77.3% (51 of 66). The estimated 5-year survival rate in the 61 patients in whom remission was evaluated was 84% (after 6 deaths and 17 remaining cases; Figure 2, Table 3). None of the deaths noted was associated with the Barrett s carcinoma. The causes of death were cardiovascular diseases (n 2), cholangiocellular carcinoma (n 1), cerebral stroke (n 1), lymphoma (n 1), and pulmonary asbestosis (n 1). Discussion During the last decade, ET for mucosal (pt1a) EAC has gained increasing international acceptance 1 11 as a curative form of treatment, and it was included in national and international guidelines. 28,33,34 To the present, the gold standard for the treatment of submucosal (pt1b) EAC has been esophageal resection with LN dissection. 25,26,35 However, surgical series 15,16 were able to show that no LN metastases were found to occur in lesions limited to the upper third of the submucosa (sm1). Our own research group 27 defined LR sm1 EAC as lesions that are macroscopically polypoid or flat, on the one hand, and histologically show sm1 invasion plus a G1 2, L0, and V0 status. In 2008, it was shown for the first time that LR sm1 patients defined in this way may be candidates for ER with curative intent. 27 The present study now confirms in a much larger group of 66 patients that ET can be carried out effectively and safely in patients with sm1 EAC. The prerequisite for this is that all macroscopic and histologic LR criteria must be met. A total of 87% of the patients achieved CER. In small focal lesions up to 2 cm, the CER rate was 97%. During the subsequent course, MNs were noted in 10 patients, but 9 of 10 patients returned to remission with repeat ET. An LN metastasis was only observed in 1 patient. LTR was achieved in a total of 84% of the patients, with a mean FU period of almost 4 years; in patients with small lesions of up to 2 cm, LTR was 90%. The calculated 5-year survival rate was 84%. No tumor-associated deaths were noted. The rate of major complications after ER was 1.5%, and the mortality rate was 0%. When the results for ER presented here are compared with those for surgical esophageal resection with LN dissection, which has been the previous therapeutic gold standard, the long-term survival rate is comparable, 25,26,35 but the morbidity and mortality associated with the endoscopic approach are much lower or even nonexistent. The present results also make it clear that despite an LR sm1 situation, LN metastasis cannot be completely ruled out, and this fact underlines the importance of a strict EUS FU program as it was performed in the present trial. However, the rate of 1.9% observed in the present study is lower than the known mortality rate (2% 5%) associated with the gold standard treatment, radical esophageal resection with LN dissection. 18,19 However, the view that the LN risk in sm1 EAC is very low is not uncontroversial in a number of retrospective surgical series reporting an LN rate of up to 23% However, surgical series are mostly relatively small retrospective analyses. In addition, not all of the histologic risk parameters for LN metastasis eg, L, V, or G status were mentioned. 21,23 Therefore, not all high-risk patients may have been correctly identified. This may have led to a virtual increase in the LN rate. In the present study by contrast, only patients were included in whom all macroscopic and histologic LR parameters were met. In particular, patients were initially selected for curative ET not only by using histologic risk parameters but also on the basis of the primary endoscopic assessment, and patients with ulcerated carcinomas were not considered for ER. The processing of the material by the pathologist might also have played an important role. For patients treated with ER, the pathology department receives a specimen stretched on cork, usually with a diameter of up to 20 mm. 2,3 For surgical patients, by contrast, the pathologist receives an esophageal specimen several centimeters long in which the lesion with the greatest depth of invasion may be more difficult to determine. 25,26 The present study has several limitations. As in other series on curative ER, the rate of LN metastases was investigated by using regular EUS during FU. The question arises whether LN metastases might have been missed, so that the real rate of LN metastasis was actually higher. The fact that the patients received regular EUS checkups for a mean of 4 years after ET, without any metastases or tumor-associated deaths being observed with negative EUS findings, argues against this hypothesis. Despite this, the patients in the present series will continue to receive long-term FU so that definitive statements can be made at a later time. During the present study from a European center, abdominal ultrasound was used for the exclusion of organ metastasis. However, it has to be critically remarked that in the United States, magnetic resonance imaging or positron emission tomography CT might have been chosen for the staging protocol because of a higher sensitivity for the detection of metastases. Another limitation is that the present study is a retrospective one, despite being based on prospective data collection. In addition, the number of cases is limited. Nevertheless, to our knowledge this is the largest series on the treatment of patients with sm1 EAC so far. Additional studies from other centers are needed to test the present results, which were obtained in a specialist center for ET of early carcinoma. A randomized study of ET vs surgical therapy would be the best way of definitely clarifying the value of the 2 treatment options. Table 3. Overview of Survival Data for Patients in Whom Remission Status Was Evaluated FU (mo) Cumulative survival Events (n) Patients at risk (n)

6 June 2013 ENDOSCOPIC THERAPY IN sm1 ESOPHAGEAL ADENOCARCINOMA 635 In summary, the results of the present study and the currently available data in literature show that ET appears to be a good alternative to esophagectomy in patients with LR pt1b EAC of the esophagus. References 1. Ell C, May A, Gossner L, et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett s esophagus. Gastroenterology 2000;118: Ell C, May A, Pech O, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett s cancer). Gastrointest Endosc 2007;65: Pech O, Behrens A, May A, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett s oesophagus. Gut 2008;57: Nijhawan PK, Wang KK. Endoscopic mucosal resection for lesions with endoscopic features suggestive of malignancy and high-grade dysplasia within Barrett s esophagus. 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Best Pract Res Clin Gastroenterol 2005;19: American Gastroenterological Association, Spechler SJ, Sharma P, et al. American Gastroenterological Association medical position statement on the management of Barrett s esophagus. Gastroenterology 2011;140: Bennett C, Vakil N, Bergman J, et al. Consensus statements for management of Barrett s dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology 2012; 143: Tian J, Prasad GA, Lutzki L, et al. Outcomes of T1b esophageal adenocarcinoma patients. Gastrointest Endosc 2011;74: Reprint requests Address requests for reprints to: Hendrik Manner, MD, Department of Internal Medicine II, HSK Wiesbaden, Ludwig-Erhard-Strasse 100, Wiesbaden, Germany. hendrik.manner@hsk-wiesbaden.de; fax: Acknowledgments This study formed the basis for Yvonne Heldmann s doctoral thesis at the University of Mainz, Germany. Conflicts of interest The authors disclose no conflicts.