Dislocation of the gastric conduit reconstructed via the posterior mediastinal route is a significant risk factor for anastomotic disorder after McKeown esophagectomy

Abstract Background Anastomotic disorder of the reconstructed gastric conduit is a life‐threating morbidity after thoracic esophagectomy. Although there are various reasons for anastomotic disorder, the present study focused on dislocation of the gastric conduit (DGC). Methods The study cohort comprised 149 patients who underwent transthoracic esophagectomy. The relationships between DGC and peri‐ and postoperative morbidities were analyzed retrospectively. Data were analyzed to determine whether body mass index (BMI) and extension of the gastric conduit were related to DGC. Uni‐ and multivariate Cox regression analyses were performed to identify the factors associated with anastomotic disorder. Results DGC was significantly related to anastomotic leakage (P < .001), anastomotic stricture (P = .018), and mediastinal abscess/empyema (P = .031). Compared with the DGC‐negative group, the DGC‐positive group had a significantly larger mean preoperative BMI (23.01 ± 3.26 kg/m2 vs. 21.22 ± 3.13 kg/m2, P = .001) and mean maximum cross‐sectional area of the gastric conduit (1024.75 ± 550.43 mm2 vs. 619.46 ± 263.70 mm2, P < .001). Multivariate analysis revealed that DGC was an independent risk factor for anastomotic leakage (odds ratio: 4.840, 95% confidence interval: 1.770‐13.30, P < .001). Body weight recovery tended to be better in the DGC‐negative group than in the DGC‐positive group, although this intergroup difference was not significant. Conclusion DGC reconstructed via the posterior mediastinal route is a significant cause of critical morbidities related to anastomosis. In particular, care is required when performing gastric conduit reconstruction via the posterior mediastinal route in patients with a high BMI.


| INTRODUC TI ON
Esophageal cancer is the seventh most common type of cancer and the sixth leading cause of overall mortality worldwide. 1 Despite recent developments in surgical technique and perioperative management, esophagectomy for esophageal cancer is one of the most invasive gastroenterological surgeries with a very high morbidity rate. [2][3][4][5] Anastomotic disorder of the reconstructed organs, especially the gastric conduit, is a common, severe, and life-threatening complication of esophagectomy. 6,7 Esophageal reconstruction with a gastric conduit is typically performed via the subcutaneous, retrosternal, or posterior mediastinal (PM) route. [8][9][10] Among these three routes, the PM route is considered the most physiological. 11,12 However, PM reconstruction carries a risk of severe morbidities such as mediastinal abscess, empyema, and tracheobronchial fistula. [13][14][15][16] Therefore, it is important to identify the risk factors for anastomotic disorder of the gastric conduit reconstructed through the PM route.
Previous studies have reported that anastomotic disorder, especially anastomotic leakage, results from ischemia of the gastric conduit, 17,18 compression 19 or tension 20,21 of the anastomotic site, or poor anastomotic technique. 22 However, dislocation of the gastric conduit (DGC) is rarely discussed.
DGC is often seen after esophagectomy and has an unfavorable effect on postoperative quality of life (QOL) in patients who have undergone esophagectomy in clinical practice. However, this seems to be an empirical finding. Despite a thorough search, we could not find any previous reports on the relationship between esophagectomy and DGC.
In this study, we investigated the risk of post-esophagectomy anastomotic disorder of the gastric conduit reconstructed through the PM route, focusing on DGC.

| Patients
We retrospectively reviewed the medical records of 273 patients with esophageal cancer who underwent radical thoracic esophagectomy and gastric conduit reconstruction between January 2009 and December 2018 at Dokkyo Medical University Hospital. We excluded patients who underwent transhiatal esophagectomy (28 cases) and salvage esophagectomy after definitive chemoradiotherapy (nine cases) or laryngopharyngoesophagectomy (four cases).
We also excluded 69 cases of retrosternal reconstruction and one of subcutaneous reconstruction. Thus, data from 163 patients who underwent McKeown esophagectomy with gastric conduit reconstruction via the PM route were extracted. Of these 163 patients, we excluded nine who underwent hand-sewn anastomosis and five who underwent mechanical anastomosis using a linear stapler because we performed these anastomoses on rare occasions in unfavorable condition, such as in patients with a short gastric conduit or short remnant esophagus.

| Definition of DGC
We focused on DGC as a risk factor for anastomotic leakage because DGC results in tension at the anastomotic site. In cases where the gastric conduit is reconstructed via the PM route, the gastric conduit usually dislocates to the right pleural cavity because the mediastinal pleura is resected with the thoracic esophagus. DGC was defined as dislocation of more than 2/3 of the width of the gastric conduit to

| Definitions of peri-and postoperative morbidities
Peri-and postoperative morbidities were defined as complications that seemed to be related to the reconstruction procedure.
Complications were assessed in accordance with the Clavien-Dindo classification, and complications of grade II or above were regarded as significant.

| Comparison between preoperative body mass index and DGC
Patients with a high body mass index (BMI) may have a small PM space after esophagectomy and a large volume of greater omentum associated with the gastric conduit. As a result, DGC may occur more easily in patients with a high BMI than in patients with a normal BMI. Therefore, we compared the preoperative BMI between the DGCpositive and DGC-negative groups.

| Examination of the relationship between extension and DGC
We noticed that the gastric conduits that had dislocated to the pleural cavity tended to be more extended than the non-dislocated gastric conduits. Therefore, we examined the relationship between the maximum cross-sectional area of the gastric conduit and DGC.

| Examination of body weight change
Body weight change was examined as an indicator of long-term QOL.

| Statistical analysis
The chi-squared test and Fisher's exact test were used for statistical comparisons of nominal variables where appropriate. Continuous data were compared with the Student's t-test or analyzed by repeated measures one-way analysis of variance. Multivariate analysis was performed using logistic regression. Differences were considered significant if the P value was ˂.05. All statistical analyses were carried out using EZR (version 1.54) (Saitama Medical Center, Jichi Medical University), which is a graphical user interface for R (The R Foundation for Statistical Computing).

| Patients' characteristics and DGC
The characteristics of the eligible patients are described in Table 1.
In summary, the population was typical for Japanese patients with esophageal cancer. The mean age was 65.15 years, and the main histologic type was squamous cell carcinoma (91.9%). Sixtyseven cases (45.0%) were node-positive clinically, and 35 patients  In this study, DGE tended to be more frequent in the DGC-positive group although the increase in frequency was not significant (P = .070; Table 2).

| Factors associated with anastomotic disorder
Univariate Cox regression analysis revealed that the factors significantly associated with anastomotic leakage were the preoperative BMI, thoracoscopic esophagectomy, HALS, and DGC (all P < .05).
These factors were entered in the multivariate model. Multivariate analysis revealed that DGC was an independent risk factor for anastomotic leakage (odds ratio: 4.840, 95% confidence interval: 1.770-13.30, P < .001) ( Table 3). Uni-and multivariate analyses were also performed to identify the factors associated with anastomotic stricture, mediastinal abscess/empyema, and entire anastomotic disorders. However, no independent risk factors were identified (data not shown).

| Body weight change and DGC
Among the 149 eligible patients, the patients who survived more than 2 years without recurrence were selected. As a result, the postoperative body weight change of 101 patients was analyzed (58 in the DGC-negative group and 43 in the DGC-positive group).
The body weight recovery tended to be better in the DGC-negative group than in the DGC-positive group; however, this intergroup difference was not significant ( Figure 5).

| D ISCUSS I ON
The present study is the first to demonstrate that DGC is an independent risk factor for anastomotic leakage and is closely related to other anastomotic disorders.
Anastomotic leakage is one of the most frequent and lifethreatening complications that often results in mediastinitis, mediastinal abscess, and empyema, especially in patients who undergo PM reconstruction. 13 To improve peri-and postoperative QOL, it is very important to investigate the cause of anastomotic leakage and identify preventative measures. Although previous studies have reported that the causes of anastomotic leakage are tension, compression, ischemia, hyperemia, and an unskilled anastomotic technique, we focused on DGC because we had subjectively noticed that DGC was common in cases with anastomotic leakage.
Even in cases without anastomotic leakage, the gastric conduit is sometimes dislocated to the right pleural cavity after reconstruction via the PM route. Such dislocation may occur because of the weight of the gastric conduit itself or a mismatch between the volume of the gastric conduit and the mediastinal space after esophagectomy.
The gastric conduit may be increasingly pulled toward the pleural cavity and distended by the negative breathing pressure. As seen in the present study, the dislocated gastric conduits became distended.
However, distension of the gastric conduit was not found in the patients without DGC. Therefore, gastric distension must be partly a We often experienced the phenomenon that we could not pull the gastric conduit up to the level that we estimated in advance, and we could not avoid anastomosing at a more distal site than that we had planned. In such cases, we observed a finding suggestive of DGC (bending nasogastric tube to the right side) on X-ray images just after the operation. However, there were cases where the finding suggestive of DGC was first observed on postoperative day 1 or later. In the cases where DGC occurs earliest, DGC must be the first cause of anastomotic disorder because the anastomotic site is strongly tensioned and more distal and ischemic due to bending. However, among the cases of DGC that occur after postoperative day 1, a gastric conduit that is too long may be the cause of anastomotic disorder and DGC. The anastomotic site of a gastric conduit that is too long must be ischemic, and the too long gastric conduit may be gradually pulled into the right pleural cavity. Thus, even though DGC may not be a cause of anastomotic disorder in every case, there is a significant relationship between DGC and anastomotic disorder.
DGE is a well-known postoperative morbidity of esophagectomy. The incidence of clinically relevant DGE is in the range of 10%-20%. 23   According to the examination of body weight change, body weight recovery tended to be poorer in the DGC-positive group. DGC may indirectly impair body weight recovery via DGE. However, the body weight recovery in patients with high BMI was poorer than that in patients with low BMI (data not shown). There is a possibility that the preoperative BMI was related to the difference in body weight recovery between the DGC-positive and -negative group because the DGC rate was higher in patients with high preoperative BMI.
As mentioned above, DGC certainly has some unfavorable effects on patients who have undergone esophagectomy. Therefore, the strategy to prevent DGC is important. We usually pull the gastric conduit down to the abdominal cavity after esophago-gastric anastomosis. In fatty cases, we attenuate the greater omentum accompanying the gastric conduit. However, very often the gastric conduit will not stay in the mediastinal space after esophagectomy.
Because a strong upward vertical force may lead to straightening of the gastric conduit and avoid dislocation, we examined the effect of tumor location and anastomotic level on DGC. However, both were found to be unrelated. Nevertheless, we might not be able to avoid DGC using only a strong upward vertical force.
Numerous studies have evaluated the peri-and postoperative QOL of patients who have undergone PM vs retrosternal reconstruction after esophagectomy. 8,9,12,18,24,25 However, the optimal reconstruction route remains controversial, and the variation between studies may be due to the interstudy differences in the outcomes being evaluated. Regarding the frequency of anastomotic leakage, many studies have shown the superiority of the PM route. [26][27][28] In The present study had some limitations. First, these operations were performed in a single institution. In such a situation, there is some possibility of continuing inadequate procedures.
Second, this was a retrospective study, and the patients may have had various comorbidities that affected the incidences of postoperative morbidities. The present findings require confirmation in a multicenter prospective study that includes patients who undergo retrosternal reconstruction. Further studies will aid in the identification of the best reconstruction method in consideration of not only short-term morbidity but also longterm QOL.

| CON CLUS IONS
DGC after reconstruction via the PM route is a significant cause of critical morbidities related to anastomosis. In particular, care is required when performing PM reconstruction in patients with a high BMI.

ACK N OWLED G EM ENTS
We thank Kelly Zammit, BVSc, and John Holmes, MSc, from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.

D I SCLOS U R E
Conflict of interest: Masanobu Nakajima and all co-authors declare no conflicts of interest for this article.  The body weight recovery of the DGCnegative group tends to be better than that of the DGC-positive group, although this intergroup difference was not significant. DGC, dislocation of the gastric conduit; SD, standard deviation O RCI D Masanobu Nakajima https://orcid.org/0000-0003-4204-7184