Study For The Pathogenesis Of Reflux Esophagitis And Outcome Of Anti-reflux Surgery After Esophagogastrostomy For Cancer

Gastroesophageal reflux occurs after surgery for esophageal and cardiac cancer because the normal anti-reflux mechanisms have been resected and disrupted. Long-term occurrence of gastroesophageal reflux has influence on quality of life of the patients who underwent esophagectomy. Duodenogastroesophageal reflux (DGER) which is an importamt component of gastroesophageal reflux can be presented isolatedly and damage the esophageal mucosa itself. The simultaneous acid reflux and DGER is responsible for the severity of injury of esophageal mucosa. The development of Barrett's esophagus and dysplasia of esophageal mucosa is likely induced by DGER. The relationship among pathological presence, endoscopic evident changes, mechanisms of the damage of esophageal mucosa and esophageal exposure to acid and duodenal juice after surgery for cancer of the esophagus and cardia has not fully been identified.Evidence of the sequential pathological changes from normal esophageal squamous mucosa to mucosal inflammatory change, then columar metaplasia (Barrett esophagus) and at last intestinal metaplasia was documented in many patients with gastroesophageal reflux disease (GERD). This raises concern that the development of Barrett esophagus could result in a new carcinoma in patients who have achieved long term survival after esophagectomy. In recent years, the apparent role for gastroesophageal reflux in the development of Barrett esophagus has trigged to search for the transformative mechanism of esophageal epithelium cell at gene and molecule level. The changes at genic level, such as cytokine (IL-8), cyclin D1, Cyclooxygennase -2 (COX-2), tumor necrosis factor-α(TNF-α), P53 and p16 mutation, genic methylation, oncogene (c-myc), apoptosis protein (cleaved caspase-3), as well as their abnormal expression in esophageal mucosa induce by chronic reflux have been investigated in patients with GERD. The postoperative patients may be served as the human body model of GERD because of the occurrence of long history reflux after esophagectomy. The expression of COX-2 and TNF-αin the remnant esophagus is evaluated using a human model in which the exact duration of gastroesophageal reflux is known. This may provide insight into pathogenesis of inflammation and meteplastic process induced by reflux. It is possible that the transformative mechanism of esophageal epithelium cell is elucidated by investigating changes of gene expression occurring in the esophageal mucosa during long-history reflux.A number of surgical techniques were refined to control reflux because of chronic gastroesophageal reflux occurring in all patient's life. Although some surgical techniques, for example, intercostal muscle grafts fashioned anti-reflux valves, the inkwell style of anastomosis, a globe type of anastomosis, a posterior invagination technique and an insertive esophagogastrostomy, were described as sufficient to control reflux, they were too complex to be generalized in clinical setting. 3600 fundoplication surgery has been used successfully to control GERD for many years. It is conceivable that using the gastric fundus to perform a fundoplication at the conventional anastomosis and 2~3 cm distal section of remnant esophagus by wrapping the stomach around the anastomosis orifice and the remnant esophagus could be effective for controlling reflux. It has the advantage of being very simple to perform, requiring no major alteration to surgical technique or posing no any particular surgical risk. The use of this technique is expected to result in improving quality of life for patients who underwent esophagectomy for cancer.The patients who underwent esophagectomy for esophageal and cadiac cancer were divided into two groups including the group of conventional anastomosis and the group of antireflux anstomosis according to the randomized controlling method. Questionaire of EORTC OLO-C30 and tumor-specific module QLQ-OES24, esophageal intraluminal manometry, simultaneous ambulatory 24 hours pH and spectrometric bilirubin monitoring, endoscopy, histology were perform to evaluate the role of modified fundoplication following esophagectomy in controlling reflux, with the purpose of investigate the relationship between acid reflux and DGER and the pathogenesis of reflux esophagitis. Expression of COX-2 and TNF-αin the remnant esophagus is evaluated by immunohistochemistry in order to document the hypothesis that gene expression induced by gastroesophageal reflux involves in the transformative mechanism of esophageal mucosa.Part one The effects of anti-reflux anastomosis on the quality of life following esophagectomy for cancerObjective: The occurrence of gastroesopageal reflux and abnormal function of gastrointestinal tract after surgery for esophageal and cardiac cancer has influences on quality of life of patients who underwent esophagectomy. Reflux is important factor influencing quality of life. The anti-reflux surgical technique has been expected to reduce the extent of reflux and to improve quality of life after surgery. In the study, the operative mortality and complication was investigated to assess the operative risk of anti-reflux surgical technique. Quality of life for postoperative patient was evaluated by questionnaire of quality of life.Methods: Seventy patients with esophageal and cardiac cancer were divided into two groups by method of randomized double-blind trail: one group with conventional anastomosis and another group with anti-reflux anastomosis (modified fundoplication type anastomosis following esophagectomy). Fourty-nine patients were invited to take part in the questionnaire of quality of life 3 months after surgery. In the group of conventional anastomosis, there were 25 patients (19 male and 6 female) with a mean age of 59 years, including 12 patients with esophageal carcinoma in the middle third, 1 patient with esophageal carcinoma in the lower third, 12 patients had cardiac carcinoma. In the group of anti-reflux anastomosis, there were 24 patients (20 male and 4 female) with a mean age of 61 years, including 12 patients with esophageal carcinoma in the middle third, 5 patients with esophageal carcinoma in the lower third and 7 patients with cardiac carcinoma. The operative morbidity and complication were obtained from hospital record. Metastasis and recurrence at anastomotic orifice was also inquired at 1 year after surgery. The questionnaire of life quality (EORTC QLQ C-30 and tumor specific module QLQ-OES24) was used for accessing postoperative patient's quality of life.Results: (1) There was no significant difference in operative morbidity and mortality between the groups with conventional anastomosis and anti-reflux anastomosis (P>0.05). Cancer recurrence at the anastomotic site was not detected in the two groups. There was no significant difference in the rate of metabasis between two groups (P>0.05). The 1-year survival rate was 100% in each of the two groups.(2) Anti-reflux procedure resulted in comparable mean scores for physical functioning, role functioning, emotion functioning and social functioning between the two grops (P>0.05). In contrast, the scores of fatigue, loss of appetite and insomnia had the tendency of reduction in the group of anti-reflux anastomosis compared to that in the group of conventional anastomosis and differences did not reach statistically significant level (P>0.05). However, the scores of insomnia, heart burn and regurgitation in the group of anti-reflux anastomosis significantly improved in comparison with the group of conventional nastomosis (P<0.05). But the score of dysphasia, change of eating, loss of weight in the group with anti-reflux anastomosis was similar to that in the group with conventional anastomosis (P>0.05).Conclusion: (1) Modified fundoplication following esophagogastrostomy does not increase operative risk. (2) The anti-reflux surgery is performed to reduce symptoms of gastroesophageal reflux and improve the quality of life in postoperative patients with esophageal and cardiac carcinoma. But furthur study on the efficacy of anti-reflux procedure is needed.Part two The study of anti-reflux for modified fundoplication following esophagogastrostomy for cancerObjective: Gastroesophageal reflux occurs after surgery for esophageal and cardiac cancer is very common. The medical treatment may only reduce reflux symptoms rather than eliminate of gastroesophageal reflux. Anti-reflux procedure had been performed in clinical setting. It had been demonstrated that the modified fundoplication following esophagectomy was responsible for reducing symptoms of reflux. The aim of this study was to investigate the role of anti-reflux procedure in controlling reflux by many objective examinations.Methods: Seventy patients with esophageal and cardiac cancer were divided into two groups randomizely: one group include the patients who underwent conventional anastomosis and another group anti-reflux anastomosis. Thirty patients were recruited to undergo esophageal manometry, 24-hour pH monitoring of the esophagus, spectrometric bilirubin monitoring, endoscopy, biopsy 3 months after surgery. In group of conventional anastomosis, there were 16 patients (13 men and 3 women) with a mean age 59, including 8 patients with esophageal carcinoma in the middle third, 2 with esophageal carcinoma in the lower third, 5 cardiac carcinoma. In group of anti-reflux anastomosis, there were 14 patients (12 male and 2 female) with a mean age 58, including 7 patients with esophageal carcinoma in the middle third, 2 esophageal carcinoma in the lower third, 5 cardiac carcinoma. Three patients refused all examinations except esophageal intraluminal manometry.Results: (1) The score of reflux esophagitis in group of anti-reflux anastomosis was lower than that in group of conventional anastomosis (t=2.21, P=0.0320). There was no significant difference in score of esophageal mucosal inflammation between the two groups (t=1.16, P=0.2553).(2) Manometry was performed in 30 patients, of whom 16 patients underwent conventional anastomosis, 14 patients underwent anti-reflux anastomosis. Ineffective esophageal motility was observed in the remnant esophageal in 8 patients in group of anti-reflux anastomosis and in 11 patients in group of conventional anastomosis. Primary motility was found in remaining patients in the two groups. The resting pressure of remnant esophagus was higher than that of intrathoracic stomach in group of anti-reflux anastomosis (t=2.4037, P=0.0319). There was no significant difference in the resting pressure between the remnant esophagus and intrathoracic stomach in group of conventional anastomosis (t=0.7792, P=0.4480).(3) Twenty-four-hour pH and spectrometric bilirubin monitoring was performed in a total of 27 patients in the two groups. One patient had no reflux in group of conventional anastomosis, while 2 patients had no reflux in group of anti-reflux anastomosis. Reflux with varying extent occurred in remaing patients in two groups. There was no significant difference in the number of reflux episodes, the number of reflux episodes longer than 5 minutes, total reflux time of pH<4.00(min) between the two groups (P>0.05). Time of longest reflux episode (min) in group of anti-reflux anastomosis was evidently lower than that in group of conventional anastomosis (z=2.099, P=0.0358). DeMeester score, fraction time of pH<4.00(%) (total, upright, supine) and fraction time of abs>0.14 (%) (total, upright, supine) in group of anti-reflux anastomosis significantly reduced compared to that in group of conventional anastomosis (P<0.05).Conclusion: (1) The modified fundoplication following esophagogastostomy has the role of reducing gastroeophageal reflux. However, the anti-reflux procedure does not achieve ideal result. The outcome of anti-reflux procedure will be further demonstrated by long-term observation. (2) It is likely that the mild increase of resting pressure of the remnant esophagus producing the high pressure zone above anastomotic orifice results in the decrease of reflux after anti-reflux procedure is added.Part three The correlation between duodenogastrosophageal reflux and acid relux after esophagectomy for cancerObjective: Duodenogastroesophageal reflux (DGER) is defined as regurgitation of duodenal contents through the pylorus into the stomach, with subsequent reflux into the esophagus. Reflux of duodenal contents mixed with acidic contents of the stomach causes more severe damage of esophageal mucosa. The aim of this study was to investigate the effect of acid reflux and DGER on reflux symptoms and damage to remnant esophageal mucosa including esophagitis and Barrett esophagus. Methods: Thirty-two patients who ever underwent esophagectomy at the Department of Thoracic surgery, Fourth Hospital, Hebei Medical University between January 2006 and November were assessed for gastroesophageal reflux. Of the 32 patients, 15 patients had esophageal carcinoma in the middle third, 4 esophageal carcinoma in the lower third, and 13 cardiac carcinoma. There were 26 male and 6 female with the mean age of 61 years. The symptom was graded and scored by questionnaire of all patients according to the method of DeMeester. Reflux esophagitis and Barrett esophagus were endoscopically diagnosed and graded and scored. Twenty-four hour pH and spectrometric bilirubin monitoring of the esophagus was performed to record the number of reflux episodes, the number of reflux episodes longer than 5.0 minutes, longest reflux episodes, total time of pH below 4.00, fraction time of pH<4.00 , DeMeester score as well as fraction time of bilirubin abs>0.14 to evaluate the extent of acid reflux and DGER.Results: (1) Varing extent of reflux esophagitis was endoscopically observed in 24 patients (75.0%). Barrett esophagus was observed in 2 patients (6.2%).(2) Acid reflux was identified in 24 patients (75%) by 24-hour pH and spectrometric bilirubin monitoring. The mean fraction time of pH<4.00 was 32.49±31.17(%). The mean score of DeMeester was 115.49±95.01. Meanwhile, DGER was identified in 22 patients (68.7%). The mean fraction of abs>0.14 was 15.91±17.45 (%). One patient (3.1%) had neither acid reflux nor DGER, 9 patients (28.1%) had only acid reflux, 5 patients (15.6%) had only DGER, the remaining 17 patients (53.1%) had both acid reflux and DGER by analysis of acid reflux and DGER profile. No correlation was demonstrated between fraction time of pH<4.00 or DeMeester score and fraction time of abs>0.14 (P>0.05). Fraction time of pH<4.00 and fraction time of abs>0.14 in supine position were significantly higher than that in upright position (P<0.05).(3) Most esophageal bilirubin exposure occurred in the range of pH 3~6 by moment-moment comparison of pH and bilirubin absorbance.(4) There was no correlation among fraction time of pH<4.00, DeMeester score, fraction time of abs>0.14 and score of reflux symptoms (P>0.05), while positive correlation was significant among fraction time of pH<4.00, DeMeester score, fraction time of abs>0.14 and score of reflux esophagitis (P<0.05). Simultaneous occurrence of acid reflux and DGER causes severe reflux esophagitis and Barrett esophagus.Conclusion: (1) Acid reflux and DGER is common pattern after esophagectomy for cancer. Acid and GGER occur simultaneously in the majority of the reflux episodes.(2) DGER alone is significantly associated with occurrance of reflux esophagitis and Barrett esophagus. Positive correlation was significant between the extent of reflux esophagitis and acid reflux and/or DGER. Exposure of DGER in lower acid environment increases the damage extent to esophageal mucosa.(3) The extent of both acid reflux and DGER is influenced by change of body position.Part four The effects of gastroesophageal reflux on expression of COX-2 and TNF-αafter esophagectomy for cancerObjective: Expression of COX-2 and TNF-αwas observed in remnant esophageal mucosa in order to investigate the effect of gastroesophageal reflux on expression of COX-2 and TNF-α.Methods: Esophageal mucusa samples obtained by endoscopic biopsy were from 32 patients who underwent esophagectomy for cancer between January 2006 and November 2007. There were 26 male and 6 female, with a mean age of 61 years. Twenty-four-hour pH and spectrometric bilirubin monitoring, endoscopy were also performd in the 32 patients. Expression of COX-2 and TNF-αwithin remnant esophageal mucosa was detected using immunohistochemical assay.Results: (1) The incidence of esophagitis after surgery for esophageal and cardiac cancer was 75%, and it gradually increased over time (P=0.034). Meanwhile, the extent of acid reflux gradually elevated over time (P=0.001). The change of DGER was not observed in different operative period (P> 0.05).(2) Very low level of COX-2 expression was detected in normal esophageal squamous mucosa. The expression of COX-2 was found in cytoplasm of basal cell of esophageal epithelium after esophagectomy for cancer. COX-2 expression was stronger in the cytoplasm of epithelial basal cell and submucosal glands after operative 3 years. Similarly, the high intensity of COX-2 expression was also observed in cytoplasm of glandular cell in the metaplastic columnar mucosa 2.5 or 3 years after surgery. The level of COX-2 expression (OD value) after esophagectomy for cancer was statistically higher than that of the normal control (P<0.05). The level of COX-2 expression gradually increased over time (P=0.001).(3) Very low level of TNF-αexpression was detected in normal esophageal squamous mucosa. The expression of TNF-αwas observed in cytoplasm of basic cell in the esophageal squamous epithelium in different postoperative period. But high intensity of TNF-αexpression was detected in the metaplastic columnar mucosa. The level of TNF-αexpression after esophagectomy for cancer was higher than that of normal control (P<0.05). But there was no increasing tendency in level of TNF-αexpression in different postoperative period (P=0.3246).(4) DeMeester score is significantly related to the level of COX-2 expression (r=0.4204, P=0.0029). There was no significant relationship between fraction time of abs>0.14 and COX-2 expression (r=0.3260, P=0.0971). Similarly, there was no relationship among DeMeester score, fraction time of abs>0.14 and level of TNF-αexpression (r=0.1765, P=0.3786; r=0.2664, P=0.1292).Conclusion: (1) The extent of gastroesophageal reflux and incidence of esophagitis gradually increases over time. There is evidently relationship between the extent of reflux and expression of COX-2.(2) The durative expression TNF-αis likely the pathogenesis of chronic reflux esophagitis.(3) It is possible that the human model contributes to the study of the pathogenesis of reflux esophagitis and Barrett esophagus.