Protective Effects of Contractubex® on Stricture Formation after Experimental Corrosive Esophageal Burns in Rats.

AIM/BACKGROUND: Although many agents have been tested as treatment options for caustic esophageal burn (CEB), none have successfully suppressed the formation of strictures. Thus,the purpose of this study was to determine the efficacy of Contractubex® gel (10% onion extract, 50 U/gr heparin, and 1% allantoin) in stricture preventing after CEB. METHODS: In this study, 24 Wistar-albino rats were divided into 4 groups. CEB was initiated with an instillation of 1 mL of 10% NaOH solution into the an isolated esophageal segment for 3 min. Group C (control) was uninjured and untreated. In Group CEB, was initiated but no treatment was given. In Groups CTX1 and CTX2, the animals received 100 and 200 mg/kg/d, respectively, of Contractubex® for 4 weeks via gavage after CEB was initiated. The stenosis indices (SI), histopathologic damage scores, tissue hydroxyproline (HP) levels, and weights of the rats were taken before the experiment and 4 weeks after the experiment. RESULTS: The Mean SI levels, HP levels, and histopathologic damage scores were statistically lower in Groups CTX1 and CTX2 when compared with Group CEB (p <0.05). The treatment groups increased in weight when compared to Group CEB. The results were similar between Group CTX1 and Group CTX2 (p >0,05); the efficacy of the treatment was not dose-dependent. CONCLUSION: For the first time, Contractubex® was used for its antifibrotic, antioxidant, anti-inflammatory, and wound healing effects to treat caustic esophageal burn in rats. It was effective in reducing stricture formation by decreasing the HP levels and histopathologic damage as well as preventing stenosis and weight gain in the treatment groups.

A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy.

BACKGROUND: The prevalence of esophageal stenosis caused by immune checkpoint inhibitors in the context of induced immune mucositis and esophagitis is extremely rare. CASE PRESENTATION: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral sterile conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory with fibrinous deposits. Esophagogastroduodenoscopy revealed mucositis with a scar-like structure immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. No morphologic evidence of adenocarcinoma and no signs of mycotic, bacterial or viral infection were noted. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A thoracoabdominal CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent clinical response, allowing the total resolution of the immune-related adverse events (irAEs) and leading to successful steroid tapering. CONCLUSIONS: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory esophageal stenosis and more broadly in refractory immune-related adverse events.

The efficacy of single-dose 5-fluorouracil therapy in experimental caustic esophageal burn.

INTRODUCTION: Accidental ingestion of caustic substances may cause serious problems in children. Approximately 20% of caustic ingestions result in esophageal stricture formation, resulting from excessive collagen synthesis to the extracellular matrix by fibroblasts. Recent studies showed that a single application of 5-fluorouracil (5-FU) is a very effective inhibitor of fibroblast proliferation and differentiation for prolonged periods. Using an experimental model, we investigated the efficacy of single-dose 5-FU on stricture formation after caustic esophageal burn. MATERIALS AND METHODS: Forty Wistar-Albino rats were divided randomly into 4 equal groups: group 1 (sham-operated group), the esophagus was uninjured and untreated; group 2 (control group), the esophagus was injured and left untreated; group 3 (intraperitoneal treatment group), the esophagus was injured and treated immediately after the burn injury with a single intraperitoneal dose (20 mg/kg) of 5-FU; group 4 (local treatment group), the esophagus was injured and treated immediately after the burn injury with a single intraesophageal application of 5-FU at a concentration of 25 mg/mL. Caustic esophageal burn was produced by instilling 10% NaOH in the distal esophagus. The distal esophagi were harvested at 28 days postoperatively. Histologic sections were assessed by measuring the stenosis index (SI) and histopathologic damage score. Hydroxyproline (HP) levels in the tissues were determined biochemically. RESULTS: There were significant reductions in the SI (P < .05), histopathologic damage score (P < .05), and HP level (P < .05) in the intraperitoneal treatment group when compared with the control group. No significant differences in the SI and histopathologic damage score were detected between the control and local treatment groups (P > .05), whereas significant reduction in the HP level was determined between these groups (P < .05). CONCLUSION: A single intraperitoneal dose of 5-FU had a preventive effect on stricture formation after caustic esophageal burn. This observation suggests that 5-FU may prevent this undesirable complication in the clinical setting. Clinical studies are now required to verify this form of treatment. Local intraesophageal application of 5-FU immediately after the burn injury was not effective. Further investigations are required to determine the appropriate timing of application of 5-FU at the local site of injury.

Mercaptoethylguanidine attenuates caustic esophageal injury in rats: a role for scavenging of peroxynitrite.

INTRODUCTION: After ingestion of caustic material, tissue damage is caused by reactive oxygen species and reactive nitrogen species such as peroxynitrite. Mercaptoethylguanidine (MEG) is a well-known scavenger of peroxynitrite. This study was designed to determine whether MEG has a beneficial effect on caustic esophageal injury. MATERIALS AND METHODS: Forty-five rats were allocated into 3 groups: sham-operated, untreated, and treated groups. Caustic esophageal burn was created by instilling 15% NaOH in the distal esophagus. The rats were left untreated or treated with 10 mg/kg per day MEG intraperitoneally for 5 days. All rats were killed at 28 days. Efficacy of the treatment was assessed both histopathologically and biochemically. RESULTS: Of 15 rats, 6 (40%) died in the untreated group, and only 1 (7%) rat died in the treated group. The stenosis index (SI) and the histopathologic damage score were significantly lower in the MEG treatment group than the untreated group, which showed a correlation with tissue hydroxyproline level. In the untreated group, tissue oxidative stress parameters (malondialdehyde and protein carbonyl content) were significantly higher; and antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) were significantly lower. Administration of MEG ameliorated oxidative stress parameters and antioxidant enzyme activities. Urinary nitrate and nitrite levels increased in the treated and untreated groups in the first 3 days, suggesting increased nitrosative stress; but at the fourth day, nitrate and nitrite level reached control values in the treated group. CONCLUSION: Peroxynitrites play an important role in the healing process of caustic esophagitis. As a peroxynitrites scavenger, MEG potentially might be a useful adjuvant agent in the treatment of esophageal caustic burn by modulating the antioxidant defense mechanism.

[Efficacy of sorption therapy in patients with cicatricial esophageal stenosis].

We examined 110 patients treated conservatively for cicatricial esophageal stenosis including expansion on the string. The patients were divided into three groups: controls (n = 35), receiving adjuvant SUMS-1 (n = 38) and given adjuvant enterosgel (n = 37). According to electron microscopy, enterosorbents make esophageal mucosa denser by decreasing interstitial spaces as a result of microcirculatory improvement and reduction of edema. Enterosorbents elevate total protein and sugar in the blood.

Trimetazidine reduces the degree of fibrosis in alkali burns of the esophagus.

PURPOSE: The aim of this study was to investigate the efficacy of trimetazidine (TMZ), an antioxidant agent, on the prevention of stricture development after esophageal caustic injuries in rat. METHODS: Thirty rats were divided into 3 equal groups. A standard esophageal caustic burn was produced by application of 37.5% NaOH for a period of 90 seconds followed by water rinse. Group A (sham) animals were uninjured. Group B rats were injured but untreated. Group C rats were injured and received TMZ (5 mg/kg/d) via intraperitoneal route. Efficacy of the treatment was assessed in 28 days by measuring stenosis index and histopathologic damage score and by determining tissue hydroxyproline content. RESULTS: The stenosis index in the TMZ-treated group was significantly lower than the untreated group, similarly in the sham laparotomy group (stenosis index: 0.34 +/- 0.10, 0.94 +/- 0.21, 0.38 +/- 0.05, respectively; P < .05). The hydroxyproline level (microgram per milligram of wet tissue) was significantly lower in the TMZ-treated group compared with untreated group, similarly in the sham laparotomy group (1.06 +/- 0.14, 1.33 +/- 0.08, 0.68 +/- 0.15 microg/mg wet tissue, respectively; P < .05). In the untreated group, histopathologic damage score was significantly higher than TMZ-treated group (P < .05). CONCLUSIONS: Trimetazidine reduces the degree of fibrosis and ameliorates histopathologic damage in experimental model of corrosive esophagitis in rats.

High-dose omeprazole in esophagitis with stenosis after surgical treatment of esophageal atresia.

The authors describe 4 children with recurrent stenosis and persistent esophagitis after secondary repair of a long gap esophageal atresia. They underwent an esophageal reconstruction by elongation of the lesser gastric curvature according to Schärli at the age of 11 to 14 months. All had esophagitis grade III to IV (Savary-Miller classification), esophageal stenosis, and failure to thrive. Effective treatment of the esophagitis and prevention of stenosis consisted in high doses of omeprazole (1.9 to 2.5 mg/kg/d). After this treatment, the need for esophageal dilatation disappeared, and nutritional status normalized.

Prevention of recurrence of oesophageal stricture, a comparison of lansoprazole and high-dose ranitidine.

OBJECTIVE: To determine the efficacy of lansoprazole 30 mg given in the morning compared with high-dose ranitidine 300 mg twice daily in the treatment of patients with oesophageal strictures. DESIGN: A multicentre, outpatient, double-blind, parallel group, prospectively randomized clinical trial. PATIENTS: One hundred and fifty-eight patients (lansoprazole 30 mg n = 78, ranitidine 600 mg n = 80) were enrolled from 19 centres in the UK over 23 months. INTERVENTIONS: Patients with an oesophageal stricture were randomized to receive either lansoprazole 30 mg once daily or high-dose ranitidine 300 mg twice daily for 12 months. Dilatation was performed at entry and repeat endoscopies were scheduled at 6 and 12 months and additionally at other times if there was symptomatic relapse. Redilatation was performed as required and according to a predefined scale. The patient's assessment of dysphagia over the previous 7 days was recorded by the investigator at 1, 3, 6, 9 and 12 months. Safety was assessed by laboratory tests, physical examination and all adverse events. MAIN OUTCOME MEASURES: Efficacy was assessed primarily by the time to redilatation, the proportion of patients requiring at least one redilatation, and the number of redilatations over 12 months. The relief of dysphagia and reduction in stricture grade were secondary efficacy measures. RESULTS: The time to redilatation was longer and the probability of no redilatation were higher in the lansoprazole group than in the ranitidine group; for all patients randomized (intention to treat principle), this difference was of borderline significance (life table, P = 0.053). The proportions of patients requiring at least one redilatation during the 12-month treatment period were 30.8% (24/78) with lansoprazole and 43.8% (35/80) with ranitidine (all patients randomized, chi 2 test, P = 0.092). Compared to ranitidine, patients receiving lansoprazole reported significantly lower dysphagia grades at 6 months (stratified Wilcoxon test, P = 0.0086) but not at 12 months (stratified Wilcoxon test, P = 0.074). A greater proportion of patients in the ranitidine group-33.8% (27/80)-withdrew prematurely compared to the lansoprazole group (26.9%, 21/78). The most frequent reasons for premature withdrawal were adverse events and protocol violations. There were no clinically significant differences in incidence or severity of adverse events between the two groups. The mean increase in gastrin levels after 12 months' treatment was significantly greater for patients in the lansoprazole group (124.2 pg/ml, P = 0.0056) than those in the ranitidine group (31.9 pg/ml). No significant changes in gastric mucosal histology were detected for patients in either group. CONCLUSION: It is concluded that lansoprazole 30 mg once daily is superior to ranitidine 300 mg twice daily in relieving dysphagia, and at least as effective in reducing the need for a repeat dilatation.