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.

Pirfenidone prevents rat esophageal stricture formation.

BACKGROUND: Accidental ingestion of caustic substances induces esophageal injuries and stenosis formation. The main aim for acute phase treatment is to prevent esophageal stenosis. Pirfenidone (PFD) is a pyridone with antifibrotic and anti-inflammatory effects. Esophagus stenosis takes place after a strong inflammation process where proinflammatory and profibrogenic cytokines play an important role. The present study investigates the efficacy of PFD on the prevention of stricture development after esophageal caustic injuries in a rat model. MATERIAL AND METHODS: Caustic esophageal burn was produced by application of 32% of NaOH to the distal esophagus of healthy rats. PFD in the form of 8% gel was administered at a dose of 200 mg/kg/d. Animals were divided in three experimental groups as follows: healthy rats, animals injured with NaOH without PFD treatment, and rats injured with NaOH and treated with PFD. Efficacy of the treatment was assessed by measuring image esophagoscopy and esophagography with contrast barium at the 21st d. Histology staining with Sirius-red was performed to evaluate collagen deposition and stenosis area. Gene expression of transforming growth factor ß1, collagen-1, plasminogen activator inhibitor-1, connective tissue growth factor, and matrix metalloproteinase 2 were measured by quantitative reverse transcription polymerase chain reaction. RESULTS: There was significant difference in means of stenosis by esophagoscopy and esophagogram. Collagen deposition in the damaged area increased significantly when rats were burned with NaOH, and decreased notably in PFD treated group. Profibrogenic key molecules transforming growth factor ß1, collagen 1, plasminogen activator inhibitor-1 and connective tissue growth factor expression were significantly lower respect to control group without PFD treatment where matrix metalloproteinase 2 expression was no different in all groups. CONCLUSIONS: This study suggests that PFD reduces stenosis on caustic esophageal burn by decreasing profibrogenic genes expression and ameliorates fibrosis significantly in the chronic phase.

Beneficial effects of Ankaferd Blood Stopper on caustic esophageal injuries: an experimental model.

Ankaferd Blood Stopper (ABS) is an herbal extract that enhances mucosal healing. The aim of this study was to investigate the efficacy of ABS on the healing of the esophagus and prevention of stricture development after esophageal caustic injuries in rats. The study included 50 rats. Rats were divided into five groups: group 1 (no injury, sham surgery), group 2 (injury + no ABS + study after 2 weeks of injury), group 3 (injury + ABS + study after 2 weeks of injury), group 4 (injury + no ABS + study after 4 weeks of injury), and group 5 (injury + ABS + study after 4 weeks of injury). Standard esophageal burn injury was created by applying 50% NaOH solution to distal esophagus of about 1.5 cm. To rats in the sham group, isotonic solution was given instead of NaOH. ABS (2 mL/day) was given via oral route to group 3 and 5 rats. Fourteen days (group 2 and 3) and 28 days (group 4 and 5) later, all the live rats were killed. The distal esophageal segments of all rats were removed and divided into two equal parts for biochemical and histopathological examination. Mortality rate, weight changes, inflammation, stenosis index (SI), and biochemical measurements were evaluated. The SI was found as 0.31 ± 0.03 in group 1, 0.533 ± 0.240 in group 2, 0.568 ± 0.371 in group 3, 0.523 ± 0.164 in group 4, and 0.28 ± 0.03 in group 5. The SI and inflammation in ABS-treatment group 5 was significantly lower than that in non-treatment group 4 (P= 0.005). There were no significant differences between inflammation and SI among other groups. The mortality rate was 14.2% in group 1, 37.5% in untreated group 2, 14.2% in ABS-treated group 3, 80% in untreated group 4, and 33.3% in ABS-treated group 5. The mortality rate in group 4 was significantly higher than other groups (P= 0.025). Decrease rates in mean body weights of the groups were as follows: group 1, 1%; group 2, 15%; group 3, 14%; group 4, 46%; and group 5, 15%. Biochemical tests other than albumin and creatinine were comparable among the groups. Treatment with ABS prevents inflammation, scar formation, weight loss, and mortality in esophageal caustic injuries. Additional studies to evaluate the clinical benefits of ABS in esophageal caustic injury are recommended.

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.

Gastrocoele: a complication of combined oesophageal and antral corrosive strictures.

Corrosive strictures of the gastrointestinal tract are a surgical challenge. We describe a previously undescribed condition called gastrocoele, a rare condition caused by combined oesophageal and antral strictures and review our results. We present our experience with nine cases of gastrocoele due to combined corrosive strictures of oesophagus and antrum between 1993 and 2005. The age group was 21-65 years with female preponderant (66%) sex distribution. The presentation was at a median of 110 days (range 45-400 days) following the corrosive ingestion. The standard investigations included barium swallow, endoscopy, jejunostomy tubogram and barium enema. The surgical procedures performed were antrectomy and coloplasty in six (one staged), antrectomy and oesophageal dilatation in two and gastrojejunostomy and coloplasty in one. There was no major morbidity or mortality with a median follow-up of 3 years. Gastrocoele is a rare entity where good results can be achieved with surgery, however, prevention of corrosive injuries by public education is the best cure!

The efficacy of ozone therapy in experimental caustic esophageal burn.

INTRODUCTION: Ozone has been proposed as an antioxidant enzyme activator, immunomodulator and cellular metabolic activator. This study was designed to investigate the efficacy of ozone therapy in the prevention of esophageal damage and stricture formation developed after esophageal caustic injuries in the rat. MATERIALS AND METHODS: Forty-five rats were allocated into three groups; sham-operated, un-treatment and treatment groups. Caustic esophageal burn was created by instilling 15% NaOH in the distal esophagus. The rats were left untreated or treated with 1 mg/kg/day ozone intraperitoneally. All rats were sacrificed at 28 days. Efficacy of the treatment was assessed by measuring the stenosis index (SI) and histopathologic damage score, and biochemically by determining tissue hydroxyproline content (HP), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) and protein carbonyl content (PCC) in esophageal homogenates. RESULTS: Whereas seven (47%) rats died in the un-treatment group, all rats in the sham-operated and the treatment group survived during the study. SI, the histopathologic damage score, was significantly lower in the ozone-therapy group than the un-treatment group. HP levels were significantly higher in the un-treatment group than the group treated with ozone. Caustic esophageal burn increased MDA and PCC levels and also decreased SOD and GPx enzyme activities. In contrast, ozone therapy decreased the elevated MDA and PCC levels and also increased the reduced SOD and GPx enzyme activities. CONCLUSION: Ozone has a preventive effect in the development of fibrosis by decreasing tissue damage and increasing the antioxidant enzyme activity in an experimental model of corrosive esophageal injury.

Aluminium phosphide-induced esophageal stricture palliation with polyflex stent.

A 21-year-old woman developed midesophageal stricture two weeks after ingestion of aluminium phosphide (AlP) tablets. Aluminium phosphide is a lethal protoplasmic toxin and is also the most common cause of suicidal poisoning in northern India. Upper gastrointestinal endoscopy (UGIE) showed a tight esophageal stricture 29 cm from the incisors with a circumferential ulcer. Dilatation up to 17 mm was done using Savary-Gilliard dilators. She had repeated dilatations three times at nearly two-week intervals. In view of the resistant stricture, a silicone Polyflex stent was placed across the stricture and removed after 3 months; there was no recurrence of stricture even after three months of follow-up. Patients with recurrent esophageal stricture and those with fistula may benefit from silicone expandable stents.

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.

Foley catheter self dilatation for strictures of the upper end of oesophagus.

Three patients having corrosive stricture of the upper end of oesophagus and two patients of impassable corrosive stricture of oesophagus who were subjected to coloplasty using descending colon and who developed stricture at the site of upper anastomosis were being treated by antegrade dilatations with oesophageal bougies under general anaesthesia. These patients were put on controlled, progressive, self, domiciliary, dilatation with foley catheter. Four patients became asymptomatic and did not require any other type of dilatation. One patient initially was not able to do the dilatations properly so she required re-training, after which she remained asymptomatic. Foley catheter dilatation of the strictures of the upper end of oesophagus was found to be simple, effective, easy to carry out, comfortable for the patient and economical.

[Nutritional treatment in the therapeutic strategy in benign esophageal stenosis]. / Il trattamento nutrizionale nella strategia terapeutica delle stenosi esofagee benigne.

Oesophageal strictures prevent a normal alimentation, and in chronic and more prolonged cases are the cause of severe denutrition. Many organs then undergo changes reflected on ultrastructural morphology, that in most severe and lasting cases can demonstrate irreversible. The functional aspect of such changes correspond to a hindered performance of the damaged organs with possible sudden cardiovascular accidents, which are particularly meaningful in the surgical steps of reconstruction, that is heavy for the patient not only in the perioperative period but also during the recovery when higher are the caloric energetic requirements. For the positive outcome of the surgical therapy of these strictures it is therefore necessary to preventively restore an acceptable nutritional status of the patient by the use of one or more of the nowadays available techniques of artificial nutrition. A particular topic of the need of a efficacious nutritional treatment can be pointed in the cases of oesophageal caustic burns, where the caloric requirements is high since the beginning to meet the catabolic effects of the traumatic condition, while malnutrition represents one of the negative factors in prolonging connettival and fibroblastic proliferation, cause of most severe strictures and recurrences. After a general survey of the whole problem, the characteristics of the various artificial nutrition techniques are discussed, with the identification of an optimal scheme of global and nutritional treatment in oesophageal caustic burns.

[The use of copper-vapor laser radiation on patients with chemical burns of the esophagus via fiber esophagoscopy]. / Ispol'zovanie izlucheniia lazera na parakh medi u bol'nykh s khimicheskimi ozhogami pishchevoda pri fibroézofagoskopii.

Fifty patients with chemical burns of the esophagus were examined fibroesophagoscopically. All of them underwent local endoscopic irradiation by a copper vapour laser. Laser treatment promoted more rapid healing of the esophageal wall. No cicatrization-induced strictures were noted. Adjuvant local laser therapy is believed valid in management of esophageal chemical trauma.

[Our experience with surgery of esophageal stenosis caused by caustic soda. Apropos of 128 cases]. / Notre expérience dans la chirurgie des sténoses oesophagiennes d'origine sodique. A propos de 128 cas.

The authors report a series of 128 cases of esophageal burns due to caustic soda, treated between 1974 and 1987 in the Dept. of Surgery of the Friguia Kimbo Alumina Factory Hospital. 95% of patients were children aged less than 15. Ingestion was generally accidental. In view of the delay before patients were seen, in addition to parenteral alimentation, nutrition was covered by an alimentation gastrostomy performed in 96% of patients immediately following admission. Dilator treatment was used in 37 patients with 29 good result, 6 failures, and 2 perforations with 1 death. Retrosternal esophagoplasty using the transverse colon was performed in 95 cases with a 96.8% cure rate over a total follow-up period of 1 to 10 years, and 3 deaths. Overall mortality taking all categories together was 5.4%. The authors used these results as a basis for reviewing this condition, attempting to define as a basis for reviewing this condition, attempting to define the therapeutic methods successively used in the Guinea medico-social context.