al News Esophagus Regeneration Successful in Human Patient Janis C. Kelly |April 08, 2016 US physicians successfully regenerated a patient's badly damaged esophagus using off-the-shelf components approved by the US Food and Drug Administration and autologous platelet-rich plasma adhesive gel. Seven years after the surgery and 3.5 years after removal of the metal stents, the patient is able to eat and swallow normally. The epithelium at the wound site now appears normal and contains the proper tissue layers. Kulwinder S. Dua, MD, from the Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, and colleagues report the landmark case in a paper published online April 8 in the Lancet. The case report provides proof of concept that regrowth of lost esophagus is possible without complex tissue engineering, but the new approach requires validation in animal studies before proceeding to clinical trials. The physicians undertook the novel approach in an attempt to save the life of a critically ill 24-year-old patient suffering from a 5-cm, full-thickness hole in his esophagus. Five years earlier, the patient had been rendered quadriplegic in a car accident and undergone cervical spine stabilization with metal plates. Tissue deterioration and a large paraspinal abscess caused destruction of the posterior pharyngeal wall, such that at the time of presentation, the metal plate in the cervical spine could be seen within the pharynx, and there was free communication between the pharynx and the mediastinum. The authors write, "The cervical spine essentially composed the back wall of the pharynx. The anterior plates were removed by a neurosurgeon, which resulted in a large hole in the posterior wall of the pharynx and pharyngo-esophageal junction with a large caudal defect." The patient, who had dysphagia, odynophagia, neck pain, fever, and chills, was intubated and provided with a percutaneous gastrostomy feeding tube, and had purulent fluids and phlegmon-type debris drained and debrided from the posterior mediastinum. More conventional esophageal repair procedures were not possible because of the size of the gap and the patient's fragile condition, so the surgical team first tried closing the defect with multiple interrupted mattress sutures to bring the pharyngeal walls together, in the hope of reestablishing gastrointestinal continuity. That did not work, and imaging during the next 6 weeks showed substantial leakage into the mediastinum and a defect that could not be closed despite multiple surgeries. The patient was then referred to the gastroenterology service, where the ultimately successful repair plan was devised. Formal institutional review board was not required because the interventions were a result of clinical necessity, used only products already approved by the US Food and Drug Administration, and used techniques that were standard of care at the institute. The patient gave written informed consent for each intervention. Multiple Attempts Needed An attempt to get the large oesophageal defect to heal by insertion of an Alimaxx-ES(Merit Medical) self-expanding metal stent (18 mm diameter, 120 mm long) to maintain the three-dimensional shape of the esophagus was unsuccessful and was followed by 3 weeks of spiking fevers, contrast medium leaking into the mediastinum along the outer wall of the stent, and partial encircling of the stent by granulation tissue. Dr Dua's team then attempted regeneration of the esophagus in vivo, using commercially available AlloDerm extracellular matrix and autologous platelet-rich plasma (PRP) with stenting. First, taking care to avoid platelet activation, they slowly drew 60 mL blood from the patient. The blood was centrifuged, and the resulting 3 mL PRP was mixed with 7 mL platelet-low plasma and transferred to a 10-mL syringe. A second 0.1-mg syringe contained calcium chloride and topical thrombin to make the PRP tensile and adhesive. Both were connected to a sprayer to dispense the solutions in a ratio of 10:1. The use of autologous PRP meant no immune suppression was needed. AlloDerm, derived from donated human skin, is required to test negative for bacterial and fungal pathogens and is processed aseptically. Cells are removed, and the dermal matrix is retained. The extracellular matrix was rehydrated in saline and wrapped circumferentially around the stent, with the dermal side (which readily absorbs blood) oriented toward the mediastinum to facilitate vascularization. The graft was sutured in place and sprayed with the autologous PRP adhesive gel. The sternocleidomastoid muscle was retracted and wrapped over the graft. This stopped the leak into the mediastinal cavity, and the patient was allowed oral intake, which the use of metal stents made possible. However, 4 weeks later, granulation tissue blocked the lower end of the stent, and the patient developed dysphagia. An attempt to fix this problem by telescoping another self-expanding metal stent into the first one failed because the two stents migrated proximally to the point of overhanging the larynx, producing throat discomfort and stridor, so these two stents were removed and replaced with three stents, all 18 mm diameter, aligned with the proximal stent across the upper esophageal sphincter and the upper end of the proximal stent at the level of the inter-arytenoid folds to avoid interfering with the epiglottis during swallowing, and the lower end of the distal stent above the lower esophageal sphincter to prevent reflux into the hypopharynx. This third stent attempt worked, and the patient was eating soft foods by the time of discharge, supplemented by gastric tube feeding. The medical team had intended to remove the stent at 12 weeks after insertion, but having regained the ability to eat, the patient was not willing to risk leakage or stricture developing after removal. This situation continued for 3 years until stent-induced granulation tissue again obstructed the lower end of the distal stent. Partial ablation of the granulation was temporarily effective, but the patient decided to have the stents removed after recurrent problems. This was done by endoscopy. Eight weeks later, endoscopy showed "normal squamous mucosa with no stricture or fistula." At 1 year after stent removal, the patient had normal-appearing squamous epithelium covering the repaired site showing five layers: mucosa, muscularis mucosa, submucosa, muscularis propria, and adventitia. Swallowing was normal, as was peristalsis in the repaired esophagus and bolus transit into the stomach. By 4 years after stent removal, the patient was eating normally, maintaining normal weight, and no longer needing supplemental gastric tube feeding. In an accompanying editorial, Martin Birchall, MD, from the Royal National Throat, Nose and Ear Hospital and University College, London, and Paolo De Coppi, from Great Ormond Street for Children NHS Foundation Trust and University College London's Institute for Child Health, United Kingdom, write, "The endoscopic ultrasound data are crucial to understanding the contribution of the implanted graft material. These data seem to confirm complete regeneration of all layers of the oesophagus with a cell-free engineered construct, a remarkable finding given the presumed complexity of this organ." The authors note that the extended delay (3.5 years) before stent removal meant they were not able to determine the time required for regeneration, which has taken up to 1 year in animal studies. If the techniques are replicated, "this method might have substantial effects on the treatment of patients who need conduits after oesophageal resection," the authors conclude. In a press release, Dr Dua said, "This is a first in human operation and one that we undertook as a life-saving measure once we had exhausted all other options available to us and the patient. The use of this procedure in routine clinical care is still a long way off as it requires rigorous assessment in large animal studies and phase 1 and 2 clinical trials. The approach we used is novel because we used commercially available products which are already approved for use in in the human body and hence didn't require complex tissue engineering." The study authors and the editorialists all warned against viewing this case as a shortcut to clinical trials. Dr Birchall and De Coppi said much can be learned from the early use on compassionate grounds of new technologies in patients for whom no conventional treatments are suitable, but added, "uch seriously ill patients are not usually typical, having highly disordered physiology and, in patients with surgical disorders, anatomy, and sceptics argue that the underlying mechanisms for success or failure cannot be understood on the basis of data from such patients. Instead, well designed animal studies are the most appropriate precedents to early phase clinical trials." The authors and editorialists have disclosed no relevant financial relationships. Lancet. Published online April 8, 2016.
What a joke. First time? Nieponice had five reconstructed esophagus patients in his initial study. Complete restoration of full thickness, indistinguishable tissue. Evidence of innervation, Eating at 7 days. I would be embarrassed to publish this. How long till the stent was removed and you call that regeneration? How many returns to the OR due to stricture? Dangerous proposition. This is not remodeling and not in the same realm as regenerative medicine.
