Shinichiro Kobayashi

Prevention of esophageal strictures after endoscopic submucosal dissection

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have recently been accepted as less invasive methods for treating patients with early esophageal cancers such as squamous cell carcinoma and dysplasia of Barretts esophagus. However, the large defects in the esophageal mucosa often cause severe esophageal strictures, which dramatically reduce the patients quality of life. Although preventive endoscopic balloon dilatation can reduce dysphagia and the frequency of dilatation, other approaches are necessary to prevent esophageal strictures after ESD. This review describes several strategies for preventing esophageal strictures after ESD, with a particular focus on anti-inflammatory and tissue engineering approaches. The local injection of triamcinolone acetonide and other systemic steroid therapies are frequently used to prevent esophageal strictures after ESD. Tissue engineering approaches for preventing esophageal strictures have recently been applied in basic research studies. Scaffolds with temporary stents have been applied in five cases, and this technique has been shown to be safe and is anticipated to prevent esophageal strictures. Fabricated autologous oral mucosal epithelial cell sheets to cover the defective mucosa similarly to how commercially available skin products fabricated from epidermal cells are used for skin defects or in cases of intractable ulcers. Fabricated autologous oral-mucosal-epithelial cell sheets have already been shown to be safe.

Oral epithelial cell sheets engraftment for esophageal strictures after endoscopic submucosal dissection of squamous cell carcinoma and airplane transportation

Endoscopic submucosal dissection (ESD) permits en bloc removal of superficial oesophageal squamous cell carcinoma (ESCC). However, post-procedure stricture is common after ESD for widespread tumours, and multiple endoscopic balloon dilation (EBD) procedures are required. We aimed to evaluate the safety and effectiveness of endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets that had been transported by air over a distance of 1200 km in controlling postprocedural oesophageal stricture. Ten patients who underwent complete circular or semicircular ESD for ESCC were transplanted with cell sheets. The safety of the entire process including cell sheet preparation, transport, ESD and cell sheet transplantation was assessed. The incidence of oesophageal stricture, number of EBD sessions, and time until epithelialization were investigated. Each ESD was successfully performed, with subsequent cell sheet engrafting carried out safely. Following cell sheet transplantation, the luminal stenosis rate was 40%, while the median number of EBD sessions was 0. The median post-ESD ulcer healing period was rather short at 36 days. There were no significant complications at any stage of the process. Cell sheet transplantation and preparation at distant sites and transportation by air could be a safe and promising regenerative medicine technology.

Multidisciplinary therapy for granulocyte-colony-stimulating factor producing carcinosarcoma of the esophagus: report of a case.

The granulocyte‐colony‐stimulating factor (G‐CSF)‐producing esophageal carcinosarcoma is extremely rare in esophageal cancer. In the present case, multidisciplinary therapy, which is surgical resection with preoperative chemotherapy, has been effectively treatment to granulocyte‐colony‐stimulating factor producing esophageal carcinosarcoma of the esophagus.

Regenerative medicine for the esophagus

Advances in tissue engineering techniques have made it possible to use human cells as biological material. This has enabled pharmacological studies to be conducted to investigate drug effects and toxicity, to clarify the mechanisms underlying diseases, and to elucidate how they compensate for impaired organ function. Many researchers have tried to construct artificial organs using these techniques, but none has succeeded in growing a whole organ. Unlike other digestive organs with complicated functions, such as the processing and absorption of nutrients, the esophagus has the relatively simple function of transporting content, which can be replicated easily by a substitute. In regenerative medicine, various combinations of materials have been applied, including scaffolding, cell sources, and bioreactors. Exciting results of tissue engineering techniques for the esophagus have been reported. In animal models, replacing full-thickness and full-circumferential defects remains challenging because of stenosis and leakage after implantation. Although many reports have manipulated various scaffolds, most have emphasized the importance of both epithelial and mesenchymal cells for the prevention of stenosis. However, the results of repair of partial full-thickness defects and mucosal defects have been promising. Two successful approaches for the replacement of mucosal defects in a clinical setting have been reported, although in contrast to the many animal models, there are few pilot studies in humans. We review the recent results and evaluate the future of regenerative medicine for the esophagus.

Relationship between immune function recovery and infectious complications in patients following living donor liver transplantation

The ImmuKnow (IK) assay enables the evaluation of peripheral blood CD4+ adenosine triphosphate activity to facilitate an objective assessment of the cellular immune function in immunosuppressed patients. However, it is unclear whether the IK assay is utilized during the acute postoperative periods following living donor liver transplantation (LDLT).

Transplantation of epidermal cell sheets by endoscopic balloon dilatation to avoid esophageal re-strictures: initial experience in a porcine model

Background and study aims: Epidermal cell sheet (ECS) transplantation immediately after aggressive endoscopic submucosal dissection (ESD) has been shown to be safe and effective in the prevention of esophageal strictures. This study evaluated the feasibility of ECS transplantation after endoscopic balloon dilation (EBD) in a porcine model. Methods: Six pigs underwent circumferential esophageal ESD under general anesthesia. Two weeks later, two pigs underwent EBD and transplantation of an autologous ECS, two underwent EBD alone, and two underwent endoscopic observation only (control). Results: The two pigs in the transplantation group underwent six ECS transplants after EBD with five of the six (83 %) being successful, as shown by engraftment of transplanted ECSs after 7 days. No adverse events were observed. Stricture rates were lower in the two transplanted pigs (55 % and 60 %) than in the control (92.2 % and 87.7 %) and EBD-treated (71.7 % and 78.2 %) pigs. Infiltration of inflammatory cells was significantly lower in the transplanted pigs than in the control and EBD-treated pigs. Conclusion: Preliminary results indicate the stability of the ECS transplantation procedure and the engraftment of transplanted ECS in the tears after EBD. This proof-of-concept study suggests that covering tears with ECSs after EBD may avoid re-strictures.

Extent of intraluminal exfoliated malignant cells during surgery for colon cancer: Differences in cell abundance ratio between laparoscopic and open surgery: Exfoliated malignant cells during LC

Laparoscopic colectomy with intracorporeal anastomosis is a minimally invasive surgical procedure for patients with colon cancer. However, there are often concerns about the presence of intraluminal exfoliated malignant cells in the intracorporeal anastomosis. This study investigated the relationship between colon cancer surgery and the incidence of intraluminal exfoliated malignant cells and several factors.

Autologous adipose-derived stem cell sheets enhance the strength of intestinal anastomosis

Objective Adipose-derived stem cells (ASCs) are capable of multiple differentiation pathways, imparting immunomodulatory effects, and secreting factors that are important for wound healing. These characteristics can be exploited to decrease the incidence of anastomotic leakage. Methods In order to delay local wound healing at the anastomotic site, we induced ischemia in a portion of porcine small intestine by ligating vessels. Then, we injected mitomycin C into the serosa of the small intestine above the ligated vessels. Anastomotic sites were created by 2 cm incisions made in the opposite mesenteric area. ASCs were isolated from the porcine subcutaneous fat tissues and expanded under culture conditions. ASCs were trypsinized and seeded on temperature-responsive dishes and cultured to form confluent sheets. Three ASC sheets were transplanted onto the serous membrane after suturing. The extent of anastomotic wound healing was evaluated by bursting pressure, hydroxyproline content, and mRNA expression of collagen-1 alpha1 and collagen-3 alpha1. Results We found that transplantation of ASC sheets increased anastomotic site bursting pressure. Additionally, transplantation of ASC sheets increased the hydroxyproline content of the anastomoses. Furthermore, transplantation of ASC sheets increased mRNA expression of collagen-1 alpha1 and collagen-3 alpha1. Conclusions Our findings showed that transplantation of autologous ASC sheets enhanced collagen synthesis and anastomotic strength. Further studies are necessary to identify substances that, in combination with ASC sheets, might enhance collagen synthesis and healing in sites of anastomosis.

Cellular events and behaviors after grafting of stratified squamous epithelial cell sheet onto a hydrated collagen gel

Autologous stratified squamous epithelial cell sheets have been successfully used to treat epithelial defects in tissues such as the cornea and the esophagus. However, the regenerative cellular events occurring in the grafted epithelial cells are unclear in the early stages of wound healing. In this study, we created an in vitro grafting model using cultured normal human epidermal keratinocyte (NHEK) sheets and a type I collagen gel to investigate the cellular processes that occur within the grafted cell sheet. Cultured NHEK cells successfully became a stratified squamous cell sheet resembling epithelial tissue, retained expression of cellular integrins and adhesion proteins, and adhered successfully to a type I collagen gel. After culture on the collagen gel, expression of E‐cadherin, and β‐catenin decreased in the cells of the basal layer of the grafted cell sheet, resembling events characteristic of a partial epithelial–mesenchymal transition (EMT). These basal cells also induced migration of the cell sheet. Those phenomena are consistent with the essential events that occur in the wound‐healing process observed previously in cell studies. Therefore, the epithelial cell sheet grafted onto a type I collagen gel is a suitable model in vitro to study cellular events and behaviors. Furthermore, we also addressed the therapeutic mechanisms by which the epithelial cell sheet promotes wound healing.

Severe neutrophilic leukocytosis as a progression marker in granulocyte colony-stimulating factor-producing squamous cell carcinoma of the esophagus

There are very few reports of esophageal carcinoma producing granulocyte colony‐stimulating factor (G‐CSF). G‐CSF‐producing esophageal squamous cell carcinoma is an extremely aggressive carcinoma. Leukocyte counts, neutrophil counts, and serum C‐reactive protein levels may be markers of its progression.