Masayasu Aikawa

A novel treatment for bile duct injury with a tissue-engineered bioabsorbable polymer patch

BACKGROUND With the recent widespread use of laparoscopic cholecystectomy and living-donor liver transplantation, complications involving the biliary system, and stenosis in particular, are encountered frequently. Although various invasive and noninvasive techniques are now available for the treatment of biliary stenosis, recurrence and other problems limit their value and utility. Our group sought to investigate whether a bioabsorbable polymer (BAP) patch could serve as a novel treatment for biliary stenosis. METHODS In anesthetized hybrid pigs (n = 12), a spindle-shaped portion of the lower common bile duct wall was excised, and a BAP patch was implanted at the excision site. The animals underwent repeat laparotomy at 5 weeks (n = 6) and at 4 months (n = 6) after implantation to recover the graft sites for gross and histologic studies. Blood chemistry was analyzed from samples taken during the patch implantation and recovery. RESULTS All of the recipient pigs survived until killing. All gained weight and showed no evidence of jaundice. The BAP-patched duct remained patent without obstruction at 5 weeks postimplantation. Blood chemistry did not reveal any increases in hepatobiliary enzyme activities. Histology showed accessory glandular structures in the neo-bile duct. At 4 months, the graft site was indistinguishable from the native duct. Intra-operative cholangiography revealed dilation of the patched site, but no dilatation of the intrahepatic bile ducts. Blood chemistry values were within normal ranges. Histology at the site of the patch confirmed the growth of a cuboidal columnar epithelium similar to that of the native duct. CONCLUSION The bile duct was dilated only focally at the site of implantation. This newly designed substitute has potential for application as a novel treatment for biliary injury and stenosis.

Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model

BackgroundStricture formation is one of the major complications after endoscopic removal of large superficial squamous cell neoplasms of the esophagus, and local steroid injections have been adopted to prevent it. However, fundamental pathological alterations related to them have not been well analyzed so far. The aim of this study was to analyze the time course of the healing process of esophageal large mucosal defects resulting in stricture formation and its modification by local steroid injection, using an animal model.MethodsEsophageal circumferential mucosal defects were created by endoscopic mucosal dissection (ESD) for four pigs. One pig was sacrificed five minutes after the ESD, and other two pigs were followed-up on endoscopy and sacrificed at the time of one week and three weeks after the ESD, respectively. The remaining one pig was followed-up on endoscopy with five times of local steroid injection and sacrificed at the time of eight weeks after the ESD. The esophageal tissues of all pigs were subjected to pathological analyses.ResultsFor the pigs without steroid injection, the esophageal stricture was completed around three weeks after the ESD on both endoscopy and esophagography. Histopathological examination of the esophageal tissues revealed that spindle-shaped α-smooth muscle actin (SMA)-positive myofibroblasts arranged in a parallel fashion and extending horizontally were identified at the ulcer bed one week after the ESD, and increased contributing to formation of the stenotic luminal ridge covered with the regenerated epithelium three weeks after the ESD. The proper muscle layer of the stricture site was thinned with some myocytes which seemingly showed transition to the myofibroblast layer. By contrast, for the pig with steroid injection, esophageal stricture formation was not evident with limited appearance of the spindle-shaped myofibroblasts, instead, appearance of stellate or polygocal SMA-positive stromal cells arranged haphazardly in the persistent granulation tissue of the ulcer site.ConclusionsProliferation of spindle-shaped myofibroblasts arranged in a parallel fashion is likely to play an important role in stricture formation after circumferential mucosal defects by esophageal ESD, which may be related to the thinning of the proper muscle layer in the healing course of the defects. Local steroid injection seems to be effective to prevent the stricture through the modification of this process.

Regeneration of extrahepatic bile ducts by tissue engineering with a bioabsorbable polymer

With the widespread adoption of laparoscopic cholecystectomy and living-donor liver transplantation in recent years, complications involving the biliary system, stenosis in particular, are increasing. Various invasive and non-invasive techniques are now available for the treatment of biliary stenosis, but all are compromised by a high risk of recurrence and other problems. As a potential solution, our group has developed a bioabsorbable polymer (BAP) tube for implantation as a bypass graft. In the study reported here, we implanted this BAP tube and confirmed bile duct regeneration at the graft site after the tube had been degraded and absorbed into the body. We briefly describe our findings on extrahepatic biliary tissue regeneration, focusing on the possibility of its clinical application. This artificial bile duct may promote the development of novel treatments for biliary disease.

Experimental trial for perforation caused by esophageal endoscopic submucosal dissection using a biodegradable polymer stent in an animal model

Our group has developed a biodegradable covered stent (BDCS) composed of bioabsorbable polymer for the repair of emergent esophageal perforation. The BDCS is composed of a 50:50 copolymer of polylactic acid and polycaprolactone reinforced with polyglycolic acid fibers (Fig. 1a). This study was conducted at the animal facility in Saitama Medical University International Medical Center, Saitama, Japan, after the approval of the Animal Care and Use Committee. Under general anesthesia, a mucosal defect with a major axis of approximately 15 mm was prepared in the middle esophagus by endoscopic submucosal dissection (ESD) in four pigs. Then, ESD was carried out with a Flash knife (KD-2618 JN-15; Fujinon Corp., Saitama, Japan) at a length of 1.5 mm. An approximately 5-mm perforation was also prepared in the defective mucosal region (Fig. 1b). Perforation was confirmed by observing tissue moving with respiratory variation paradoxically against the submucosal layer. The BDCS was inserted inside the esophagus endoscopically to cover the opening (Fig. 1c).The animals started taking fluid at 1 day after the procedure and started feeding on a normal diet at 5 days. The animals that received the BDCS survived until killing without any complications. The stent was still observed at 1 week after the implantation (Fig. 2a) but was wholly undetectable by 2 weeks (Fig. 2b). There was no stenosis or any kind of infection around therepaired wall (Fig. 2c). Normal mucosa similar to that of the native wall was confirmed histologically (Fig. 2c). In the future, the BDCS should be applied in humans through further case accumulation/review. However, this procedure may become a useful strategy for treating esophageal wall injury, which may otherwise lead to a fatal outcome, including esophageal ESD-related perforation.

Extensive regeneration of the stomach using bioabsorbable polymer sheets

BACKGROUND The growing prevalence of endoscopic surgery in recent years has led to the minimization of postoperative scarring. However, this procedure does not allow for the regeneration of the resected digestive tract, which compromises the postoperative maintenance of digestive function. In this preliminary study, we developed an artificial gastric wall (AGW) using bioabsorbable polymer (BAP), and evaluated the ability of this BAP patch to repair and regenerate a widely defective gastric wall in an animal model. METHODS Pigs were laparotomized under general anesthesia. An 8 × 8-cm, round portion of the anterior gastric wall was excised and replaced by an AGW. The AGW was composed of a copolymer comprising 50% lactic acid and 50% caprolactone. The animals were relaparotomized 4, 8, or 12 weeks after implantation, after which they underwent resection of the entire stomach for gross and histologic evaluation of the graft sites. RESULTS All recipient pigs survived until killing. By 4-8 weeks, the graft site revealed progressively fewer mucosal defect after each day. Moreover, the grafted area was indistinguishable from the native stomach 12 weeks after AGW implantation. The structures of the regenerated mucous membrane and muscle layers were identical to those of the native stomach. Furthermore, proton pumps were found in the regenerated tissue. CONCLUSION The BAP sheets helped to restore extensive gastric defects without causing any deformation. The use of BAP sheets may become a new therapeutic method that prevents alterations of gastric volume after extensive gastrectomy for stomach cancer and other diseases.

A case of aggressive solid pseudopapillary neoplasm: Comparison of clinical and pathologic features with non-aggressive cases

Solid pseudopapillary neoplasms (SPNs) may have an aggressive clinical course, but clinical predictors of this condition have not been thoroughly evaluated. We performed a retrospective study of 11 cases of SPN managed in our hospital between January 2007 and April 2015. Of these 11 cases, we encountered a single case with an aggressive clinical course. Histological, immunohistochemical, and clinical features were compared to identify predictors of poor prognosis. The 11 patients comprised four women and seven men with a median age of 41 years (range, 26–58 years). Clinical symptoms were nonspecific and the median tumor size was 4.6 cm (range, 1.4–18 cm). The patient with an aggressive clinical course developed multiple liver metastases within three months and died seven months after surgery. Pathological features of the tumor in this case included lymph node metastases, a diffuse growth pattern, extensive tumor necrosis, high mitotic rate, and immunohistochemistry. These features were not observed in patients who survived without recurrence at a median follow‐up of 25 months (range, 6–82 months). Characteristic pathological features and a high proliferative index, as assessed by Ki‐67 staining, may predict poor outcome in cases of SPN.

Fibrin Glue Closure for Intractable Pancreatic Fistulae after Pancreaticoduodenectomy

CONTEXT Treatment of pancreatic fistulae after pancreaticoduodenectomy is extremely important because it determines the patients postoperative course. In particular, treatment of grade B cases should be conducted in a timely manner to avoid deterioration to grade C. OBJECTIVE We report the successful treatment of six cases of postoperative intractable, grade B pancreatic fistulae, in which fistula closure was achieved through the use of tissue adhesive. METHODS Six subjects presented at our hospital with grade B pancreatic fistulae after pancreaticoduodenectomy. In all cases, the drain amylase values were high immediately after the operation, and the replacement of the drain was enforced. Closure of the fistula was performed by pouring tissue adhesive into the fistula from the drain, after the fistula had been straightened. RESULTS Closure of the fistula was achieved in all six cases at the first attempt. The average fistula length was 13.2 cm, the average volume of pancreatic fluid discharge just before treatment was 63.3 mL, the average amylase value in the drainage was 40,338.5 IU/L, and the subjects were discharged from hospital an average of 8.8 days after treatment. There were no recurrences after treatment. CONCLUSION Intractable pancreatic fistulae can be effectively treated using the tissue adhesive method.

Status of the Gastric Mucosa with Endoscopically Diagnosed Gastrointestinal Stromal Tumor

Background. Since gastrointestinal stromal tumor (GIST) is a mesenchymal submucosal tumor, the endosonographic, CT, and MRI features of gastric GISTs have been widely investigated. However, the GIST-bearing gastric mucosa status has not been reported. Objective. To characterize the GIST-bearing gastric mucosa status in terms of the degree of inflammation and atrophy, assessed endoscopically. Subjects and Methods. The subjects were 46 patients with submucosal tumors (histologically proven gastric GISTs) who had undergone upper gastrointestinal endoscopy in our hospital between April 2007 and September 2012. They were retrospectively evaluated regarding clinicopathological features, the endoscopically determined status of the entire gastric mucosa (presence or absence and degree of atrophy), presence or absence and severity of endoscopic gastritis/atrophy (A-B classification) at the GIST site, and presence or absence of H. pylori infection. Results. Twenty-three patients had no mucosal atrophy, but 17 and 6 had closed- and open-type atrophy, respectively. Twenty-six, 5, 12, 1, 1, and 1 patients had grades B0, B1, B2, B3, A0, and A1 gastritis/atrophy at the lesion site, respectively, with no grade A2 gastritis/atrophy. Conclusion. The results suggest that gastric GISTs tend to arise in the stomach wall with H. pylori-negative, nonatrophic mucosa or H. pylori-positive, mildly atrophic mucosa.

A Newly Designed Anal Fistula Plug: Clinicopathological Study in an Experimental Iatrogenic Fistula Model

We report on a clinicopathologic study in an animal model of treatment with a new bioabsorbable polymer plug (BAPP). Over a 2-week period, 6 porcine models, which each had 4 anal fistulae, were created using Blake drains. The pigs were divided into 2 groups: the BAPP-treatment group (n = 12 fistulae) and the control group (n = 12 fistulae). Two weeks later, the pigs were humanely killed, and the perianal sites were excised and examined with gross and pathologic studies. Each fistula in the BAPP group was completely cured. In the pathologic study, the treatment sites had little disarray, few defects in the muscular layer, and small numbers of inflammatory cells. The control group had a significantly greater number of inflammatory cells and microabscesses than the BAPP group. The newly developed BAPP reduced the infection and induced good healing in anal fistulae. The BAPP may be a useful new device for the clinical treatment of anal fistulae.

Liver resection using a soft-coagulation system without the Pringle maneuver.

BACKGROUND/AIMS The Pringle maneuver is generally performed to reduce the amount of blood loss during hepatic resection. We have developed a method to sufficiently control blood loss during hepatectomy without applying the Pringle maneuver. This study was performed to determine the safety and operative blood loss in hepatectomy performed by this new method. METHODOLOGY We performed 102 hepatic resections without the Pringle maneuver. We retrospectively compared the short-term operative outcome between these 102 cases and another 75 hepatic resections performed with the Pringle maneuver. The resections without the Pringle maneuver were performed using a soft-coagulation system. RESULTS The median length of the surgery using the soft-coagulation system without the Pringle maneuver was 135 minutes, significantly shorter than the surgical time required for resection with the Pringle maneuver 297 minutes (p<0.001). The median volume of operative blood loss was significantly lower in the non-Pringle-maneuver group (200cc vs. 704cc; p<0.001). Regarding postoperative liver function, AST, ALT, T-Bil and PT, levels were all significantly improved in the non-Pringle-maneuver group (p<0.01). CONCLUSIONS Our data suggest that hepatic resection using a soft-coagulation system without the Pringle maneuver is extremely safe and effective in controlling bleeding.