Isamu Koyama

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.

Intraductal papillary mucinous neoplasm (IPMN) is a unique pancreatic neoplasm developing in the ductal system. Two major histologic subtypes have been reported, that is the gastric type and the intestinal type. However, their histopathologic features, especially those of the gastric type, have not been fully described. To evaluate the features of these two types and refine their differences, we analyzed 80 IPMNs including 50 cases of the gastric type and 30 cases of the intestinal type with mucin immunohistochemistry. By defining a main duct-type lesion as predominantly involving the main pancreatic duct with or without branch ducts, and a branch duct-type lesion as exclusively centered on branch ducts or consisting of a collection of small cystic lesions, gastric-type IPMNs were mostly branch duct-type lesions (98%), whereas the intestinal-type IPMNs were usually main duct type (73%). The histologic grade of the intestinal type was generally higher than that of the gastric type. The intestinal type was also characterized by frequent intraluminal nodular growth, and severe atrophy and fibrosis of the surrounding parenchyma with mucous lake formation. In contrast, pyloric glandlike structures at the base of the papillae and pancreatic intraepithelial neoplasia (PanIN)-like complexes were more frequently observed in the gastric type. A significant difference was observed between the gastric type and the intestinal type with regard to all the above features (P<0.05). Seven cases (23%) of the intestinal type were associated with an invasive adenocarcinoma (6 mucinous and 1 ductal), versus only 1 case (2%) of the gastric type (invasive ductal carcinoma). All cases of both gastric and intestinal types expressed MUC5AC; however, high immunolabeling scores for MUC2 were mostly observed in the intestinal type (P<0.05). In conclusion, gastric and intestinal types of IPMNs have distinct histopathologic features and mucin profiles, suggesting that they may follow different biologic pathways.

Intraductal Tubulopapillary Neoplasms of the Pancreas Distinct From Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of “intraductal tubulopapillary neoplasms (ITPNs)” and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of β-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, 1 patient died of liver metastases, and 1 patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

A novel rescue drug, 15-deoxyspergualin: first clinical trials for recurrent graft rejection in renal recipients

The present multicentral clinical study performed in 6 institutes demonstrated that the novel immunosuppressive agent, 15-deoxyspergualin (DSG), is very effective on rejection. In 34 cases of rejection, 30 were treated with DSG at 40 mg/m2 (1 case), 80 mg/m2 (7 cases), 120 mg/m2 (9 cases), 180 mg/m2 (9 cases), and 220 mg/m2 (8 cases). The overall remission rate was 79% in 34 cases of rejection including accelerated, acute, and chronic rejection in different periods after transplantation. Analyzing the remission rates of early phase acute rejection occurring within 3 months after transplantation according to treatment pattern, the remission rate was 100% in 3 cases treated with DSG alone (using DSG 1 week or longer after other agents), 88% in 8 cases treated by rescue use of DSG (using DSG within 1 week after other agents), and 86% in 7 cases treated by combined use of DSG with other agents. Adverse reactions included reductions in WBC and platelets, anemia, perioral numbness, gastrointestinal troubles, and others. However all these symptoms were so mild that DSG treatment was not discontinued. Further studies are necessary on the effect of DSG, especially in acute rejection under conditions that reduce the many influences of other agents as much as possible.

Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P=0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P=0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P<0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P<0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients’ prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

A Tissue‐Engineered Artificial Bile Duct Grown to Resemble The Native Bile Duct

The aim of this study was to fabricate an artificial bile duct for the development of a new treatment for biliary diseases. Eighteen hybrid pigs were implanted with a bile duct organoid unit (BDOU) made of a bioabsorbable polymer. Twelve of the transplanted BDOUs had been seeded with autologous bone marrow cells (BMCs) in advance. Six animals, the controls, were grafted with the scaffold alone with no BMCs seeded. The common bile duct was cut, the hepatic cut end of the native common bile duct was anastomosed to the BDOU and the other end was anastomosed to the duodenum. The controls underwent a similar operation. The neo‐bile duct was removed at pre‐determined time points and investigated histologically. All 18 recipient pigs survived until their sacrifice at 6 weeks, 10 weeks or 6 months. Histological examination revealed incomplete epithelialization of the neo‐bile duct at 6 weeks and 10 weeks after transplantation. At 6 months, the organoid exhibited a morphology almost identical to that of the native common bile duct. No differences were found between the controls and BMC‐seeded pigs. These results show that the artificial bile duct thus fabricated can serve as a substitute for the native bile duct.

Autologous blood transfusion in patients with hepatocellular carcinoma undergoing hepatectomy

BACKGROUND Homologous blood transfusion (HBT) has the risk of an immunosuppressive effect and may adversely affect the prognosis of patients with carcinomas. Autologous blood transfusion (ABT) has not yet become a standard procedure in gastroenteric cancer surgery. We investigated the usefulness and problems of ABT combined with the use of recombinant human erythropoietin (rh-EPO). METHODS An evaluation of autologous blood transfusion (ABT) combined with recombinant human erythropoietin (rh-EPO) treatment was conducted in 46 patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative autologous blood donation (ABD) was accomplished for 25 of the 46 patients. The preoperative changes in hemoglobin and hematocrit in relation to route of administration of erythropoietin were studied. In addition, intraoperative blood requirements and the postoperative complications for patients who predonated were compared with those of patients who underwent surgery without autologous predonation. RESULTS The proportion of patients not requiring additional homologous blood transfusions (HBT) during operation was significantly higher in the ABD group than in the non-ABD group (88% versus 38%). The incidence of postoperative complications was significantly higher in patients receiving HBT than in nontransfused patients and in those receiving ABT. CONCLUSIONS Preoperative autologous blood donation in combination with rh-EPO therapy markedly reduced the requirement for homologous blood transfusion during surgery in patients with hepatocellular carcinoma having hepatectomy.

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.

Epidermoid Cyst in Intrapancreatic Accessory Spleen: Radiological Findings Including Superparamagnetic Iron Oxide-enhanced Magnetic Resonance Imaging

It is crucial to differentiate between nonneoplastic and neoplastic cysts of the pancreas by images. An epidermoid cyst in intrapancreatic accessory spleen (IPAS) is a rare pancreatic cyst that should be managed nonsurgically as well as other nonneoplastic cyst. However, the imaging features of an epidermoid cyst in IPAS have not been organized. We therefore reviewed articles describing cases of epidermoid cyst in IPAS, with 6 additional cases to explore the imaging findings.

Imaging studies of intraductal tubulopapillary neoplasms of the pancreas: 2-tone duct sign and cork-of-wine-bottle sign as indicators of intraductal tumor growth.

Objective The objective of this study was to describe the imaging findings for intraductal tubulopapillary neoplasms of the pancreas. Methods Eleven pancreatic tumors pathologically confirmed as intraductal tubulopapillary neoplasm were retrospectively collected. The dynamic contrast-enhanced computed tomography (CT), magnetic resonance (MR) imaging including MR cholangiopancreatography (MRCP), ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP) results were reviewed. The 2-tone duct sign and cork-of-wine-bottle sign were reviewed as indicators of intraductal tumor growth on CT/MR and MRCP/ERCP images, respectively. Results A 2-tone duct sign was noted on the dynamic CT images (7/10, 70%) and on the MR imaging (5/8, 63%). The distal main pancreatic duct was dilated in all the patients except one, who had a branch duct lesion. A cork-of-wine-bottle sign was observed on the MRCP image (3/8, 38%) and on the ERCP image (3/6, 50%). Conclusions Intraductal tubulopapillary neoplasms are rare tumors showing characteristic imaging findings such as the 2-tone duct sign and the cork-of-wine-bottle sign that represent their intraductal growth.