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The pathologic features of invasive carcinoma associated with IPNB remain to be clarified. By using 82 cases of IPNB, the pathologic spectrum of associated invasive carcinoma and its correlation with their post-operative overall survival (OS) were examined. Invasive carcinoma was found in 52 cases (63 %) of IPNB and was classifiable into three patterns (patterns A, B and C). Pattern A was characterized by microscopic foci of invasive carcinoma in the fibrovascular stalks or confined to the bile duct mucosa and wall beneath the intraluminal pre-invasive neoplastic components of IPNB (23 cases) and pattern B by invasive carcinoma in the periductal connective tissue and in the adjacent organ(s) mainly near or beneath the intraluminal component(s) of IPNB (15 cases). Pattern C showed nodular invasive carcinoma considerably involving the intraluminal pre-invasive components and the bile duct mucosa and wall adjacent to the intraluminal pre-invasive components of IPNB (14 cases). Recognition of these three patterns of invasive carcinoma associated with IPNB may expand the pathologic spectrum of IPNB. IPNBs without invasive carcinoma showed a favorable post-operative-OS compared with those with invasion as a whole and those of pattern B and C, respectively, but showed a similar post-operative-OS to that of pattern A. IPNB of pattern B and C showed an unfavorable post-operative outcome, though there was no difference between pattern B and C. Understanding of the pathologic spectrum of associated invasive carcinoma may facilitate further pathological analysis of IPNB.

The current WHO classification proposed high-grade biliary intraepithelial neoplasm (BilIN) and intracholecystic papillary neoplasm (ICPN) as precursors of the gallbladder carcinoma (GBC). Herein, conventional GBCs (cGBCs) were pathologically examined with respect to these two precursors.Forty-seven cases of GBC with grossly visible invasions were collected from Fukui Saiseikai Hospital. The association of two precursors was analyzed referring to pathologic features of cGBCs and post-operative survival.20 cGBCa (42.6%) were associated with either of two precursors in the surrounding mucosa: high-grade BilIN in 15 cases (31.9%) or ICPN in 5 cases (10.6%). Association of precursors was not related to gross types of and histological differentiation of cGBC. cGBCs without precursors showed frequent vascular/perineural invasion and lymph node metastasis, though cGBCs with and without precursors presented a similar post-operative survival. High-grade BilIN and ICPN associated with cGBCs showed more complicated cytoarchitectural features compared with those with no or focal invasion.More than 40% of cGBCs were associated with high-grade BilIN or ICPN, and the former was a frequent precursor. cGBCs without precursors showed aggressive pathologic features. Clinical detection of these precursors may make early treatment of cGBCs possible.

Recently, "polypoid invasive carcinoma (PICA)" showing grossly visible polypoid, invasive carcinoma with no adenoma component was proposed as a neoplastic polyp of the gallbladder. Herein, we report four cases of PICA of the bile duct. PICA cases of bile duct showed single, sessile polypoid growth grossly, and polypoid components were composed of invasive carcinoma of papillary/tubular patterns with active desmoplasia, and invaded directly and continuously into the bile duct wall and periductal tissue. While PICA and other intraductal papillary neoplasm of bile duct (IPNB) shared several features, PICA showed an invasive carcinoma growing in the duct lumen and also invading into the bile duct wall, thus different from IPNB which is the intraluminal polypoid, preinvasive epithelial neoplasia with back-to-back epithelial units. Taken together, PICA and IPNB could be differentiated from each other.

Intracholecystic papillary neoplasm (ICPN) is a recently proposed gallbladder neoplasm. Its prevalence and pathologies remain to be clarified. A total of 38 ICPN cases (28 ICPNs identified among 1904 cholecystectomies (1.5%) and in 100 surgically resected primary gallbladder neoplasms (28%) in Fukui Prefecture Saiseikai Hospital, Japan, and other 10 ICPNs) were examined pathologically and immunohistochemically. They were composed of 21 males and 17 females with a mean age of 75 years old, and presented intraluminal growth of papillary lesions with fine fibrovascular stalks. ICPNs were relatively frequent in the fundus (n = 11) and body (n = 9). Grossly, the conglomerated sessile type (n = 30) was more frequent than the isolated polypoid type (n = 8). All cases were classified as high-grade dysplasia, and they were further divided into 22 cases presenting irregular structures and 16 cases presenting regular structures. The former showed frequent complicated lesions and stromal invasion (54.5%) compared to the latter (12.5%). Twenty-four cases showed predominantly either of four subtypes (11 gastric, 7 intestinal, 4 biliary and 2 oncocytic subtype), while the remaining14 cases showed mixture of more than two subtypes. In conclusion, ICPN presented unique preinvasive neoplasm with characteristic histopathologies. Irregular histologies and complicated lesions of ICPN were related to stromal invasion.

Pyloric gland adenoma (PGA) of the gallbladder is a polypoid, preinvasive epithelial neoplasm composed of uniform back-to-back, pyloric glands in a tubular configuration. Intracholecystic papillary neoplasm (ICPN), another preinvasive grossly visible neoplasm of the gallbladder, is subdividable into four subtypes, including gastric subtype. In this study, PGA was reappraised referring to gastric subtype of ICPN (gICPN).PGA and gICPN pathologically defined by WHO 2019 classification were surveyed in a total of 104 cases of gallbladder epithelial neoplasms of our Hospital (2002 January to 2021 May) and were pathologically and immunohistochemically compared.PGA (7 cases) was characterized by i) a well-demarcated, polypoid lesion and ii) packed tubular components resembling pyloric glands. gICPNs (14 cases) were subdivided into i) pyloric gland predominant (2 cases), ii) foveola predominant (6 cases) and iii) mixed foveola and pyloric gland type (6 cases). gICPNs were also divided into a solitary, polypoid lesion with well demarcation from the surrounding mucosa (5 cases) and a conglomerated polypoid and granular lesions with poor demarcation (9 cases). PGA shared gross and histologic features with solitary, polypoid gICPNs, and PGA could be regarded as solitary gICPN predominantly composed of pyloric glands. Nuclear expression of β-catenin was found in 6 of 7 PGA, but absent in gICPN, including solitary, polypoid gICPN.PGA could correspond to a solitary gICPN mainly composed of pyloric glands, but may undergo a different molecular pathway from gICPN.

Intraductal papillary neoplasm of the bile duct (IPNB), a pre-invasive neoplasm of the bile duct, is being established pathologically as a precursor lesion of invasive cholangiocarcinoma (CCA), and at the time of surgical resection, approximately half of IPNBs show stromal invasion (IPNB associated with invasive carcinoma). IPNB can involve any part of the biliary tree. IPNB shows grossly visible, exophytic growth in a dilated bile duct lumen, with histologically villous/papillary neoplastic epithelia with tubular components covering fine fibrovascular stalks. Interestingly, IPNB can be classified into four subtypes (intestinal, gastric, pancreatobiliary and oncocytic), similar to intraductal papillary mucinous neoplasm of the pancreas (IPMN). IPNBs are classified into low-grade and high-grade based on lining epithelial features. The new subclassification of IPNB into types 1 (low-grade dysplasia and high-grade dysplasia with regular architecture) and 2 (high-grade dysplasia with irregular architecture) proposed by the Japan–Korea pathologist group may be useful in the clinical field. The outcome of post-operative IPNBs is more favorable in type 1 than type 2. Recent genetic studies using next-generation sequencing have demonstrated the existence of several groups of mutations of genes: (i) IPNB showing mutations in KRAS, GNAS and RNF43 belonged to type 1, particularly the intestinal subtype, similar to the mutation patterns of IPMN; (ii) IPNB showing mutations in CTNNB1 and lacking mutations in KRAS, GNAS and RNF43 belonged to the pancreatobiliary subtype but differed from IPMN. IPNB showing mutation of TP53, SMAD4 and PIK3CA might reflect complicated and other features characterizing type 2. The recent recognition of IPNBs may facilitate further clinical and basic studies of CCA with respect to the pre-invasive and early invasive stages.

Aims This study aimed to identify the pathological features of high-grade PanIN that presents with imaging-detectable abnormalities. Methods and results Ten cases of isolated, main-duct, high-grade PanIN as the primary clinical presentation were identified. All patients presented with stenosis of the main pancreatic duct, with two being associated with extensive upstream duct dilatation (>5 mm in diameter). Pancreatic juice cytology suggested adenocarcinoma in all seven cases examined. In resected specimens, high-grade PanIN was present chiefly in the main pancreatic duct, with longitudinal extension ranging between 3 and 40 mm in length (median = 18 mm). In four cases, in which hypoechoic or hypovascular masses were observed on imaging, radiopathology correlations suggested that they represented parenchymal atrophy and subsequent fibrosis around affected ducts, but not invasive malignancy. On immunohistochemistry, the loss of p16 expression was found in five (50%), p53 overexpression in two (20%) and loss of SMAD4 expression in none (0%). KRAS mutations were detected in nine cases, with two dominant clones being found in three by ultrasensitive droplet digital polymerase chain reaction, suggesting the genetic heterogeneity of dysplastic cells composing individual lesions. Mutant GNAS was also observed in one case. Conclusions Isolated high-grade PanIN may present with pancreatic duct stenosis. Therefore, intensive investigations including pancreatic juice cytology will be required for patients with unexplained pancreatic duct stenosis. The abnormal expression of p53 and SMAD4 is infrequent, while GNAS may be mutated in premalignant lesions mainly affecting the main pancreatic duct, similar to KRAS.

The mortality rate of patients with ruptured pancreaticoduodenal artery aneurysms is high; therefore, it is recommended to treat pancreaticoduodenal artery aneurysms regardless of their size. In small pancreaticoduodenal artery aneurysms, however, identification of the access route on two-dimensional arteriography is sometimes difficult because of the superimposition of many hypertrophied branches of pancreaticoduodenal arteries on the aneurysm. We report two cases of ruptured pancreaticoduodenal artery aneurysm embolized successfully with metallic coils, assisted by automated feeder-detection software using cone-beam computed tomography data. This new technology may reduce physicians’ workload during the procedure.

Objective The right gastroepiploic artery (GEA) is a reliable conduit for coronary artery bypass grafting. Recently, ultrasonic skeletonization in graft harvesting has attracted attention as an alternative technique to increase the length and caliber size of grafts. The influence of GEA skeletonization using an ultrasonically activated device with that using an electrosurgical unit was compared from the viewpoint of production of nitric oxide (NO). Methods Fourteen pigs were used in this study. The GEA were harvested using an ultrasonically activated device (group ultrasonically activated device [USAD], n = 7) or electrocautery (group E, n = 7). Blood sampling was performed at the following three times from the distal end of the GEA: (1) preskeletonization, (2) pedicle, and (3) postskeletonization. Plasma NOx (NO metabolites) levels were measured by chemiluminescent assay. Moreover, in excised specimens, the expression of nitric oxide synthase was examined immunohistologically. Results In group USAD, the preskeletonization basal level of plasmaNOx in GEA was 25.7 ± 10.9 μmol/L, which then increased to 26.9 ± 10.5 μmol/L (pedicle) and 32.2 ± 12.1 μmol/L (postskeletonization). In group E, the preskeletonization basal plasma NOx level in GEA was 28.9 ± 11.4 μmol/L, which changed to 27.5 ± 8.9 μmol/L (pedicle) and 21.8 ± 8.3 μmol/L (postskeletonization). The results of multivariate analysis indicated that the patterns of changes in plasma NOx level were significantly different in both groups (P = 0.024). In group USAD, post hoc multiple comparison tests revealed a significant difference between preskeletonization and postskeletonization (P = 0.037). Conclusions Ultrasonically skeletonized GEA showed increased effective graft length, higher free flow capacity, and increased endothelial NO production than that prepared using an electrosurgical unit.

A 51-year-old man with a ruptured pancreaticoduodenal artery (PDA) aneurysm caused by compression of the celiac artery by the median arcuate ligament and aortic dissection involving the celiac axis was transferred to our hospital for endovascular treatment. A 4-F catheter was advanced into the superior mesenteric artery through the narrow true lumen via the left brachial artery, and coil embolization of the aneurysm was successfully performed. In this case, rapid increase of blood flow in the superior mesenteric artery, which compensated for the decreased celiac blood flow by aortic dissection, increased hemodynamic stress on the PDA, leading to aneurysmal rupture.

We report an autopsy case of mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome. A 38-year-old Japanese male was found to have Zollinger-Ellison syndrome and pancreatic gastrinoma, and gastrectomy and resection of the pancreatic tumor were performed. However, hypergastrinemia persisted, and the patient died of disseminated carcinomatosis at 62 years of age, 24 years after the onset of Zollinger-Ellison syndrome. At autopsy, the main tumor was present in the residual pancreas, and metastases were noted in many organs. In the pancreas and other organs, ductal and endocrine carcinoma areas were mixed and there was a gradual transition between the two. No acinar differentiation was noted. The ductal elements were positive for mucins and carcinoembryonic antigen but negative for neuroendocrine markers, while endocrine elements were positive for chromogranin A and synaptophysin and to a lesser extent for gastrin, but negative for mucins and carcinoembryonic antigen. The ductal elements comprised about 30% of the tumor cells, and endocrine elements 70%. According to the revised World Health Organization classification, our case was diagnosed as mixed ductal-endocrine carcinoma. Our case is rare because the tumor manifested as gastrinoma with Zollinger-Ellison syndrome and the patient survived for 24 years. To the best of our knowledge, no such case has been reported. Our case suggests that pancreatic endocrine tumors may evolve into mixed ductal-endocrine carcinomas.

Pancreatic digestive enzymes have rarely been reported in human nonpancreatic organs. We examined their expression in the epithelial cells of the nonpancreatic gastrointestinal organs, looking for pancreatic alpha-amylase, trypsin, chymotrypsin and pancreatic lipase. Western blotting, enzyme assay and pancreatic alpha-amylase mRNA were also used in selected specimens. In normal tissues, immunoreactivity of one or more of these enzymes was frequently noted in cells of the salivary glands, stomach, duodenum, large pancreatic ducts, extrahepatic bile ducts and gall bladder. The epithelium of the normal oesophagus, small intestine and colon were consistently negative for these enzymes. In pathologic tissues, immunoreactivity for one or more enzymes was present in epithelial cells of pleomorphic adenomas of the salivary glands, oesophageal squamous cell carcinoma, gastric adenoma and adenocarcinoma, pancreatic adenocarcinoma, cholecystitis, adenocarcinoma of the gall bladder and extrahepatic bile duct, and colon adenoma and adenocarcinoma. Western blotting showed a specific band of each enzyme in some specimens of normal stomach. In situ hybridization for pancreatic alpha-amylase mRNA showed specific signals in the normal stomach, but not in the normal colon. Reverse transcriptase polymerase chain reaction analysis for pancreatic alpha-amylase mRNA revealed specific signals in the normal stomach. Enzyme assay revealed that the stomach and gall bladder showed these activities. The data suggest that pancreatic digestive enzymes are produced by several epithelial cell types of the nonpancreatic gastrointestinal organs, that the organs positive for pancreatic enzyme have a common cell lineage, and that neoplasms continue to express or neoexpress these enzymes after neoplastic transformation.

Background The authors examined parameters of cardiovascular function using Starfish and deep pericardial sutures (DPS) in a beating heart porcine model and to clarify toleration of right ventricular function with Starfish in lateral wall displacement. Methods Eight healthy pigs were used. In addition to normal pressure monitor catheters, a Swan-Ganz continuous cardiac output (CO) and end diastolic volume thermodilution catheter was used for precise and quantitative monitoring of the right ventricular function. Results Lateral displacement of the heart with DPS resulted in a significant hemodynamic compromise. Cardiac output and right ventricular ejection fraction (RVEF) decreased from 3.0 ± 0.9 to 2.6 ± 1.0 L/min (P = 0.014) and from 27.9 ± 3.0% to 23.3 ± 4.8% (P = 0.019). With Starfish™, CO and RVEF were maintained from 3.0 ± 0.9 to 3.0 ± 0.9 L/min (P = 0.743) and from 27.9 ± 3.0% to 28.3 ± 3.8% (P = 0.476). Conclusion Starfish™ contributed to the stability of hemodynamics by maintaining the right ventricular function. Lateral displacement with PDS resulted in significant hemodynamic compromised compared with Starfish™ and baseline neutral position.