Loss of nectin-3 expression as a marker of tumor aggressiveness in pancreatic neuroendocrine tumor.

Pancreatic neuroendocrine tumors (PanNETs) are rare, and prediction of aggressive characteristics, such as recurrence and metastasis and prognosis of PanNETs remain difficult. Nectins are cell adhesion molecules that regulate the formation of adherens and tight junctions. In this study, we investigated the clinicopathological significance of nectin-3 expression in patients with PanNETs. Immunohistochemical analysis of nectin-3 expression was performed on 78 cases of PanNET. Low nectin-3 expression in the membrane (positive ratio ≤25%) was observed in 62 cases (79.5%) and was significantly correlated with larger tumor size (>20 mm; P = 0.003), G2/G3 tumors (P = 0.025), higher Ki67 labeling index (≥3%; P = 0.009), lymphatic involvement (P = 0.047), advanced pT-factor (T2-T4; P = 0.003), lymph node metastasis (P = 0.006), advanced Union for International Cancer Control/American Joint Committee on Cancer-stage (Stage II-IV; P = 0.001), advanced ENETS stage (Stage IIa-IV; P = 0.001), nonfunctioning tumors (P = 0.002), and a shorter disease-free survival (P = 0.019). However, there was no significant correlation between nectin-3 expression in the membrane and/or cytoplasm and the clinicopathological parameters. The present results suggest that decreased nectin-3 expression in the membrane is associated with increased tumor aggressiveness of PanNETs. Clinically, immunohistochemical analysis of nectin-3 may help predict tumor aggressiveness for PanNETs.

Hyalinized stroma is a characteristic feature of pancreatic intraductal oncocytic papillary neoplasm: An immunohistochemical study.

Hyalinized stroma (HS) is a dense, eosinophilic, and amorphous extracellular material in the stroma. HS is observed in several tumors; however, it has not been comprehensively studied in pancreatic intraductal papillary mucinous neoplasm (IPMN) or intraductal oncocytic papillary neoplasm (IOPN). Here, we aimed to evaluate the immunohistochemical and microscopic characteristics of HS in IPMN and IOPN. The prevalence of HS was determined in 168 cases of IPMN, including intestinal type (IPMN-I), gastric type (IPMN-G), and pancreatobiliary type (IPMN-PB), as well as in 11 cases of IOPN. Immunohistochemical staining for laminin and collagen (types I, II, III, IV, and V), as well as Congo red staining were performed in IPMN and IOPN cases containing HS. The prevalence of HS among the IPMN and IOPN specimens was 1.2% (2/168 cases) and 45.5% (5/11 cases), respectively. The prevalence rates of HS in each IPMN subtype were as follows: 2.2% (2/91 cases) in IPMN-G, and 0% in IPMN-PB and IPMN-I. All seven HS cases were positive for collagen I, III, IV, and V but were negative for Congo red staining. Most cases showed negative, focal, or weak expression of laminin and type II collagen. These findings indicate that HS is associated with IOPN and is primarily composed of collagen fibers.

Histological and immunohistochemical analyses of splenic epidermoid cysts.

Splenic epidermoid cyst (SEC) is a rare condition. We aimed to evaluate the immunohistochemical profiles of the epithelial lining of SECs. A total of 7 SEC cases were analyzed: 2 cases involved a monolayered epithelial lining and 5 cases involved a multilayered epithelial lining. Among the multilayered SECs, the superficial/luminal layer showed mucin 4 (MUC4), cytokeratin 5/6 (CK5/6), and CK7 expression in 5 cases (100%); MUC1, carcinoembryonic antigen (CEA), CA19-9, and thrombomodulin expression in 4 cases (80%); Wilms' tumor-1 (WT-1) and Hector Battifora mesothelial-1 (HBME-1) expression in 2 cases (40%), but it did not express p63 or D2-40. The basal layer expressed MUC1, CK5/6, p63, and thrombomodulin in 5 cases (100%); CK7 and WT-1 in 4 cases (80%); D2-40 in 3 cases (60%); CA19-9 and HBME-1 in 2 cases (40%) and MUC4 in 1 case (20%) but it did not express CEA. The analysis showed that all cases of multilayered SECs were negative for MUC2, MUC5AC, MUC6, CK20, calretinin, uroplakin-II, and uroplakin-III. Both cases of monolayered SECs expressed CK5/6, CK7, HBME-1, WT-1, and thrombomodulin but not MUC2, MUC4, MUC5AC, MUC6, p63, CEA, CK20, CA19-9, D2-40, uroplakin-II, or uroplakin-III. One case of monolayered SEC expressed MUC1 and calretinin. Our findings indicate that monolayered SECs have mesothelial-like characteristics, whereas multilayered SECs have glandular and squamous-like characteristics besides mesothelial-like characteristics. Furthermore, monolayered SECs may develop from mesothelial inclusion and monolayered SECs develop squamous and glandular metaplasia, which results in multilayered SECs.

Low-grade Appendiceal Mucinous Neoplasm with Appendiceal Reduction and Re-expansion Over a Two-year Period: A Case Report.

A 71-year-old woman was found to have submucosal tumor-like lesion on colonoscopy (CS) before gastric surgery, and computed tomography (CT) showed a 12-mm structure at the base of the appendix. The lesion could not be clearly detected on CT nine months later, but it had enlarged again on CT one year later; therefore, CS and endoscopic ultrasound (EUS) were performed. The lesion was determined to be cystic with viscous contents, and laparoscopic appendicectomy was performed. This is the first report of low-grade appendiceal mucinous neoplasm (LAMN) diagnosed by a histopathologic examination of a resected specimen showing shrinkage and re-expansion of the appendix.

Ectopic Adrenocorticotropic Hormone Syndrome due to Pancreatic Neuroendocrine Carcinoma: A Case Report.

A 55-year-old woman presented to her primary care physician with facial and lower leg edema. After being referred to our hospital because of hypothyroidism and hypokalemia on blood tests, she also had elevated adrenocorticotropic hormone (ACTH) and cortisol levels, but a dexamethasone suppression test showed no cortisol suppression. Ectopic ACTH syndrome due to pancreatic neuroendocrine carcinoma (PNEC) was suspected. endoscopic ultrasound-guided fine-needle aspiration was performed, and a histopathological examination of the obtained specimen revealed multiple liver metastases of the PNEC. Imaging after etoposide and cisplatin therapy showed cystic changes in the primary lesions and shrinkage of the liver metastases, and the ACTH levels were within the normal range.

A case of breast cancer with extensive colon metastasis.

Breast cancer is one of the most common malignancies in women worldwide. Although most breast cancers are curable, in cases of metastasis, many are often found in the lungs, bones, liver, and central nervous system; however, metastasis to the gastrointestinal tract is rare. Invasive lobular carcinoma, which represents only 5%-10% of breast cancers, has a higher risk of metastasis to the gastrointestinal tract than invasive ductal carcinoma. Here, we report a rare case of gastrointestinal metastasis of invasive lobular carcinoma that spread extensively to the colonic mucosa. Given the improved survival rates of breast cancer patients with current treatments, many rarer metastatic diseases, including gastrointestinal metastases, are likely to be increased in the future.

miR-4653-3p overexpression is associated with a poor prognosis of pancreatic ductal adenocarcinoma via HIPK2 downregulation.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignant tumor. Several upregulated and downregulated microRNAs (miRNAs) are associated with invasiveness, tumorigenesis, and prognosis of PDAC. Herein, using in situ hybridization, we evaluated miR-4653-3p expression and pancreatic intraepithelial neoplasia (PanIN) and the association between miR-4653-3p expression and clinicopathological factors in PDAC patients. The miR-4653-3p target was also identified. Ninety PDAC cases, including 30 each with normal pancreatic ducts, low-grade PanINs, and high-grade PanINs, were evaluated. miR-4653-3p expression increased in the order-normal pancreatic duct, low-grade PanIN, high-grade PanIN, and PDAC-with no expression detected in normal pancreatic duct. High expression significantly correlated with advanced pathological T stage, lymph node metastasis, advanced Union for International Cancer Control stage, perineural invasion, venous involvement, and shorter overall and disease-specific survival. Homeodomain Interacting Protein Kinase 2 (HIPK2) was identified as a miR-4653-3p target based on mRNA microarray analysis and database screening. In MIA PaCa-2 cells, miR-4653-3p significantly downregulated HIPK2 expression. HIPK2 expression, unlike that of miR-4653-3p, decreased in the order-normal pancreatic duct, low-grade PanIN, high-grade PanIN, and PDAC. Low HIPK2 expression was associated with shorter overall and disease-specific survival in PDAC patients. Thus, miR-4653-3p associates with tumorigenesis and worse prognosis, partly by reducing HIPK2 expression.

Low expression of DDX5 is associated with poor prognosis in patients with pancreatic ductal adenocarcinoma.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC. METHODS: DDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival. RESULTS: The nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2-pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC. CONCLUSION: These results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis.

The Impact of a Heterozygous SLCO1B3 Null Variant on the Indocyanine Green Retention Test.

Indocyanine green (ICG) retention test is widely used for preoperative evaluation of liver function. OATP1B3 (gene symbol: SLCO1B3) is the major transporter for hepatic ICG uptake. We previously demonstrated that the individuals with a homozygous SLCO1B3 null allele revealed markedly impaired ICG clearance. However, the effect of heterozygosity of this variant on ICG clearance remains unknown. We compared the results of ICG retention rate at 15 min (ICG-R15) and hepatic OATP1B3 expression among individuals whose SLCO1B3 genotype was determined. Although OATP1B3 expression was significantly lower in the heterozygosity than the wild-type, the ICG-R15 results were comparable; 8.4 ± 3.4 (mean ± SD) % in the heterozygosity and 8.7 ± 6.0% in the wild-type. A homozygous individual revealed markedly high ICG-R15 (79.8%) and lacked OATP1B3 expression. In conclusion, the individuals with a heterozygous SLCO1B3 null variant had similar ICG clearance capacity to those with the wild-type despite decreased hepatic OATP1B3 expression.

Increase in the Lipopolysaccharide Activity and Accumulation of Gram-Negative Bacteria in the Stomach With Low Acidity.

INTRODUCTION: Lipopolysaccharides (LPSs) of Gram-negative bacteria (GNB) are highly toxic and induce inflammation. Therefore, we investigated both the LPS activity and composition of GNB in the gastric fluid (GF) to assess the potential toxicity of them accumulated in the stomach. METHODS: GF and saliva samples were obtained from 158 outpatients who were undergoing upper gastrointestinal endoscopy and 36 volunteers using a nasogastric tube. The LPS activity was measured by assay kits including recombinant Factor C or Limulus amebocyte lysate. To assess the bacterial composition in the samples, a 16S ribosomal DNA-based operational taxonomic unit analysis was performed. We focused on the genera representing >0.1% of the whole microbiota. RESULTS: We found a high LPS activity in the GF samples with weak acidity (approximately > pH 4), whereas little/no activity in those with strong acidity (approximately < pH 2). Spearman test also demonstrated a close correlation between pH and LPS in those samples (r = 0.872). The relative abundance of GNB in the saliva showed no significant difference between the subject groups with weak- and strong-acidity GF. In addition, in the subjects whose GF acidity was weak, the GNB abundance in the GF was almost the same as that in the saliva. By contrast, in the subjects whose GF acidity was strong, the GNB abundance in the GF was significantly lower than that in the saliva. DISCUSSION: GNB that have recently moved from the oral cavity might account for the prominent LPS activity in a stomach with weak acidity.

Successful Endoscopic Removal of a Biliary Stent with Stent-Stone Complex after Long-Term Migration.

A 49-year-old man was referred to our hospital for an abnormality of the hepatobiliary enzyme. The patient was diagnosed with primary sclerosing cholangitis 9 years ago, and he had a biliary stent with a string placed as an inside stent. We attempted to remove the stent 6 months later, but the string was cut off, so the stent could not be removed. Removal was attempted again, but the patient cancelled the outpatient appointments. During the examination performed at the present visit, we discovered that the biliary stent had migrated into the bile duct, and a stone had formed around the stent. We attempted to remove the stent-stone complex by endoscopic retrograde cholangiopancreatography, but it was difficult; thus, we decided to implant a new biliary stent and remove the other stent later. When we performed endoscopic retrograde cholangiopancreatography again 2 days later, the bile duct axis was linearized thanks to the additional stent, enabling us to grab the migrated stent with stent-stone complex using grasping forceps and to successfully pull it out. By implanting an additional plastic stent temporarily, we were able to straighten the biliary axis and endoscopically remove the biliary stent that migrated and caused the development of stent-stone complex in a 2-staged approach.

A Case of Mesentero-axial Type of Acute Gastric Volvulus Successfully Reduced by a Balloon-assisted Endoscopy.

A 95-year-old man was admitted to the hospital due to a sudden onset of nausea and abdominal pain. Physical examination revealed abdominal distension with mild epigastric tenderness. Computed tomography showed a grossly distended stomach with displacement of the antrum above the esophago-gastric junction, and he was diagnosed with acute mesentero-axial gastric volvulus. We attempted urgent reduction using conventional endoscopy, but failed. He and his family did not want surgery because of his extreme advanced age, and a nasogastric tube was inserted to his stomach for decompression expecting a natural reduction. On the next day, however, it was not improved, so endoscopic reduction was tried again by a balloon-assisted endoscope without an overtube under X-ray fluoroscopy. When the scope reached the descending portion of the duodenum, the balloon on the scope tip was inflated, and the stomach position was reduced by pulling back the scope with twisting to the right. He was discharged from the hospital without any complication, and no recurrence has been observed for 12 months thereafter. We suggest a balloon-assisted endoscope as a useful tool for reduction of gastric volvulus especially in cases of reduction failure by a conventional one.