Makiko Yasumoto

A case of IgG4-related sclerosing mesenteritis

IgG4-related disease has been recognized as a systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration and sclerosis. This disease has been identified in various sites, including the pancreas, retroperitoneum, lung, head, and neck. Herein we report a case of IgG4-related sclerosing mesenteritis. An 82-year-old woman was admitted to our hospital due to persistent abdominal pain. Abdominal computed tomography demonstrated a solitary mass with a maximal diameter of 11.7cm in mesentrium of the small intestine. On her laboratory examination, only C-reactive protein level was elevated. Although the pre-operative diagnosis was indefinite, she underwent ileocecectomy. Grossly, an elastic soft mass with foci of hemorrhage was seen in the mesentrium. Microscopically, the lesion was composed of fibroblastic or myofibroblastic spindle cells with abundant stromal fibrosis and inflammatory infiltrate, such as lymphocytes and plasma cells accompanied by lymphoid follicles with a germinal center. Obstructive phlebitis was observed. Immunohistochemically, numerous IgG4-positive plasma cells were observed, and the IgG4/IgG ratio was 75.9%. The serum level of IgG4 examined at post-operation was high. These findings suggested that this lesion was consistent with IgG4-related sclerosing mesenteritis.

Intraductal neoplasm of the intrahepatic bile duct: Clinicopathological study of 24 cases

AIM To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and β-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ, high grade including tumors with microinvasion). RESULTS Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P < 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of β-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.

N-myc downstream regulated gene1/Cap43 overexpression suppresses tumor growth by hepatic cancer cells through cell cycle arrest at the G0/G1 phase

N-myc downstream regulated gene-1 (NDRG1)/Cap43 regulates tumor growth and metastasis in various carcinomas. In this study we examined whether and how NDRG1/Cap43 modulates tumor growth by human hepatocellular carcinoma (HCC) cells. NDRG1/Cap43 cDNA was used to transfect HCC cell lines (KIM-1), and stable transfectants overexpressing NDRG1/Cap43 (KIM-1/Cap43) were obtained. Cell cycle analysis showed that KIM-1/Cap43 cells were arrested in the G0/G1 phase. Western blot analysis demonstrated an increase in p21 in KIM-1/Cap43 cells in culture under full confluency as compared with KIM-1/Mock. When KIM-1 cells, which are very low in NDRG1/Cap43 expression, were treated with mimosine, a G0/G1 cell cycle blocker, expression of NDRG1/Cap43 was induced in a dose dependent manner, together with p21 induction and CDK4 reduction. In vivo, KIM-1/Cap43 cells showed markedly decreased tumor growth rates compared with those of KIM-1/Mock. Immunohistochemical staining demonstrated markedly higher p21 labeling index in the KIM-1/Cap43 tumor than KIM-1/Mock tumor, and lower CDK4 and Ki-67 labeling index in the KIM-1/Cap43 than KIM-1/Mock. In order to confirm suppressive effects of NDRG1/Cap43, we further established a stable transfectant expressing NDRG1/Cap43 (HAK-1B/Cap43) using another HCC cell line, HAK-1B. Western blot analysis demonstrated an increase in p21 and a decrease in CDK4 in HAK-1B/Cap43 cells in culture under full confluency as compared with HAK-1B/Mock. HAK-1B/Cap43 also showed decreased tumor growth rates as compared with its control counterpart in vivo. NDRG1/Cap43 overexpression thus induced cell cycle arrest at the G0/G1 phase accompanied by increased p21 and decreased CDK4 expression in HCC cells. NDRG1/Cap43 might play a key role in the cell cycle control of G0/G1 in HCC cells.

RECQL1 DNA Repair Helicase: A Potential Therapeutic Target and a Proliferative Marker against Ovarian Cancer

Objective This study analyzed the clinicopathological correlation between ovarian cancer (OC) and RECQL1 DNA helicase to assess its therapeutic potential. Methods Surgically resected OC from 118 retrospective cases, for which paraffin blocks and all clinical data were complete, were used in this study. RECQL1 and Ki-67 immunostaining were performed on sections to correlate RECQL1 staining with subtype and patient survival. Ten OC and two normal cell lines were then examined for RECQL1 expression and were treated with siRNA against RECQL1 to assess its effect on cell proliferation. Results Of the 118 cases of adenocarcinoma (50, serous; 26, endometrioid; 21, clear cell; 15, mucinous; 6, other histology), 104 (90%) showed varying levels of RECQL1 expression in the nuclei of OC cells. The Cox hazards model confirmed that diffuse and strong staining of RECQL1 was correlated with histological type. However, RECQL1 expression did not correlate with overall patient survival or FIGO stage. In vitro, RECQL1 expression was exceptionally high in rapidly growing OC cell lines, as compared with normal cells. Using a time-course analysis of RECQL1-siRNA transfection, we observed a significant inhibition in cell proliferation. Conclusions RECQL1 DNA helicase is a marker of highly proliferative cells. RECQL1-siRNA may offer a new therapeutic strategy against various subtypes of OC, including platinum-resistant cancers, or in recurrent cancers that gain platinum resistance.

Pathomorphologic study of undifferentiated carcinoma in seven cases: relationship between tumor and pancreatic duct epithelium

BACKGROUND/PURPOSE By the time undifferentiated carcinoma is detected, it has formed a large mass, and it is reportedly difficult to pathologically observe its relationship with the pancreatic duct. In this study, we examined the pancreatic ducts of seven patients of surgical samples, and pathomorphologically investigated the relationship between the adenocarcinomatous and sarcomatous components and the pattern of tumor extension. In addition, we evaluated the usefulness of pancreatic juice cytology by comparison with the findings of the main pancreatic duct (MPD). METHODS Seven primary undifferentiated carcinomas of the pancreas (from three male and four female patients with a mean age of 59 years) were analyzed. Histopathological evaluation was based on the WHO diagnostic criteria. Pancreatic juice cytology was performed and evaluated in two patients. RESULTS All the undifferentiated carcinomas contained adenocarcinomatous and sarcomatous components, and two had a distinct glandular structure. However, we could not pathomorphologically confirm the continuity of the adenomatous with the sarcomatous components in any of the patients. Three undifferentiated carcinomas contained osteoclast-like giant cells. Pathological observation of the tumor and MPD was possible in three of the seven undifferentiated carcinomas. PanIN-3 was observed in the MPD of three patients, suggesting extension into the MPD. In one of these three, the tumor presented intraductal growth in the MPD, and preoperative pancreatic juice cytology revealed atypical cells with osteoclast-like giant cells. In the remaining two, the tumor extraductally compressed the MPD upward. CONCLUSIONS Undifferentiated carcinoma showed two patterns of cancer extension: (1) invasion and expansive growth during the sarcomatous transformation of adenocarcinoma, and (2) intraductal extension. In addition, some undifferentiated carcinomas showed extension in the MPD. Of note, postoperative pancreatic juice cytology may be useful for the diagnosis.

Pegylated interferon-α2a inhibits proliferation of human liver cancer cells in vitro and in vivo.

Purpose We investigated the effects of pegylated interferon-α2a (PEG-IFN-α2a) on the growth of human liver cancer cells. Methods The effect of PEG-IFN-α2a on the proliferation of 13 liver cancer cell lines was investigated in vitro. Cells were cultured with medium containing 0–4,194 ng/mL of PEG-IFN-α2a, and after 1, 2, 3, or 4 days of culture, morphologic observation and growth assay were performed. After hepatocellular carcinoma (HCC) cells (HAK-1B and KIM-1) were transplanted into nude mice, various doses of PEG-IFN-α2a were subcutaneously administered to the mice once a week for 2 weeks, and tumor volume, weight, and histology were examined. Results PEG-IFN-α2a inhibited the growth of 8 and 11 cell lines in a time- and dose-dependent manner, respectively, although the 50% growth inhibitory concentrations of 7 measurable cell lines on Day 4 were relatively high and ranged from 253 ng/mL to 4,431 ng/mL. Various levels of apoptosis induction were confirmed in 8 cell lines. PEG-IFN-α2a induced a dose-dependent decrease in tumor volume and weight, and a significant increase of apoptotic cells in the tumor. Subcutaneous administration of clinical dose for chronic hepatitis C (3 μg/kg, 0.06 μg/mouse) was effective and induced about 30-50% reduction in the tumor volume and weight as compared with the control. Conclusions Although in vitro anti-proliferative effects of PEG-IFN-α2a were relatively weak, PEG-IFN-α2a induced strong anti-tumor effects on HCC cells in vivo. The data suggest potential clinical application of PEG-IFN-α2a for the prevention and treatment of HCC.

DIRECT CHOLANGIOSCOPY USING A DOUBLE‐BALLOON ENTEROSCOPE: CHOLEDOCHOJEJUNOSTOMY WITH INTRADUCTAL BILIARY CARCINOMA

A 75‐year‐old man who underwent choledochojejunostomy for gallstones 30 years ago was hospitalized for general malaise. Abdominal computed tomography revealed marked dilation of the intrahepatic bile duct in the right lobe and an image of a hypervascular tumor. Endoscopic retrograde cholangiography using double‐balloon enteroscopy (DBE) showed a filling defect that was localized to the right hepatic bile duct. Furthermore, the scope was able to readily pass through the anastomosed site of the choledochojejunostomy and, therefore, we observed the interior of the bile duct using the same scope. We obtained an image showing a whitish, papillary‐like tumor, and a biopsy of the tumor rendered the pathology of intraductal papillary mucinous carcinoma. Direct cholangioscopy using DBE is a useful diagnostic tool, particularly in patients with a past history of choledochojejunostomy.

Usefulness of lavage cytology during endoscopic transpapillary catheterization into the gallbladder in the cytological diagnosis of gallbladder disease.

Many studies have reported methods of cell collection involving percutaneous transhepatic cholangiodrainage (PTCD) and fine‐needle aspiration cytology for the diagnosis of gallbladder disease. However, few studies have described the use of a transpapillary approach, i.e., endoscopic transpapillary catheterization into the gallbladder (ETCG). In this study, we analyzed cells collected by ETCG to evaluate its usefulness in the cytological diagnosis of gallbladder disease.

Multi-centric pancreatic cancer without PanIN lesion

The patient was a 67-year-old man under follow-up after gastric cancer surgery. An abdominal CT scan performed 1 year earlier had shown an approximately 14-mm hypovascular mass in the pancreatic body; however, he did not consent to treatment and was followed up for 1 year. A blood workup showed that the fasting blood glucose level, which had been within normal limits, was elevated to 174 mg/dl (normal, 70-109 mg/dl), and the HbA1c level was 12.0% (normal, 4.3-5.8%). Abdominal CT revealed an approximately 20-mm mass in the pancreatic body and an approximately 12-mm mass in the pancreatic tail, and magnetic resonance imaging cholangiopancreatography (MRCP) showed discontinuity of the main pancreatic duct (MPD). Since these findings led to the suspicion of invasive ductal carcinoma (IDC) of the pancreas developing in the pancreatic body and tail, we performed distal pancreatectomy with splenectomy. Histologically, IDCs were observed in the pancreatic body and tail. However, PanIN was not observed in the MPD between the two carcinomas. They were diagnosed as independent invasive ductal carcinomas of the pancreas.

ENDOSCOPIC RETRIEVAL OF MIGRATED PLASTIC STENT INTO BILE DUCT OR PANCREATIC PSEUDOCYST

Proximally migrated biliary plastic stent and migrated stent in the pancreatic pseudocyst are relatively rare complications. A migrated stent causes poor drainage conditions, which leads to secondary complications such as infection, abscess, perforation and, moreover, becomes a foreign object in the body, and retrieval or re‐stenting is therefore necessary. The retrieval of a migrated stent includes surgical, percutaneous and endoscopic approaches, and the most non‐invasive method is endoscopic retrieval. However, because very few devices are exclusively designed for retrieval, the current situation is that the available devices are used while taking advantage of various ideas and techniques. From previously reported cases and our experiences of such cases, we herein describe the methods of endoscopic retrieval for stents that have migrated into a bile duct or pancreatic pseudocysts.