The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT-liver communication.

While brown adipose tissue (BAT) is well-recognized for its ability to dissipate energy in the form of heat, recent studies suggest multifaced roles of BAT in the regulation of glucose and lipid homeostasis beyond stimulating thermogenesis. One of the functions involves interorgan communication with metabolic organs, such as the liver, through BAT-derived secretory factors, a.k.a., batokine. However, the identity and the roles of such mediators remain insufficiently understood. Here, we employed proteomics and transcriptomics in human thermogenic adipocytes and identified previously unappreciated batokines, including phospholipid transfer protein (PLTP). We found that increased circulating levels of PLTP, via systemic or BAT-specific overexpression, significantly improve glucose tolerance and insulin sensitivity, increased energy expenditure, and decrease the circulating levels of cholesterol, phospholipids, and sphingolipids. Such changes were accompanied by increased bile acids in the circulation, which in turn enhances glucose uptake and thermogenesis in BAT. Our data suggest that PLTP is a batokine that contributes to the regulation of systemic glucose and lipid homeostasis as a mediator of BAT-liver interorgan communication.

[A case of 8-cm metastatic lymph node rupture from early gastric cancer with low papillary structure].

A 79-year-old man experiencing sudden abdominal pain was admitted to our hospital. Upper gastrointestinal endoscopy and computed tomography images revealed an 8-cm lesion, suggestive of submucosal tumor in the gastric antrum and a type 0-IIc early gastric cancer in the gastric body. The tumor ruptured during preoperative examinations, which necessitated emergency D1+ distal gastrectomy. Pathological findings confirmed the penetration of the gastric cancer into the submucosa. The cancer comprised well-differentiated tubular carcinoma cells with a low papillary structure. At the submucosa, small clusters of carcinoma cells were surrounded by clear spaces. These clusters displayed a characteristic "inside out pattern" on immunohistochemical examination, suggesting that the clusters were probably incipient lesions of invasive micropapillary carcinoma. The ruptured tumor was identified as a lymph node metastasis from the gastric cancer. We herein report this extremely rare case in which lymph node metastasis from early gastric cancer enlarged and ruptured. The findings of this study suggest that the characteristic pathological type identified in this report, which signified high-grade malignancy, was associated with the rupture.

[Case of protein plug in the pancreatic duct mimicking pancreatic cancer concomitant with branch-type intraductal papillary mucinous neoplasm].

A 65-year-old male was referred to our hospital 2 years ago for a multilocular cyst accompanied with a protein plug in the pancreas tail. He was diagnosed as having branch duct-type intraductal papillary mucinous neoplasm and was followed-up. Two years later, endoscopic ultrasonography revealed a hypoechoic lesion, 10mm in diameter, near the cyst-like lesion. Finally, he was diagnosed with small pancreatic adenocarcinoma concomitant with intraductal papillary mucinous neoplasm and underwent radical distal pancreatectomy with splenectomy. Resected specimen revealed that the protein plug in the main pancreatic duct had caused distal pancreatic duct dilatation, resembling a multilocular cyst and pancreatic duct stenosis with inflammatory changes and fibrosis around the pancreatic parenchyma. Here, we report a rare case of protein plugs in the pancreatic duct mimicking pancreatic cancer concomitant with branch-type intraductal papillary mucinous neoplasm.

[A case of polyp-type ampullary carcinoma-in-adenoma within the ampullary channel, displaying an intraductal growth pattern].

A 70-year-old woman with jaundice was referred to our hospital. Obstructive jaundice caused by common bile duct (CBD) stones was diagnosed based on the results of blood tests, abdominal computed tomography, and endoscopic retrograde cholangiopancreatography. We attempted to remove the CBD stones endoscopically. After endoscopic sphincterotomy, a polypoid lesion was exposed at the ampulla of Vater. Histological examination of a biopsy specimen from the ampullary lesion revealed a tubular adenoma, and the patient underwent pylorus-preserving pancreatoduodenectomy. Pathological examination of the resected specimen revealed a polyp-type ampullary carcinoma-in-adenoma arising from the ampullary channel. Herein, we report a rare case of polyp-type ampullary carcinoma-in-adenoma displaying an intraductal growth pattern.

[A case of calcifying fibrous tumor in the abdominal wall, morphologically resembling a gastric submucosal tumor].

We report an extremely rare case of a calcifying fibrous tumor (CFT) occurring in the abdominal wall. A 43-year-old woman was referred to our hospital because of a gastric submucosal tumor. Imaging findings revealed a gastric submucosal tumor with calcification. Endoscopic ultrasound-guided fine-needle aspiration was attempted to obtain a tissue specimen; however, the tumor was not adequately visualized because of calcification. Local excision was performed because of the tumor growth and the risk of progression to gastrointestinal stromal tumor. The tumor was histologically diagnosed as a CFT. We describe the imaging and pathological findings, and discuss the differential diagnosis and histogenesis of CFT.

[A case of pancreatic mucinous carcinoma with special reference to diagnostic usefulness of contrast enhanced ultrasonography].

A 72-year-old man was admitted to our hospital for further investigation of pancreatic mass. Ultrasonography revealed hypoechoic mass with hyperechoic and aechoic area. Contrast enhanced ultrasonography (CE-US) revealed a vascular image in the lesion. CT showed some enhanced parts of low density mass in the pancreatic body, which was recognized as low-, high- and relatively high-intensity mass on T1-, T2-WI MRI and MRCP, respectively. The final pathological diagnosis showed mucinous carcinoma. CE-US may be useful for diagnosis of mucinous carcinoma.

Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways.

Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron-sulfur (Fe-S) cluster synthesis. Heme and Fe-S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways-gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

Usefulness of Endoscopic Transpapillary Tissue Sampling for Malignant Biliary Strictures and Predictive Factors of Diagnostic Accuracy.

BACKGROUND/AIMS: It is sometimes difficult to distinguish between malignant and benign biliary strictures using imaging studies alone, and pathological diagnosis is necessary. The aim of this study was to determine the usefulness of endoscopic transpapillary tissue sampling and factors predictive of diagnostic accuracy. METHODS: From April 2008 to December 2014, 136 patients underwent endoscopic transpapillary tissue sampling for malignant biliary strictures. The cytological and histological findings were reported as negative, suspicious, or positive. Suspicious and positive findings were defined as pathologically positive. RESULTS: The sensitivity was 65.0% for forceps biopsy, 49.5% for brush cytology, 46.2% for bile aspiration cytology, and 21.9% for endoscopic nasobiliary drainage cytology. The combination of these procedures improved the sensitivity (72.8%). Endoscopic transpapillary tissue sampling was more sensitive for lesions of biliary origin (91.4%) than for extrabiliary lesions (66.3%). In surgical cases, the sensitivity for tumors with an infiltrative growth pattern (53.3%) was significantly lower than for a tumor with an expanding or intermediate growth pattern (87.5%). CONCLUSIONS: Combining procedures can improve diagnostic accuracy. It may be possible to predict the sensitivity of endoscopic transpapillary tissue sampling by evaluating the etiology and tumor growth pattern using preoperative imaging studies.

Role of bile acids in the regulation of the metabolic pathways.

Recent studies have revealed that bile acids (BAs) are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions. Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs. BAs regulate their own homeostasis via signaling pathways. BAs also affect diverse metabolic pathways including glucose metabolism, lipid metabolism and energy expenditure. This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome.

The right hepatic artery syndrome.

Various benign and malignant conditions could cause biliary obstruction. Compression of extrahepatic bile duct (EBD) by right hepatic artery was reported as a right hepatic artery syndrome but all cases were compressed EBD from stomach side. Our case compressed from dorsum was not yet reported, so it was thought to be a very rare case. We present here the first case of bile duct obstruction due to the compression of EBD from dorsum by right hepatic artery.

So-called carcinosarcoma of the duodenum with a chondrosarcomatous component.

Carcinosarcoma is a biphasic malignant tumor consisting of both carcinomatous and sarcomatous components, and its occurrence in the duodenum is very rare. In the present report, we describe a case of so-called carcinosarcoma of the duodenum with a chondrosarcomatous component. A 79-year-old man was referred to our hospital because of anorexia, weight loss, and jaundice. A preoperative imaging examination showed a hypovascular mass located in the pancreatic head. Histological examination of specimens obtained through a forceps biopsy revealed anaplastic carcinoma (spindle cell type), and a pancreatoduodenectomy was performed. Histologically, the tumor showed an elevated lesion with a wide base in proximity to duodenal mucosal carcinoma. The tumor was found to be predominantly composed of sarcoma with carcinomatous and chondrosarcomatous components. There was a transitional zone between the carcinomatous and sarcomatous components, and a portion of the sarcomatous component was positive for cytokeratin, and negative for vimentin. As mentioned above, we diagnosed the lesion as so-called carcinosarcoma with a chondrosarcomatous component.

A case of a resectable single hepatic epithelioid hemangioendothelioma with characteristic imaging by ADC map.

A 47-year-old woman with a single-nodule hepatic tumor was referred to our hospital. She had no symptoms. The tumor was located at the surface of the right lobe of the liver; it showed peripheral low signal intensity on a magnetic resonance imaging apparent diffusion coefficient (ADC) map, and an influx of blood flow into the peripheral area of the tumor at the early vascular phase on perflubutane microbubble (Sonazoid(®)) contrast-enhanced (CE) ultrasonography. Since we suspected a malignant tumor, the patient underwent surgical resection. The hepatic tumor was resected curatively. Pathological examination revealed that the tumor was composed of epithelioid cells with an epithelioid structure and/or cord-like structure. Immunohistochemical staining was positive for cluster of differentiation 34 and factor VIII-related antigen. Based on the above, a final diagnosis of hepatic epithelioid hemangioendothelioma (EHE) was made. Hepatic EHE is a rare hepatic tumor: only a few cases of hepatic EHE with curative resection have been reported. We were unable to reach a diagnosis of hepatic EHE by imaging studies; however, an ADC map was useful in showing the malignant potential of the tumor, and CE ultrasonography was useful in revealing the peripheral blood flow of the tumor. When an unusual hepatic mass is encountered, hepatic EHE should be kept in mind, and the mass should be inspected with more than one imaging modality, including an ADC map, in the process of differential diagnosis.

Surgical treatment of hilar bile duct carcinoma: experience with 25 consecutive hepatectomies.

To evaluate our recent surgical policy regarding hilar bile duct carcinoma, we evaluated 62 cases treated between 1976 and 1993, and 25 cases treated between 1994 and 2000. In the late period we used percutaneous transhepatic portal vein embolization (PTPE) before extended right hepatectomy; S4a + S5 + S1 hepatectomy for elderly patients and those with poor liver function; and routine total caudate lobectomy including the paracaval portion and resection of the inferior portion of the medial segment (S4a). Sixty-five (74.7%) of the 87 patients underwent hepatectomy: 40 in the early period and 25 in the late period. Bile duct resection alone was performed in 22 patients, all in the early period. Resection was curative in 54.8% in the early period and 88.0% in the late period. The 3- and 5-year survival rates in the early period were 27.1% and 20.2%, respectively, as compared to 59.9% and 49.9% in the late period. Analysis of the 25 hepatectomies in the late period revealed improved survival times compared to patients treated by PTPE with extended right hepatectomy. No complications occurred after extended left hepatectomy or S4a + S5 + S1 hepatectomy, but four patients (16%) who underwent extended right hepatectomy plus PTPE died postoperatively. Our policy has resulted in improved outcome in patients with hilar bile duct carcinoma.

Management of advanced pancreatic cancer: staging laparoscopy and immunochemotherapy--a new treatment strategy.

BACKGROUND/AIMS: Pancreatic cancer remains a challenging disease with a dismal prognosis. This study investigated the effect of two-route immunochemotherapy via artery (2-ICA) and usefulness of staging laparoscopy in the management of advanced cases. METHODOLOGY: Fifty-five patients admitted to our Department between April 1993 and April 2000 for resection of pancreatic cancer were the subjects of this study. Staging laparoscopy was performed in 16 of the patients, and 2-ICA was used to treat three of 16 because they were found to have small liver metastases during staging laparoscopy. RESULTS: According to the TNM staging system (UICC), 9 (56%) in the 16 patients who underwent staging laparoscopy were found to have Stage IVb disease, 4 (25%) to have Stage IVa disease and only 3 (19%) to have Stage III disease. The three patients with small liver metastases received 2-ICA therapy. The metastatic lesions in the liver had completely disappeared in one patient, and decreased to about half the size in the other two cases. CONCLUSIONS: Staging laparoscopy is useful for correctly diagnosing tumor stage in pancreatic cancer patients and selecting appropriate treatment. The 2-ICA therapy is a new and effective method of treatment for advanced cases.

[Adjuvant chemotherapy for unresectable locally advanced pancreatic cancer in light of its characteristics].

The use of neoadjuvant chemotherapy for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors, especially for patients with Stage IV b (Japan criteria). We report our experience with a six-drug chemotherapeutic regimen that resulted in sufficient downstaging of the tumor in some patients to justify surgical resection. From Jan. 2001 through December 2003, 6 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg), according to the UCLA regimen and gemcitabine weekly (600 mg/m2) and heparin as a continuous infusion (0-3,000 U/day) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response and survival. There were 5 partial responses (83% response rate) and 1 no response. Four of 5 responding patients had sufficient tumor regression to meet clinical criteria for resectability, three of whom underwent a curative resection. All patients who underwent downstage operation were still alive for the follow-up period (4-23 months).