Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study.

BACKGROUND: IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. METHODS: Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. RESULTS: Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the "Jang & Kim's modified anatomical classification," 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010-4.433]). CONCLUSIONS: This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells.

UNLABELLED: The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecules that mediate glutamine and glucose metabolism in cancer cells have not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor alpha (RORα). Up-regulation of RORα in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate reduced (NADP+ /NADPH) ratio, which was consistent with a reduction in the glutathione/glutathione disulfide (GSH/GSSG) ratio. Adenovirus (Ad)-mediated overexpression of RORα (Ad-RORα) or treatment with the RORα activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-RORα and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of pyruvate dehydrogenase and subsequently shifted pyruvate to complete oxidation. The RORα-mediated decrease in PDK2 levels was caused by up-regulation of p21, rather than p53. Furthermore, RORα inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of RORα than adjacent nontumor tissue, supporting a potential beneficial effect of RORα activation in the treatment of liver cancer. CONCLUSION: RORα mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, RORα expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism.

Confinement to the intrapancreatic bile duct is independently associated with a better prognosis in extrahepatic cholangiocarcinoma.

BACKGROUND: Actual differences of long term outcome of extrahepatic cholangiocarcinoma according to the location of the tumor have not yet been studied. The aim of this study was to evaluate the prognosis and optimal surgical procedure for middle (BD) cancer. METHODS: Among 109 patients with carcinoma of the extrahepatic BD underwent surgical resection, curative resection of extrahepatic BD cancer was performed in 90 patients. They were classified into three groups according to the location of tumors: DISTAL (n = 32), tumor was confined to the intrapancreatic bile duct; MID (n = 20), tumor was located between below the confluence of the hepatic duct bifurcation and suprapancreatic portion of the BD; and DIFFUSE (n = 38), tumor was located diffusely. RESULTS: Tumor involving the middle BD (MID or DIFFUSE) had a higher rate of perineural invasion as compared to the DISTAL group. The overall and disease-free survival rate for the MID or DIFFUSE group was significantly worse than that of DISTAL. In the MID/DIFFUSE group, there was no significant difference of survival according to the type of the operation (pancreaticoduodenectomy or segmental BD resection). The multivariate analysis showed that tumor involving middle BD (MID or DIFFUSE group) and node metastasis were independently poor prognostic factors for the disease free and overall survival. CONCLUSION: Extrahepatic cholangiocarcinoma involving the extrapancreatic BD has a worse prognosis than those confined to the intrapancreatic BD. In patients with tumors confined to the middle BD, BD resection can be considered as an alternative surgical procedure to pancreaticoduodenectomy, if an R0 resection can be accomplished.

Small heterodimer partner attenuates profibrogenic features of hepatitis C virus-infected cells.

BACKGROUND & AIMS: An atypical orphan nuclear receptor small heterodimer partner (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of them inhibit TGF-ß and Smad signalling and exhibit antifibrotic activity in the liver. However, little is known about the protective effects of SHP and AMPK against hepatitis c virus (HCV)-induced hepatic fibrosis. METHODS: Levels of SHP, p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells infected with HCV genotype 2a (JFH-1) were investigated. The effect of adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on fibrotic gene expression was evaluated in HCV-infected cells. Finally, we examined the effect of Ad-SHP and AMPK activators on invasion and activation of LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM). RESULTS: In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP mRNA and protein levels were diminished compared with controls, whereas profibrotic factors were increased. Pharmacological AMPK activation recovered SHP expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, an inducer of TGF-ß. Moreover, CytoSelect invasion assay revealed that enhanced activity and invasiveness of hepatic stellate cells induced by CM. CONCLUSION: These results demonstrate that overexpression of SHP and activation of AMPK reverses profibrogenic features of HCV-infected cells by decreasing TGF-ß and fibrotic gene expression. These findings provide a rationale for SHP as a possible therapeutic target against HCV-induced hepatic fibrosis.

Microcystic stromal tumor of the ovary with mutation in exon 3 of ß-catenin: a case report.

Microcystic stromal tumor of the ovary is a very rare ovarian tumor with distinctive microcystic histologic features and a characteristic immunophenotype of stromal tumor. However, its origin, tumor pathogenesis, and prognosis have not been well established until now. We report a very unusual case of a microcystic stromal tumor of the ovary with a mutation in exon 3 of the ß-catenin (CTNNB1) gene. Macroscopically, the fragmented ovarian tumor showed a diffuse solid mass. Microscopically, the tumor had a pathognomonic histologic pattern of solid and cellular areas with microcysts and fibrous hyalinized stroma. Immunohistochemical staining with CD10, vimentin, CD99, and ß-catenin showed positive expression. However, α-inhibin and E-cadherin showed negativity. Mutational analysis revealed a point mutation in exon 3 of the ß-catenin (CTNNB1) gene.

PIK3CA Amplification Is Common in Left Side-Tubular Adenomas but Uncommon Sessile Serrated Adenomas Exclusively with KRAS Mutation.

Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation.

An imported case of cystic echinococcosis in the liver.

A 25-year-old Uzbek male presented with right upper abdominal pain for 20 days. On radiologic studies, a huge cystic mass was noticed in the right liver which was suspected as parasitic. The patient received right hepatic segmentectomy (segment 7), and the surgically resected mass was confirmed as cystic echinococcosis (CE), measuring 10.5 cm in its diameter. The inner surface of the cyst was bile-stained. The patient was discharged on the 8th hospital day, and was rechecked 6 months after the surgical intervention without any evidence of recurrence. The present report describes findings of an imported case of CE which represented ultrasound images of the 'ball of wool'.

Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connetive Tissue Growth Factor.

The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor ß (TGF-ß)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.

Protein losing enteropathy in severe atopic dermatitis in an exclusively breast-fed infant.

We first report a case of protein losing enteropathy in severe atopic dermatitis in an exclusively breast-fed 5-month-old infant. Protein losing enteropathy was confirmed by fecal alpha1-antitrypsin clearance test and imaged successfully by 99mTc-human serum albumin scintigraphy. The present case highlights that protein losing enteropathy in severe infantile atopic dermatitis is being a topic of concern and also an issue even in exclusive breast feeding patients.

Draft Genome Sequencing of the Pathogenic Fungus Cladosporium phlei ATCC 36193 Identifies Candidates of Novel Polyketide Synthase Genes Involved in Perylenequinone-Group Pigment Production.

Cladosporium phlei, which causes purple eyespot disease, has been focused on as a source of phleichrome from the perylenequinone group of pigments. Although this agent is important in photodynamic therapy, there are no genome sequences for the species. Here, we sequenced the genome of C. phlei and reported the draft sequence. The total length of the draft genome was approximately 31.8 Mb, and 9571 genes were predicted. Phylogenetic analysis showed that Cladosporium sphaerospermum, Rachicladosporium sp., and Rachicladosporium antarcticum were closely related, and this result corresponded to the taxonomic data. In addition to the draft genome sequence, we report four candidates of new polyketide synthase (PKS) genes, involved in the production of perylenequinone-group pigments.

Clusterin Attenuates Hepatic Fibrosis by Inhibiting Hepatic Stellate Cell Activation and Downregulating the Smad3 Signaling Pathway.

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis.

Prognostic subclass of intrahepatic cholangiocarcinoma by integrative molecular-clinical analysis and potential targeted approach.

BACKGROUND: Although molecular characterization of iCCA has been studied recently, integrative analysis of molecular and clinical characterization has not been fully established. If molecular features of iCCA can be predicted based on clinical findings, we can approach to distinguish targeted treatment. We analyzed RNA sequencing data annotated with clinicopathologic data to clarify molecular-specific clinical features and to evaluate potential therapies for molecular subtypes. METHODS: We performed next-generation RNA sequencing of 30 surgically resected iCCA from Korean patients and the clinicopathologic features were analyzed. The RNA sequences from 32 iCCA resected from US patients were used for validation. RESULTS: Patients were grouped into two subclasses on the basis of unsupervised clustering, which showed a difference in 5-year survival rates (48.5% vs 14.2%, p = 0.007) and similar survival outcome in the US samples. In subclass B (poor prognosis), both data sets were similar in higher carcinoembryonic antigen and cancer antigen 19-9 levels, underlying cholangitis, and bile duct-type pathology; in subclass A (better prognosis), there was more frequent viral hepatitis and cholangiolar-type pathology. On pathway analysis, subclass A had enriched liver-related signatures. Subclass B had enriched inflammation-related and TP53 pathways, with more frequent KRAS mutations. CCA cell lines with similar gene expression patterns of subclass A were sensitive to gemcitabine. CONCLUSIONS: Two molecular subtypes of iCCA with distinct clinicopathological differences were identified. Knowledge of clinical and pathologic characteristics can predict molecular subtypes, and knowledge of different subtype signaling pathways may lead to more rational, targeted approaches to treatment.

Tumorigenic role of YAP in hepatocellular carcinogenesis is involved in SHP2 whose function is different in vitro and in vivo.

Yes-associated protein (YAP) is a nuclear effector of the cell-density sensing Hippo pathway and interacts with Src homology phosphotyrosine phosphatase 2 (SHP2), which controls cell proliferation and survival. The tumor promoting/suppressing activities of YAP and SHP2 during liver tumorigenesis remain controversial. This study aimed to investigate the tumorigenic roles of YAP and SHP2 in hepatocellular carcinogenesis. Cell density associated subcellular distributions of YAP and SHP2 in normal human hepatocytes (THLE-2) and hepatocellular carcinoma (HCC) cells (SK-Hep1, SNU-182) were investigated by Western blotting and cell block immunohistochemistry. The effects of YAP knockdown on proliferation, migration and invasion were studied using YAP-specific siRNAs. The prognostic significance of YAP and SHP2 expressions was investigated immunohistochemically using a tissue microarray (TMA) from 50 HCC cases. High-cell density decreased the nuclear expression of YAP and SHP2 in normal hepatocytes as compared with low-cell density. However, in HCC cells, nuclear YAP and SHP2 were observed regardless of cell density. Nuclear YAP influenced SHP2 expression and cell proliferation. In particular, YAP knockdown impacted nuclear levels of SHP2 protein in SK-Hep1 cells. In HCC tissues, nuclear YAP expression was elevated and cytoplasmic SHP2 expression was diminished as compared with adjacent non-tumor tissues. Notably, these expressions were found to be significantly associated with poor recurrence-free and overall survival rate in patients with HCC. Consequently, the tumor promoting role of YAP is involved in SHP2 which functions as a tumor promoter in vitro but as a tumor suppressor in vivo. YAP and SHP2 can be unfavorable prognostic markers in HCC.

Bile Granuloma Mimicking Peritoneal Seeding: A Case Report.

Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography-computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance.

Diagnostic Accuracy of Combined Acetylcholinesterase Histochemistry and Calretinin Immunohistochemistry of Rectal Biopsy Specimens in Hirschsprung's Disease.

BACKGROUND: Acetylcholinesterase (AchE) histochemistry has been established as an accurate diagnostic tool for Hirschsprung's disease (HD). In addition, calretinin immunohistochemistry is also reported as a reliable and adjunctive method to diagnose HD. We investigated the diagnostic value of combined AchE histochemistry and calretinin immunohistochemistry in rectal suction biopsies from HD and non-HD patients. METHODS: We retrospectively reviewed 99 rectal suction biopsy specimens including 4 repeat biopsies from 95 patients (34 HD and 61 non-HD). Each specimen was evaluated with hematoxylin-eosin, AchE histochemistry, and calretinin immunohistochemistry. RESULTS: Of 95 patients, only 21 (22.1%) showed some ganglion cells. All 61 non-HD cases revealed no abnormal AchE-positive fibers. Of 34 HD patients, 32 exhibited abnormal AchE fibers, but 2 showed no stained fibers. None of the tissues from the HD patients exhibited calretinin immunoreactivity. Test sensitivity and specificity of AchE histochemistry alone were 93.5% and 100.0%, respectively, while calretinin immunohistochemistry were 100.0% and 85.2%, respectively. CONCLUSIONS: AchE histochemistry is a good diagnostic method for HD, if feasible, and a combination of AchE histochemistry and calretinin immunohistochemistry will help increase the accuracy of the diagnosis of HD.

Carcinosarcoma of the liver: a case report.

Primary hepatic carcinosarcoma is a rare tumor comprised of a mixture of carcinomatous and sarcomatous elements. Less than 20 adequately documented cases have been reported, however the imaging features of two cases were briefly described. We present here a case of carcinosarcoma of the liver in a 46-year-old woman, which was confirmed based on pathology. Imaging showed a large mass with large necrotic portions, small cystic portions, calcifications and bone formations.

Traumatic neuroma around the celiac trunk after gastrectomy mimicking a nodal metastasis: a case report.

Traumatic neuroma is a well-known disorder that occurs after trauma or surgery involving the peripheral nerve and develops from a nonneoplastic proliferation of the proximal end of a severed, partially transected, or injured nerve. We present a case of traumatic neuroma around the celiac trunk after gastrectomy in a 56-year-old man, which was confirmed by pathology. CT demonstrated the presence of a lobulated, homogeneous, hypoattenuating mass around the celiac trunk, mimicking a nodal metastasis.

[A case of sclerosing cholangitis showing response to prednisolone].

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibrosis and destruction of intra- and extrahepatic bile ducts resulting in hepatic failure and death. Only the liver transplantation is the possible treatment for patients to survive. There has been a few reports that steroid is an effective treatment in autoimmune variant sclerosing cholangitis, which is thought to be a familial diseases with different etiology, and steroid responsive biliary strictures be named as immunoglobulin G4 (IgG4)-associated cholangitis (IAC). There is no reliable data regarding effective steroid treatment in autoimmune variant sclerosing cholangitis in Korea. We report a case of 32-year-old male with sclerosing cholangitis, who was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) and liver biopsy, showing favorable response to prednisolone therapy.

Absence of GNAS mutation in colorectal carcinogenesis.

AIMS AND BACKGROUND: The incidence rate of colorectal cancer (CRC) increases every year in Korean populations. However, association between the GNAS mutation and colorectal precancerous lesions has not been studied in in Korean populations. To contribute to better understanding of colorectal carcinogenesis, we analyzed GNAS mutation in 100 cancerous and 96 precancerous colorectal lesions. METHODS: The records of colonoscopic polypectomy performed at Dongsan Medical Center between 1999 and 2003 were reviewed retrospectively. Precancerous lesions included 7 villous adenomas, 59 tubular adenomas, and 18 sessile serrated adenomas, and 12 hyperplastic polyps. Keimyung Human Bio-Resource Bank at Dongsan Medical Center provided 100 CRC samples. RESULTS: GNAS mutation was not found in any colorectal cancer or any precancerous colorectal lesions, including villous adenoma, which is thought to harbor the mutation. CONCLUSIONS: The role of GNAS mutation might be limited in colorectal neoplasms of the Korean population.

Colonic Parasitic Infection Mimicking Peritoneal Seeding on 18F-FDG PET/CT.

A 77-year-old man with anorexia and weight loss for 6 months received a diagnosis of gastric cancer by endoscopy and referred for F-FDG PET/CT for initial staging. F-FDG PET/CT showed multiple foci of increased FDG uptake with diffuse wall thickening and multiple diverticula. The differential diagnoses were peritoneal seeding and multiple diverticulitis. The patient underwent curative total gastrectomy, and the lesion was diagnosed as poorly differentiated adenocarcinoma by histological examination. He underwent anterior resection of the sigmoid colon for exploration. The nodular lesions of the sigmoid colon were diagnosed by histopathologic examination as chronic diverticulitis caused by a parasitic infection.