菅野 敦

1995年に疾患概念が提唱されてから、自己免疫性膵炎(AIP)に関する様々な知見が積み重ねられた。現在、AIPは、主に国際コンセンサス診断基準(ICDC)に基づき診断される。ICDCは、組織学的診断を重要視しているが、EUS-FNAにより採取された組織は対象とされていない。近年、EUS-FNAを用いて採取した組織を用いたAIP診断の報告が散見される。本稿では、EUS-FNAを用いてAIPの組織を採取し診断する要点につき概説する。本稿で紹介した手技が普及し、AIPの診断と研究がさらに発展することを期待したい。(著者抄録)

症例は68歳男性。早期胃癌に対する加療時に施行したスクリーニング目的のCTにて、膵尾部に遅延濃染を呈する30mm大の腫瘤を認めた。血清IgG4値が258mg/dlと高値であり自己免疫性膵炎(AIP)も疑われたが、EUS-FNAにて腺癌の組織像を認め、膵尾部癌の診断で膵体尾部切除術を施行した。病理組織学的所見では、膵癌組織に加えて周囲に著明な線維化とリンパ球形質細胞浸潤を認めた。あわせて閉塞性静脈炎と著明なIgG4陽性形質細胞浸潤というAIPに類似した組織像も認めた。術後、血清IgG4値は144mg/dlに低下した。近年、AIPに膵癌を合併した症例や、AIPに類似した間質所見を呈する膵癌症例の報告がある。膵腫瘍の鑑別には、臨床像とあわせてEUS-FNAを用いた病理組織学的診断が有用と考えられた。(著者抄録)

The patient was a 30-year-old female who had undergone excision of the extrahepatic bile duct and Rouxen- Y hepaticojejunostomy for congenital biliary dilatation at the age of 7. Thereafter, she suffered from recurrent acute pancreatitis due to pancreaticobiliary maljunction and received subtotal stomach-preserving pancreaticoduodenectomy. She developed a pancreatic fistula and an intra-abdominal abscess after the operation. These complications were improved by percutaneous abscess drainage and antibiotic therapy. However, upper abdominal discomfort and the elevation of serum pancreatic enzymes persisted due to stenosis from the pancreaticojejunostomy. Because we could not accomplish dilation of the stenosis by endoscopic retrograde cholangiopancreatography, we tried an endoscopic ultrasonography (EUS) guided rendezvous technique for pancreatic duct drainage. After transgastric puncture of the pancreatic duct using an EUS-fine needle aspiration needle, the guidewire was inserted into the pancreatic duct and finally reached to the jejunum through the stenotic anastomosis. We changed the echoendoscope to an oblique-viewing endoscope, then grasped the guidewire and withdrew it through the scope. The stenosis of the pancreaticojejunostomy was dilated up to 4 mm, and a pancreatic stent was put in place. Though the pancreatic stent was removed after three months, the patient remained symptomfree. Pancreatic duct drainage using an EUS-guided rendezvous technique was useful for the treatment of a stenotic pancreaticojejunostomy after pancreaticoduodenectomy. © 2013 Baishideng. All rights reserved.

胆嚢は壁構造の特異性から，癌が周囲臓器に浸潤しやすい．胆嚢癌の予後は，胆嚢周囲進展度とリンパ節転移に規定される．腹部超音波や超音波内視鏡は，胆嚢内腔を詳細に観察することが可能であり，胆嚢癌の壁深達度診断に有用である．ERCPは，肝十二指腸間膜浸潤の診断や胆汁細胞診に有用である．CTは，客観性のある画像を得ることができるため，胆嚢癌の進行度診断には必須である．MRIは拡散強調画像や肝細胞特異的造影剤の開発から，その有用性が増している．FDG-PETはリンパ節転移など遠隔転移の診断に有用である．各々の画像診断の特徴を理解し，組み合わせて総合的に胆嚢癌の進行度を診断することが重要である．<br>

Background and Aim IgG4-related sclerosing cholangitis (IgG4-SC) must be precisely distinguished from primary sclerosing cholangitis and cholangiocarcinoma (CC) because the treatments are completely different. However, the pathological diagnosis of IgG4-SC is difficult. Therefore, highly specific non-invasive criteria such as serum IgG4 should be established. This study established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers. Methods A total of 344 IgG4-SC patients were enrolled in this study. As controls, 245, 110, and 149 patients with pancreatic cancer, primary sclerosing cholangitis, and CC, respectively, were enrolled. IgG4-SC patients were classified into three groups: type 1 (stenosis only in the lower part of the common bile duct), type 2 (stenosis diffusely distributed throughout the intrahepatic and extrahepatic bile ducts), and types 3 and 4 (stenosis in the hilar hepatic region) with 246, 56, and 42 patients, respectively. Serum IgG4 levels were compared, and the cut-offs were established. Results The cut-off obtained from receiver operator characteristic curves showed similar sensitivity and specificity to that of 135mg/dL when all IgG4-SC and controls were compared. However, a new cut-off value was established when subgroups of IgG4-SC and controls were compared. A cut-off of 182mg/dL can increase the specificity to 96.6% (4.7% increase) for distinguishing types 3 and 4 IgG4-SC from CC. A cut-off of 207mg/dL might be useful for completely distinguishing types 3 and 4 IgG4-SC from all CC. Conclusions Serum IgG4 is useful for the differential diagnosis of IgG4-SC and controls.

Invasive ductal adenocarcinoma (IDA) of the pancreas manifests poor prognosis due to the early invasion and distant metastasis. In contrast, intraductal papillary mucinous adenoma or carcinoma (IPMA or IPMC) reveals better clinical outcomes. Various molecular mechanisms contribute to these differences but entire picture is still unclear. Recent researches emphasized the important role of miRNA in biological processes including cancer invasion and metastasis. We previously described that miR-126 is down-regulated in IDA compared with IPMA or IPMC, and miR-126 regulates the expression of invasion related molecule disintegrin and metalloproteinase domain-containing protein 9 (ADAM9). Assessing the difference of miRNA expression profiles of IDA, IPMA, and IPMC, we newly identified miR-197 as an up-regulated miRNA specifically in IDA. Expression of miR-197 in pancreatic cancer cells resulted in the induction of epithelial-mesenchymal transition (EMT) along with the down-regulation of p120 catenin which is a putative target of miR-197. Direct interaction between miR-197 and p120 catenin mRNA sequence was confirmed by 3′UTR assay, and knockdown of p120 catenin recapitulated EMT induction in pancreatic cancer cells. In situ hybridization of miR-197 and immunohistochemistry of p120 catenin showed mutually exclusive patterns suggesting pivotal role of miR-197 in the regulation of p120 catenin. This miR-197/p120 catenin axis could be a novel therapeutic target. © 2012 Wiley Periodicals, Inc.

Objectives: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. Connexins (Cxs) allow direct intercellular communications as components of gap junction but also play important roles in the regulation of cell proliferation, cell differentiation, and tissue development. We here examined the expression of Cxs and Cx-mediated regulation of cell functions in PSCs. Methods: Human PSCs were isolated from patients undergoing operation for chronic pancreatitis or pancreatic cancer. The expression of Cxs was examined by reverse transcription polymerase chain reaction, Western blotting, and immunofluorescent staining. The roles of Cxs in PSC functions were examined by using carbenoxolone, a broad-spectrum Cx inhibitor, and small interfering RNA for Cx43. Results: Human activated PSCs expressed a variety of Cxs including Cx43 both in vitro and in vivo. Carbenoxolone inhibited platelet-derived growth factor-BB-induced proliferation and migration, and type I collagen expression in PSCs. In addition, carbenoxolone inhibited the activation of quiescent PSCs to a myofibroblastlike phenotype. Decreased Cx43 expression by small interfering RNA resulted in decreased proliferation and type I collagen expression. Conclusions: Pancreatic stellate cells expressed a variety of Cxs. Connexins, especially Cx43, might regulate the cell functions and activation of PSCs.

Background and study aims: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. Patients and methods: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. Results: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. Conclusions: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality. © Georg Thieme Verlag KG Stuttgart · New York.

A 50-year-old woman had undergone left nephrectomy for renal cell carcinoma 13 years previously. Ten years later, a solitary metastatic tumor had been detected in the pancreatic tail and she had undergone subsequent resection of the pancreatic tail and spleen. Three years after surgery, she was admitted to our hospital for severe anemia resulting from gastrointestinal tract bleeding. Esophagogastroduodenoscopy revealed a 3-cm solid tumor at the oral side of the papilla of Vater. Histology of the bioptic duodenal tissue revealed inflammatory granulation without malignancy. Computed tomography showed a well-contrasted hypervascular tumor in the descending portion of the duodenum. We diagnosed the patient with metachronous duodenal metastasis of renal cell carcinoma and performed a pancreaticoduodenectomy. An ulcerated polypoid mass was detected at the oral side of the papilla of Vater. Histology revealed clear cell carcinoma coated by granulation tissue across the surface of the tumor. Immunohistology demonstrated that the cells were positive for vimentin, CD10 and epithelial membrane antigen and negative for CK7. After a repeated pancreatectomy, the patient had no symptoms of gastrointestinal bleeding and maintained good glucose tolerance without insulin therapy because the remnant pancreas functioned well. In conclusion, for the diagnosis of patients who have previously undergone nephrectomy and present with gastrointestinal bleeding, the possibility of metastasis to the gastrointestinal tract, including the duodenum, should be considered. With respect to surgical treatment, the pancreas should be minimally resected to maintain a free surgical margin during the first surgery taking into account further metachronous metastasis to the duodenum and pancreas.

症例は40代，女性．幼少期にNeurofibromatosis type I（NF1）と診断された．貧血，黒色便にて他院を受診した．カプセル内視鏡にて小腸出血と診断され当院紹介となった．腹部造影CT検査では，多発する腫瘤を空腸および膵頭部近傍に認め，EUS-FNAにて多発消化管GISTと診断し，膵頭十二指腸切除術，小腸部分切除術を行った．文献的検討によると，NF1関連性GISTは散発性GISTとは異なる臨床的特徴を有し診療上注意を要すると考えられた．<br>

Chronic pancreatitis (CF) has been considered an intractable inflammatory disease that is progressive and irreversible after definite structural changes appear in the pancreas. The Japanese diagnostic criteria for CF were revised in 2009. One of the reasons for this revision was to define a diagnostic criterion for the early phase of CF (early CF) to improve a patient's clinical outcome, because the disease progression might be reversed in this phase by a therapeutic intervention. However, the clinical features and outcome of early CP remain largely unknown, and the diagnostic reliability of early CP needs to be verified. Here, we show two patients who met the diagnostic criteria of early CF and then progressed to the advanced, late phase of CF (definite CP). A 64-year-old man with recurrent acute pancreatitis was diagnosed as early CF and later progressed to definite CF with multiple pancreatic calcifications at the age of 69. The etiology of CF in this patient was thought to be idiopathic. The other patient was a 57-year-old man with alcohol abuse (ethanol consumption &gt; 120 g/day). He was diagnosed as early CF and then rapidly progressed to definite CP without any acute attack. He could not remain abstinent after the diagnosis of early CP. In the present report, we retrospectively demonstrated distinct clinical features of the two patients, both of whom were diagnosed as early CF first and then progressed to definite CP. Thus, our findings support the disease concept of early CF and also suggest the validity of the revised Japanese criteria for the diagnosis of early CP.

The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI. One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit. Ten patients with the p.N34S variant, 7 with the IVS3+2T &gt; C variant, two with both the p.N34S and the IVS3+2T &gt; C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 +/- A 9.6 ng/ml (mean +/- A SD), and that in healthy controls was 10.7 +/- A 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T &gt; C variant (5.1 +/- A 3.4 ng/ml), but not in those with the p.N34S variant (8.9 +/- A 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (&lt; 6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T &gt; C and p.P45S carriers from non-carriers. Serum PSTI levels were decreased in patients with the IVS3+2T &gt; C and p.P45S variants of the SPINK1 gene.

Objective: The objective of this study was to describe the imaging findings for intraductal tubulopapillary neoplasms of the pancreas. Methods: Eleven pancreatic tumors pathologically confirmed as intraductal tubulopapillary neoplasm were retrospectively collected. The dynamic contrast-enhanced computed tomography (CT), magnetic resonance (MR) imaging including MR cholangiopancreatography (MRCP), ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP) results were reviewed. The 2-tone duct sign and cork-of-wine-bottle sign were reviewed as indicators of intraductal tumor growth on CT/MR and MRCP/ERCP images, respectively. Results: A 2-tone duct sign was noted on the dynamic CT images (7/10, 70%) and on the MR imaging (5/8, 63%). The distal main pancreatic duct was dilated in all the patients except one, who had a branch duct lesion. A cork-of-wine-bottle sign was observed on the MRCP image (3/8, 38%) and on the ERCP image (3/6, 50%). Conclusions: Intraductal tubulopapillary neoplasms are rare tumors showing characteristic imaging findings such as the 2-tone duct sign and the cork-of-wine-bottle sign that represent their intraductal growth.

Objectives: The usefulness of early severity assessment of acute pancreatitis (AP) by contrast-enhanced computed tomography (CECT) was investigated. Methods: Data were obtained from a 2007 nationwide survey in Japan. Clinical data of 983 patients with AP were analyzed. All were examined by CECT on the day of admission. Results: Early findings of CECT demonstrated that low enhanced pancreatic parenchyma (LEPP) was associated with the incidence of organ failure (OF), multiple OF, and infectious complications as well as mortality (P &lt; 0.0001). Next, patients were further divided into 4 groups according to the CECT findings, which focused on the LEPP and peripancreatic collections (PPCs). The LEPP/PPC (+/+) group was characterized as high morbidity and high mortality. The incidence of OF (28.2%), multiple OF (15.5%), and mortality (11.4%) in patients assigned to the (+/+) group was significantly higher than in those assigned to the other groups. The incidence of infectious complications was significantly higher in patients assigned to the (+/+) group (16.7%), the (+/-) group (9.0%), and the (-/+) group (7.0%) than those assigned to the (-/-) group (1.8%). Conclusions: The detection of LEPP and PPC was a useful CECT finding for the early assessment of the severity of AP.

Background: It is controversial whether EUS-guided FNA by using 22-gauge (G) needles is useful for the diagnosis or evaluation of autoimmune pancreatitis (AIP). Objective: To evaluate the usefulness of EUS-FNA by 22-G needles for the histopathological diagnosis of AIP. Design: A retrospective study. Setting: Single academic center. Patients: A total of 273 patients, including 25 with AIP, underwent EUS-FNA and histological examinations. Results: EUS-FNA by using 22-G needles provided adequate tissue samples for histopathological evaluation because more than 10 high-power fields were available for evaluation in 20 of 25 patients (80%). The mean immunoglobulin G4-positive plasma cell count was 13.7/high-power field. Obliterative phlebitis was observed in 10 of 25 patients (40%). In the context of the International Consensus Diagnostic Criteria for AIP, 14 and 6 of 25 patients were judged to have level 1 (positive for 3 or 4 items) and level 2 (positive for 2 items) histological findings, respectively, meaning that 20 of 25 patients were suggested to have lymphoplasmacytic sclerosing pancreatitis based on the International Consensus Diagnostic Criteria. The diagnosis in 1 patient was type 2 AIP because a granulocytic epithelial lesion was identified in this patient. Limitations: A retrospective study with a small number of patients. Conclusions: The results of this study suggest that EUS-FNA by using 22-G needles provides tissue samples adequate for histopathological evaluation and greatly contributes to the histological diagnosis of AIP. (Gastrointest Endosc 2012;76:594-602.)

Background IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases. Methods The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012. Results The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC. Conclusion These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

自己免疫性膵炎(AIP)は膵癌(PC)との鑑別が臨床上の問題である。本研究では、Perfusion CTによる膵血流解析が両者の鑑別に有用であるかを検討した。AIP12症例(全例type1)とPC22症例にPerfusion CTを施行し、single-compartment kinetic model法を用いて画像解析を行い、3つのパラメータを用いて両者を比較した。FV値はAIPで平均81.3/分に対しPCでは平均19.3/分と有意に低値(p=0.0005)、VD値はAIPが28.8に対しPCでは93.6と有意に高値(p=0.0084)、R2値はAIPが0.659に対しPCでは0.250と有意に低値(p<0.0001)であった。また、カラーマップ画像も鑑別に有用であった。本研究は、AIPとPCの鑑別におけるPerfusion CTの有用性を示す最初の報告である。(著者抄録)

慢性膵炎に対する内視鏡的治療の意義を栄養改善の観点から検討した。12ヵ月以上の内視鏡的治療を要した19例を対象とし、栄養状態の評価指標としてBMI、血清アルブミン(Alb)、総リンパ球数(Lym)、小野寺のPrognostic Nutritional Index(PNI)、総コレステロールの経時的変化をレトロスペクティブに解析した。治療開始後、腹痛発作がなかった12例では各栄養指標は有意に改善したが、腹痛発作が1回以上発生した7例では改善がみられなかった。Alb、Lym、PNIは治療後1〜3ヵ月の期間に有意な改善を示し、BMIについては7〜9ヵ月で有意な増加を認めた。内視鏡治療によって、腹痛発作を完全に防止できれば栄養指標の改善効果が得られ、その効果は10ヵ月以内に達成された。外科治療に先行する短期間の内視鏡治療は栄養障害の改善という見地からも有効な治療ストラテジーとなり得る。(著者抄録)

Objectives: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, the nationwide survey was conducted. Methods: Patients with AIP who had visited the selected hospitals in 2007 were surveyed. Autoimmune pancreatitis was diagnosed according to the Japanese clinical diagnostic criteria 2006. The study consisted of 2-stage surveys: the number of patients with AIP was estimated by the first questionnaire and their clinical features were assessed by the second questionnaire. Results: The estimated total number of AIP patients in 2007 was 2790 (95% confidence interval, 2540-3040), with an overall prevalence rate of 2.2 per 100,000 populations. The number of patients, who were newly diagnosed as AIP, was estimated to be 1120 (95% confidence interval, 1000-1240), with an annual incidence rate of 0.9 per 100,000 populations. Sex ratio (male to female) was 3.7, and the mean (SD) age was 63.0 (11.4) years. Among the 546 patients whose clinical information was obtained, 87.6% of the patients presented high serum immunoglobulin G4 levels (&gt;= 135 mg/dL), and 83% received steroid therapy. Conclusions: The data represent the current clinical features of AIP in Japan. From the results, most AIP patients in Japan can be categorized to type 1 AIP according to the recent classification of AIP.

The patient was a 73 year old man for whom surgery under general anesthesia was difficult to perform because of pulmonary emphysema. In April 2003, he visited our hospital complaining of epigastralgia and dorsal pain, and was admitted under a diagnosis of acute exacerbation of chronic pancreatitis. In 2005, acute cholangitis concomitantly developed with acute exacerbation of chronic pancreatitis, for which a plastic stent was placed in the common bile duct. Cholangitis repeatedly developed every 23 months thereafter, and admission was required each time to exchange the stent. Surgery was considered but not applicable because of his poor respiratory function, and a partially covered self-expandable metallic stent was inevitably placed in the bile duct. Ten months later, an aberration of the metallic stent in the bile duct occurred, but it was dealt with by placing an additional metallic stent, and no cholangitis or pancreatitis developed until the patient died of respiratory insufficiency 3 years later. Placement of a covered self-expandable metallic stent might be an option for the treatment of benign biliary stricture, especially in patients at high risk from surgery.

慢性膵炎の疼痛に対して、外科治療に先行して内科治療を行うことが一般的である。膵管ステントなどによる内視鏡的治療は、疼痛や膵液流出障害を軽減することで栄養障害を改善し、たとえ後に外科手術へ移行するような難治症例であっても、一定のメリットを患者にもたらすことが期待できる。このような観点から、内視鏡的治療の難治症例を対象に栄養状態の変化を検討した。内視鏡的治療開始後、腹痛などのイベント発生のなかったグループでは、血清アルブミン、総リンパ球数、BMIなどの栄養状態の指標は有意に改善したが、イベントが1回以上発生したグループでは改善がみられなかった。BMIは内視鏡的治療開始後7〜9ヵ月で有意な増加を認めた。すなわち、10ヵ月程度の短期内科治療によって栄養障害の改善効果が得られ、たとえ手術に移行した場合でも、合併症発生率の低減などのメリットを得られる可能性が考えられた。(著者抄録)

Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer. J. Cell. Physiol. (C) 2011 Wiley Periodicals, Inc.

It is now clear that are two histological types (Type-1 and Type-2) of autoimmune pancreatitis (AIP). The histological pattern of Type-1 AIP or traditional AIP is called lymphoplasmacytic sclerosing pancreatitis (LPSP). The histological pattern of Type-2 AIR is characterized by neutrophilic infiltration in the epithelium of the pancreatic duct. In general, Type-2 AIR patients are younger, may not have a male preponderance, and rarely show elevation of serum IgG4 compared with Type-1 AIP patients. Unlike Type-1 AIP patients, Type-2 AIP patients rarely have associated sclerosing diseases, but they are more likely to have acute pancreatitis and ulcerative colitis. Although Type-2 AIP is sometimes observed in the USA and Europe, most AIP cases in Japan and Korea are Type-1. The international consensus diagnostic criteria for AIP comprise 5 cardinal features, and combinations of one or more of these features provide the basis for diagnoses of both Type-1 and Type-2 AIP Due to the fact that steroid therapy is clinically, morphologically, and serologically effective in AIP patients, it is the standard therapy for AIP The indications for steroid therapy in AIP include symptoms such as obstructive jaundice and the presence of symptomatic extrapancreatic lesions. Oral prednisolone (0.6 mg/kg/day) is administered for 2-4 weeks and gradually tapered to a maintenance dose of 2.5-5 mg/day over a period of 2-3 months. Maintenance therapy by low-dose prednisolone is usually performed for 1-3 years to prevent relapse of AIP

The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 30 untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells. Mol Cancer Res; 10(1); 3-10. (C) 2011 AACR.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P &lt; 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P &lt; 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

Objectives: The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. Methods: Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time (T) were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. Results: The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and (T) values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial FV value was normal (168.09/min) did not change after the treatment. Conclusions: Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.

Background/Aims: The feasibility of neoadjuvant chemoradiation therapy for cholangiocarcinoma, followed by conventional resection, has not been determined yet. Here, a phase I study of neoadjuvant chemoradiation therapy, named NACRAC, was performed to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of gemcitabine when combined with external beam radiation therapy for resectable cholangiocarcinoma. Methodology: From August 2007 to June 2008, 12 patients provided informed consent. Preoperative radiation was administered in 1.8Gy daily fractions up to a total dose of 45Gy. Gemcitabine was administered at day land 8 every three weeks. The initial dose of gemcitabine was started from 400mg/m2(.) Results: One patient was not able to start treatment because of bleeding caused by a duodenal ulcer and cholangitis. At 800mg/m(2) of gemcitabine, one patient out of three failed to complete the treatment because of Grade 3 hematological toxicity. In another three cases of 800mg/m(2), the second case could not complete the treatment because of cholangitis. Then, 600mg/m(2) was determined to be the MTD, and the RD dose decided as 600mg/m(2). Conclusions: The RD of gemcitabine in NACRAC study was determined to be 600mg/m(2). NACRAC study should proceed to a phase II trial to evaluate the effectiveness.

BACKGROUND & AIMS: Distinction of immunoglobulin G4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC. METHODS: Seventeen physicians from centers in the United States, Japan, and the United Kingdom, unaware of clinical data, reviewed 40 preselected ERCs of patients with IAC (n = 20), PSC (n = 10), and cholangiocarcinoma (n = 10). The performance characteristics of ERC for IAC diagnosis as well as the kappa statistic for intraobserver and interobserver agreement were calculated. RESULTS: The overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18, respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success. The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor. CONCLUSIONS: Despite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases.

Objectives: The aim of this study was to compare the benefits between endoscopic drainage and surgical drainage of the pancreatic duct for patients with chronic calcified pancreatitis. Methods: A total of 68 patients were classified into endoscopic (n = 34) or surgical (n = 34) treatment groups. Patients receiving endoscopic treatment were further divided into 2 subgroups: a short-period group, patients who could discontinue serial pancreatic stenting within 1 year (n = 19); and a long-period group, patients who needed pancreatic drainage by serial endoscopic stenting for more than 1 year (n = 15). The medical records of these patients were retrospectively analyzed. Results: Hospital stays, frequency of hospitalizations, and medical expense were similar between the short-period endoscopic treatment group and surgery group. On the other hand, patients in the long-period endoscopic treatment group required significantly longer hospital stays, more frequent hospitalizations, and had higher medical expenses than the short-period endoscopic treatment group as well as than the surgery group. Conclusions: Patients who underwent serial endoscopic stenting for more than 1 year showed no benefit compared with surgical treatment in terms of the frequency of hospital stays and medical costs.

Mucin-producing intraductal papillary neoplasm (adenocarcinoma/adenoma) in the bile duct is becoming recognized as a specific type of neoplasm. Since, it bears a striking similarity to intraductal papillary mucinous neoplasms of the pancreas with regard to its histopathologic features, the term "intraductal papillary mucinous neoplasms of the bile duct" (IPMN-B) is frequently used, although no definite terminology or definition has been decided by World Health Organization. This neoplasm lacks ovarian-like stroma and communicates with the bile ducts, unlike biliary mucinous cystic neoplasm (MCN). On the other hand, malignant IPMN-B is categorized as an intraductal-growth type of intrahepatic cholangiocarcinoma (ICC). In comparison to other types of ICC, such as the mass-forming type and periductal-infiltrating type that have poor resectability and an unfavorable prognosis, malignant IPMN-B can be resected and demonstrates a more favorable prognosis. Meanwhile, unlike biliary MCN that is usually confined in a closed cyst, IPMN-B can spread along the mucosal surface of the bile ducts, and it should be widely resected. Therefore, multimodality assessment is needed to ensure the correct diagnosis of IPMN-B. We herein review the imaging findings of IPMN-B with pathologic correlation.