Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN). METHODS: We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR. RESULTS: Upon Qubit measurement and copy number assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing pre-amplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861-0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025-9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674-3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMN-associated PDA and undergoing pancreatic surveillance. CONCLUSIONS: Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.

DOI： 10.1007/s00535-020-01724-5

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Language：Japanese   Publisher：医学図書出版(株)  

近年、multi-region sequenceを用いた腫瘍の発育・進展経路の追跡による発癌機構の解明が試みられている。IPMN関連膵癌における、背景膵も含めた詳細な腫瘍分布のマッピングとゲノム解析を統合したアプローチにより、IPMN関連膵癌の形成には、sequential、de novo、branch-offの三つの経路が存在することが明らかとなった。Sequential経路は由来癌を、de novo経路は併存癌の存在を分子異常の観点から定義しうるものである。一方で、共通の創始クローンが枝分かれして、サブクローンの一部がIPMNを、別のサブクローンが浸潤性膵管癌を形成する進化経路であるbranch-off経路は、これまで臨床的には知られていたIPMNに隣接して発生する併存癌(隣接併存癌)の成り立ちを説明しうるものである。(著者抄録)

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Metachronous development of intraductal papillary mucinous neoplasms in the remnant pancreas following resection is a significant clinical burden. Our aim was to characterize the clinicopathological and molecular features of the patients with metachronous tumor development to identify predictive factors and the possible route(s) of dissemination. Seventy-four patients who underwent resection of intraductal papillary mucinous neoplasms with no invasive compartment or associated carcinoma were retrospectively analyzed. In patients with metachronous tumor development, targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical detection of four proteins (p53, SMAD4, p16, and β-catenin) were performed on both primary and metachronous tumors. The distributions of microscopic neoplastic lesions were examined at surgical margins and in apparently normal tissue apart from the primary tumor. During the median follow-up period of 52 months, 9 patients (12%) developed metachronous tumors in the remnant pancreas. Primary tumors located in the body/tail of the pancreas (odds ratio, 15; 95% confidence interval, 1.6-131) and of the pancreatobiliary type (odds ratio, 6.1; 95% confidence interval, 1.1-35.7) were identified as significant risk factors for subsequent metachronous tumor development. Eight of the nine patients shared molecular aberrations between their primary and metachronous tumors, suggesting migrations from the primary tumor to the pancreatic duct as the cause of metachronous tumor development. Our data suggest that these post-resection metachronous tumors develop by skip dissemination of the primary tumor, potentially via the pancreatic duct. The development of strategies to better predict and prevent this form of tumor progression is necessary.

DOI： 10.1038/s41379-019-0405-7

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

DOI： 10.1053/j.gastro.2018.10.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

G protein αs (GNAS) mediates receptor-stimulated cAMP signalling, which integrates diverse environmental cues with intracellular responses. GNAS is mutationally activated in multiple tumour types, although its oncogenic mechanisms remain elusive. We explored this question in pancreatic tumourigenesis where concurrent GNAS and KRAS mutations characterize pancreatic ductal adenocarcinomas (PDAs) arising from intraductal papillary mucinous neoplasms (IPMNs). By developing genetically engineered mouse models, we show that GnasR201C cooperates with KrasG12D to promote initiation of IPMN, which progress to invasive PDA following Tp53 loss. Mutant Gnas remains critical for tumour maintenance in vivo. This is driven by protein-kinase-A-mediated suppression of salt-inducible kinases (Sik1–3), associated with induction of lipid remodelling and fatty acid oxidation. Comparison of Kras-mutant pancreatic cancer cells with and without Gnas mutations reveals striking differences in the functions of this network. Thus, we uncover Gnas-driven oncogenic mechanisms, identify Siks as potent tumour suppressors, and demonstrate unanticipated metabolic heterogeneity among Kras-mutant pancreatic neoplasms.

DOI： 10.1038/s41556-018-0122-3

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Other Link： http://orcid.org/0000-0002-1068-7024

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Pancreatic ductal adenocarcinoma (PDA), one of the most lethal cancers worldwide, is associated with two main types of morphologically distinct precursors-pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Although the progression of PanIN into invasive cancer has been well characterized, there remains an urgent need to understand the biology of IPMNs, which are larger radiographically detectable cystic tumors. IPMNs comprise a number of subtypes with heterogeneous histopathologic and clinical features. Although frequently remaining benign, a significant proportion exhibits malignant progression. Unfortunately, there are presently no accurate prognosticators for assessing cancer risk in individuals with IPMN. Moreover, the fundamental mechanisms differentiating PanIN and IPMN remain largely obscure, as do those that distinguish IPMN subtypes. Recent studies, however, have identified distinct genetic profiles between PanIN and IPMN, providing a framework to better understand the diversity of the precursors for PDA. Here, we review the clinical, biological, and genetic properties of IPMN and discuss various models for progression of these tumors to invasive PDA.

DOI： 10.1038/ctg.2017.3

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Other Link： http://orcid.org/0000-0002-1068-7024

Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

BACKGROUND & AIMS: Little is known about the genetic factors that contribute to the development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS via inactivation of tumor suppressor pathways. We investigated whether subjects with multiple SSAs carry germline loss-of-function mutations (nonsense and splice site) in genes that regulate OIS: the p16-Rb and ATM-ATR DNA damage response pathways. METHODS: Through a bioinformatic analysis of the literature, we identified a set of genes that function at the main nodes of the p16-Rb and ATM-ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated subjects with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 subjects matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms. RESULTS: We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2, XAF1, and RBL1) in 5 of 20 subjects with multiple SSAs (odds ratio, 3.0; 95% confidence interval, 0.9-8.9; P=.04). In 2 subjects, we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (odds ratio, 460; 95% confidence interval, 23.1-16,384; P=6.8 x 10(-5)). In knockdown experiments with pancreatic duct cells exposed to UV light, RNF43 appeared to function as a regulator of ATM-ATR DNA damage response. CONCLUSIONS: We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs. We identified RNF43 as a regulator of the DNA damage response and associated nonsense variants in this gene with a high risk of developing SSAs.

DOI： 10.1053/j.gastro.2013.10.045

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：B M J PUBLISHING GROUP  

Background and aim: Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules.
Methods: Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months).
Results: Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months).
Conclusions: Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.

DOI： 10.1136/gut.2007.129684

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Other Link： http://orcid.org/0000-0002-1068-7024

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.

DOI： 10.1158/1078-0432.CCR-07-0111

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Other Link： http://orcid.org/0000-0002-1068-7024

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/nm1294

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Other Link： http://www.nature.com/articles/nm1294

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DOI： 10.1002/1878-0261.70011

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We report the rare case of severe cognitive disorder and ataxia caused by entrectinib in a patient with NTRK1 fusion gene-positive intrahepatic cholangiocarcinoma. The case was a 56-year-old woman after nine courses of GCS therapy. The patient experienced grade 1 muscle weakness on day 4 and grade 3, cognitive disorder on day 7 after receiving entrectinib, which led to hospitalization. The symptoms were reversible and tended to improve after withdrawal of entrectinib. It is crucial to increase awareness of TRKi-specific adverse events and their proper management.

DOI： 10.1007/s12328-024-02076-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by germline variants in the APC gene, leading to the development of numerous colorectal polyps and significantly increases the risk of colorectal cancer. A diagnosis is typically made using colonoscopy, and genetic testing can assist in patient surveillance and carrier identification. Recent advances include the use of whole-genome array comparative genomic hybridization (a-CGH), which provides better resolution of genetic imbalances. We aimed to explore the specific features of FAP patients with whole APC gene deletions using high-resolution a-CGH and to compare patient characteristics. Two polyposis patients with whole APC deletions were identified, and the lost genetic sizes ranged from 0.3–1.1 Mb. Nervous abnormalities were a characteristic symptom in a patient with a 1.1 Mb loss. A patient with an approximately 0.3 Mb loss, which included the entire APC gene, presented a polyposis phenotype without intellectual disability. The comparison of genetic losses, with or without intellectual disability, revealed 7 genetic changes. Consequently, EPB41L4A is a candidate gene associated with the neurogenic phenotype.

DOI： 10.1038/s41439-024-00301-z

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Other Link： https://www.nature.com/articles/s41439-024-00301-z

Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

ゲノム解析技術の進歩を背景に,包括的がんゲノムプロファイリング検査(CGP検査)が実臨床に導入された.これら「プレシジョンメディスン」はがん薬物治療の個別化への道を開く一方で,検査に耐えうる十分量の検体採取が困難な例も存在する.膵胆道癌におけるEUS-FNA/Bでは,デバイスを含めたアプローチの選択や穿刺回数の増加,病理部門との連携による標本作製の工夫により,CGP検査の成功率を高めることも可能である.また近年,EUS-FNA/B検体を用いた核酸解析に加えて蛋白発現の評価を行うことで膵胆道癌診断能の向上を図るなど,多角的な分子診断を目指す取り組みが報告されている.病理診断の補完のみならず,病勢把握や再発予測,新規治療法の探索など,今後のゲノム診療がカバーする領域は多岐にわたることが想定され,さらなる発展が期待される.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J02025&link_issn=&doc_id=20241105300004&doc_link_id=10.2958%2Fsuizo.39.316&url=https%3A%2F%2Fdoi.org%2F10.2958%2Fsuizo.39.316&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本胆道学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objective:

This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection.

Summary Background Data:

Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown.

Methods:

Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated.

Results:

These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways.

Conclusion:

Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

DOI： 10.1097/sla.0000000000006444

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

The molecular mechanisms underpinning the development of metachronous tumors in the remnant bile duct following surgical resection of primary biliary tract carcinomas (BTCs) are unknown. This study aimed to elucidate these mechanisms by evaluating the clinicopathologic features of BTCs, the alterations to 31 BTC-related genes on targeted sequencing, and the aberrant expression of p53, p16, SMAD4, ARID1A and β-catenin on immunohistochemistry. Twelve consecutive patients who underwent resection of metachronous BTCs following primary BTC resection with negative bile duct margins were enrolled. Among the 12 metachronous tumors, six exhibited anterograde growth in the lower portion and six exhibited retrograde growth in the upper portion of the biliary tree. Surgical resection of metachronous BTCs resulted in recurrence-free survival in seven, local recurrence in five, and death in two patients. Nine achieved 5-year overall survival after primary surgery. Molecular analyses revealed that recurrently altered genes were: TP53, SMAD4, CDKN2A, ELF3, ARID1A, GNAS, NF1, STK11, RNF43, KMT2D and ERBB3. Each of these was altered in at least three cases. A comparison of the molecular features between 12 paired primary and metachronous BTCs indicated that 10 (83%) metachronous tumors developed in clonal association with corresponding primary tumors either successionally or phylogenically. The remaining two (17%) developed distinctly. The successional tumors consisted of direct or evolved primary tumor clones that spread along the bile duct. The phylogenic tumors consisted of genetically unstable clones and conferred a poor prognosis. Metachronous tumors distinct from their primaries harbored fewer mutations than successional and phylogenic tumors. In conclusion, over 80% of metachronous BTCs that develop following primary BTC resection are probably molecularly associated with their primaries in either a successional or a phylogenetic manner. Comparison between the molecular features of a metachronous tumor and those of a preceding tumor may provide effective therapeutic clues for the treatment of metachronous BTC. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

DOI： 10.1002/path.6265

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Language：English   Publishing type：Research paper (scientific journal)  

A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.

DOI： 10.1038/s41439-024-00270-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Visualization of the pancreatobiliary junction is one of the challenges faced by endoscopic ultrasonography (EUS). The water-filling technique, which allows for the observation of the ampulla at a suitable distance by injecting water into the lumen of the duodenum, was used for this purpose. However, a new gel immersion technique has recently been introduced for visualizing the gastrointestinal tract. This study investigated the effectiveness of visualizing the pancreatobiliary junction in EUS by comparing both water filling and the new gel immersion technique in identical cases. METHODS: The study ran from June to December 2021. Ten images from each technique were retrospectively compared by three independent researchers. The primary result of the study was the number of images depicting the "Pancreatic and Biliary Ducts Penetrating the Duodenal Muscularis Propria" (defined as Excellent observation) in each technique. The secondary outcome was defined as gel immersion technique's safety and impact on duodenal lumen distension. RESULTS: Ten patients used the gel immersion technique. All patients underwent the water-filling technique first, followed by gel injection after the water was completely aspirated. The average number of pictures rated as "Excellent observation," which is the primary outcome, was significantly higher with the gel immersion technique than with water filling, and no adverse events were observed. The subanalysis revealed that both convex and radial echoendoscopes are equally effective at depicting the ampulla with the gel immersion technique. CONCLUSIONS: The ability to depict the pancreatobiliary junction using the gel immersion technique is superior to that of the water-filling method, which may allow for a more detailed assessment of the ampullary region with both radial and convex echoendoscopes. This can be a useful EUS technique for diagnosing pancreaticobiliary maljunction or periampullary tumors.

DOI： 10.1007/s00464-024-10762-6

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DOI： 10.1016/j.ejcskn.2024.100025

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objectives

The role of long noncoding RNAs (lncRNAs) in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Extracellular vesicle (EV)–encapsulated RNAs could be effective targets for liquid biopsy. We aimed to identify previously unknown EV-encapsulated lncRNAs in PDAC and establish highly accurate methods for isolating EVs.

Materials and Methods

Extracellular vesicles were isolated using existing and newly developed methods, namely, PEViA-UC and PEViA-IP, from serum samples of 20 patients with PDAC, 22 patients with intraductal papillary mucinous neoplasms, and 21 healthy individuals. Extracellular vesicle lncRNA expression was analyzed using digital PCR.

Results

Gene expression analysis using cDNA microarray revealed a highly expressed lncRNA, HEVEPA, in serum EVs from patients with PDAC. We established PEViA-UC and PEViA-IP using PEViA reagent, ultracentrifugation, and immunoprecipitation. Although detection of EV-encapsulated HEVEPA using existing methods is challenging, PEViA-UC and PEViA-IP detected EV HEVEPA, which was highly expressed in patients with PDAC compared with non-PDAC patients. The detection sensitivity for discriminating PDAC from non-PDAC using the combination of HEVEPA and HULC, which are highly expressed lncRNAs in PDAC, and carbohydrate antigen 19-9 (CA19-9), was higher than that of HEVEPA, HULC, or CA19-9 alone.

Conclusions

Extracellular vesicle lncRNAs isolated using PEViA-IP and CA19-9 together could be effective targets in liquid biopsy for PDAC diagnosis.

DOI： 10.1097/mpa.0000000000002315

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.job.2024.01.007

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Multiple myeloma (MM), a neoplasm of plasma cells (PCs), is a highly heterogeneous disease with multifocal dissemination throughout the body. Minimal residual disease (MRD) detected using PCs in bone marrow (BM) is important for MM management; however, frequent invasive examinations impose a significant burden on patients. METHODS: Analysis using plasma cell-free DNA (cfDNA) might represent an alternative tool for disease monitoring. In this study, we observed the disease status in a patient with MM by examining the KRAS mutation allele frequency (MAF) in plasma cfDNA using digital PCR. RESULTS: During treatment, the MAF was correlated with serum immunoglobulin A and free light chain-kappa levels. After the second autologous peripheral blood stem cell transplantation, the KRAS MAF became immediately positive after confirming MRD negativity using PCs from BM. Shortly thereafter, the patient experienced clinical relapse primarily involving bone lesions. CONCLUSION: Mutant KRAS monitoring in cfDNA using serial blood collection might reflect the disease status more accurately than invasive BM examinations, especially in patients with MM whose primary lesions have extra-BM locations. It could also help predict treatment responses and outcomes.

DOI： 10.1016/j.cca.2023.117590

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.modpat.2023.100358

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DOI： 10.1245/s10434-023-13451-1

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide.

DOI： 10.1111/cas.15837

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.37656

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Low-grade papillary Schneiderian carcinoma (LGPSC) is a relatively new entity of the sinonasal tract and is characterized by a bland morphology simulating sinonasal papilloma, invasive growth pattern with pushing borders, and aggressive clinical behavior with multiple recurrences and metastatic potential. Recently, DEK::AFF2 fusions were identified in LGPSC. However, some LPGSCs lack DEK::AFF2 fusion, and the molecular features of these tumors have not been clarified.

Case presentation

A 69-year-old man presented with a discharge of pus from his left cheek. Computed tomography revealed a mass involving the left maxillary sinus, ethmoid sinus, and nasal cavity with the destruction of the orbital wall. The biopsy specimens showed that the tumor had a predominantly exophytic, papillary growth and did not have an apparent stromal invasion. The tumor was composed of multilayered epithelium that showed bland morphology with a round to polygonal shape, abundant eosinophilic cytoplasm, and uniform nuclei. Dense neutrophilic infiltrates were focally present. Immunohistochemically, CK5/6 was strongly and diffusely positive, and p16 was negative. p63 was mainly positive in the basal layer, and EMA was predominantly expressed in the outermost cell layer. DNA-based targeted sequencing showed TP53 R175H mutation, whereas neither EGFR nor KRAS mutation was identified. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization revealed no DEK::AFF2 fusion.

Conclusions

We describe the first case of TP53-mutant LGPSC and review the literature. LGPSC is a genetically heterogeneous entity, and the recognition of this rare entity and comprehensive assessment of clinicopathological and molecular findings are crucial for the correct pathological diagnosis and clinical management.

DOI： 10.1186/s13000-023-01334-8

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Other Link： https://link.springer.com/article/10.1186/s13000-023-01334-8/fulltext.html

Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jmoldx.2023.02.007

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00428-023-03524-7

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Other Link： https://link.springer.com/article/10.1007/s00428-023-03524-7/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Inc.  

DOI： 10.4251/wjgo.v15.i1.186

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DOI： 10.1016/j.modpat.2023.100102

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BACKGROUND: Life-threatening cytomegalovirus infection (CMVI) has been reported even in patients with malignant lymphoma (ML) who have not received hematopoietic stem cell transplantation (w/o HSCT) but had been treated with chemotherapy or radiotherapy. However, the CMVI incidence and risk factors (RFs) in patients with ML w/o HSCT have not been fully elucidated. This study aimed to evaluate the clinical aspects, including incidence and RFs, of CMVI in patients with ML w/o HSCT. METHODS: We retrospectively reviewed all patients with ML who received chemotherapy or radiotherapy in our department from 2005 to 2013. The overall survival (OS), incidence and RFs of CMVI, and other characteristics of patients with CMVI were analyzed. RESULTS: Overall, 236 patients with ML w/o HSCT were evaluated. Of these, 5.5% (13/236) developed CMVI; 54% (7/13) received steroid pretreatment before primary therapy (PT) for ML; and 62% (8/13) received > 2 therapeutic regimens for ML. The OS curve of patients with CMVI was significantly worse than that of patients without CMVI (p < 0.0001, log-rank test). A univariate analysis identified B symptoms (p = 0.00321), serum albumin < 3.5 g/dL (p = 0.0007837), C-reactive protein level > the upper limit of normal (p = 0.0006962), steroid pretreatment before PT for ML (p = 0.0004262), > 2 therapeutic regimens for ML (p = 0.0000818), T cell lymphoma (p = 0.006406), and non-complete remission (p = 0.02311) as RFs for CMVI. A multivariate analysis identified steroid pretreatment before PT for ML [odds ratio (OR): 4.71 (95% confidence interval [CI]: 1.06-21.0); p = 0.0419] and > 2 therapeutic regimens for ML [OR: 9.25 (95% CI: 2.33-36.8); p = 0.00159] as independent RFs for CMVI in patients with ML w/o HSCT. CONCLUSIONS: Attention should be paid to CMVI development in patients with ML w/o HSCT pretreated with steroids or who had multiple therapeutic regimens.

DOI： 10.1186/s12885-022-10008-5

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-022-11735-6

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Background and study aims  Recent advances in cancer treatment have involved the clinical application of immune checkpoint inhibitors (ICIs) for various type of cancers. The adverse events associated with ICIs are generally referred to as immune-related adverse events (irAEs). Gastrointestinal irAEs are a major disorder, but gastritis is not frequently observed. The aims of this study were to elucidate the clinical, endoscopic, and histological characteristics of irAE gastritis. Patients and methods  Information on patients treated with ICIs were collected from a single institute over 3 years. IrAE gastritis was identified based on the clinical course and endoscopic and histopathological findings. Of the 359 patients treated with ICIs, four cases of irAE gastritis were identified in clinical records from the endoscopy unit. The endoscopic and histopathological findings were analyzed, and further immunohistochemical studies with immune subtype markers and programmed cell death ligand-1 (PD-L1) antibody were conducted. Results  Among four patients with irAE gastritis, the remarkable endoscopic characteristics were network-pattern erosion, erythematous and edematous mucosa with thick purulent discharge, and fragile mucosa. Corresponding histological features were fibrinopurulent exudate, severe inflammatory cell infiltration, and epithalaxia, respectively. The PD-L1 expression rate was ≥ 1 % in the gastric tissue of all patients with gastritis. These patients were treated with prednisolone (PSL) and their symptoms improved within a few days to 2 weeks. Conclusions  IrAE gastritis were characterized by specific endoscopic findings. The appropriate endoscopic diagnosis may lead to effective treatment with PSL.

DOI： 10.1055/a-1839-4303

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gie.2022.02.009

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INTRODUCTION: Posttransplant lymphoproliferative disease (PTLD) is a critical complication of hematopoietic stem cell transplantation (HSCT). PTLD is classified into early and late-onset PTLDs. In post-HSCT patients, late-onset PTLD is rare, particularly PTLD after HSCT for Epstein-Barr virus (EBV)-related lymphoproliferative disease. Here, we report the case of a patient diagnosed with late-onset EBV-related hemophagocytic lymphohistiocytosis (HLH), that of PTLD, after HSCT for chronic active EBV infection (CAEBV), that of EBV related lymphoproliferative disease, probably because of EBV reactivation. PATIENT CONCERNS AND DIAGNOSIS: A 22-year-old woman with abdominal fullness visited our hospital. Blood examination showed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed slight hemophagocytosis with increased natural-killer cells (NK cells). As serum antibodies against EBV were atypical, we calculated the EBV-DNA level in peripheral blood and this level was significantly high. EBV was infected with NK cells, and EBV's monoclonality in NK cells was confirmed. Thus, the patient was diagnosed with CAEBV. INTERVENTIONS AND OUTCOMES: The patient received chemotherapy and cord blood cell transplantation (CBT); CAEBV was well controlled. Approximately 6years from CBT for CAEBV, she visited our hospital because of fever. Blood examination revealed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed hemophagocytosis with increased B and T cell counts without increased NK cell count. Additionally, serum antibody titers against EBV were atypical, and the EBV-DNA level in the peripheral blood was high. EBV was infected with only B cells, and EBV's monoclonality was confirmed. A more detailed analysis indicated that EBV-specific cytotoxic T lymphocytes were inactive. Therefore, she was diagnosed with late-onset EBV-related HLH. She received extensive treatment, but EBV-related HLH did not improve. Finally, she died about 3 weeks after diagnosis. CONCLUSION: PTLD, including HLH, is a life-threatening complication after transplantation, including HSCT. To our knowledge, this is the first case of late-onset EBV-related HLH after CBT for CAEBV. Late-onset PTLD has an indolent clinical course, but our patient's disease course was extremely aggressive. Therefore, late-onset EBV-related PTLD may be life-threatening.

DOI： 10.1097/MD.0000000000029055

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The profile of the human small intestinal microbiota remains to be uncovered primarily due to sampling difficulties. Ileostomy provides the intestinal luminal contents as ileostomy effluents (IE) that offer opportunity for performing extensive analyses of nutrients, gastrointestinal fluids, metabolites, and microbiome. In the present study, we evaluated changes in the microbiome, pH, and bacterial short-chain fatty acids (SCFAs) in IE obtained from patients who had undergone ileostomy following surgical resection of colon cancer and inflammatory bowel disease (IBD). We enrolled 11 patients who varied in the duration of ileostomy from 3 days to >5 years after surgery and had no inflammation in the small intestine. The analyses suggested that IE from patients previously having IBD had less diversity and greater intraday and interday fluctuations, and increased pH and decreased levels of propionic acid and acetic acid than those in IE from patients previously having cancer. Furthermore, correlation analysis suggested a possible effect of the intestinal microbiome on luminal pH, presumably via SCFA production. The present study suggested that inflammation in the colon may induce long-term dysbiosis in the small intestine even after removal of diseased parts of the colon. Moreover, pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) was found to have beneficial effects on postoperative bowel dysfunction and the human small intestinal microbiota. Taken together, these results suggest the necessity of a direct remedy for dysbiosis and the treatment of gastrointestinal lesions to achieve favorable outcomes for chronic gastrointestinal disorders.

DOI： 10.1016/j.gene.2022.146266

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The RNA exosome is a multi-subunit ribonuclease complex that is evolutionally conserved and the major cellular machinery for the surveillance, processing, degradation, and turnover of diverse RNAs essential for cell viability. Here we performed integrated genomic and clinicopathological analyses of 27 RNA exosome components across 32 tumor types using The Cancer Genome Atlas PanCancer Atlas Studies' datasets. We discovered that the EXOSC4 gene, which encodes a barrel component of the RNA exosome, was amplified across multiple cancer types. We further found that EXOSC4 alteration is associated with a poor prognosis of pancreatic cancer patients. Moreover, we demonstrated that EXOSC4 is required for the survival of pancreatic cancer cells. EXOSC4 also repressed BIK expression and destabilized SESN2 mRNA by promoting its degradation. Furthermore, knockdown of BIK and SESN2 could partially rescue pancreatic cells from the reduction in cell viability caused by EXOSC4 knockdown. Our study provides evidence for EXOSC4-mediated regulation of BIK and SESN2 mRNA in the survival of pancreatic tumor cells.

DOI： 10.3390/ijms23010496

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BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

DOI： 10.1002/cam4.4461

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Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC.

DOI： 10.3389/fonc.2022.988527

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort. Computed tomography imaging and esophagogastroduodenoscopy revealed ulcerated tumors at the EGJ. Endoscopic biopsy revealed small tumor cells with a high nuclear/cytoplasmic ratio, suggesting small-cell NEC. Immunohistochemistry (IHC) analysis showed tumor cells with an MIB-1 index of 80%. The patient achieved complete response after 10 cycles of chemotherapy. Follow-up endoscopic examination revealed small red-colored mucosal lesions in the center of the cicatrized primary lesion. Re-biopsy detected cancer cells harboring large eosinophilic cytoplasm with keratinization and no evidence of NEC components. IHC of the cells were cytokeratin 5/6-positive and p53-negative. The tumor persisted without evidence of metastases after chemoradiotherapy, and total gastrectomy with lymph node dissection was performed. Pathological assessment of the resected specimens revealed SCC, without evidence of NEC. The patient survived without a recurrence for &amp;gt;3 years after the initial presentation. Somatic mutation profiles of the primary NEC and recurrent SCC were analyzed by targeted amplicon sequencing covering common cancer-related mutations. Both tumors possessed <italic>TP53</italic> Q192X mutation, whereas <italic>SMAD4</italic> S517T was found only in SCC, suggesting that both tumor components originated from a founder clone with a stop-gain mutation in <italic>TP53</italic>. The somatic mutation profile of the tumors indicated that that loss of heterozygosity (LOH) at the <italic>TP53</italic> gene might have occurred during the differentiation of the founder clone into NEC, while a <italic>SMAD4</italic> mutation might have contributed to SCC development, indicating branching and subclonal evolution from common founder clone to both NEC and SCC. The mutation assessments provided valuable information to better understand the clonal evolution of metachronous cancers.

DOI： 10.3389/fgene.2021.608324

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本膵臓学会  

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本膵臓学会  

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BACKGROUND/OBJECTIVES: Decrease in skeletal muscle mass and function is associated with a poor prognosis following surgical resection of pancreatic ductal adenocarcinomas (PDAs). This study evaluated whether skeletal muscle mass decrease affects PDA outcomes. METHODS: Data of 112 patients with advanced and unresectable PDA who underwent chemotherapy in a single institution were retrospectively analyzed. Information on age, sex, hematological investigations, including systemic inflammation-based markers and nutritional assessment biomarkers, and imaging parameters of skeletal muscle mass and visceral adipose tissue were retrieved from the patients' medical records. The efficiency of the Cox, Weibull, and standardized exponential models were compared using hazard ratios and the Akaike Information Criterion (AIC). RESULTS: Results from the Weibull, Cox, and standardized exponential model analyses indicated that low skeletal muscle mass, Eastern Cooperative Oncology Group performance status (PS), and the requirement of biliary drainage were associated with the highest risk of death, followed by carcinoembryonic antigen (CEA) levels and the presence of ascites. The AIC value from the four significant parameters was lowest for the Weibull-exponential distribution (222.3) than that of the Cox (653.7) and standardized exponential models (265.7). We developed a model for estimating the 1-year survival probability using the Weibull-exponential distribution. CONCLUSIONS: Low-skeletal muscle index, PS, requirement of biliary drainage, CEA levels, and presence of ascites are independent factors for predicting poor patient survival after chemotherapy. Improved survival modeling using a parametric approach may accurately predict the outcome of patients with advanced-stage PDA.

DOI： 10.1016/j.pan.2021.03.002

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The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC-CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS- or HRAS/Myc-induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte-derived liver tumors were induced in heterozygous and homozygous p53-knockout (KO) mice by hydrodynamic tail vein injection of HRAS- or Myc-containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase-expressing plasmid. The HRAS-induced and HRAS/Myc-induced tumors in the wild-type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53-KO mice was consistent with cHCC-CCA. The expression of fetal/neonatal liver proteins, including delta-like 1, was detected in the HRAS/Myc-induced but not in the HRAS-induced cHCC-CCA tissues. The dedifferentiation in the HRAS/Myc-induced tumors was more marked in the homozygous p53-KO mice than in the heterozygous p53-KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte-derived tumor cells through either transdifferentiation or Myc-mediated dedifferentiation.

DOI： 10.1111/cas.14996

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INTRODUCTION: Neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NAC/NACRT) for resectable/borderline resectable pancreatic cancers was recently performed to improve clinical outcomes and led to good results, although it remains controversial whether NAC/NACRT is beneficial for resectable pancreatic cancer. A few recent studies revealed longer patency and lower cost related to the stent occlusion of a metal stent than those of a plastic stent during NAC/NACRT. It also remains controversial which type of self-expandable metal stent (SEMS) is the most suitable for patients with resectable/borderline resectable pancreatic cancer during NAC/NACRT: an uncovered SEMS (USEMS), a fully covered SEMS (FCSEMS) or a partially covered SEMS (PCSEMS). So far, two randomised controlled trials indicated that a USEMS and an FCSEMS were similar in preoperative stent dysfunction and adverse event rate. Thus, we aimed to verify the non-inferiority of a PCSEMS to a USEMS in this multicentre randomised controlled trial. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial, for which we will recruit 100 patients with resectable/borderline resectable pancreatic cancer and distal biliary obstruction scheduled for NAC/NACRT from 13 high-volume institutions. Patients will be randomly allocated to the PCSEMS group or USEMS group. The primary outcome measure is the preoperative biliary event rate. Data will be analysed after completion of the study. We will calculate the 95% CIs of the incidence of preoperative biliary events in each group and analyse whether the difference between them is within the non-inferiority margin (10%). ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of Hokkaido University Hospital. The results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000041737; jRCT1012200002.

DOI： 10.1136/bmjopen-2020-045698

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Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein-Barr virus (EBV) and microsatellite-unstable tumors are considered to be the two major subtypes as they are clearly defined by well-established methodologies, such as in situ hybridization and polymerase chain reaction-based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re-evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low- and high-grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re-evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV-positive (11.1%), 7 MSI-high (MSI-H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI-H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death-ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI-H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV-positive carcinomas were poorly differentiated (83.8%), and MSI-H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV-positive subtype presented with high-grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

DOI： 10.1002/cjp2.209

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Pancreatic cancer currently has no subtypes that inform clinical decisions; hence, there exists an opportunity to rearrange the morphological and molecular taxonomy that guides a better understanding of tumor characteristics. Nonetheless, accumulating studies to date have revealed the large-duct type variant, a unique subtype of pancreatic ductal adenocarcinoma (PDA) with cystic features. This subtype often radiographically mimics intraductal papillary mucinous neoplasms (IPMNs) and involves multiple small cysts occasionally associated with solid masses. The "bunch-of-grapes" sign, an imaging characteristic of IPMNs, is absent in large-duct PDA. Large-duct PDA defines the mucin profile, and genetic alterations are useful in distinguishing large-duct PDA from IPMNs. Histologically, neoplastic ducts measure over 0.5 mm, forming large ductal elements. Similar to classic PDAs, this subtype is frequently accompanied by perineural invasion and abundant desmoplastic reactions, and KRAS mutations in codon 12 are nearly ubiquitous. Despite such morphological similarities with IPMNs, the prognosis of large-duct PDA is equivalent to that of classic PDA. Differential diagnosis is therefore essential.

DOI： 10.3748/wjg.v27.i23.3262

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BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is categorized into four distinct types: the gastric, intestinal, pancreatobiliary, and oncocytic. Each type is associated with specific clinicopathological features. We aimed to uncover the molecular mechanisms underlying the development of these types of IPMN. METHODS: We obtained 103 lesions of various types, including 49 gastric, 26 intestinal, 22 pancreatobiliary, and 6 oncocytic lesions, from 43 IPMNs, including 36 with multiple types. Comparative analysis was performed by targeted sequencing of 37 genes in different lesion types within each pancreas. RESULTS: Gastric-type low-grade lesions were observed in all 36 tumors with multiple types, with 245 mutations identified across all samples. The average number of mutations was significantly different between different lesion grades and types: 1.88 for low-grade lesions, 2.77 for high-grade lesions, and 2.38 for invasive lesions (p = 0.0067); and 1.96 for gastric-type lesion, 2.92 for intestinal-type lesion, 2.73 for pancreatobiliary-type lesion, and 2.17 for oncocytic-type lesion (p = 0.0163). Tracing of mutations between lesions containing multiple types in the same pancreas suggested three developmental pathways, denoted as "progressive", "divergent", and "independent". The progressive and divergent pathways indicate an ancestral lesion that was mostly gastric-type and low-grade may progress or diversify into lesions of other types and/or higher grades. The independent pathway suggests that some high-grade lesions of any type may develop independently. CONCLUSION: These findings suggest that gastric-type low-grade lesions have a risk of progression into high-grade lesions of other types. Therefore, low-grade gastric-type IPMNs should be under constant surveillance.

DOI： 10.1007/s00535-021-01783-2

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Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.

DOI： 10.1111/cas.14879

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Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

DOI： 10.3892/ol.2021.12681

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DOI： 10.1053/j.gastro.2021.04.049

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INTRODUCTION: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD. HISTORY: A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled. CONCLUSION: It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.

DOI： 10.1097/MD.0000000000025518

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An 83-year-old man without specific symptoms was referred to our hospital for further evaluation and treatment of apparent double primary tumors of the cystic duct and common bile duct. Computed tomography showed contrast-enhanced solid tumors in the cystic duct and common bile duct. Magnetic resonance imaging showed that the bile duct tumor was isointense on T1-weighted images and had low intensity on T2-weighted images. In addition, the bile duct tumor showed high intensity on diffusion-weighted images. Endoscopic ultrasonography revealed the tumor of the common bile duct and endoscopic retrograde cholangiopancreatography demonstrated a filling defect in the bile duct. The cystic duct was not identified on endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography. Transpapillary biopsy of the bile duct tumor showed adenocarcinoma. The patient was diagnosed with double primary tumors of the cystic duct and the common bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy. Microscopic examination with molecular profiling of the tumors revealed a high-grade noninvasive intracholecystic papillary neoplasm of the cystic duct extending into the common bile duct and forming a tubulopapillary neoplasm with invasion of the common bile duct.

DOI： 10.1007/s12328-020-01311-4

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BACKGROUND: We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS: We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS: Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS: The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS: Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

DOI： 10.1007/s10620-020-06747-9

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Myeloid sarcoma (MS), which involves extramedullary lesions, is classified as a unique subtype of acute myeloid leukemia (AML). At present, no standard treatments for MS have been established. The patient was an 89-year-old man with myelodysplastic syndrome-excess blast-2 (MDS-EB-2) with a 2-year history of intermittent treatment with azacitidine (AZA) during a 4-year history of MDS. He developed painful cutaneous tumors 8 months after the second discontinuation of AZA. They were refractory for antibiotics and topical tacrolimus hydrate. A tumor biopsy was performed, and the histological findings of the tumor lesion showed a proliferation of tumor cells that were positive for myeloperoxidase and CD68 and negative for CD4 and CD123. The patient was diagnosed with MDS-associated MS. MDS-EB-2 quickly progressed to AML with the appearance of peripheral blood blasts and 25% bone marrow blasts. Monotherapy with reduced-dose AZA (37.5 mg/m2 for 7 days, every 4-6 weeks) was restarted, and the MS quickly disappeared. The patient's MS was successfully treated with 16 cycles of AZA treatment over a 22-month period. There have been 10 reported cases in which MS was successfully treated with AZA. Among the 10 cases, the patient in the present case was the oldest. Treatment with reduced-dose AZA should be considered as a therapeutic option for MS in elderly patients with MDS, especially patients who are ineligible for intensive chemotherapy.

DOI： 10.1155/2021/6640597

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Non-coding RNAs (ncRNAs), or RNA molecules that do not code for proteins, are generally categorized as either small or long ncRNA (lncRNA) and are involved in the pathogenesis of several diseases including many cancers. Identification of a large number of ncRNAs could help to elucidate previously unknown mechanisms in phenotype regulation. Some ncRNAs are encapsulated by extracellular vesicles (EVs) and transferred to recipient cells to regulate cellular processes, including epigenetic and post-transcriptional regulations. Recent studies have uncovered novel molecular mechanisms and functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC), one of the most intractable cancers that is highly invasive and metastatic. As the epithelial-mesenchymal transition (EMT) triggers tumor cell invasion and migration, clarification of the roles of lncRNA in EMT and tumor cell stemness would be critical for improving diagnostic and therapeutic approaches in metastatic cancers. This review provides an overview of relevant studies on lncRNA and its involvement with EMT in PDAC. Emerging knowledge offers evidence for the dysregulated expression of lncRNAs and essential insights into the potential contribution of both lncRNAs and EVs in the pathogenesis of PDAC. Future directions and new clinical applications for PDAC are also discussed.

DOI： 10.3389/fmolb.2021.717890

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Background: Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas that mainly occurs in children and involves abnormalities in the WNT/β-catenin pathway, such as CTNNB1 mutation. However, the molecular abnormalities in adult pancreatoblastoma are not well known. Case Presentation: An elderly man, who underwent elective distal pancreatectomy and splenectomy, was referred to our hospital with a mass in the tail of the pancreas. Histologically, the lesion revealed proliferation of clear, basophilic, and cartilaginous tumor cells with lymphatic metastasis. Each of the morphologically distinct tumor components showed different immunohistochemical patterns, indicating heterogeneous differentiation, including epithelial (both acinar and ductal), mesenchymal, and neuroendocrine differentiation. All tumor components showed nuclear expression of β-catenin and cyclin D1. Per next-generation sequencing (NGS), the clear and basophilic tumor cells shared mutations in APC, GRM8, LAMP1, and AKA9. Among the mutations, APC, c.1816_1817insA showed the highest frequency in both cell types, indicating that APC mutation was a driver mutation of the tumor. A diagnosis of PB was rendered. Summary: In conclusion, the clear and basophilic cells of the tumor were supposedly derived from the same clone and subsequently acquired additional mutations. This is the first report of clonal evolution in pancreatoblastoma.

DOI： 10.3389/fonc.2021.725290

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© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Introduction: Familial adenomatous polyposis (FAP) is typically characterized by more than hundred adenomatous polyps in the colorectum, caused by germline APC mutation. A small proportion of the polyps progress to colorectal adenocarcinoma via adenoma-carcinoma sequence. Serrated lesions and polyps, characterized by a serrated architecture of the epithelium, are noted for two types of genetic pathways in colorectal carcinogenesis. BRAF and KRAS mutations are observed in the serrated pathway. Case Report: We report a young FAP patient with rectal serrated adenomas that were removed by colonoscopic procedures. The histological features with villiform projections and slit-like serration indicated traditional serrated adenoma. A genetic examination with next-generation sequencing showed a somatic BRAF mutation in the serrated adenoma and APC mutations in the tubular adenomas. His germline mutation was found at APC p.Q1928fs*. Conclusion: Serrated adenomas with dual genetic alterations in a FAP patient may be associated with colorectal carcinogenesis and should be considered a target lesion for treatment. The present study demonstrated the malignant potential of serrated adenoma in a FAP patient.

DOI： 10.1007/s00384-020-03657-0

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© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. Background: Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients. Methods: We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer. Results: Germline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged—based on a database search—to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis. Conclusion: The colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.

DOI： 10.1002/mgg3.1348

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Language：Japanese   Publisher：(一社)日本膵臓学会  

膵癌のゲノム解析では,4つの遺伝子異常(KRAS,CDKN2A,TP53,SMAD4変異)を高率に認める.最近の研究により,ゲノム,遺伝子発現,タンパク,代謝などの様々なレベルでの異常が明らかとなり,これらのプロファイリングによる個々の患者の発癌や進行パターン,治療効果予測に応用されることが期待される.2019年に適切な薬物治療の提供を目的とした遺伝子パネル検査が保険収載され,本格的なゲノム医療の時代を迎えた.このような新しい診断技術を早期膵癌の発見や遺伝素因など高い発癌リスクを有する人々の発病予防を目指した医療へと拡大するには,多様な分子異常の検出方法の確立が求められる.これら膵癌の分子診断には,膵内の多発病変の存在と腫瘍内の不均一性,癌のクローン進化の理解が重要となる.本稿では,膵癌の発生過程でみられる分子異常を概説し,診療への活用が期待される最新の技術革新について紹介する.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02025&link_issn=&doc_id=20200907320008&doc_link_id=%2Fcq0pancr%2F2020%2F003504%2F009%2F0302-0312%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcq0pancr%2F2020%2F003504%2F009%2F0302-0312%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

It is challenging to secure a cytopathologic diagnosis using minute amounts of tumor fluids and tissue fragments. Hence, we developed a rapid, accurate, low-cost method for detecting tumor cell-derived DNA from limited amounts of specimens and samples with a low tumor cellularity, to detect KRAS mutations in pancreatic ductal carcinomas (PDA) using digital PCR (dPCR). The core invention is based on the suspension of tumor samples in pure water, which causes an osmotic burst; the crude suspension could be directly subjected to emulsion PCR in the platform. We examined the feasibility of this process using needle aspirates from surgically resected pancreatic tumor specimens (n = 12). We successfully amplified and detected mutant KRAS in 11 of 12 tumor samples harboring the mutation; the positive mutation frequency was as low as 0.8%. We used residual specimens from fine-needle aspiration/biopsy and needle flush processes (n = 10) for method validation. In 9 of 10 oncogenic KRAS pancreatic tumor samples, the "water-burst" method resulted in a positive mutation call. We describe a dPCR-based, super-sensitive screening protocol for determining KRAS mutation availability using tiny needle aspirates from PDAs processed using simple steps. This method might enable pathologists to secure a more accurate, minimally invasive diagnosis using minute tissue fragments.

DOI： 10.1038/s41598-020-69221-6

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Other Link： http://www.nature.com/articles/s41598-020-69221-6

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DOI： 10.1101/gad.335166.119

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Intestinal-type intraductal papillary mucinous neoplasm (IPMN) of the pancreas is clinicopathologically distinctive. Our research aimed to elucidate the molecular mechanism of the development and progression of the intestinal-type IPMN. In 60 intestinal-type IPMN specimens, histological transitions from gastric-type epithelia to intestinal-type epithelia were observed in 48 cases (80%). CDX2/MUC2/alcian blue triple staining indicated that CDX2 appeared to precede MUC2 expression and subsequent alcian blue-positive mucin production. Expression of p21 and Ki-67 seemed to be accelerated by CDX2 expression (p = 6.02e-13 and p = 3.1e-09, respectively). p21/Ki-67 double staining revealed that p21 was mostly expressed in differentiated cells in the apex of papillae, while Ki-67 was expressed in proliferative cells in the base of papillae. This clear cellular arrangement seemed to break down with the progression of atypical grade and development of invasion (p = 0.00197). Intestinal-type IPMNs harbored frequent GNAS mutations (100%, 25/25) and RNF43 mutations (57%, 8/14) and shared identical GNAS and KRAS mutations with concurrent gastric-type IPMNs or incipient gastric-type neoplasia (100%, 25/25). RNF43 mutations showed emerging or being selected in intestinal-type neoplasms along with ß-catenin aberration. Activation of protein kinase A and extracellular-regulated kinase was observed in CDX2-positive intestinal-type neoplasm. These results suggest that gastric-type epithelia that acquire GNAS mutations together with induction of intrinsic CDX2 expression may evolve with clonal selection and additional molecular aberrations including RNF43 and ß-catenin into intestinal-type IPMNs, which may further progress with complex villous growth due to disoriented cell cycle regulation, acceleration of atypical grade, and advance to show an invasive phenotype.

DOI： 10.1007/s00428-020-02806-8

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fonc.2020.00728

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Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands and the type 2 IPNBs consist of complex branching glands, seldom with foci of solid-tubular components. However, clinicopathological and molecular characteristics of these types of IPNBs are yet to be identified. We aimed to uncover clinicopathological and molecular characteristics of the types of IPNBs. Thirty-six IPNBs were studied retrospectively. Clinicopathological features as well as molecular alterations of 31 genes were evaluated by means of targeted next-generation sequencing and immunohistochemical examination of expression of mucin and cancer-associated molecules. The 36 IPNBs were classified into 22 of type 1 and 14 of type 2. The type 1 IPNBs were associated with a non-invasive phenotype, intestinal and oncocytic subtypes, development in the intrahepatic bile duct, overt mucin production, and a relatively good prognosis. The type 2 IPNBs were associated with an invasive phenotype, the pancreatobiliary subtype, development within the extrahepatic bile duct, and worse prognosis compared with the type 1 IPNBs. In the molecular analysis, recurrent mutations were found in TP53 (34.3%), KRAS (31.4%), STK11 (25.7%), CTNNB1 (17.1%), APC (14.3%), SMAD4 (14.3%), GNAS (11.4%), PBRM1 (11.4%), ELF3 (8.6%), KMT2C (8.6%), NF1 (8.6%), PIK3CA (8.6%), ARID1A (5.7%), ARID2 (5.7%), BAP1 (5.7%), BRAF (5.7%), EPHA6 (5.7%), ERBB2 (5.7%), ERBB3 (5.7%), KMT2D (5.7%), and RNF43 (5.7%). Mutations in KRAS and GNAS were enriched in the type 1 IPNBs, whereas mutations in TP53, SMAD4, and KMT2C were enriched in the type 2 IPNBs. These results indicate that IPNBs consist of two distinct types of neoplasms specifically associated with clinicopathological features and molecular phenotypes. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.5398

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/MD.0000000000020564

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Authorship：Corresponding author   Language：English  

Background and study aims  Needle tract seeding during endoscopic ultrasound fine-needle biopsy (EUS-FNB) remains a concern. We investigated whether such seeding occurred in a patient with pancreatic ductal adenocarcinoma (PDA). Patient and methods  Surgically resected and EUS-FNB-derived specimens were genotyped to determine if a gastric wall tumor that emerged 3 years after curative resection of an early-stage PDA was clonally related to the original tumor. Results  The gastric tumor histologically resembled the primary PDA; the lesions also shared KRAS , SMAD4 , and RNF43 mutations. Genotyping of the preoperative EUS-FNB specimen, in which cancer was not detected, nevertheless revealed mutations that were identical to those in the resected primary and recurrent tumors. While the primary PDA had a low frequency of mutant SMAD4 , such mutations were highly prevalent in both the EUS-FNB and recurrent tumor specimens. Conclusions  The genetic lineages of sampled tissues from our patient revealed that needle tract seeding may have incidentally occurred when a subset of neoplastic cells within a heterogeneous tumor ( i. e. , an aggressive clone) was targeted during EUS-FNB.

DOI： 10.1055/a-1034-7700

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Background: Immuno-oncology is a novel target of cancer therapy. Nivolumab is a monoclonal anti-programed death-1 antibody recently used to treat patients with chemotherapy-resistant gastric and gastroesophageal cancer. Although the disease control rate is reported to be very high, few cases demonstrate a complete response. Case Presentation: A 25-year-old man diagnosed with gastroesophageal cancer was treated with chemotherapy followed by surgical resection. Pathological diagnosis was poorly differentiated adenocarcinoma with distant lymph node metastasis. Residual lymph node metastasis was treated with nivolumab monotherapy, resulting in complete disappearance. No recurrence has been observed for 2 years since discontinuation of nivolumab. This rare case was additionally subjected to pathological and genetic analysis, suggesting that a high tumor mutation burden (10.7 mutations/Mb) might be associated with sensitivity to nivolumab. Summary: We reported a case of advanced gastroesophageal junction cancer with distal lymph node metastasis that was successfully treated with chemotherapy, surgical resection, and nivolumab therapy. An aggressive search for biomarkers implying benefit effects of nivolumab should be performed.

DOI： 10.3389/fonc.2019.01375

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Objectives: Isolated superior mesenteric arterial dissection (ISMAD) is an uncommon type of arterial dissection and treated with surgery, stenting, or conservative management. This study aimed to evaluate the criteria for conservative therapy for ISMAD patients based on imaging findings. Methods: Eighteen consecutive ISMAD patients without peritoneal irritation at onset were retrospectively studied. The decision to perform stenting was based on the emergence of peritoneal irritation, aneurysm, or mesenteric ischemia. Clinical manifestations, follow-up contrast-enhanced computed tomography (CECT) findings, and patient outcome were evaluated. Results: Most patients (16, 89%) were successfully treated conservatively; two patients (11%) required endovascular stenting because of an aneurysm or ulcer-like projection (ULP) sign. The median duration of fasting and hospital stays was 3 (range, 1-8) and 9 (range, 4-34) days, respectively. On CECT, the median distance from the superior mesenteric artery (SMA) origin to the entry site was 12 mm (range, 5-35 mm), and the median length of dissection was 87.5 mm (range, 20-150 mm). Among 16 patients treated conservatively, serial imaging was obtained in 11 patients (69%), and disappearance of the dissection within 4 months occurred in five patients. Two patients treated with endovascular stent underwent follow-up CECT 1 year after onset, and there were no complications. Conclusions: ISMAD patients without peritoneal irritation can be treated conservatively if there are no signs of an aneurysm, ULP, or mesenteric ischemia. When an aneurysm or ULP sign exists, endovascular stenting was able to preserve SMA blood flow with the improvement of the dissection.

DOI： 10.1016/j.ejro.2019.05.004

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Background: Autofluorescence imaging (AFI) is useful for diagnosing colon neoplasms, but what affects the AFI intensity remains unclear. This study investigated the association between AFI and the histological characteristics, aberrant methylation status, and aberrant expression in colon neoplasms. Methods: Fifty-three patients with colorectal neoplasms who underwent AFI were enrolled. The AFI intensity (F index) was compared with the pathological findings and gene alterations. The F index was calculated using an image analysis software program. The pathological findings were assessed by the tumor crypt density, cell densities, and N/C ratio. The aberrant methylation of p16, E-cadherin, Apc, Runx3, and hMLH1 genes was determined by a methylation-specific polymerase chain reaction. The aberrant expression of p53 and Ki-67 was evaluated by immunohistochemical staining. Results: An increased N/C ratio, the aberrant expression of p53, Ki-67, and the altered methylation of p16 went together with a lower F index. The other pathological findings and the methylation status showed no association with the F index. Conclusions: AFI reflects the nuclear enlargement of tumor cells, the cell proliferation ability, and the altered status of cell proliferation-related genes, indicating that AFI is a useful and practical method for predicting the dysplastic grade of tumor cells and cell proliferation.

DOI： 10.3390/molecules24061106

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

DOI： 10.1007/s12029-018-0078-3

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© 2019 National Academy of Sciences. All rights reserved. Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5′-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5′- terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4Edependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.

DOI： 10.1073/pnas.1901765116

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Gastric hyperplastic polyps are common and generally regarded as benign lesions, whereas gastric adenocarcinomas infrequently occur from gastric hyperplastic polyps. Although gastric hyperplastic polyps have received a lot of attention because of their association with malignant transformation, it remains unclear whether gastric hyperplastic polyps are neoplastic lesions that have sporadic genetic changes similar to colorectal hyperplastic polyps. We performed genome-wide analyses of two gastric adenocarcinomas with hyperplastic polyp components. The interface between "adenocarcinoma" and "hyperplastic polyp" components was fairly sharp, and the adenocarcinoma components had copy number alterations and TP53 mutations, whereas the hyperplastic polyp components had only single nucleotide polymorphisms, which were also found in adenocarcinoma components. We did not detect any somatic changes in the hyperplastic polyp components, even in genome-wide analyses, which was in contrast to the adenocarcinoma components. However, due to the small number of cases examined herein, further genetic analyses of more cases are needed.

DOI： 10.1007/s00428-019-02592-y

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BACKGROUND: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. AIMS: To reveal the incidence of VTE in IBD patients in Japan. METHODS: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1-2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. RESULTS: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. CONCLUSION: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD.

DOI： 10.1159/000495289

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background  Despite advances in the diagnosis of pancreatic ductal adenocarcinoma (PDA), histological evaluation of small and poorly defined masses in the pancreas is uncomfortable and unsafe. Methods  We herein report a case of early stage PDA, in which multiple KRAS mutations were detected in the pancreatic juice preoperatively. A small hypoechoic area adjacent to the portal vein was detected through endoscopic ultrasound in the pancreatic body. KRAS mutations were evaluated using plasma, and the pancreatic juice by digital PCR. Results  Pancreatic duct biopsy and pancreatic juice cytology were performed with no evidence of malignancy; however, KRAS mutations, KRAS G12V and G12D, were detected in the pancreatic juice. Histological assessment of the resected specimen demonstrated a solid tumor with desmoplastic reaction accompanied by carcinoma in situ in the main pancreatic duct where KRAS G12V mutation was identified. More detailed analysis demonstrated KRAS G12D mutation in the cluster of low grade pancreatic intraepithelial neoplasia, implying that the lesion developed independently. Conclusions  Our study indicates the potential of "endoscopic liquid biopsy" to capture the driver gene for PDA diagnosis.

DOI： 10.1055/a-0721-1747

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KOREAN ASSOC STUDY INTESTINAL DISEASES  

Background/Aims: Venous thromboembolism (VTE) is a major extraintestinal manifestation in inflammatory bowel disease (IBD), regarded as an independent risk factor for VTE according to reports from Western countries. However, the incidence and risk factors of VTE in Asian IBD patients are not fully understood. We aimed to reveal the incidence and risk factors of VTE in Japanese IBD inpatients. Methods: The incidence of VTE in inpatients with IBD (n=340), gastrointestinal cancers (n=557), and other gastrointestinal diseases (n=569) treated at our hospital from 2009 to 2013 was retrospectively investigated. The characteristics and laboratory data of IBD inpatients with and without VTE were compared in univariate and multivariate analyses. Clinical courses of VTE in IBD were surveyed. Results: VTE was detected in 7.1% of IBD inpatients, significantly higher than in gastrointestinal cancer inpatients (2.5%) and inpatients with other gastrointestinal diseases (0.88%). The incidence of VTE in ulcerative colitis (UC) patients (16.7%) was much higher than that in those with Crohn's disease (3.6%). In the univariate analysis, the risk factors were an older age, central venous catheter, prednisolone, surgery, low serum albumin, high serum C-reactive protein and D-dimer. According to a multivariate analysis, >50 years of age and surgery were the only risk factors. The in-hospital mortality rate of IBD inpatients with VTE was 4.2%. Conclusions: The incidence of VTE with IBD, especially UC, was found to be high compared with other digestive disease, which was almost equivalent to that of Western countries. The efficacy of prophylaxis needs to be investigated in Asian IBD patients.

DOI： 10.5217/ir.2018.16.3.416

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Takayasu's arteritis (TA) is a large-vessel vasculitis pathologically characterized by granulomatous necrotizing vasculitis with giant cells. Although the cause of TA is still unclear, genetic factors as well as immunological abnormalities, particularly the overactivation of Th1 and Th-17, are considered to play important roles in the pathogenesis of this disease. Eosinophilic gastroenteritis (EGE) is a type of refractory inflammation in which numerous eosinophils infiltrate the inflammatory area. It is known that the overactivation of Th2 is associated with the pathogenesis of EGE, although the cause of EGE is still unclear. The immunological abnormalities in TA are therefore thought to be different from those in EGE. To date, no cases of complication of TA and EGE have been reported. Case presentations: An 18 year-old female was diagnosed with EGE and treated with prednisolone. At 6 months after completion of the treatment, the patient experienced chest pain, and was diagnosed with TA. TH1 and TH17 immunity are thought to be involved with TA, while TH2 are considered to be involved with EGE. In this case, the expression of IL-17 mRNA in the colon mucosa greatly decreased after prednisolone treatment for EGE. Conclusions: This is the first report of TA complicated with EGE, and the overactivation of TH17 is considered to be associated with the pathogenesis of these two diseases.

DOI： 10.1186/s13099-018-0251-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. Methods: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls
n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. Results: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p &lt
0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5-20% superior to those of three serum bulky circulating miRs (e.g.
ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). Conclusions: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).

DOI： 10.1186/s12885-018-4006-5

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BACKGROUND: On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC. However, feasible protocol for the simultaneous detection of multiple secondary ALK mutations using droplet digital PCR (ddPCR) has not been developed. An efficient strategy using cfDNA in cancer diagnostics, the development of more accurate and cost-effective tools to identify informative multiple secondary ALK mutations is clinically required. METHODS: To establish a feasible assay to monitor ALK-TKI resistance mutations, we first evaluated the feasibility of ddPCR-based screening for cfDNA mutation detection of 10 distinct secondary ALK mutations. Positive samples were then re-analyzed using mutation-specific probes to track the growth of mutation clones with a high sensitivity. RESULTS: Blood samples from seven ALK-positive patients were analyzed using the ddPCR protocol. Secondary G1202R ALK mutations were identified in 2 of 7 patients by the screening assay. Using the mutation-specific probes, monitoring the resistant clone during the clinical course of the disease was well demonstrated in each of the patients. CONCLUSION: The protocol for ddPCR-based liquid biopsy has a feasibility for the screening of secondary ALK-TKI resistance mutations and offers a tool for a cost-effective monitoring of progression in NSCLC.

DOI： 10.1186/s12885-018-5031-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Genetic alterations responsible for the initiation of cancer may serve as immediate biomarkers for early diagnosis. Plasma levels of cell-free DNA (cfDNA) in patients with cancer are higher than those in healthy individuals; however, the major technical challenge for the widespread implementation of cfDNA genotyping as a diagnostic tool is the insufficient sensitivity and specificity of detecting early-stage tumors that shed low amounts of cfDNA. To establish a protocol for ultrasensitive droplet digital polymerase chain reaction (ddPCR) for quantification of low-frequency alleles within a limited cfDNA pool, two-step multiplex ddPCR targeting eight clinically relevant mutant KRAS variants was examined. Plasma samples from patients with colorectal (n = 10) and pancreatic cancer (n = 9) were evaluated, and cfDNA from healthy volunteers (n = 50) was utilized to calculate reference intervals. Limited cfDNA yields in patients with resectable colorectal and pancreatic cancers did not meet the requirement for efficient capture and quantification of rate mutant alleles by ddPCR. Eight pream-plification cycles followed by a second-run ddPCR were sufficient to obtain approximately 5000-10 000 amplified copies per ng of cfDNA, resolving the subsampling issue. Furthermore, the signal-to-noise ratio for rare mutant alleles against the extensive background presented by the wild-type allele was significantly enhanced. The cutoff limit of reference intervals for mutant KRAS was determined to be similar to 0.09% based on samples from healthy individuals. The modification introduced in the ddPCR protocol facilitated the quantification of low-copy alleles carrying driver mutations, such as oncogenic KRAS, in localized and early-stage cancers using small blood volumes, thus offering a minimally invasive modality for timely diagnosis.

DOI： 10.1002/1878-0261.12110

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: Pancreatic involvement of angiosarcoma is extremely rare.
Methods: We herein report a rare case of angiosarcoma associated with chronic lymphedema (Stewart-Treves syndrome) with pancreatic metastasis that was diagnosed using endoscopic ultrasound (EUS)/fine needle aspiration (FNA).
Results: A 43-year-old woman with a history of radical hysterectomy with bilateral inguinal lymphadenectomy and chemoradiotherapy for cervical cancer 15 years prior noticed the presence of erythematous indurative plaques on her right femoral region, where chronic lymphedema had developed. Contrast-enhanced computed tomography (CT) revealed not only multiple nodules in the subcutaneous tissue of the right femoral region but also a 25mm x 20mm solid mass in the region of the pancreatic tail. A histological analysis of the specimens obtained using EUS/FNA revealed angiosarcoma that was immunohistochemically positive for platelet/endothelial cell adhesion molecule-1 but negative for cytokeratin. The patient was diagnosed as Stewart-Treves syndrome that had metastasized to the pancreas. Chemotherapy was performed, but the patient died 14 months after her diagnosis.
Conclusion: Unfortunately, this patient was not followed up, even though she had chronic lymphedema of the right femoral region due to the repeated occurrence of phlegmon. To improve the survival rate of this fatal secondary malignant complication of radical lymphadenectomy, an early diagnosis with consecutive and long-term clinical follow-up and close monitoring for Stewart-Treves syndrome is therefore important.

DOI： 10.1097/MD.0000000000004316

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. (C) 2016 AACR.

DOI： 10.1158/0008-5472.CAN-16-0810

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Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness.
SIGNIFICANCE: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. (C) 2016 AACR.

DOI： 10.1158/2159-8290.CD-15-1442

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Adenosquamous carcinoma (ASC) is an uncommon variant of pancreatic neoplasm. We sought to trace the mode of tumor progression using specimens of ASC associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. A resected specimen of the primary pancreatic ASC, developed in a 72-year-old man, was subjected to mutation profiling using amplicon-targeted sequencing and digital polymerase chain reaction. DNA was isolated from each histological compartment including noninvasive IPMN, squamous cell carcinoma (SCC), and adenocarcinoma (AC). Histologically, an IPMN with a large mural nodule was identified. The invasive tumor predominantly consisted of SCC, and a smaller AC was found around the lesion. Squamous metaplasias were sporadically distributed within benign IPMNs. Mutation alleles KRAS(G12D) and GNASR(201C) were identified in all specimens of IPMN including the areas of squamous metaplasia. In addition, these mutations were found in SCC and AC. Clear transition from flat/low-papillary IPMN to SCC indicated a potent invasion front, and the SCC compartment was genetically unique, because the area has a higher frequency of mutation KRAS(G12D). The invasive tumors with distinct histological appearances shared the form of noninvasive IPMN as a common precursor, rather than de novo cancer, suggesting the significance of a genetic profiling scheme of tumors associated with IPMN.

DOI： 10.1097/MPA.0000000000000556

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Epidermoid cysts arising from both the pancreas and spleen are rare. We herein report a case of a surgically resected epidermoid cyst in the pancreatic tail invaginated from the spleen. A multi-locular cyst, 2 cm in diameter, without a solid component was discovered incidentally in the pancreatic tail. During the 11-year follow-up, the emergence of satellite cystic lesions with distinct appearances was seen, and surgical resection was selected despite the lack of any associated symptoms or evidence of cytological abnormalities. Histologically, these cysts were lined with benign multi-layered flattened epithelium surrounded by a thin layer consisting of cells positive for CD8 and CD68 and connecting to the spleen.

DOI： 10.2169/internalmedicine.55.7466

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VESALIUS UNIV MEDICAL PUBL  

The hedgehog pathway is known to promote proliferation of pancreatic ductal adenocarcinoma (PDA) and has been shown to restrain tumor progression. To understand how hedgehog causes these effects, we sought to carefully examine protein expression of hedgehog signaling components during different tumor stages. Genetically engineered mice, Pdx1-Cre; LSL-Kras(G12D) and Pdx1-Cre; LSL-Kras(G12D); p53(lox/+), were utilized to model distinct phases of tumorigenesis, pancreatic intraepithelial neoplasm (PanIN) and PDA. Human pancreatic specimens of intraductal papillary mucinous neoplasm (IPMN) and PDA were also employed. PanIN and IPMN lesions highly express Sonic Hedgehog, at a level that is slightly higher than that observed in PDA. GLI2 protein is also expressed in both PanIN/IPMN and PDA. Although there was no difference in the nuclear staining, the cytoplasmic GLI2 level in PDA was modest in comparison to that in PanIN/IPMN. Hedgehog interacting protein was strongly expressed in the precursors, whereas the level in PDA was significantly attenuated. There were no differences in expression of Patched1 at early and late stages. Finally, a strong correlation between Sonic Hedgehog and GLI2 staining was found in both human and murine pancreatic tumors. The results indicate that the GLI2 protein level could serve as a feasible marker of ligand-dependent hedgehog activation in pancreatic neoplasms.

DOI： 10.5114/PJP.2016.61449

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DOI： 10.1002/cjp2.8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The purpose of this study was to describe the cyst infection of intraductal papillary mucinous neoplasm in 2 patients. The patients were 62- and 74-year-old men. The initial symptom was acute febrile abdominal pain. Laboratory tests revealed severe infection (C-reactive protein concentrations were 23.3 mu g/mL in patient 1 and 22.3 mu g/mL in patient 2) and multilocular cystic masses (the diameters were 70 mm in patient 1 and 50 mm in patient 2) at the pancreatic head that involved peripancreatic vessels were demonstrated by computed tomography. Laboratory and radiographic findings were markedly improved by endoscopic transpapillary drainage. The enteric bacteria were detected in the drainage specimens. Curative resection was achieved, and histological findings indicated a carcinoma in situ in patient 1 and an invasive carcinoma in patient 2. Neither hyperamylasemia nor histological fat necrosis, frequently observed in acute pancreatitis, was evident. Both patients were free from recurrence after surgery (17 months in patient 1, and 18 months in patient 2). Cyst infection is an unknown complication of intraductal papillary mucinous neoplasm. Transpapillary drainage is highly recommended as an initial intervention. It is difficult to distinguish between cyst infection and unresectable invasive carcinoma with imaging modalities; however, surgical intervention after drainage may contribute to long-term survival.

DOI： 10.1097/MPA.0000000000000036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Human peripheral blood mononuclear cells (PB-MNCs) have angiogenic properties, which make them promising cells for use in angiogenic therapy approaches in regenerative medicine. To explore an efficient method for expanding pro-angiogenic cells from PB-MNCs, we developed a novel serum-free culture system composed of X-VIVO15 medium supplemented with vascular endothelial growth factor, basic fibroblast growth factor, and thrombopoietin (TPO). Using this ex vivo culture, we obtained floating spheres composed mainly of CD11b(+) monocytes expressing c-Mpl (TPO receptor) and which exhibited acetylated low-density lipoprotein uptake and phagocytosis. Expression of IL-8, CXCR4, and vasohibin-2 mRNA was upregulated in these cells. In the presence of TPO, the number and size of the spheres were increased. In a nude mouse hind-limb ischemia model, the intramuscular injection of spheroid cells treated with TPO rescued blood perfusion more effectively than that without TPO. These results indicate that the ex vivo addition of TPO augments the pro-angiogenic activity of peripheral CD11b(+) monocytes, suggesting that this method shows promise for uses in human cell therapy aimed at the induction of vascular regeneration by activating the angiogenic properties of human peripheral blood-derived monocytes.

DOI： 10.1007/s12185-013-1423-8

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Language：English   Publisher：ROCKEFELLER UNIV PRESS  

Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor. B transcriptional program in normal pancreatic acinar cells, resulting in acinar-ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.

DOI： 10.1083/jcb.201307066

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Background: Prostacyclin (PGI(2)) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI2 in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI2 in EPC-mediated angiogenesis using BM-specific IP deletion mice.
Methods and Results: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IF-deleted BM (WT/BM(IP-/-). Recovery of blood flow (RBF) in WT/BM(IP-/-) was impaired for 28 days after HLI, whereas RBF in IP-/-/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP-/-) was completely recovered by intramuscular injection of WT EPCs but not IP-/- EPCs. The impaired effects of IP-/-EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP-/-EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin beta 1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects.
Conclusions: PGI2 may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects. (Circ J 2013; 77: 1053-1062)

DOI： 10.1253/circj.CJ-12-0897

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION  

High-fat diet is one of the causes of nonalcoholic fatty liver disease. We have previously demonstrated that high-fat diet induces upregulation of adipose differentiation-related protein mRNA expression accompanied by lipid droplet formation in mouse liver. Vanin-1 is a ubiquitous epithelial ectoenzyme that has pantetheinase activity and produces cysteamine, a potent endogenous antioxidant. In the present study, we analyzed the expression of hepatic vanin-1 mRNA following the administration of a high-fat diet in mice as well as free fatty acids in hepatocyte cultures and speculated its possible mechanism. Vanin-1 mRNA levels in the livers of mice were upregulated within a day of the high-fat diet, even before the expression of adipose differentiation-related protein mRNA and lipid accumulation. An in vitro analysis using HuH-7 cells revealed a significant upregulation of vanin-1 mRNA by as low as 0.01 mM oleic acid; however, lipid accumulation in hepatocytes was not affected at this concentration. Furthermore, vanin-1 mRNA was differentially upregulated by various free fatty acids irrespective of the grade of lipid accumulation. These findings indicate that the upregulation of vanin-1 precedes lipid accumulation and is differentially mediated by various types of free fatty acids in the model, presenting vanin-1 as a novel player in the pathogenesis of nonalcoholic fatty liver disease.

DOI： 10.3164/jcbn.12-06

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Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. These probiotic effects are considered to be displayed through the mediation of effective molecules derived from these bacteria because live bacteria as well as their conditioned media exhibit beneficial effects in many cases. However, many of the probiotic-derived molecules which mediate such benefits have so far been poorly characterized. We previously found that competence and sporulation factor (CSF) activates the Akt and p38 MAPK pathways and protects epithelial cells from oxidant stress in the mammalian intestine. The purpose of this study is to determine the CSF effect on reducing intestinal inflammation.
A protein array demonstrated that CSF induced the anti-inflammatory cytokine, IL-10, and decreased the release of pro-inflammatory mediators, IL-4, IL-6 and CXCL-1, induced by TNF-alpha in Caco2/(bbe) cells. CSF also induced the cytoprotective protein Hsp 27 in Caco2/(bbe) cells. The histological score of intestinal inflammation in 2% dextran sodium sulfate (DSS)-treated mice with the administration of 10 nM CSF was significantly lower than that of control mice. CSF also improved the survival rate of mice treated with a lethal concentration of DSS.
Therefore, CSF is a potentially effective treatment for intestinal inflammation.

DOI： 10.1007/s00384-012-1416-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Some patients under close colonoscopic surveillance still develop colorectal cancer, thus suggesting the overlook of colorectal adenoma by endoscopists. AFI detects colorectal adenoma as a clear magenta, therefore the efficacy of AFI is expected to improve the detection ability of colorectal adenoma. The aim of this study is to determine the efficacy of AFI in detecting colorectal adenoma.
Methods: This study enrolled 88 patients who underwent colonoscopy at Asahikawa Medical University and Kushiro Medical Association Hospital. A randomly selected colonoscopist first observed the sigmoid colon and rectum with conventional high resolution endosopy (HRE). Then the colonoscopist changed the mode to AFI and handed to the scope to another colonoscopist who knew no information about the HRE. Then the second colonoscopist observed the sigmoid colon and rectum. Each colonoscopist separately recorded the findings. The detection rate, miss rate and procedural time were assessed in prospective manner.
Results: The detection rate of flat and depressed adenoma, but not elevated adenoma, by AFI is significantly higher than that by HRE. In less-experienced endoscopists, AFI dramatically increased the detection rate (30.3%) and reduced miss rate (0%) of colorectal adenoma in comparison to those of HRE (7.7%, 50.0%), but not for experienced endoscopists. The procedural time of HRE was significantly shorter than that of AFI.
Conclusions: AFI increased the detection rate and reduced the miss rate of flat and depressed adenomas. These advantages of AFI were limited to less-experienced endoscopists because experienced endoscopists exhibited a substantially high detection rate for colorectal adenoma with HRE.

DOI： 10.1186/1471-230X-12-75

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Duerr EM, Mizukami Y, Moriichi K, Gala M, Jo WS, Kikuchi H, Xavier RJ, Chung DC. Oncogenic KRAS regulates BMP4 expression in colon cancer cell lines. Am J Physiol Gastrointest Liver Physiol 302: G1223-G1230, 2012. First published March 1, 2012; doi:10.1152/ajpgi.00047.2011.-Activating mutations in the KRAS oncogene are common in colorectal cancer. However, the complete spectrum of KRAS targets that mediate its tumorigenic effect has not yet been fully delineated. We identified bone morphogenetic protein 4 (Bmp4), a transforming growth factor-beta family member that regulates development and tissue homeostasis, as a new target of KRAS. In SW480, Hela, and 293 cells, oncogenic KRAS(V12) downregulated BMP4 RNA levels, a BMP4 promoter luciferase construct, and Bmp4 protein levels. The MEK inhibitor PD98059 but not the phosphatidylinositol 3-kinase inhibitor LY294002 blocked this downregulation of BMP4. To identify the region of the BMP4 promoter that mediated this regulation by KRAS, serial 5'-deletions of the promoter were generated. An inhibitory region was identified between -3,285 and -3,258 bp in the Bmp4 promoter. In summary, oncogenic KRAS can downregulate Bmp4 through a transcriptional pathway that depends on ERK. These findings point to a unique link between two pathways that are frequently altered in colon cancer.

DOI： 10.1152/ajpgi.00047.2011

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Language：English   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1443-1661.2011.01188.x

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Language：English   Publisher：GEORG THIEME VERLAG KG  

DOI： 10.1055/s-0031-1291502

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Autofluorescence imaging (AFI) is a novel technology which can capture fluorescence emitted from intestinal tissues. While AFI is useful for detecting colorectal neoplasms, it is unclear whether AFI can facilitate the diagnosis by differentiating the extent of dysplasia of colorectal neoplasms. This study investigated the efficacy of AFI in discriminating high-grade from low-grade adenoma.
Sixty-seven patients who underwent colonoscopy with AFI were enrolled in this study. The AFI images obtained from 158 lesions in these patients were visually classified into four categories, namely, green (G), green with magenta spots (GM), magenta with green spots (MG), and magenta (M), according to their color intensities, immediately after the examination. The AFI images of the lesions were quantified using an image-analytical software program (F index). Either the F index or the visual assessment was prospectively compared with the dysplastic grade.
The F index of the high-grade adenomas was significantly lower than that of the low-grade adenomas, hyperplasia, and normal mucosa (p &lt; 0.05). The incidence of the lesions classified into the M classification for high-grade adenomas (55.6%) was significantly higher than that of either low-grade adenomas (20.8%) or hyperplasia (0%). No correlation was observed between the F index or the visual classification and the tumor shape. The F index was not influenced by the size of the lesion, while the size was significantly associated with the visual classification of AFI.
AFI, particularly the F index, is considered to be a useful procedure for estimating the dysplastic grade of colonic adenomas.

DOI： 10.1007/s00384-011-1311-8

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Tumor-derived signals systemically induce an angiogenic switch that allows cancer cells to survive and grow. However, the vascular network in tumors is not well organized and fails to meet metabolic needs to maintain tissue homeostasis, resulting in significant hypoxia. Among various tumors, pancreatic ductal adenocarcinoma (PDAC) typically develops in an unusually disordered microenvironment, which contributes to its highly aggressive behavior. Since anti-vascular endothelial growth factor (VEGF) (Avastin) has failed to demonstrate a survival benefit in PDAC, we need to re-visit the basic biology of this disease and understand what makes it so refractory to the anti-angiogenic approaches that are clinically effective in other neoplasms. To address this issue, we specifically focused on the process of neovascularization where bone marrow-derived cells (BMDCs) play a role during pancreatic tumorigenesis. We have identified subsets of BMDCs that regulate key processes during development of the neovessels through paracrine Hedgehog signaling. Considering the importance of systemic responses occurring in tumor bearing hosts, we are currently using genetically engineered mice, which spontaneously develop PDAC, Pdx1-Cre;LSL-KrasG12D;p53lox/+ strain, to clarify critical events that can trigger aberrant angiogenesis in pancreatic cancer. These studies allow us to provide insights into the cellular and molecular mechanisms of pancreatic tumorigenesis and have an implication for the design of therapies against this difficult disease.

DOI： 10.1111/j.1440-1746.2011.07012.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Tumor-derived factors affect the stroma of cancer tissue by activating pro-angiogenic signals. One of the key components of this response is the mobilization of the pro-angiogenic cells from bone marrow (BM), which contribute to the development of abnormal tumor vasculature. Evidence is accumulating that the pro-angiogenic cells derived from BM are involved in the physiological processes of tissue repair and wound healing. However, vascular structure in cancer tissue is impaired, resulting in the formation of chaotic neo-vessels and hypoxic microenvironments. Ultimately, these structural and functional abnormalities result in the limited delivery of chemotherapeutic agents and create regions of metabolic derangement, both of which enhance resistance to chemotherapy. In spite of recent advances in targeted therapy using anti-vascular agents, clinical results from studies using individual agents have unsatisfactory, necessitating the combinatorial use of anti-cancer drugs and a targeting agent. We suggest the possibility of a new therapeutic approach in which aberrant tumor vessels are normalized by BM-derived pro-angiogenic cells, and the delivery of anti-cancer drugs is maximized. In this review, we focus on the current understanding of the structure and function of tumor vessels, and an alternative approach to the repair of abnormal tumor vasculature by the use of BM-derived pro-angiogenic cells. This approach may improve both the delivery and the efficacy of anti-cancer drugs by restoring aberrant tumor vascularization and hypoxia.

DOI： 10.1007/s12185-012-1017-x

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DOI： 10.4236/fns.2012.34077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background: Probiotics have been clinically administered to improve intestinal damage in some intestinal inflammations. However, probiotic treatments are not always effective for these intestinal disorders because live bacteria must colonize and maintain their activity under unfavorable conditions in the intestinal lumen when displaying their functions. This study investigated the physiological functions of a heat-killed body of a novel probiotic, Lactobacillus brevis SBC8803, on the protection of intestinal tissues, the regulation of cytokine production, the improvement of intestinal injury, and the survival rate of mice with dextran sodium sulfate (DSS)-induced colitis.
Methods: Heat shock protein (Hsp) induction and mitogen-activated protein kinase (MAPK) phosphorylation in intestinal epithelia by heat-killed L. brevis SBC8803 were examined by Western blotting. The barrier function of intestinal epithelia was measured with [(3)H]-mannitol flux in the small intestine under oxidant stress. The effects of the bacteria on improving epithelial injury and cumulative survival rate were investigated with a DSS colitis model.
Results: Heat-killed L. brevis SBC8803 induced Hsps, phosphorylated p38 MAPK, regulated the expression of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta and IL-12, and improved the barrier function of intestinal epithelia under oxidant stress. The induction of Hsp and the protective effect were negated by p38 MAPK inhibitor. These functions relieve intestinal impairments and improve the survival rate in mice with lethal colitis.
Conclusions: The administration of heat-killed L. brevis SBC8803 helps to successfully maintain intestinal homeostasis, while also curing intestinal inflammation. A therapeutic strategy using heat-killed bacteria is expected to be beneficial for human health even in conditions unsuitable for live probiotics because the heat-killed body is able to exhibit its effects without the requirement of colonization. (Inflamm Bowel Dis 2011;17:2235-2250)

DOI： 10.1002/ibd.21597

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

Background and study aims: Conventional colonoscopy can result in unnecessary biopsy or endoscopic resection due to its inability to distinguish adenomas from hyperplastic polyps. This study therefore evaluated the efficacy of high-resolution endoscopy (HRE), autofluorescence imaging (AFI), and narrow-band imaging (NBI) in discriminating colon adenoma from hyperplastic polyps.
Patients and methods: This was a prospective multicenter study in patients undergoing AFI and NBI examinations. HRE, AFI, and NBI images were classified into two groups based on morphological characteristics, the predominant color intensities, and the visibility of meshed capillary vessels, respectively. Each of the endoscopic photographs were independently evaluated by a single endoscopist. The images were then assessed by three specialists and three residents, the latter having performed &lt; 500 colonoscopies and &lt; 30 NBI and AFI examinations. Diagnostic test statistics were calculated to compare the accuracy in differentiating colon adenoma from hyperplastic polyps for each method.
Results: A total of 183 patients were enrolled in the study and 339 adenomas and 85 hyperplastic polyps were identified. AFI and NBI could distinguish adenoma from hyperplastic polyps with an accuracy of 84.9% and 88.4 %, respectively, whereas HRE exhibited an accuracy of 75.9 %. In the 358 lesions in which the AFI diagnosis was consistent with that of NBI, the accuracy, sensitivity, and specificity were high, at 91.9 %, 92.7 %, and 92.9 %, respectively. During the study comparing specialists and residents, AFI and NBI dramatically improved the diagnostic accuracy of residents from 69.1% to 86.1% and 84.7 %, respectively.
Conclusions: Both AFI and NBI are considered to be feasible tools that can discriminate colon adenoma from hyperplastic polyps, and their use may be particularly beneficial for less-experienced endoscopists.

DOI： 10.1055/s-0030-1256510

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Language：English   Publisher：B M J PUBLISHING GROUP  

DOI： 10.1136/gut.2009.205526

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective: The aim of this study was to define the relevance of mural nodules (MNs) as a "direct" indicator of malignancy of intraductal papillary mucinous neoplasm (IPMN) of the pancreas.
Methods: Thirty-nine surgically resected IPMNs excluding obviously invasive carcinomas were examined. The distribution of the most severely dysplastic lesions was mapped on specimens. Immunohistochemical analysis for MUC1 and MUC2 was performed on sections containing the histologically predominant lesions and the most severely dysplastic areas.
Results: The presence of MNs correlated well with the histological grade of IPMN (P &lt; 0.01); however, the most severely dysplastic lesions were associated with a flat/nonelevated area rather than MNs (78.9%). In the MUC1-positive subgroup, minimally invasive carcinoma was colocalized to MNs, whereas most severely dysplastic foci including minimally invasive carcinoma with components of mucinous and tubular adenocarcinoma were observed in the areas apart from MNs in the MUC2-positive and MUC1/2-negative subgroups, respectively.
Conclusions: Although our data support the concept that MNs represent areas of higher-grade dysplasia within IPMN, development of invasive lesions from MNs may be limited to cases that are MUC1-positive. Careful attention should be paid to the emergence of invasive IPMN from flat foci in MUC2-positive and MUC1/2-negative cases.

DOI： 10.1097/MPA.0b013e31820d1a03

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DOI： 10.1136/gut.2009.186650D

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

An isodicentric (X)(q13) (idicXq13) is a rare, acquired chromosomal abnormality originated by deletion of the long arm from Xq13 (Xq13-qter), and is found in female patients with hematological disorders involving increased ringed sideroblasts (RSs), which are characterized by mitochondrial iron accumulation around the erythroblast nucleus. The cause of increased RSs in idicXq13 patients is not fully understood. Here, we report the case of a 66-year-old female presenting with refractory anemia with ringed sideroblasts (RARS), and idicXq13 on G-banded analysis. We identify the loss of the ABCB7 (ATP-binding cassette subfamily B member-7) gene, which is located on Xq13 and is involved in mitochondrial iron transport to the cytosol, by fluorescent in situ hybridization (FISH) analysis and the decreased expression level of ABCB7 mRNA in the patient&apos;s bone marrow cells. Further FISH analyses showed that the ABCB7 gene is lost only on the active X-chromosome, not on the inactive one. We suggest that loss of ABCB7 due to deletion of Xq13-qter at idicXq13 formation may have contributed to the increased RSs in this patient. These findings suggest that loss of the ABCB7 gene may be a pathogenetic factor underlying mitochondrial iron accumulation in RARS patients with idicXq13.

DOI： 10.1007/s12185-011-0786-y

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Amyloidosis occurs as a result of the extracellular deposition of protein fibrils in organs and tissues, thus causing mild to severe pathophysiological changes. The gastrointestinal tract is a common site of amyloid deposition. While intestinal amyloidosis frequently results in polypoid lesions, ulcerations, nodules and petechial mucosal haemorrhage, tumour-like lesions are rarely developed and infrequently diagnosed before the resection because of the difficulty in differentiating them from colon cancer. The authors herein reported a case of intestinal amyloid A amyloidosis with a complication of a tumour-like lesion endoscopically resembling a malignant lesion, which was completely diminished after 1 month of observation with bowel rest. Such conservative treatment is a feasible option to cure intestinal tumour-like lesions in patients with intestinal amyloidosis when no neoplastic change is histologically detected, possibly decreasing the need for surgery of the fragile mucosa. Copyright 2011 BMJ Publishing Group. All rights reserved.

DOI： 10.1136/bcr.01.2011.3775

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Percutaneous endoscopic jejunostomy (PEJ) has been developed and is considered to be a better method than percutaneous endoscopic gastrostomy for preventing the occurrence of aspiration pneumonia. However, the incidence of other complications associated with this procedure is less clear. We herein report a rare case with a small intestinal intussusception due to a PEJ placement. In this case, a radiologic examination with gastrografin was useful to detect the typical findings of a small intestinal intussusception, a beak-like filling defect, and identify the location of the lesion. An endoscopic examination that was carefully performed with a thin scope was effective to observe the ischaemic change of the small intestine and immediately determine the indication for surgical treatment. This case highlights the necessity to carefully manage patients with a PEJ placement, considering the risk of small intestinal intussusceptions when the patient complains of symptoms that are suspicious for an intestinal obstruction. Copyright 2011 BMJ Publishing Group. All rights reserved.

DOI： 10.1136/bcr.07.2010.3169

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Henoch-Schönlein purpura (HSP) is a type of systemic vasculitis of the small vessels, which frequently involves the skin, kidney and gastrointestinal tract. While the typical intestinal features of HSP include diffuse mucosal redness, small ring-like petechiae and haemorrhagic erosions, tumour-like lesions are rarely observed. The current study presents a rare case of HSP with an intestinal tumour-like lesion in the caecum. The intestinal lesion caused fresh melaena, and was completely resolved with the administration of factor XIII as described in previously reported cases. It is important to immediately undergo proper treatment for improving tumour-like lesions which may cause severe complications, such as excessive haemorrhage and stricture. © 2011 BMJ Publishing Group. All rights reserved.

DOI： 10.1136/bcr.08.2010.3251

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Background: The etiology of inflammatory bowel disease (IBD) is associated with an altered microflora due to a failure of the immune system. This study investigated the expression of the intestinal antimicrobial peptide a-defensin, which plays a pivotal role in the regulation of the intestinal microflora in a representative model of IBD, interleukin (IL)-10-deficient mice.
Methods: The expression of alpha-defensin/cryptdins in IL-10-deficient mice was assessed by real-time polymerase chain reaction (PCR) and acid/urea polyacrylamide gel (AU-PAGE). The alteration of alpha-defensin/cryptdins expression was compared with the inflammatory grade of mice intestine at various weeks from birth.
Results: The weight, length, and inflammation grade of the mouse intestines were assessed at 5, 7, 9, 11, 13, and IS weeks from birth. While the weight of the large intestine was heavier at 15 weeks after birth in the IL-10-deficient mice than in the control mice, histological inflammation began from 7 weeks after birth. Real-time PCR and AU-PAGE identified a significant decrease in the expression of alpha-defensin/cryptdins at 7 weeks after birth in the IL-10 knockout mice, thus illustrating the involvement of alpha-defensin/cryptdins in the etiology of the intestinal inflammation in IBD. This study also identified the expression of alpha-defensin/cryptdins to be inversely proportional to age until 11 weeks, suggesting a relationship between the formation of the intestinal microflora and a reduction in the expression of alpha-defensin/cryptdins.
Conclusions: The altered expression of antimicrobial peptide alpha-defensin may cause the onset of intestinal inflammation due to a failure to regulate intestinal microflora.

DOI： 10.1002/ibd.21253

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Diphyllobothrium is a member of Cestoda family, which is the largest parasite of humans. The diagnosis of diphyllobothriasis is based on the detection of eggs in the stool. Because the remainder of the scolex causes a relapse in diphyllobothriasis, the scolex must be completely discharged to cure the parasite infection. However, the scolex or forefront of the Diphyllobothrium is difficult to detect with gastroduodenoscopy and colonoscopy, because most Diphyllobothrium attach to the jejunal wall. In the present case, capsule endoscopy detected proglottids as well as forefront of the parasite at jejunum. Based on the results of capsule endoscopy, the patient underwent additional vermifuge (anthelminthic) treatment to cure the diphyllobothriasis and discharged a worm measuring 3m in length with a scolex. Capsule endoscopy is a practical option to determine whether additional vermifuge treatment is required through the detection of the proglottids as well as a scolex or forefront of the parasite.

DOI： 10.1136/bcr.05.2010.3023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre; LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors. Cancer Res; 70(15); 6283-92. (C) 2010 AACR.

DOI： 10.1158/0008-5472.CAN-10-0412

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A 63-year-old man was admitted with left pleural effusion, and an amylase level of 30994IU/l. A diagnosis of pancreaticopleural fistula was made, based on the findings of magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP). After the placement of an endoscopic naso-pancreatic drainage tube, the pleural effusion markedly reduced. When ERP was performed for internal drainage, the main pancreatic duct and stricture were biopsied and showed pancreatic ductal adenocarcinoma histologically. CT revealed a mass in the head of the pancreas. He underwent pylorus-preserving pancreaticoduodenectomy. To the best of our knowledge this is the first case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion. Clinicians should pay attention to the possible presence of cancer and pancreaticopleural fistula in patients with pancreatic pleural effusion.

DOI： 10.11405/nisshoshi.107.784

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Background: We developed a novel method of methylation-specific PCR (MSP) using immunoprecipitation with anti-histone antibody (IP-MSP) to efficiently detect serum methylated DNA tightly bound to de-acetylated histones. Materials and methods: The detection limit of IP-MSP for p16 methylation was determined with a standard made by cell line (SKCO-1) lysate. p16 methylation of tumor and/or serum of 51 colorectal cancers and 10 adenoma patients, and 10 healthy volunteers was detected with conventional MSP or IP-MSP. Results: IP-MSP detected p16 methylation from 0.5 pg/mu l of the cell lysate. The sensitivity of IP-MSP for detecting serum p16 methylation in 27 patients with tumors characterized by p16 methylation was significantly higher than that with conventional method (81% versus 59%), particularly in Stage II patients (91% versus 45%). IP-MSP detected no p16 hypermethylation in sera of adenoma patients and volunteers. Conclusions: IP-MSP is thus considered to be a promising procedure to detect serum methylated DNA in colorectal cancer patients. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.canep.2010.01.004

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Collagenous colitis (CC) is one of the causes of undefined watery diarrhea, which is histologically accompanied by thickening of the subepithelial collagen layer. CC associated with lansoprazole normally occurs within several weeks after initial administration, but no case presenting after long-term administration of lansoprazole has yet been reported. A 77-year-old male with 6-year history of administration of lansoprazole complained of watery diarrhea and weight loss. Colonoscopy revealed disappearance of vascular networks and red spots in the sigmoid colon. Biopsy specimen showed erosion and collagen bands thickened, so the patient was diagnosed as CC. After lansoprazole discontinuation, the watery diarrhea disappeared and histological abnormalities improved. © 2009 Springer.

DOI： 10.1007/s12328-009-0126-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Background: The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells.
Methodology/Principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity.
Conclusions/Significance: We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis.

DOI： 10.1371/journal.pone.0008824

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective: Although branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slow-growing tumors with a favorable prognosis, the synchronous occurrence of pancreatic ductal adenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. This study was aimed to elucidate the development of PDAs in long-term follow-up patients with BD-IPMNs.
Methods: We investigated 89 BD-IPMN patients who had no mural nodules and followed them up conservatively at least 2 years (median follow-up, 64 months; range, 25-158 months). All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography. We calculated the standardized incidence ratio (SIR) from the vital statistics compiled by the Ministry of Health, Labor, and Welfare of Japan.
Results: Among the 89 patients, 4 cases of PDAs distant from BD-IPMN were observed in 552 patient-years of follow-up (7.2 per 1000 patient-years). The expected number was 0.25, and the SIR of PDAs was 15.8 (95% confidence interval [CI], 4.3-40.4; P = 0.00014). Subgroup analyses showed that the incidence of PDAs was significantly increased in patients 70 years or older (SIR 16.7; 95% CI, 3.4-48.7; P = 0.0008) and in women (SIR 22.5; 95% CI, 2.7-81.1; P = 0.0037).
Conclusions: Patients with BD-IPMNs are at a high risk for PDAs. During the follow-up, careful examination is required to detect the development of PDAs in patients with BD-IPMNs.

DOI： 10.1097/MPA.0b013e3181b91cd0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: Although branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency, the incidence of concomitant pancreatic carcinoma (PC) is not well known. We investigated the incidence and clinical features of synchronous and metachronous PC in patients with BD-IPMN. Methods: We studied 168 BD-IPMN patients diagnosed by various imaging modalities, including endoscopic retrograde pancreatography, between 1990 and 2008. We reviewed the medical records and clinical features in both patients developing and not developing PC. The diagnosis of PC was histologically verified in all patients. Results: PC was observed in 9 (5.4%) of 168 patients. Five were synchronously detected at the time of BD-IPMN diagnosis, whereas four were metachronously identified during the follow-up period. All PCs occurred in regions separate from the BD-IPMN lesion. All PCs represented histologically invasive ductal adenocarcinomas, whereas the BD-IPMN lesion was diagnosed as adenoma. Patients developing PC were significantly older than patients not developing PC (p = 0.017). The diameters of the BD-IPMN lesions and main pancreatic ducts were significantly smaller in patients developing PC than patients not developing PC (p = 0.013 and p &lt; 0.001, respectively). Conclusions: It was not infrequent for PC to occur in the pancreas with BD-IPMN. Particular attention should therefore be paid to the development of PC, even in low-risk BD-IPMN, as well as to changes in BD-IPMN. Copyright (C) 2010 S. Karger AG, Basel and IAP

DOI： 10.1159/000231982

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Small cell carcinoma of the oesophagus (SCCE) is an infrequent tumour associated with a poor prognosis. We herein propose the first case of SCCE treated by endoscopic mucosal resection (EMR) and its endoscopic images with narrow band imaging (NBI) and autofluorescence imaging (AFI). A 63-year-old man complained of a loss of appetite. An upper endoscopic examination revealed a 7 mm nodule located 33 cm from the incisors. A weakly stained area was shown by iodine staining. NBI detected brownish amorphous dots with irregular vessels on the surface of the nodule and AFI distinctly embossed the lesion magenta. A biopsy specimen obtained from the lesions revealed typical SCCE. The patient underwent EMR to remove the SCCE and thereafter remained in a state of clinical remission for 18 months. In summary, NBI and AFI may be useful for detecting and differentially diagnosing SCCE from the squamous cell carcinoma of the oesophagus. EMR is therefore considered to be a potentially useful therapeutic option for removing SCCE instead of performing an oesophagotomy.

DOI： 10.1136/bcr.06.2009.2048

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Branch duct intraductal papillary-mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency. Although BD-IPMN outcomes are generally good, pancreatic ductal adenocarcinoma (PDA) is found distant from the original BD-IPMN in about 3.3-9.2% of cases. These reports raise the question of whether a possible association exists between BD-IPMN and PDA. Recent findings from follow-up studies suggest that pancreases with BD-IPMNs have a high risk of developing additional pancreatic cancer, with standardized incidence ratios (SIRs) of 15.8- to 26-fold. These studies suggest that special attention should be paid to BD-IPMN patients who are ≥70 years. Furthermore, molecular evidence supports the hypothesis that field cancerization causing multiple primary neoplastic lesions exists in pancreases harboring IPMNs. Although more extensive studies are required to clarify the magnitude of this increased risk, clinicians should pay close attention to the development of PDA in patients with BD-IPMN, as well as to changes in BD-IPMN lesions. © 2009 Springer.

DOI： 10.1007/s12328-009-0116-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

The present study reports the growth rate in two cases of main duct pancreatic intraductal papillary-mucinous neoplasms (MD-IPMNs) demonstrating significant changes over several years&apos; observation. The first patient was a 74-year-old woman with an incidental finding of diffuse dilatation of the main pancreatic duct (MPD). Endoscopic retrograde pancreatography (ERP) identified a 5 mm filling defect. Three years later computed tomography (CT) revealed a 20 rum mass occupying the MPD. The second patient was a 67-year-old woman who presented with back pain. Abdominal CT revealed a 5 mm mass in the dilated MPD. Five years later, CT and ERP showed a 20 mm mass occupying the markedly dilated MPD. Both patients Subsequently underwent pancreatectomy. Histologically, the tumors showed an intraductal papillary growth occupying the dilated MPD and comprised of mucin-containing columnar epithelial cells. The tumor volume doubling time of these MD-IPMNs was 141 and 304 days in patient 1 and 2, respectively, with a mean of 222.5 days. The present reports demonstrate the ability of benign MD-IPMNs to grow at a significant rate, supporting the current consensus guidelines that MD-IPMNs require surgical resection.

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From the Division of Gastroenterological and General Surgery, Departnient of Surgery,&apos; Division of Castroenterology and HematologylOncology, Departinent of Medicine, b Department of Clinical Laboratoiy and Blood Center&apos; Department of Su?gical Patholog," and Departnient of Radiolou,&apos; Asahikawa Medical College, Hokkaido, Japan

DOI： 10.1016/j.surg.2009.03.018

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Language：English   Publisher：(一社)日本癌学会  

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Hypoxia-inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF-1 alpha and HIF-2 alpha are induced similarly by hypoxia, but their functional roles in cancer ill be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1 alpha or HIF-2 alpha or both were established. HIF-1 alpha-deficient cells displayed lower rates of proliferation and migration. but HIF-2 alpha-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1 alpha deficiency inhibited overall tumor growth. whereas deficiency of HIF-2 alpha stimulated tumor growth. In human colon cancer tissues, expression of HIF-1 alpha and to a lesser extent. HIF-2 alpha. was linked to upregulation of VEGF and tumor angiogenesis. However. loss of expression of HIF-2 alpha but not HIF-1 alpha was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1 alpha and HIF-2 alpha target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular. HIF-1 alpha promoted the growth of SW480 colon cancer cells but HIF-2 alpha appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. (c) 2008 Wiley-Liss. Inc.

DOI： 10.1002/ijc.24032

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

The present retrospective study aimed to evaluate the anti-tumor activity and toxicity of combination chemotherapy with gemcitabine (GEM) and oral S-1 or UFT in patients with advanced or metastatic pancreatic cancer. Ninety-four patients received chemotherapy. Among them, sixty-three were treated with GEM alone, twenty-two with UFT and GEM (UFT/GEM), and nine with S-1 and GEM (S-1 /GEM). The median survival time was 8.7 months with GEM, 7.3 months with UFT/GEM, and 23.3 months with S-1/GEM. The overall response rate was 11.1%, 10.0%, and 22.2%, respectively. The 1 -year survival rate was 29.5%, 36.4%, and 85.7%, respectively. Although the treatment-related adverse effects were not infrequent in patients treated with S-1/GEM, they were moderate in intensity. The combination chemotherapy with S-1/GEM was well tolerated and yielded a high response rate in patients with pancreatic cancer.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Background & Aim: The molecular alterations that underlie carcinoid tumor pathogenesis remain poorly defined. The homeobox gene HOXC6 was highly upregulated in human gastrointestinal carcinoid tumors, and we sought to define its pathogenic role. Methods: The functional and physical properties of Hoxc6 were investigated by establishing carcinoid cells that stably overexpressed Hoxc6 or were deficient in Hoxc6. Cellular proliferation assays, luciferase reporter assays, Western blotting, immunoprecipitation, DNA affinity precipitation, and DNA microarray studies were performed. Results: Expression of Hoxc6 in cultured human BON1 carcinoid cells enhanced their proliferation, and knock-down of Hoxc6 inhibited their growth. Hoxc6 activated the oncogenic activator protein-1 signaling pathway through a physical interaction with JunD. Mutations in the homeodomain of Hoxc6 blocked this interaction and inhibited proliferation of carcinoid cells. Of note, Hoxc6 induced the expression of genes that characteristically are up-regulated in carcinoid tumors, including neurotensin and connective tissue growth factor. Conclusions: A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis.

DOI： 10.1053/j.gastro.2008.06.034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Hedgehog signaling is important in the pathogenesis of pancreatic cancer. Several recent observations suggest the involvement of sonic hedgehog (SHH) in postnatal neovascularization. We identified a novel role for SHH in tumor-associated angiogenesis in pancreatic cancer. Immunohistochemical analysis revealed that patched homolog 1 (PTCH1), both a receptor for and transcriptional target of hedgehog signaling, was expressed in a small fraction of endothelial cells within pancreatic cancer, but not in normal pancreatic tissue. When endothelial progenitor cells (EPC) isolated from human peripheral blood were cultured with supernatant from SHH-transfected 293 cells or pancreatic cancer cells, mRNA levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and angiopoietin-1 were significantly increased, whereas no such induction was observed in human umbilical vein endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMVEC). HUVEC tube formation was stimulated when cocultured with EPC, and preconditioning EPC with supernatant from KP-1 N pancreatic cancer cells highly expressing SHH significantly enhanced the effect. The effect was partially attenuated by specific inhibition of SHH with cyclopamine or a neutralizing antibody. These findings suggest that tumor-derived SHH can induce angiogenesis, and this is mediated by its effects on EPC specifically. Targeting SHH would be a novel therapeutic approach that can inhibit not only proliferation of cancer cells but also EPC-mediated angiogenesis.

DOI： 10.1111/j.1349-7006.2008.00795.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC ENDOCRINOLOGY  

Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETS) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETS (GI-NETs) differ in their molecular profile from pancreatic NETS (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a 'benign' and 'malignant' cluster that corresponded well with the WHO categories of well-differentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-beta was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.

DOI： 10.1677/ERC-07-0194

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Von Hippel-Lindau disease (VHL disease) is an inherited neoplasia syndrome. VHL disease which frequently complicates pancreatic lesions is rarely diagnosed by existence of pancreatic involvements. We report two cases of VHL disease with pancreatic lesions. The first patient was a 40-year-old woman. Adrenal pheochromocytoma spinal hemangioblastoma and pancreatic endocrine tumor were resected. The second case was a 68-year-old woman with past surgical histories included cerebellar and spinal hemangioblastoma Subtotal pancreatectomy was performed for multiple serous cystadenoma. IPMN which has been never reported as pancreatic involvement of VHL disease were documented by imaging diagnosis in the first case, and by histological examination in the second case. We considered VHL disease from coexistent multiple tumors include pancreatic involvements and finally diagnosed by genetic examination in both cases. Care should be taken regarding the patient's right for treatment against for the genetic disease. We hold a genetic conference composed of multidisciplinary team. Consequently we detected another VHL disease patient from patient's family.

DOI： 10.11405/nisshoshi.105.725

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A 59-year-old woman with a history of abdominal injury was admitted to our hospital for abdominal discomfort CT revealed a cyst showing a fluid-calcium level in the pancreatic body. EUS-FNA was performed to aspirate the fluid in a cyst Aspirated was milky-white odorless material Chemical analysis showed high amylase level in the fluid. Spectroscopic analysis revealed that the fluid mainly consists of calcium phosphate. To the best of our knowledge, this is the first case of milk-of-calcium in a pancreatic pseudocyst with an analysis of cystic fluid obtained by EUS-FNA.

DOI： 10.11405/nisshoshi.105.93

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Language：English   Publisher：(一社)日本癌学会  

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To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 x dCK/RRM1 x RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.

DOI： 10.1038/sj.bjc.6603559

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DOI： 10.1007/s11888-007-0003-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis. Hypoxia is a potent stimulator of VEGF expression, and hypoxia-inducible factor-1 (HIF-1) is considered to be critical for this induction. However, we have previously demonstrated that induction of VEGF by hypoxia was preserved when HIF-1 alpha was silenced. We sought to better define the molecular basis of this HIF-1-independent regulation. In colon cancer cells, hypoxia stimulated multiple K-ras effector pathways including phosphatidylinositol 3-kinase. VEGF promoter deletion studies identified a novel promoter region between -418 and -223 bp that was responsive to hypoxia in a PI3K/Rho/ROCK-dependent manner. Electrophoretic mobility shift assays identified a fragment between -300 and -251 bp that demonstrated a unique shift only in hypoxic conditions. Inhibition of PI3K or ROCK blocked the formation of this complex. A binding site for c-Myc, a target of ROCK, was identified at -271 bp. A role for c-Myc in the hypoxic induction of VEGF was demonstrated by site-directed mutagenesis of the VEGF promoter and silencing of c-Myc by small interfering RNA. Collectively, these findings suggest an alternative mechanism for the hypoxic induction of VEGF in colon cancer that does not depend upon HIF-1 alpha but instead requires the activation of PI3K/Rho/ROCK and c-Myc.

DOI： 10.1074/jbc.M511763200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.

DOI： 10.1161/01.RES.0000209948.50943.ea

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DOI： 10.1038/nm0206-253c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background. Gemcitabine is widely accepted as the first-line agent for advanced pancreatic cancer. The antitumor cell activity of gemcitabine is higher when administered after 5-fluorouracil (5-FU) rather than before 5-FU in an in vitro study. The present study was conducted to define the maximum tolerated dose and dose-limiting toxicity associated with an oral fluoropyrimidine prodrug that combines uracil and tegafur (UFT), given prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer. Methods: Over a 21-day cycle, gemcitabine was given intravenously over 30 min on days 8 and 15, while UFT was given orally from days 1 to 14. The dose of UFT used was 400 mg per day, given as two doses. The dose of gemcitabine was escalated in a step-wise fashion from 800 (level 1, n = 3) to 900 mg/m(2) (level 2, n = 6) and then to 1,000 mg/m(2) (level 3, n = 3), such that totally 12 patients received the combination chemotherapy. Results: During the first cycle, grade 3 leukopenia was observed in 2 patients at dose level 1. Only 1 patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 elevated transaminase), including additional patients treated at this dose level. No grade 3/4 toxicities occurred in patients treated at dose level 3. A significant response was observed in 1 out of 12 patients (8.3%). Seven patients (58.3%) had stable disease, while 4 patients (33.3%) showed disease progression. Conclusions: The combination chemotherapy of oral UFT and gemcitabine was convenient, well tolerated and may benefit patients with advanced pancreatic cancer. Doses recommended for further study of this schedule are gemcitabine 1,000 mg/m(2) and UFT 400 mg/day.

DOI： 10.1159/000092372

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LANDES BIOSCIENCE  

The induction of new blood vessels is critical to the pathogenesis of colon cancer, and inhibition of vascular endothelial growth factor (VEGF) has proven to be an effective approach to the treatment of this malignancy. Another potential therapeutic strategy would utilize endogenous anti-angiogenic molecules such as thrombospondin-1 (TSP-1). However, the regulation of TSP-1 expression in colon cancer is poorly understood. Our results demonstrate that TSP-1 is strongly expressed in normal colonic epithelial cells. However, loss of TSP-1 was observed in early colonic adenomas and it became undetectable in invasive colon cancers. Activation of the Wnt signaling pathway in intestinal epithelial cells repressed TSP-1 gene expression, and inhibition of Wnt signaling in colon cancer cells reversed this repression. Although mutant K-ras also inhibited the TSP-1 promoter in intestinal epithelial cells, silencing of mutant K-ras in colon cancer cells with an activated Wnt pathway did not upregulate TSP-1 expression. Collectively, these findings suggest that activation of the Wnt pathway rather than K-ras plays a more important role in the downregulation of TSP-1 observed in colon cancer.

DOI： 10.4161/cbt.4.12.2201

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background: Gemcitabine is a pyrimidine nucleoside analog that is clinically active against pancreatic cancer. We have recently demonstrated that p38 MAPK is specifically activated by gemcitabine and that pharmacological blockade of p38 MAPK signaling prevented gemcitabine-induced apoptosis in human pancreatic cancer cells. In this study, we further investigated the implication of p38 MAPK in the cytotoxic action of gemcitabine. Materials and Methods: Cells expressing a dominant-negative mutant of p38 MAPK were generated. Clonogenic assays were used to assess the long-term effect on cancer cell viability in the human pancreatic cancer cells, PK1 and PCI43. The p38 MAPK activation level was assessed using an antibody specific to the phosphorylated form. Results: Gemcitabine increased the activation level of p38 MAPK in a dose-dependent manner and induced apoptosis in the two tested human pancreatic cancer cell lines. The selective p38 MAPK inhibitors, SB203580 and SB202190, reduced gemcitabine-induced activation of p38 MAPK, prevented the gemcitabine-induced apoptosis and increased long-term clonogenic survival. Overexpression of a dominant-negative p38 mutant in cells resulted in the reduction of gemcitabine-induced p38 MAPK activation and apoptosis, and increases in clonogenic survival. Conclusion: These results strongly suggest that the activation of p38 MAPK signaling is necessary for gemcitabine-induced cell death in human pancreatic cancer cells. Based upon these results, we suggest that molecules of p38 MAPK signaling pathways should be listed as novel targets for gemcitabine-based therapy.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Background & Aims: Two key genetic events underlying the development of colon cancer are activation of the K-ras and Wnt signaling pathways. We have previously shown that these 2 pathways can cooperate to regulate vascular endothelial growth factor (VEGF) gene expression. The goal of this study was to define the molecular basis for this interaction. Methods: The effects of K-ras(Val12) on VEGF and T-cell factor 4 (TCF-4) promoter activity, nuclear levels of beta-catenin and beta-catenin/TCF-4 complexes, glycogen synthase kinase 3 beta (GSK-3 beta) phosphorylation, and GSK-3 beta kinase activity were measured. LY294002 and PD98059 were used to define the role of specific ras effector pathways. Results: Oncogenic K-ras up-regulated the activity of the VEGF promoter, and selective mutagenesis of TCF-4 binding sites significantly blocked this induction. K-ras(Val12) also induced the activity of a heterologous TCF-4 reporter construct in Caco-2 and HeLa cells. LY294002 and dominant negative phosphatidylinositol 3-kinase nearly completely blocked this induction. K-ras(Val12) increased the stability of beta-catenin, the levels of nuclear beta-catenin, and the formation of nuclear beta-catenin/TCF-4 complexes, and these effects were also blocked by LY294002. Finally, K-ras(Val12) inhibited the kinase activity of total cellular GSK-3 beta and GSK-3 beta complexed with Axin. This effect was not mediated through phosphorylation at serine 9 but did depend on phosphatidylinositol 3-kinase. Conclusions: Our results suggest a unique cooperative interaction between 2 critical oncogenic pathways in colorectal tumorigenesis and highlight the pivotal role of GSK-3 beta.

DOI： 10.1053/j.gastro.2005.02.067

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Cyclin D1 can stimulate proliferation by driving cells from the G1 into the S-phase of the mammalian cell cycle. Previous animal studies have implicated the G1-S transition as a key regulatory checkpoint governing the proliferation of pancreatic islet cells. We expressed cyclin DI in the beta-cells of mice and islet hyperplasia developed in a time-dependent manner. The hyperplastic P-cells exhibited higher rates of proliferation. However, blood glucose levels in fasting as well as nonfasting conditions remained normal. Furthermore, glucose tolerance tests demonstrated nearly normal responses, and diabetes did not develop in any of the animals. No islet cell tumors were observed, even among animals &gt;2 years of age. Under our experimental conditions, the proliferative stimulus provided by cyclin D1 is not tumorigenic, does not result in diabetes, and does not result in hypoglycemia. Cyclin DI may thus be considered a potential candidate to augment the P-cell population ex vivo as a prelude to islet transplantation for diabetes.

DOI： 10.2337/diabetes.54.3.712

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.

DOI： 10.1158/0008-5472.CAN-03-1788

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key mediator of this process. In colon cancer, the frequently mutated K-ras oncogene also can regulate VEGF expression, but the role that K-ras may play in hypoxia is unknown. Hypoxia induced VEGF promoter activity, mRNA, and protein levels in colon cancer cells. Although HIF-1alpha was induced by hypoxia, VEGF reporter constructs with selectively mutated hypoxia-response elements remained responsive to hypoxia. In addition, "knockdown" of HIF-1alpha by RNA interference only minimally inhibited the hypoxic induction of VEGF. A region of the VEGF promoter between -420 and -90 by mediated this HIF-independent induction by hypoxia. The introduction of K-ras(Val12) augmented the hypoxic induction of VEGF, and this was observed in wild-type and HIF-1alpha knockdown colon cancer cells. Thus, VEGF may be induced by hypoxia through HIF-dependent and HIF-independent pathways, and K-ras also can induce VEGF in hypoxia independent of HIF-1. These findings suggest the existence of multiple mechanisms regulating the hypoxic induction of VEGF in colon cancer.

DOI： 10.1158/0008-5472.CAN-03-3017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

In this study, we investigated the involvement of Akt and members of the mitogen-activated protein kinase (MAPK) superfamily, including ERK, JNK, and p38 MAPK, in gemcitabine-induced cytotoxicity in human pancreatic cancer cells. We found that gemcitabine induces apoptosis in PK-1 and PCI-43 human pancreatic cancer cell lines. Gemcitabine specifically activated p38 MAPK in a dose- and time-dependent manner. A selective p38 MAPK inhibitor, SB203580, significantly inhibited gemcitabine-induced apoptosis in both cell lines, suggesting that phosphorylation of p38 MAPK may play a key role in gemcitabine-induced apoptosis in pancreatic cancer cells. A selective JNK inhibitor, SP600125, failed to inhibit gemcitabine-induced apoptosis in both cell lines. MKK3/6, an upstream activator of p38 MAPK, was phosphorylated by gemcitabine, indicating that the MKK3/6-p38 MAPK signaling pathway is indeed involved in gemcitabine-induced apoptosis. Furthermore, gemcitabine-induced cleavage of the caspase substrate poly(ADP-ribose) polymerase was inhibited by pretreatment with SB203580, suggesting that activation of p38 MAPK by gemcitabine induces apoptosis through caspase signaling. These results together suggest that gemcitabine-induced apoptosis in human pancreatic cancer cells is mediated by the MKK3/6-p38 MAPK-caspase signaling pathway. Further, these results lead us to suggest that p38 MAPK should be investigated as a novel molecular target for human pancreatic cancer therapies. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.02.017

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Language：Japanese   Publisher：Hokkaido University  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

BACKGROUND. Multiple lesions of intraductal papillary-mutinous tumor of the pancreas (IPMT) in the same pancreas often are encountered. To elucidate field (multicentric) cancerization and clonality of IPMT, clonal analyses of IPMT and its precursor lesion of ductal hyperplasia were performed. K-ras codon 12 mutations and X-chromosome inactivation of human androgen receptor gene (HUMARA) were investigated.
METHODS. Paraffin embedded tissue samples from the pancreata of 37 patients who underwent resection for IPMTs were microdissected manually or by laser capture microdissection. Multiple samples from each surgical specimen were microdissected representing each IPMT and discrete ductal hyperplasias. DNA was extracted, and K-ras codon 12 mutations were examined by two-step polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mutations were analyzed by direct DNA sequence. The HUMARA locus was digested with or without HpaII and HhaI prior to amplification. The HUMARA assay was conducted by fluorescence-labeled PCR-RFLP and was analyzed with specialized software.
RESULTS. All 37 pancreata had at least two lesions of ductal hyperplasia, and 23 of 37 pancreata (62%) had K-ras codon 12 mutations in these precursor lesions. Of 23 pancreata with mutated K-ras hyperplasia, 15 (65%) had multiple, distinct mutations in different lesions of hyperplasia in the same pancreas, suggesting a field defect. Thirty-two of 37 IPMTs (86%) had K-ras codon 12 mutations. Among these, 16 IPMTs (50%) had multiple, distinct mutations at K-ras codon 12. The HUMARA assay showed that 12 of 15 IPMTs were informative, and 9 were considered polyclonal and/or oligoclonal origin in origin. With the combined results of multiple K-ras mutation detection and the HUMARA assay, 12 of 15 IPMTs from female patients (80%) were considered polyclonal and/or oligoclonal in origin.
CONCLUSIONS. The current results suggest that multiple, distinct K-ras mutations of different ductal hyperplasias in a given pancreas are due to afield (multicentric) cancerization effect in IPMTs. Thus, most of IPMTs are polyclonal and/or oligoclonal in origin, i.e., IPMTs may originate from multiple (molecularly distinct) precursor lesions. (C) 2001 American Cancer Society.

DOI： 10.1002/1097-0142(20011001)92:7<1807::AID-CNCR1697>3.0.CO;2-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs and are now in clinical trial. We have previously shown that farnesylamine, synthetic isoprenoid-linked with "amine" which acts as a potent FTI, induces apoptosis in human pancreatic cancer cells through the ras signaling cascade. Since the effect of FTI is usually 'cytostatic' rather than 'cytotoxic', we speculated another apoptotic machinery of farnesylamine in addition to the effect of FTI. Farnesylamine induced sustained activation of c-jun N-terminal kinase (JNK), which was not caused by other FTI, FTI-277. Blockage of JNK activity by dominant-negative mutant abrogated the DNA laddering and significantly reduced 'cytotoxic' effect of farnesylamine. Strikingly similar effect on JNK activation and apoptosis was induced by structurally related long-chain fatty amine (LFA), oleylamine, but not by farnesol, an isoprenoid analogue of farnesylamine without "amine." Taken together, apoptosis induction through JNK activation by farnesylamine based on the LFA structure rather than an effect of FTI (C) 2001 Academic Press.

DOI： 10.1006/bbrc.2001.5744

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

Endoscopic management has become the main therapeutic approach for the extraction of common bile duct (CBD) stones, and successful removal can be achieved in 80-90% patients using conventional balloon and basket techniques. However, if it is difficult to completely fragment a stone, or to clear the CBD, which may occur for a variety of reasons, the therapeutic problem will remain. When bile duct stones can not be removed, a viable management option is to place a biliary stent to ensure drainage. However, recent studies of long-term biliary stenting, with a plastic stent, showed a relatively high rate of morbidity and mortality. We report an alternative, unique treatment for unextractable common bile duct stones, using the temporal placement of an expandable metallic stent (EMS) to facilitate passage of fragments through the papilla. (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02200.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY, INC  

DOI： 10.1016/S0016-5107(00)70302-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

A case of mucinous cholangiocarcinoma (CC), a rare histological type of CC, featuring unusual images is reported. The patient was hospitalized because of acute development of jaundice and fever. Computed tomography demonstrated multiple cystic lesions in the liver and a band-like low density area parallel to the intrahepatic portal vein, a so-called 'periportal collar'. Endoscopic cholangiography revealed a stricture of the hepatic duct with slight upstream dilatation. Cytology of the bile juice and fine-needle aspiration of the cystic lesion in the liver disclosed mucinous carcinoma. The patient died of multiorgan failure 3 weeks after admission. The autopsied liver showed that multiple mucus lakes were lined with adenocarcinoma cells and signet ring cells were floating in the mucus lakes. The cancer cells had spread along the portal tract and invaded into the hepatic parenchyma. (C) 1999 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.1999.02033.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBL LTD.  

BACKGROUND/AIMS: Few data are available on the fate and incidence of epithelial hyperplasia throughout the life of anomalous pancreaticobiliary ductal union (APBD) patients. The pathological study in pediatric APBD patients is less recognized.
METHODOLOGY: Ten resected gallbladders obtained from children with APBD and control patients without APBD were examined histologically, and immunohistochemically for the detection of Ki-67 las a proliferative marker) and p53. K-ras mutations in codon 12 were also examined. Epithelial hyperplasia was classified into high-grade and low-grade hyperplasia.
RESULTS: Six (60%) of 10 patients with APBD had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. Diffuse epithelial hyperplasia was observed in 1 (50%) of 2 undilated-type APBD and 5 (63%) of 8 dilated-type. Two (33%) of 6 patients with epithelial hyperplasia exhibited high-grade hyperplasia. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. K-ras mutations and p53 overexpression were not detected in hyperplastic and normal mucosa.
CONCLUSIONS: Epithelial hyperplasia of the gallbladder accompanied by increased proliferative activity exists at birth or is acquired in childhood with APBD patients and may be an important factor predisposing to the development of gallbladder carcinoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HUMANA PRESS INC  

We report a rare case of pancreatic carcinoma producing a-fetoprotein (AFP), showing focal hepatoid differentiation in metastatic lymph nodes. A 65-yr-old female was admitted because of abdominal pain. The serum AFP was measured at 16,170 ng/mL. Radiological examinations revealed a mass measuring 6 cm in diameter in the body and tail of the pancreas. A right supraclavicular lymphadenopathy was found and biopsied. Light microscopy showed a tumor consisting of a portion of a hepatoid area and well-differentiated adenocarcinoma, which was suggestive of a hepatoid adenocarcinoma. Immunohistochemical analysis showed that the tumor cells expressed AFP, alpha(1)-antitrypsin (AT) and albumin. Although the pathological diagnosis of the primary pancreatic tumor was not obtained, this appears to be the first case of hepatoid adenocarcinoma of the pancreas.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Japan  

The significant association between pancreaticobiliary malunion (PBM), especially undilated-type PBM, and a high risk of gallbladder cancer is known. Reflux and stasis of pancreatic juice induce various epithelial changes in the gallbladder. Recently, epithelial hyperplasia of the gallbladder was shown to be significantly and frequently associated with undilated-type PBM, and it is suggested that the majority of epithelial hyperplasia may exist at birth or be acquired in early childhood, and thereafter present throughout the lives of PBM patients. Cell kinetic studies demonstrated a significant stepwise increase in cellular proliferative activity from normal gallbladder mucosa, through epithelial hyperplasia to cancer. Epithelial hyperplasia with increased proliferative activity may predispose the mucosa to mutational events, thereby increasing cancer risk in PBM patients. K-ras mutations were frequently detected in gallbladder cancer in PBM patients and in epithelial hyperplasia as well. Epithelial hyperplasia is demonstrated to be an important premalignant lesion of gallbladder cancer. A multistep process of carcinogenesis as a consequence of multiple genetic alterations of oncogenes and tumor suppressor genes has been demonstrated in various organs
however, there is limited information on the molecular mechanism in gallbladder carcinogenesis with PBM. Recent findings support the idea that epithelial hyperplasia plays an important role in gallbladder carcinogenesis with PBM and also support the concept that neoplastic development in gallbladder with PBM also evolves through a multistep process associated with hyperproliferation and genetic alterations. © Springer-Verlag 1999.

DOI： 10.1007/s005340050112

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

BAGKGROUND. Recent studies have shown that anomalous pancreaticobiliary ductal union (APBD) is an important risk factor for the development of gallbladder carcinoma. Epithelial hyperplasia of the gallbladder is one of the characteristic changes, but it is not clear whether epithelial hyperplasia is a premalignant lesion that could lead to cancer in APBD patients.
METHODS. Twenty-four APBD patients were classified into two types: patients with bile duct dilation (dilated type) (n = 13) and patients without dilation (undilated type) (n = 11). Resected gallbladders obtained from APBD patients and control patients without APBD were examined histologically and with immunohistochemical techniques for the detection of p53 and Ki-67 las a cell proliferation marker). K-ras mutations were examined using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis. The patients were also classified, according to extent of epithelial hyperplasia, as having high grade or low grade hyperplasia.
RESULTS. Fifteen (63%) of 24 APBD patients had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. The incidence of epithelial hyperplasia was significantly higher in the gallbladders of undilated-type APBD patients (91%) than in those of dilated-type patients (38%) (P &lt; 0.01). Three of 24 APBD patients (13%) had gallbladder carcinoma, and 2 of the 3 gallbladder carcinomas (67%) were accompanied by diffuse epithelial hyperplasia of the gallbladder. Among 21 nonneoplastic gallbladders, diffuse epithelial hyperplasia was observed in all (100%) of the undilated-type APBD and in 4 (33%) of 12 dilated-type APBD (P &lt; 0.001). High grade hyperplasia was observed in 7 of 11 patients (64%) with undilated-type APBD and 2 of 13 patients (15%) with dilated-type APBD (P &lt; 0.05). The incidence of high grade hyperplasia increased with age among patients older than 35 years. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. High grade hyperplasia had a significantly higher Ki-67 LI than low grade hyperplasia (P &lt; 0.001). Two (22%) of 9 high grade hyperplasia cases had K-ras mutations, whereas none of 6 low grade hyperplasia cases had. The types of K-ras mutations in codon 12 were GTT (Val) and GAT (Asp) in each case of hyperplasia; these were identical to those of concomitant carcinomas. Neither hyperplastic nor normal mucosa exhibited p53 overexpression.
CONCLUSIONS. The results of this study suggest that hyperplasia of the gallbladder mucosa in APBD patients is an early change that, because of the increased proliferative activity and presence of K-ras mutations, could be considered a premalignant lesion of the gallbladder. An increased cell population of epithelial hyperplasia may predispose the mucosa to mutational events, resulting in an increased risk for the development of gallbladder carcinoma in APBD patients. Cancer 1998;83: 267-75. (C) 1998 American Cancer Society.

DOI： 10.1002/(SICI)1097-0142(19980715)83:2<267::AID-CNCR10>3.0.CO;2-R

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

A frequent association of biliary tract carcinoma and anomalous pancreaticobiliary ductal union (APBD) is well recognized, especially gall-bladder carcinoma in undilated type APBD. However, little is known about the presence and incidence of adenomyomatosis (AMT) of the gall-bladder, a presumed premalignant lesion, in patients with APBD. This retrospective study was conducted to elucidate the clinical features and incidence of AMT in APBD patients with relation to undilated type and dilated type APBD. We reviewed the clinicopathological records of 30 patients with APBD (28 women and two men) encountered during the past 10 years. Among them, 22 patients underwent cholecystectomy and the resected specimens were subjected to histopathological examinations. Eleven cases of APBD patients were undilated type and 11 cases were dilated type. Adenomyomatosis was found in six (55%) of 11 undilated type and one (9%) of 11 dilated type, and fundal type was predominantly observed in six (86%) of seven AMT. An overall incidence of AMT in APBD patients was 32%. An undilated type of APBD is frequently associated with AMT and we believe, therefore, that clinicians should be aware of a possible coexistence of APBD and AMT.

DOI： 10.1111/j.1440-1746.1998.tb00634.x

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DOI： 10.11405/nisshoshi1964.95.900

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-YEAR BOOK INC  

Background: An anomalous pancreaticobiliary ductal union (APBD) is a high-risk factor for biliary tract carcinoma, which often is not diagnosed before overt malignancy. The early detection of APBD is therefore clinically important. We evaluated the gallbladder wall in APBD patients with endoscopic ultrasonography.
Methods: Clinicopathologic features and ultrasonographic findings of the gallbladder in 33 consecutive patients with APBD between 1986 and 1995 were studied in relation to two subtypes of APBD, that is, undilated (n = 17) and dilated (n = 16). The gallbladder wall was evaluated with conventional ultrasonography and/or endoscopic ultrasonography. Histologic examinations of 25 resected gallbladders were made.
Results: Fourteen of the seventeen patients with undilated type APBD (82%) had diffuse thickened gallbladder wall of 4 mm or more, whereas 5 of the 16 with dilated type (31%) had this finding (p &lt; 0.01). The thickened gallbladder wall consisted sonographically of two layers: diffuse thickened inner hypoechoic layer and outer hyperechoic layer. Mucosal hyperplasia was histologically found in 8 of 9 cases (89%) with thickened inner hypoechoic layer on endoscopic ultrasonography. Mucosal hyperplasia was observed in 10 of 11 undilated type APBD cases (91%) in which cholecystectomy was performed. In addition, the presence of anomalous union was shown by endoscopic ultrasonography in 9 of 11 patients with undilated type APBD (82%) and all 7 of those with dilated type. The characteristic ultrasonographic pattern of diffuse thickened inner hypoechoic layer was observed exclusively in patients with mucosal hyperplasia of the gallbladder associated with APBD among 2085 endoscopic ultrasonography examinations performed during the study period.
Conclusions: Diffuse thickened inner hypoechoic layer of the gallbladder wall was frequently observed in APBD patients, especially those with the undilated type, on ultrasonography and/or endoscopic ultrasonography. This finding corresponded histologically to mucosal hyperplasia of the gallbladder mucosa. Thickened inner hypoechoic layer is a useful ultrasonographic sign that indicates mucosal hyperplasia of the gallbladder and, particularly, the possible coexistence of undilated type APBD before the appearance of overt malignancy.

DOI： 10.1016/S0016-5107(97)70007-5

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11405/nisshoshi1964.94.10_706

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DOI： 10.11280/gee1973b.38.1548

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

A case of primary biliary cirrhosis (PBC) associated with idiopathic thrombocytopenic purpura (ITP) is reported. The patient is a 59-year-old man. When he was 49 years old, he was diagnosed with ITP and received steroid therapy that successfully increased platelet numbers. However, the steroid therapy failed to normalize the elevated gamma-glutamyl transpeptidase. Ten years after this episode, he suffered from general itching and malaise and exhibited a gradual increase of serum biliary enzyme levels. Immunologically, IgM was increased and anti-mitochondrial antibody was positive. Histological findings of liver needle biopsy showed chronic non-suppurative destructive cholangitis, confirming the diagnosis of PBC. To date, very few PBC cases associated with ITP have been reported. Our case is the second one in Japan. PBC and ITP in our patient seemed to develop simultaneously, but the effect of steroid therapy on the two conditions was different. This result suggests that the autoimmune process may have been different in PBC and ITP in the present patient.

DOI： 10.1007/BF02389532

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DOI： 10.11280/gee1973b.38.2865

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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

To clarify the clinicopathological features of tumors with submucosal invasion, especially superficial elevated and sessile ones, histological architectures of 32 cases of submucosal invasive cancers were analyzed. They were classified into 3 types based on cross-section view : PG and NPG of Shimoda's classification and PG'. Histological architectures were drawn in accordance with these findings. In 7 PG-Ca which consisted of PG only, no apparent correlation was found between the tumor sizes and invasion depth of submucosal layer. However, 12 NPG-Ca which consisted of NPG only and 12 Mixed-Ca which include various cross-section views both showed massive invasion into the submucosa with 1 cm or more in tumor size. Therefore these two types were similar in biological behavior in terms of invasion depth. And degree of submucosal invasion tended to increase in the order of PG-Ca, Mixed-Ca and NPG-Ca. Examinating histological architectures of the Mixed-Ca tumors in details, all of these cancers were consisted of both PG and PG'. Of the 12 Mixed-Ca, 91.7% were proved to be PG dominant type. Macroscopically, Is and IIa contained 88.9% and 40.0% of Mixed-Ca, respectively. In conclusion, these results suggest that PG' is a subtype of PG, and PG-Ca have a correlation between tumor invasion and alternation from PG to PG' in histological architectures among submucosal cancers. It is important to clarify morphological features of PG' in margin of Is and IIa tumors in diagnosing the depth of early colorectal cancers.

DOI： 10.11405/nisshoshi1964.92.1250

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

A 67-years-old man with chronic hepatitis C admitted to our hospital for the investiga-tion of abdominal tumor which had been detected incidentally by ultrasonography and CT scanning. The tumor was 25 x 20mm in diameter and located between stomach and left lobe of the liver. Endoscopic ultrasonography showed solid low-echoic mass with small aechoic area, connecting to the proper muscle layer and located extragastrically at the lesser curvature of the gastric body. Laparoscopic examination revealed round pedunclat-ed mass, yellowish-white in color, developing on the gastric serosa. Abdominal angiogra-phy showed fine tumor vessels and tumor stain. Based on these findings, we diagnosed this as a pedunclated gastric tumor, possibly myogenic in origin. Because the tumor showed no remarkable findings of malignancy including its small size, we performed tumor resection under laparoscopy. Histologic findings showed leiomyosarcoma of low grade malignancy. Although laparoscopic surgery is performed commonly, this is the first case report about laparoscopic resection of extragastric tumor. As the tumor was small and had few tumor vessels, the therapeutic procedure using new kind of instrument was considerably easy without any complications. We conclude that laparoscopic surgery should be perform-ed for resection of such extragastric tumors.

DOI： 10.11280/gee1973b.37.308

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：医学図書出版(株)  

近年、体液を使用した液体生検(liquid biopsy)が、腫瘍の質的診断や病勢把握に重要な位置を得つつある。膵癌における代表的なドライバー遺伝子であるKRAS、CDKN2A、TP53、SMAD4変異や、IPMNで多くみられるGNAS変異など、血中遊離DNA(cell-free DNA)を用いたliquid biopsyは、通常型膵癌のみならず、IPMNの悪性度評価にも大きく寄与する可能性がある。一方で、体液中のcell-free RNAや細胞外小胞(extracellular vesicles: EVs)内に発現するRNAも、liquid biopsyの重要な標的となる。本稿ではIPMNの発生・進展における分子異常に触れるとともに、体液中の遺伝子変異やRNA発現解析による診断、悪性度評価に関するこれまでの報告をまとめ、診療への応用が期待されるliquid biopsyの最新の動向について、われわれが得た知見と併せて概説する。(著者抄録)

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