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    Validation and head-to-head comparison of four models for predicting malignancy of intraductal papillary mucinous neoplasm of the pancreas: A study based on endoscopic ultrasound findings. Hua Jie,Zhang Bo,Yang Xiu-Jiang,Zhang Yi-Yin,Wei Miao-Yan,Liang Chen,Meng Qing-Cai,Liu Jiang,Yu Xian-Jun,Xu Jin,Shi Si World journal of gastrointestinal oncology BACKGROUND:Several models are currently available for predicting the malignancy of pancreatic intraductal papillary mucinous neoplasm (IPMN), namely, the Pancreatic Surgery Consortium (PSC), the Japan Pancreas Society (JPS), the Johns Hopkins Hospital (JHH), and the Japan-Korea (JPN-KOR) models. However, a head-to-head comparison that shows which model is more accurate for this individualized prediction is lacking. AIM:To perform a head-to-head comparison of the four models for predicting the malignancy of pancreatic IPMN. METHODS:A total of 181 patients with IPMN who had undergone surgical resection were identified from a prospectively maintained database. The characteristics of IPMN in patients were recorded from endoscopic ultrasound imaging data and report archives. The performance of all four models was examined using Harrell's concordance index (C-index), calibration plots, decision curve analyses, and diagnostic tests. RESULTS:Of the 181 included patients, 94 were categorized as having benign disease, and the remaining 87 were categorized as having malignant disease. The C-indexes were 0.842 [95% confidence interval (CI): 0.782-0.901], 0.704 (95%CI: 0.626-0.782), 0.754 (95%CI: 0.684-0.824), and 0.650 (95%CI: 0.483-0.817) for the PSC, JPS, JHH, and JPN-KOR models, respectively. Calibration plots showed that the PSC model had the least pronounced departure from ideal predictions. Of the remaining three models, the JPS and JHH models underestimated the probability of malignancy, while the JPN-KOR model overestimated the malignant potential of branch duct-IPMN. Decision curve analysis revealed that the PSC model resulted in a better clinical net benefit than the three other models. Diagnostic tests also showed a higher accuracy (0.801) for the PSC model. CONCLUSION:The PSC model exhibited the best performance characteristics. Therefore, the PSC model should be considered the best tool for the individualized prediction of malignancy in patients with pancreatic IPMN. 10.4251/wjgo.v11.i11.1043
    Stratifying Intraductal Papillary Mucinous Neoplasms by Cyst Fluid Analysis: Present and Future. Hao Scarlett,Takahashi Caitlin,Snyder Rebecca A,Parikh Alexander A International journal of molecular sciences A significant proportion of patients with intraductal papillary mucinous neoplasms (IPMNs) undergo surgical resection in order to prevent or treat pancreatic cancer at the risk of significant perioperative morbidity. Efforts have been made to stratify the potential risk of malignancy based on the clinical and radiographic features of IPMN to delineate which cysts warrant resection versus observation. An analysis of the cyst fluid obtained by preoperative endoscopic examination appears to be correlative of cyst type and risk, whereas serum markers and radiographic findings have not yet reached a level of sensitivity or specificity that proves they are clinically meaningful. In this review, we investigate the current cyst fluid analysis studies and present those that have shown promise in effectively stratifying high-risk versus low-risk lesions. While new cyst fluid markers continue to be identified, additional efforts in testing panels and marker composites in conjunction with clinical algorithms have also shown promise in distinguishing dysplasia and the risk of malignancy. These should be tested prospectively in order to determine their role in guiding the surveillance of low-risk lesions and to evaluate the new markers detected by proteomics and genetic sequencing. 10.3390/ijms21031147
    Molecular Diagnosis of Cystic Neoplasms of the Pancreas: a Review. Chen J C,Beal Eliza W,Pawlik Timothy M,Cloyd Jordan,Dillhoff Mary E Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract BACKGROUND:The prevalence of incidental pancreatic cystic neoplasms (PCNs) has increased dramatically with advancements in cross-sectional imaging. Diagnostic imaging is limited in differentiating between benign and malignant PCNs. The aim of this review is to provide an overview of biomarkers that can be used to distinguish PCNs. METHODS:A review of the literature on molecular diagnosis of cystic neoplasms of the pancreas was performed. RESULTS:Pancreatic cysts can be categorized into inflammatory and non-inflammatory lesions. Inflammatory cysts include pancreatic pseudocysts. Noninflammatory lesions include both mucinous and non-mucinous lesions. Mucinous lesions include intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm. Non-mucinous lesions include serous cystadenoma and solid-pseudopapillary tumor of the pancreas. Imaging, cyst aspiration, and histologic findings, as well as carcinoembryonic antigen and amylase are commonly used to distinguish between cyst types. However, molecular techniques to detect differences in genetic mutations, protein expression, glycoproteomics, and metabolomic profiling are important developments in distinguishing between cyst types. DISCUSSION:Nomograms incorporating common clinical, laboratory, and imaging findings have been developed in a better effort to predict malignant IPMN. The incorporation of top molecular biomarker candidates to nomograms may improve the predictive ability of current models to more accurately diagnose malignant PCNs. 10.1007/s11605-020-04537-2
    Promoter DNA Hypermethylation of the Cysteine Dioxygenase 1 (CDO1) Gene in Intraductal Papillary Mucinous Neoplasm (IPMN). Fujiyama Yoshiki,Kumamoto Yusuke,Nishizawa Nobuyuki,Nakamoto Shuji,Harada Hiroki,Yokota Kazuko,Tanaka Yoko,Igarashi Kazuharu,Oiki Hironobu,Okuwaki Kosuke,Iwai Tomohisa,Kajita Sabine,Takahashi Hiroyuki,Tajima Hiroshi,Kaizu Takashi,Sasaki Jiichiro,Watanabe Masahiko,Yamashita Keishi Annals of surgical oncology BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN. PATIENTS AND METHODS:A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy. RESULTS:The methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277). CONCLUSIONS:CDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma-carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases. 10.1245/s10434-020-08291-2
    Evolution of the immune landscape during progression of pancreatic intraductal papillary mucinous neoplasms to invasive cancer. Roth Susanne,Zamzow Katharina,Gaida Matthias M,Heikenwälder Mathias,Tjaden Christine,Hinz Ulf,Bose Promita,Michalski Christoph W,Hackert Thilo EBioMedicine BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer, which is characterized by an immunosuppressive microenvironment. Yet, the spatial distribution of the immune infiltrate and how it changes during IPMN progression is just beginning to be understood. METHODS:We obtained tissue samples from patients who underwent pancreatic surgery for IPMN, and performed comprehensive immunohistochemical analyses to investigate the clinical significance, composition and spatial organization of the immune microenvironment during progression of IPMNs. Survival analysis of pancreatic cancer patients was stratified by tumour infiltrating immune cell subtypes. FINDINGS:The immune microenvironment evolves from a diverse T cell mixture, comprising CD8 T cells, Th/c1 and Th/c2 as major players combined with Th9, Th/c17, Th22, and Treg cells in low-grade IPMN, to a Treg dominated immunosuppressive state in invasive pancreatic cancer. Organized lymphoid clusters formed in IPMN surrounding stroma and accumulated immunosuppressive cell types during tumour progression. Survival of pancreatic cancer patients correlated with Th2 signatures in the tumour microenvironment. INTERPRETATION:The major change with regards to T cell composition during IPMN progression occurs at the step of tissue invasion, indicating that malignant transformation only occurs when tumour immune surveillance is overcome. This suggests that novel immunotherapies that would boost spontaneous antitumor immunity at premalignant states could prevent pancreatic cancer development. FUNDING:The present work was supported by German Cancer Aid grants (70,112,720 and 70,113,167) to S. R., and the Olympia Morata Programme of the Medical Faculty of Heidelberg University to S. R. 10.1016/j.ebiom.2020.102714
    Promoter-Level Transcriptome Identifies Stemness Associated With Relatively High Proliferation in Pancreatic Cancer Cells. Chen Ru,Sugiyama Aiko,Kataoka Naoyuki,Sugimoto Masahiro,Yokoyama Shoko,Fukuda Akihisa,Takaishi Shigeo,Seno Hiroshi Frontiers in oncology Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a-Cre; Kras; p53 and Ptf1a-Cre; Kras; and Brg1 pancreatic ductal adenocarcinomas (PDAs). The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome. Two RNA samples extracted from three individual subcutaneous tumors generated by the transplantation of PanIN or IPMN cancer cell lines were used to generate libraries and Illumina Seq, with four RNA samples in total, to depict discrete transcriptional network between IPMN and PanIN. Moreover, in IPMN cells, the transcriptome tended to be enriched for suppressive and inhibitory biological processes. In contrast, the transcriptome of PanIN cells exhibited properties of stemness. Notably, the proliferation capacity of the latter cells in culture was only minimally constrained by well-known chemotherapy drugs such as GSK690693 and gemcitabine. The various transcriptional factor network systems detected in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. Further, we hope that these findings will enhance our mechanistic understanding of the characteristic molecular alterations underlying pancreatic cancer precursors. These data may provide a promising direction for therapeutic research. 10.3389/fonc.2020.00316
    How does intestinal-type intraductal papillary mucinous neoplasm emerge? CDX2 plays a critical role in the process of intestinal differentiation and progression. Omori Yuko,Ono Yusuke,Kobayashi Toshikazu,Motoi Fuyuhiko,Karasaki Hidenori,Mizukami Yusuke,Makino Naohiko,Ueno Yoshiyuki,Unno Michiaki,Furukawa Toru Virchows Archiv : an international journal of pathology 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. 10.1007/s00428-020-02806-8
    An elevated CA 19-9 is associated with invasive cancer and worse survival in IPMN. Ciprani D,Morales-Oyarvide V,Qadan M,Hank T,Weniger M,Harrison J M,Rodrigues C,Horick N K,Mino-Kenudson M,Ferrone C R,Warshaw A L,Lillemoe K D,Fernández-Del Castillo C Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] BACKGROUND:Current guidelines for IPMN include an elevated serum carbohydrate antigen (CA) 19-9 among the worrisome features. However, the correlation of CA 19-9 with histological malignant features and survival is unclear. Serum CEA is also currently used for preoperative management of IPMN, although its measurement is not evidence-based. Accordingly, we aimed to assess the role of these tumor markers as predictors of malignancy in IPMN. METHODS:IPMN resected between 1998 and 2018 at Massachusetts General Hospital were analyzed. Clinical, pathological and survival data were collected and compared to preoperative levels of CA 19-9 and CEA. Receiver operating characteristic (ROC) and Cox regression analyses were performed considering cut-offs of 37 U/ml (CA 19-9) and 5 μg/l (CEA). RESULTS:Analysis of 594 patients showed that preoperative CA 19-9 levels > 37 U/ml (n = 128) were associated with an increased likelihood of invasive carcinoma when compared to normal levels (45.3% vs. 18.0%, P < 0.001), while there was no difference with respect to high-grade dysplasia (32.9% vs 31.9%, P = 0.88). The proportion of concurrent pancreatic cancer was higher in patients with CA 19-9 > 37 U/ml (17.2% vs 4.9%, P < 0.001). An elevated CA 19-9 was also associated with worse overall and disease-free survival (HR = 1.943, P = 0.007 and HR = 2.484, P < 0.001 respectively). CEA levels did not correlate with malignancy. CONCLUSION:In patients with IPMN, serum CA19-9 > 37 U/ml is associated with invasive IPMN and concurrent pancreatic cancer as well as worse survival, but not with high-grade dysplasia. Serum CEA appears to have minimal utility in the management of these patients. 10.1016/j.pan.2020.04.002
    Exosomal miRNA signatures of pancreatic lesions. Vicentini Caterina,Calore Federica,Nigita Giovanni,Fadda Paolo,Simbolo Michele,Sperandio Nicola,Luchini Claudio,Lawlor Rita T,Croce Carlo Maria,Corbo Vincenzo,Fassan Matteo,Scarpa Aldo BMC gastroenterology BACKGROUND:Pancreatic and peri-pancreatic neoplasms encompass a variety of histotypes characterized by a heterogeneous prognostic impact. miRNAs are considered efficient candidate biomarkers due to their high stability in tissues and body fluids. We applied Nanostring profiling of circulating exosomal miRNAs to distinct pancreatic lesions in order to establish a source for biomarker development. METHODS:A series of 140 plasma samples obtained from patients affected by pancreatic ductal adenocarcinoma (PDAC, n = 58), pancreatic neuroendocrine tumors (PanNET, n = 42), intraductal papillary mucinous neoplasms (IPMN, n = 20), and ampulla of Vater carcinomas (AVC, n = 20) were analyzed. Comprehensive miRNA profiling was performed on plasma-derived exosomes. Relevant miRNAs were validated by qRT-PCR and in situ hybridization (ISH). RESULTS:Lesion specific miRNAs were identified through multiple disease comparisons. Selected miRNAs were validated in the plasma by qRT-PCR and at tissue level by ISH. We leveraged the presence of clinical subtypes with each disease cohort to identify miRNAs that are differentially enriched in aggressive phenotypes. CONCLUSIONS:This study shows that pancreatic lesions are characterized by specific exosomal-miRNA signatures. We also provide the basis for further explorations in order to better understand the relevance of these signatures in pancreatic neoplasms. 10.1186/s12876-020-01287-y
    Chronic inflammatory changes and oxidative stress in the background of "pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm". Matsuda Ryota,Miyasaka Yoshihiro,Yamada Yuichi,Kawata Jun,Sakihama Kukiko,Yamamoto Takeo,Saeki Kiyoshi,Yamamoto Hidetaka,Ohishi Yoshihiro,Koga Yutaka,Nakamura Masafumi,Oda Yoshinao Virchows Archiv : an international journal of pathology Cases of "pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm" (IPMN) have multiple PDAC lesions more frequently than cases of "PDAC without IPMN". However, the mechanism of carcinogenesis in this former disease category remains unknown. The main objective of this work was thus to investigate the effects of chronic inflammation on carcinogenesis in PDAC cases. We selected 31 "PDAC concomitant with IPMN" patients and 58 "PDAC without IPMN" patients and pathologically evaluated their background pancreatic parenchyma. Fibrosis and inflammation scores of background pancreas were higher in "PDAC concomitant with IPMN" than in "PDAC without IPMN" (P < 0.0001 and P < 0.0001, respectively), whereas the fatty infiltration score of background pancreas was high in "PDAC without IPMN" (P = 0.0024). Immunohistochemically, the expression of 8-hydroxy-2'-deoxyguanosine (8-OHDG), an oxidative stress marker, in the background pancreas was high in "PDAC concomitant with IPMN" compared with that in "PDAC without IPMN" (P < 0.0001). Chronic inflammation activates oxidative stress in tissue throughout the pancreas and probably confers susceptibility to tumorigenesis in "PDAC concomitant with IPMN". 10.1007/s00428-020-02844-2
    Noninvasive Discrimination of Low and High-risk Pancreatic Intraductal Papillary Mucinous Neoplasms. Roth Susanne,Bose Promita,Alhamdani Mohamed S S,Mustafa Shakhawan A,Tjaden Christine,Zamzow Katharina,Hinz Ulf,Michalski Christoph W,Neoptolemos John P,Hoheisel Jörg D,Büchler Markus W,Hackert Thilo Annals of surgery OBJECTIVE:To propose a noninvasive diagnostic approach, which allows reliable distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND:IPMNs are identifiable precursor lesions of pancreatic cancer, of which surgical resection is warranted prior to the development of invasive carcinoma, but low-grade IPMNs should not be unnecessarily resected. However, diagnostic tools that preoperatively enable accurate risk stratification of IPMNs are missing. METHODS:This single-center, retrospective cohort study included 56 patients who underwent surgical resection for IPMN including 18 low-risk (low-grade) and 38 high-risk (high-grade/invasive carcinoma) IPMNs, from whom clinical features and serum samples were prospectively obtained. An antibody microarray platform was used to analyze the serum proteome. Based on serum markers and selected clinical characteristics support vector machine models were constructed to predict the risk of IPMN malignancy. RESULTS:A serum protein signature discriminating low- and high-risk IPMN patients was identified. Combinations of established clinical features and the newly identified serum biomarkers correctly distinguished low- and high-risk IPMNs in 93% on 1000-fold cross-validation. CONCLUSIONS:This study highlights the synergistic predictive value of combining a novel serum protein signature with conventional clinical characteristics to risk-stratify IPMN patients. If these findings are supported by larger validation studies, they might enable more rational decision-making in clinical management of IPMN patients in conjunction with clinical guidelines. 10.1097/SLA.0000000000004066
    Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms. Huang Bo,Trujillo Maria A,Fujikura Kohei,Qiu Miaozhen,Chen Fei,Felsenstein Matthäus,Zhou Cancan,Skaro Michael,Gauthier Christian,Macgregor-Das Anne,Hutchings Danielle,Hong Seung-Mo,Hruban Ralph H,Eshleman James R,Thompson Elizabeth D,Klein Alison P,Goggins Michael,Wood Laura D,Roberts Nicholas J The Journal of pathology Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 10.1002/path.5515
    Genomic characterization of malignant progression in neoplastic pancreatic cysts. Noë Michaël,Niknafs Noushin,Fischer Catherine G,Hackeng Wenzel M,Beleva Guthrie Violeta,Hosoda Waki,Debeljak Marija,Papp Eniko,Adleff Vilmos,White James R,Luchini Claudio,Pea Antonio,Scarpa Aldo,Butturini Giovanni,Zamboni Giuseppe,Castelli Paola,Hong Seung-Mo,Yachida Shinichi,Hiraoka Nobuyoshi,Gill Anthony J,Samra Jaswinder S,Offerhaus G Johan A,Hoorens Anne,Verheij Joanne,Jansen Casper,Adsay N Volkan,Jiang Wei,Winter Jordan,Albores-Saavedra Jorge,Terris Benoit,Thompson Elizabeth D,Roberts Nicholas J,Hruban Ralph H,Karchin Rachel,Scharpf Robert B,Brosens Lodewijk A A,Velculescu Victor E,Wood Laura D Nature communications Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention. 10.1038/s41467-020-17917-8
    CD117 Is a Specific Marker of Intraductal Papillary Mucinous Neoplasms (IPMN) of the Pancreas, Oncocytic Subtype. Mattiolo Paola,Hong Seung-Mo,Paolino Gaetano,Rusev Borislav C,Marchegiani Giovanni,Salvia Roberto,Andrianello Stefano,Capelli Paola,Piccoli Paola,Parolini Claudia,Scarpa Aldo,Lawlor Rita T,Luchini Claudio International journal of molecular sciences The intraductal oncocytic papillary neoplasm (IOPN) of the pancreas has been recognized by WHO classification as a unique intraductal papillary mucinous neoplasm (IPMN) category. IOPN is composed of oxyphil cells, usually expressing MUC5AC, MUC6, and Hep Par-1, and harboring / fusion genes as their genetic hallmark. Although IOPNs are associated with an infiltrative adenocarcinoma in up to 30% of cases, the survival rate after surgical resection approaches 100%. This highlights the importance of the correct IOPN diagnosis, above all in cases with an associated invasive component. In this study, the immunohistochemical expression of CD117 was investigated in 111 IPMNs, including 17 oncocytic, 45 gastric, 20 pancreatico-biliary, and 29 intestinal IPMNs. We also tested the expression of MUC5AC, MUC6, and Hep Par-1 in the IOPN cohort. CD117 positivity was significantly more frequent in IOPNs compared to the other IPMN subtypes ( < 0.0001). Furthermore, within IOPN, a lower or absent CD117, MUC5AC, MUC6, and Hep Par-1 expression tended to be associated with the presence of an infiltrative component. Our findings shed light into the biology of these complex lesions, which are confirmed to be a distinctive IPMN subtype; notably, CD117 emerged as a potential, additional tool in the differential diagnosis of IPMNs. 10.3390/ijms21165794
    Marker Identification of the Grade of Dysplasia of Intraductal Papillary Mucinous Neoplasm in Pancreatic Cyst Fluid by Quantitative Proteomic Profiling. Do Misol,Kim Hongbeom,Shin Dongyoon,Park Joonho,Kim Haeryoung,Han Youngmin,Jang Jin-Young,Kim Youngsoo Cancers The incidence of patients with pancreatic cystic lesions, particularly intraductal papillary mucinous neoplasm (IPMN), is increasing. Current guidelines, which primarily consider radiological features and laboratory data, have had limited success in predicting malignant IPMN. The lack of a definitive diagnostic method has led to low-risk IPMN patients undergoing unnecessary surgeries. To address this issue, we discovered IPMN marker candidates by analyzing pancreatic cystic fluid by mass spectrometry. A total of 30 cyst fluid samples, comprising IPMN dysplasia and other cystic lesions, were evaluated. Mucus was removed by brief sonication, and the resulting supernatant was subjected to filter-aided sample preparation and high-pH peptide fractionation. Subsequently, the samples were analyzed by LC-MS/MS. Using several bioinformatics tools, such as gene ontology and ingenuity pathway analysis, we detailed IPMNs at the molecular level. Among the 5834 proteins identified in our dataset, 364 proteins were differentially expressed between IPMN dysplasia. The 19 final candidates consistently increased or decreased with greater IPMN malignancy. CD55 was validated in an independent cohort by ELISA, Western blot, and IHC, and the results were consistent with the MS data. In summary, we have determined the characteristics of pancreatic cyst fluid proteins and discovered potential biomarkers for IPMN dysplasia. 10.3390/cancers12092383
    Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification. Nasca Vincenzo,Chiaravalli Marta,Piro Geny,Esposito Annachiara,Salvatore Lisa,Tortora Giampaolo,Corbo Vincenzo,Carbone Carmine International journal of molecular sciences Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized. 10.3390/ijms21176386
    Mutations in IPMN Cases: A Potential Prognostic Factor. Chang Xiao Yan,Wu Yan,Jiang Ying,Wang Peng Yan,Chen Jie Gastroenterology research and practice An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in , , and . To clarify the molecular profiles of IPMNs, we conducted mutation analysis of , , and in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in and codon 201 in were detected by Sanger sequencing. Next-generation sequencing was performed on , and the results were further verified by Sanger sequencing. We identified and mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. mutations were significantly correlated with the morphologic subtype ( < 0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients ( = 0.002), while KRAS and GNAS mutations did not affect the prognosis of patients. 10.1155/2020/1457452
    Fate of Patients With Intraductal Papillary Mucinous Neoplasms of Pancreas After Resection According to the Pathology and Margin Status: Continuously Increasing Risk of Recurrence Even After Curative Resection Suggesting Necessity of Lifetime Surveillance. Kim Hyeong Seok,Han Youngmin,Kang Jae Seung,Choi Yoo Jin,Byun Yoonhyeong,Kim Haeryoung,Lee Kyung Bun,Kim Hongbeom,Kwon Wooil,Jang Jin-Young Annals of surgery OBJECTIVE:This study evaluated the associated factors and prognosis according to pathology and margin after surgical resection of intraductal papillary mucinous neoplasms (IPMN). BACKGROUND:There is limited information on recurrence patterns according to pathology and margin in IPMN. METHODS:Total 577 patients who underwent operation for IPMN at a tertiary center were included. Factors associated with recurrence, survival and recurrence outcomes according to pathology and margin were analyzed. RESULTS:Among 548 patients analyzed, 353 had low-grade dysplasia (LGD); 78, high-grade dysplasia (HGD); and 117, invasive IPMN. Total 50 patients developed recurrences, with four resection margins, eight remnant pancreas, 11 locoregional, and 35 distant recurrences. Invasive IPMN showed worse 5-year cumulative recurrence risk (LGD vs HGD vs invasive: 0.7% vs 4.3% vs 37.6%, p < 0.001) and 5-year survival rate (89.0% vs 84.0% vs 48.4%, p < 0.001). Recurrence risk increased after 5 years, even in LGD and HGD. Malignant margin (HGD and invasive) had worse 5-year cumulative recurrence rate (R0 vs LGD vs malignant: 8.3% vs 5.9% vs 50.6%, p < 0.001) and 5-year survival rate (80.7% vs 83.0% vs 30.8%, p < 0.001). CA19-9 > 37 (p = 0.003), invasive IPMN (p < 0.001), and malignant margin (p = 0.036) were associated with recurrence. CONCLUSIONS:Invasive IPMN developed more recurrences and had worse survival than LGD or HGD, indicating the need for more efficient postoperative treatment strategies. Patients with LGD and HGD also need regular follow-up for recurrence after 5 years. Malignant margins need additional resection to achieve negative or at least LGD margin. 10.1097/SLA.0000000000004478
    Survival Outcomes of Pancreatic Intraepithelial Neoplasm (PanIN) versus Intraductal Papillary Mucinous Neoplasm (IPMN) Associated Pancreatic Adenocarcinoma. McGinnis Timothy,Bantis Leonidas E,Madan Rashna,Dandawate Prasad,Kumer Sean,Schmitt Timothy,Paluri Ravi Kumar,Kasi Anup Journal of clinical medicine Pancreatic intraepithelial neoplasms (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) are common pancreatic adenocarcinoma precursor lesions. However, data regarding their respective associations with survival rate and prognosis are lacking. We retrospectively evaluated 72 pancreatic adenocarcinoma tumor resection patients at the University of Kansas Hospital between August 2009 and March 2019. Patients were divided into one of two groups, PanIN or IPMN, based on the results of the surgical pathology report. We compared baseline characteristics, overall survival (OS), and progression free survival (PFS) between the two groups, as well as OS and PFS based on local or distant tumor recurrence for both groups combined. 52 patients had PanINs and 20 patients had IPMNs. Patients who had an IPMN precursor lesion had better median PFS and OS when compared to patients with PanIN precursor lesions. However, the location of tumor recurrence (local or distant) did not show a statistically significant difference in OS. 10.3390/jcm9103102
    S6 ribosomal protein phosphorylation is associated with malignancy of intraductal papillary mucinous neoplasm of the pancreas. Hirashita Teijiro,Hirashita Yuka,Iwashita Yukio,Endo Yuichi,Kiyonaga Maki,Matsumoto Shunro,Hijiya Naoki,Moriyama Masatsugu,Murakami Kazunari,Inomata Masafumi Annals of gastroenterological surgery Background:Glucose metabolism of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas is unclear. S6 ribosomal protein (S6) phosphorylation is involved not only in controlling cell growth but also in glucose metabolism in cancer. The aim of this study was to investigate the role of S6 phosphorylation and the significance of glucose metabolic changes in IPMN. Methods:Records of 39 patients who underwent preoperative FDG-PET and curative resection were enrolled in this study. S6 phosphorylation and GLUT1 expression were evaluated immunohistochemically in these patients. The effect of S6 phosphorylation on glucose uptake was examined in cancer cell lines. To examine the change of glucose metabolism in IPMN clinically, the relation between clinical factors including FDG-PET and malignancy of IPMN was investigated. Results:S6 phosphorylation and GLUT1 expression were significantly higher in carcinoma than in normal cells or adenoma. Cell lines with high level of S6 phosphorylation showed high glucose uptake, and inhibition of S6 phosphorylation reduced glucose uptake. In clinical examination, FDG-PET was the independent factor related to the diagnosis of adenoma or carcinoma (odds ratio = 20.0, 95% confidence interval = 1.837-539.9,  = .012). FDG-PET detected carcinoma with a sensitivity of 81.8%, specificity of 96.4%, and accuracy of 92.3%. Conclusion:S6 phosphorylation was associated with glucose uptake and malignancy of IPMN. Moreover, glucose uptake increased in malignant cells of IPMN, and FDG-PET is useful for detecting malignancy of IPMN. 10.1002/ags3.12367
    Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic mutations predominantly in low-grade regions. Fujikura Kohei,Hosoda Waki,Felsenstein Matthäus,Song Qianqian,Reiter Johannes G,Zheng Lily,Beleva Guthrie Violeta,Rincon Natalia,Dal Molin Marco,Dudley Jonathan,Cohen Joshua D,Wang Pei,Fischer Catherine G,Braxton Alicia M,Noë Michaël,Jongepier Martine,Fernández-Del Castillo Carlos,Mino-Kenudson Mari,Schmidt C Max,Yip-Schneider Michele T,Lawlor Rita T,Salvia Roberto,Roberts Nicholas J,Thompson Elizabeth D,Karchin Rachel,Lennon Anne Marie,Jiao Yuchen,Wood Laura D Gut OBJECTIVE:Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. DESIGN:We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. RESULTS:Our multiregion whole exome sequencing identified , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. CONCLUSION:Hotspot mutations in occur at high prevalence in IPMNs. Unique among pancreatic driver genes, mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway. 10.1136/gutjnl-2020-321217
    Establishing a living biobank of patient-derived organoids of intraductal papillary mucinous neoplasms of the pancreas. Beato Francisca,Reverón Dayana,Dezsi Kaleena B,Ortiz Antonio,Johnson Joseph O,Chen Dung-Tsa,Ali Karla,Yoder Sean J,Jeong Daniel,Malafa Mokenge,Hodul Pamela,Jiang Kun,Centeno Barbara A,Abdalah Mahmoud A,Balasi Jodi A,Tassielli Alexandra F,Sarcar Bhaswati,Teer Jamie K,DeNicola Gina M,Permuth Jennifer B,Fleming Jason B Laboratory investigation; a journal of technical methods and pathology Pancreatic cancer (PaCa) is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect PaCa at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic PaCa precursors that comprise nearly 50% of pancreatic cysts detected incidentally via cross-sectional imaging. Since IPMNs can progress from low- and moderate-grade dysplasia to high-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish a living biobank of patient-derived organoids (PDO) from IPMNs. IPMN tumors and adjacent normal pancreatic tissues were successfully harvested from 15 patients with IPMNs undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between May of 2017 and March of 2019. Organoid cultures were also generated from cryopreserved tissues. Organoid count and size were determined over time by both Image-Pro Premier 3D Version 9.1 digital platform and Matlab application of a Circular Hough Transform algorithm, and histologic and genomic characterization of a subset of the organoids was performed using immunohistochemistry and targeted sequencing, respectively. The success rates for organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different epithelial subtypes showed different morphologies in vitro, and organoids recapitulated histologic and genomic characteristics of the parental IPMN tumor. In summary, this preclinical model has the potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for early detection and targets for chemoprevention. 10.1038/s41374-020-00494-1
    A Blood-based Gene-expression Scoring System for Cancer Screening in Patients With Branch-duct Intraductal Papillary Mucinous Neoplasms. Suzuki Rei,Tamura Hirosumi,Honma Reiko,Konno Naoki,Irie Hiroki,Takagi Tadayuki,Sugimoto Mitsuru,Asama Hiroyuki,Sato Yuki,Yoshinori Okubo,Nakamura Jun,Takasumi Mika,Kato Tsunetaka,Hashimoto Minami,Hikichi Takuto,Imai Jun-Ichi,Watanabe Shinya,Ohira Hiromasa Anticancer research BACKGROUND:In patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMN), we aimed to develop a novel blood-based biomarker utilizing a gene-expression profile for the detection of pancreatic malignancies, such as IPMN-derived carcinoma (IPMC) or pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS:We enrolled 40 patients with pancreatic tumors (24 BD-IPMNs, four IPMCs and 12 PDACs) and identified the characteristic gene-expression profiles in pancreatic malignancies. Subsequently, we constructed a gene-expression scoring system for the proper diagnosis of pancreatic malignancies. The result was validated in 14 patients (five IPMNs, three IPMCs and six PDACs). RESULTS:The scoring system utilizing the expression levels of 13 genes showed high diagnostic yield (sensitivity=94.0%, specificity=92.0% and area under the curve=0.94), which was confirmed in the validation set. Furthermore, its diagnostic yield was not reduced even in early-stage pancreatic malignancies (sensitivity=85.0%, specificity=93.0% and area under the curve=0.88). CONCLUSION:We developed a blood-based gene expression scoring system for cancer screening in patients with BD-IPMNs. 10.21873/anticanres.14680
    Circulating extracellular vesicle-encapsulated microRNA as screening biomarkers for intraductal papillary mucinous neoplasm. Sato Yuki,Suzuki Rei,Takagi Tadayuki,Sugimoto Mitsuru,Ohira Hiromasa Oncology letters Since intraductal papillary mucinous neoplasms (IPMNs) occasionally contain pancreatic malignancies, it is vital to develop a screening program that can detect IPMNs in the general population and that can identify IPMNs with high malignant potential. The present study investigated whether microRNAs (miRNAs/miRs) in the blood may be diagnostic markers for IPMN screening. Initially, extracellular vesicle-encapsulated miRNAs (EV-miRNAs) in the serum with altered expression between IPMN, IPMN-derived carcinoma (IPMC) and control samples, were identified using microarray analysis. To validate the microarray results, the expression levels of selected EV-miRNAs were detected. Briefly, serum EV-miRNAs were extracted from 38 patients with IPMN (11 patients with IPMC and 27 patients with benign IPMN) and 21 non-tumor controls. The results of the microarray analysis revealed that the expression levels of EV-miR-22-3p, EV-miR-4539 and EV-miR-6132 were higher in the IPMN and IPMC serum samples compared with those in the control samples. With regards to discriminating IPMNs from controls, only miR-4539 exhibited a significant difference (P=0.004). In the comparison between IPMN and IPMC, carcinogenic antigen 19-9 (CA19-9) and EV-miR-6132 exhibited significant differences (P=0.01 and P=0.007, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that EV-miR-4539 could discriminate patients with IPMNs from control patients, with an area under the curve (AUC) of 0.72. Additionally, ROC analysis indicated that the markers could discriminate patients with IPMC from benign IPMN, with AUC values of 0.77 for EV-miR-6132 and 0.74 for CA19-9. In conclusion, the present study suggested that EV-miRNAs may be used as diagnostic markers for the detection of IPMNs in the general population as well as for identifying IPMNs with high malignant potential. 10.3892/ol.2020.12178
    The pathological features and prognoses of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm after surgical resection: a single institution series. Li Yuqiong,Zhu Zhongfei,Peng Lisi,Jin Zhendong,Sun Liqi,Song Bin World journal of surgical oncology BACKGROUND:Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) represent the tumors with malignant transformation potential. The objective of the study was to verify their pathological characteristics, prognoses, and recurrence factors. METHODS:Two hundred eighteen IPMNs and 27 MCNs resected at a single institution were included. The demographic, preoperative, histopathological, and follow-up data of the patients were recorded and analyzed. Overall survival (OS) and disease-free survival (DFS) were defined as the interval from the date of initial surgery to death or the last follow-up (OS) and to diagnosis of recurrence or death at follow-up (DFS). RESULTS:Of the 218 IPMN and 27 MCN patients, 93 (42.7%) and 8 (29.6%) cases were malignant, respectively. IPMNs occurred in older patients compared with MCN patients (median 63 years vs 54 years, P < 0.0001), and MCNs occurred exclusively in females (100%). Of the overall study cohort, the pathological specimens presented peripheral invasion in 37 (15.1%) patients and incisal margin invasion was observed in 46 (18.8%) patients. After a median follow-up of 34 months, 37 (14.9%) patients relapsed. The 5-year OS and DFS rates of IPMNs were 97.5% and 80.6%; and the OS and DFS rates of MCNs were 95.7% and 87.0%, respectively. There were four independent risk factors associated with recurrence: pathological diagnoses with malignancy (odds ratio, OR = 3.65), presence of oncocytic type for IPMN (OR = 1.69), peripheral invasion (OR = 12.87), and incisal margin invasion (OR = 1.99). CONCLUSIONS:IPMNs and MCNs are indolent tumors with favorable prognoses after surgical resection in terms of their relatively high OS and DFS rate. Patients with malignant pathological-related diagnoses should accept strict tumor surveillance in view of their higher risk of recurrence. 10.1186/s12957-020-02063-8
    Metabolic characterization of plasma and cyst fluid from cystic precursors to pancreatic cancer patients reveal metabolic signatures of bacterial infection. Morgell Ann,Reisz Julie A,Ateeb Zeeshan,Davanian Haleh,Reinsbach Susanne E,Halimi Asif,Gaiser Rogier,Valente Roberto,Arnelo Urban,Chiaro Marco Del,Sällberg Chen Margaret,D'Alessandro Angelo medRxiv : the preprint server for health sciences Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, with a 5-year survival rate as low as 9%. One factor complicating the management of pancreatic cancer is the lack of reliable tools for early diagnosis. While up to 50% of the adult population has been shown to develop precancerous pancreatic cysts, limited and insufficient approaches are currently available to determine whether a cyst is going to progress into pancreatic cancer. Recently, we used metabolomics approaches to identify candidate markers of disease progression in patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) undergoing pancreatic resection. Here we enrolled an independent cohort to verify the candidate markers from our previous study with orthogonal quantitative methods in plasma and cyst fluid from serous cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic ductal adenocarcinoma). We thus validated these markers with absolute quantitative methods through the auxilium of stable isotope-labelled internal standards in a new independent cohort. Finally, we identified novel markers of IPMN status and disease progression - including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO. We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. Overall, our findings are interesting per se, owing to the validation of previous markers and identification of novel small molecule signatures of IPMN and disease progression. In addition, our findings further fuel the provoking debate as to whether bacterial infections may represent an etiological contributor to the development and severity of the disease in pancreatic cancer, in like fashion to other cancers (e.g., and gastric cancer). Key points:We identified and quantified novel markers of IPMN cyst status and pancreatic cancer disease progression - including amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated fatty acids, purine oxidation products and TMAO.We show that the levels of these metabolites of potential bacterial origin correlated with the degree of bacterial enrichment in the cyst, as determined by 16S RNA. 10.1101/2020.11.03.20225524
    Expression of CD117, CK17, CK20, MUC4, villin and mismatch repair deficiency in pancreatic intraductal papillary mucinous neoplasm. Detlefsen Sönke,Jakobsen Mark,Nielsen Michael Friberg Bruun,Klöppel Günter,Mortensen Michael Bau Pathology, research and practice Among pancreatic intraductal papillary neoplasms, gastric, intestinal, and pancreatobiliary intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN) have been defined, differing regarding association with invasive carcinoma and prognosis. Immunohistochemistry (IHC) can help in the distinction of these neoplasms, but a proportion is unclassifiable using recommended markers. Hence, additional markers useful for the typing of pancreatic intraductal papillary neoplasms are needed. The reported frequencies of the different types of IPMNs in surgical series vary to some extent, and such data based on Danish patients are currently lacking. Besides, the role of mismatch repair (MMR) deficiency in these neoplasms has not been fully elucidated. We aimed to evaluate the frequency of different types of pancreatic intraductal papillary neoplasms in a Danish cohort. Furthermore, we aimed to examine the utility of CD117, CK17, CK20, MUC4, and villin as markers for their distinction, in addition to the recommended markers MUC1, MUC2, MUC5AC, MUC6 and CDX2, and to evaluate the frequency of MMR deficiency. We typed 40 consecutively resected pancreatic intraductal papillary neoplasms according to the WHO criteria from 2019. IHC for CD117, CDX2, CK17, CK20, MLH1, MSH2, MSH6, MUC1 (H23), MUC1 (Ma695), MUC2, MUC4, MUC5AC, MUC6, PMS2, and villin was performed and evaluated using a five-tiered semiquantitative scale. A subset of the tumours was examined with PCR for microsatellite instability (MSI). Most tumours were intestinal (40 %) and gastric (40 %) IPMNs, followed by pancreatobiliary (17 %) IPMNs and IOPN (3 %). All cases were MMR proficient. We found a higher expression of MUC4, CK20 and villin in intestinal compared to gastric IPMNs (p < 0.01, p < 0.001 and p < 0.001). MUC4 was more strongly expressed in intestinal compared to pancreatobiliary IPMNs, while the opposite was found for CK17 (p < 0.05 and p < 0.05). IOPN showed strong CD117 expression (score 4), while all gastric IPMNs were negative and 50 % and 29 % of intestinal and pancreatobiliary IPMNs only showed weak expression (score 1). Our data suggest that CK20, MUC4 and villin may aid in the identification of intestinal IPMNs, while CK17 and CD117 may aid in the identification of pancreatobiliary IPMNs and IOPN, in some cases. However, additional studies evaluating these markers in pancreatic intraductal papillary neoplasms are needed. 10.1016/j.prp.2020.153312
    Nomogram for the Prediction of High-Grade Dysplasia and Invasive Carcinoma in Patients With Intraductal Papillary Mucinous Neoplasms of the Pancreas Based on Variables of Noninvasive Examination. Li Bo,Shi Xiaohan,Gao Suizhi,Shen Shuo,Bian Yun,Cao Kai,Pan Yaqi,Zhang Guoxiao,Jiang Hui,Li Gang,Guo Shiwei,Jin Gang Frontiers in oncology Intraductal papillary mucinous neoplasms (IPMNs) are a heterogeneous group of neoplasms and represent the most common identifiable precursor lesions of pancreatic cancer. Clinical decision-making of the risk for malignant disease, including high-grade dysplasia and invasive carcinoma, is challenging. Moreover, discordance on the indication for resection exists between the contemporary guidelines. Furthermore, most of the current nomogram models for predicting malignant disease depend on endoscopic ultrasonography to evaluate the precise size of mural nodules. Thus, this study aimed to propose a model to predict malignant disease using variables from a noninvasive examination. We evaluated patients who underwent resection of pathologically confirmed IPMNs between November 2010 and December 2018 and had preoperative clinical data available for review. Based on binary multivariable logistic regression analysis, we devised a nomogram model to predict malignant IPMNs. The area under the receiver operating characteristics curve (AUC) was used to evaluate the discrimination power of the model. Of the 333 patients who underwent resection of IPMNs, 198 (59.5%) had benign and 135 (40.5%) had malignant IPMNs. Multivariable logistic regression analysis showed that cyst size, cyst location, cyst wall enhancement, multicystic lesion, diameter of main pancreatic duct, neutrophil-to-lymphocyte ratio, serum carbohydrate antigen 19-9, and carcinoembryonic antigen were significantly associated with malignancy. The nomogram, constructed based on these variables, showed excellent discrimination power with an AUC of 0.859 (95% CI: 0.818-0.900, < 0.001). In conclusion, we have developed a nomogram consisting of a combination of cross-sectional imaging features and blood markers, variables that can readily be obtained by noninvasive examinations during the surveillance period, which can distinguish benign from malignant IPMNs. Nevertheless, external validation is warranted. 10.3389/fonc.2021.609187
    The diagnostic and prognostic values of inflammatory markers in intraductal papillary mucinous neoplasm. Kim Hongbeom,Jung Woohyun,Chan Shin Yong,Han In W,Byun Yoonhyeong,Lee Hae W,Heo Jin S,Choi Dong W,Lim Chang-Sup HPB : the official journal of the International Hepato Pancreato Biliary Association BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN) is an broad-spectrum disease from benign to malignant. Inflammatory markers are known as prognostic predictors in various diseases. The purpose of this study was to determine the predictive value of inflammatory markers for prognosis in IPMN. METHODS:From April 1995 to December 2016, patients who underwent pancreatectomy with pathologically confirmed IPMN at four tertiary centers were enrolled. Patients with a history of pancreatitis or cholangitis, and other malignancies were excluded. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and advanced lung cancer inflammation index (ALI) were calculated. RESULTS:Of all, ninety-eight patients (26.8%) were diagnosed as invasive IPMN. The NLR and PLR were significantly elevated in invasive IPMN than in non-invasive disease (2.0 vs 1.8, p = 0.004; 117.1 vs 107.4, p = 0.009, respectively). ALI was significantly higher in non-invasive IPMN than in invasive disease (58.1 vs 45.9, p < 0.001). In multivariate analysis, only NLR showed significant association among the inflammatory markers studied (p = 0.044). In invasive IPMN, the five-year recurrence-free survival rate for NLR less than 3.5 was superior to the rest (59.1 vs 42.2, p = 0.023). CONCLUSION:NLR may help to rightly select IPMN patients who will require surgery and may serve as a useful prognostic factor. 10.1016/j.hpb.2021.04.001
    Micro-RNA Analysis of Pancreatic Cyst Fluid for Diagnosing Malignant Transformation of Intraductal Papillary Mucinous Neoplasm by Comparing Intraductal Papillary Mucinous Adenoma and Carcinoma. Shirakami Yohei,Iwashita Takuji,Uemura Shinya,Imai Hisashi,Murase Katsutoshi,Shimizu Masahito Journal of clinical medicine Although intraductal papillary mucinous neoplasm (IPMN) is thought to be a precursor lesion of pancreatic cancer, diagnosing malignant transformation of IPMN using non-invasive diagnostic methods is difficult and complicated. Micro-RNAs (miRNAs) are currently recognized as biomarkers and molecular targets of various diseases, including malignancy. In this study, we investigated a potential diagnostic approach using miRNA in pancreatic cyst fluid as a marker for evaluating malignant alternation of IPMN. Cystic fluid was sampled mainly during surgical resection. The collected samples were evaluated by performing comprehensive analysis of miRNA using a highly sensitive DNA chip. miRNA expression was compared between IPM adenoma (IPMA) and IPM carcinoma (IPMC) to evaluate the related biomarkers for malignant transformation of IPMN. miRNA analysis revealed that six miRNAs (miR-711, miR-3679-5p, miR-6126, miR-6780b-5p, miR-6798-5p, and miR-6879-5p) in IPMC were significantly enriched compared to those in IPMA. The difference was validated using quantitative real-time PCR. Cyst fluid miRNA analysis might be useful for diagnosing malignant alteration of IPMN. Further evaluations of diagnostic capability as well as functional analysis using the identified miRNAs are required with larger cohorts to confirm its efficacy. 10.3390/jcm10112249
    MicroRNAs Deregulated in Intraductal Papillary Mucinous Neoplasm Converge on Actin Cytoskeleton-Related Pathways That Are Maintained in Pancreatic Ductal Adenocarcinoma. Fernandez-Castañer Elena,Vila-Casadesus Maria,Vila-Navarro Elena,Parra Carolina,Lozano Juan Jose,Castells Antoni,Gironella Meritxell Cancers Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue ( = 3) and IPMN lesions ( = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients ( = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues ( = 4 Healthy; = 3 IPMN; = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC. 10.3390/cancers13102369
    Magnetic resonance imaging-derived fat fraction predicts risk of malignancy in intraductal papillary mucinous neoplasm. Evrimler Sehnaz,Yip-Schneider Michele T,Swensson Jordan,Soufi Mazhar,Muraru Rodica,Tirkes Temel,Schmidt C Max,Akisik Fatih Abdominal radiology (New York) PURPOSE:Assess the relationship between MRI-derived pancreatic fat fraction and risk of malignancy in intraductal papillary mucinous neoplasm (IPMN). METHODS:MRIs of patients with IPMN who underwent pancreaticoduodenectomy were analyzed. IPMN with low-grade dysplasia (n = 29) were categorized as low-risk while IPMN at high risk of malignancy consisted of those with high-grade dysplasia/invasive carcinoma (n = 33). Pancreatic fat-fraction (FF) was measured using the 2-point Dixon-method. Images were evaluated for the high-risk stigmata and worrisome features according to the revised 2017 Fukuoka consensus criteria. Data on serum CA19-9, Diabetes Mellitus (DM) status, body mass index (BMI), and histological chronic pancreatitis were obtained. RESULTS:A significant difference in FF was found between the high-risk IPMN (11.45%) and low-risk IPMN (9.95%) groups (p = 0.027). Serum CA19-9 level (p = 0.021), presence of cyst wall enhancement (p = 0.029), and solid mass (p = 0.008) were significantly associated with high-risk IPMN. There was a significant correlation between FF and mural nodule size (r = 0.36, p ˂ 0.01), type 2 DM (r = 0.34, p ˂ 0.01), age (r = 0.31, p ˂ 0.05), serum CA 19-9 (r = 0.30, p ˂ 0.05), cyst diameter (r = 0.30, p ˂ 0.05), and main pancreatic duct diameter (r = 0.26, p ˂ 0.05). Regression analysis revealed FF (OR 1.103, p = 0.035) as an independent predictive variable of high-risk IPMN. CONCLUSION:FF is significantly associated with high-risk IPMN and an independent predictor of IPMN malignant risk. FF may have clinical utility as a biomarker to complement the current IPMN treatment algorithm and improve clinical decision making regarding the need for surgical resection or surveillance. 10.1007/s00261-021-03146-0
    Early detection of pancreatic cancer using DNA-based molecular approaches. Singhi Aatur D,Wood Laura D Nature reviews. Gastroenterology & hepatology Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease. 10.1038/s41575-021-00470-0
    PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions. Nimmakayala Rama Krishna,Rauth Sanchita,Chirravuri Venkata Ramakanth,Marimuthu Saravanakumar,Nallasamy Palanisamy,Vengoji Raghupathy,Lele Subodh M,Rachagani Satyanarayana,Mallya Kavita,Malafa Mokenge P,Ponnusamy Moorthy P,Batra Surinder K Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Metabolic reprogramming and cancer stem cells drive the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). However, the metabolic and stemness programs of pancreatic precursor lesions (PPL), considered early PDAC development events, have not been thoroughly explored. EXPERIMENTAL DESIGN:Meta-analyses using gene expression profile data from NCBI Gene Expression Omnibus and IHC on tissue microarrays (TMA) were performed. The following animal and cellular models were used: cerulean-induced Kras; Pdx1 Cre (KC) acinar-to-ductal metaplasia (ADM) mice, Kras; Smad4; Pdx-1 Cre (KC) intraductal papillary mucinous neoplasm (IPMN) mice, LGKC1 cell line derived from the doxycycline-inducible Gnas IPMN model, and human IPMN organoids. Flow cytometry, Seahorse extracellular flux analyzer, qRT-PCR, and sphere assay were used to analyze metabolic and stemness features. SR18292 was used to inhibit PGC1α, and short hairpin RNA was used to knockdown (KD) PGC1α. RESULTS:The meta-analysis revealed a significant upregulation of specific stemness genes in ADM-mediated pancreatic intraepithelial neoplasms (PanIN) and IPMN. Meta- and TMA analyses followed by and validation revealed that ADM/PanIN exhibit increased PGC1α and oxidative phosphorylation (OXPhos) but reduced CPT1A. IPMN showed elevated PGC1α, fatty acid β-oxidation (FAO) gene expression, and FAO-OXPhos. PGC1α was co-overexpressed with its coactivator NRF1 in ADM/PanINs and with PPARγ in IPMN. PGC1α KD or SR18292 inhibited the specific metabolic and stemness features of PPLs and repressed IPMN organoid growth. CONCLUSIONS:ADM/PanINs and IPMNs show specific stemness signatures with unique metabolisms. Inhibition of PGC1α using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively. 10.1158/1078-0432.CCR-20-5020
    Sites of Distant Metastases and Cancer-Specific Survival in Intraductal Papillary Mucinous Neoplasm With Associated Invasive Carcinoma: A Study of 1,178 Patients. Huang Xiaoyi,You Siting,Ding Guiling,Liu Xingchen,Wang Jin,Gao Yisha,Zheng Jianming Frontiers in oncology Background:To explore the impact of distant metastases on cancer-specific survival in patients with intraductal papillary mucinous neoplasm (IPMN) with associated invasive carcinoma and identify the risk factor of distant metastases in IPMN with associated invasive carcinoma. Methods:Patients with IPMN with associated invasive carcinoma between 2010 and 2015 were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database. The survival analyses were assessed by Kaplan-Meier analyses and log-rank test. The impact of distant metastases was evaluated by Cox regression model and the risk factors of distant metastases were identified by logistic regression analyses, respectively. Results:The median cancer-specific survival time of patients with no metastases, isolated liver, isolated lung, and multiple site metastases were 19 months, 4 months, 7 months, and 3 months, respectively. In patients with isolated liver metastases, multivariate analysis after adjustment indicated that chemotherapy (Hazard Ratio [HR]=0.351, 95% confidence interval [CI]=0.256-0.481, P<0.001) was a protective prognostic factor for cancer-specific survival (CSS) in patients with isolated liver metastases. In isolated lung metastases subgroup, old age (HR=1.715, 95% CI=1.037-2.838, P=0.036) and chemotherapy (HR=0.242, 95% CI=0.134-0.435, P<0.001) were related to CSS in multivariable Cox regression analysis(P<0.05). Tumor located in the pancreatic body/tail (HR=2.239, 95% CI=1.140-4.400, P=0.019) and chemotherapy (HR=0.191, 95% CI=0.108-0.340, P<0.001) were independent prognostic factors for CSS in patients with multiple metastases. Finally, a nomogram was constructed for cancer-specific survival and the predicted C-index was 0.780 (95% CI=0.762-0.798). Conclusion:The liver is the most common site of distant metastases in IPMN with associated invasive carcinoma. Tumor located in the pancreatic body/tail and chemotherapy are independent prognostic factors for CSS in patients with multiple metastases. Further, tumor located in body/tail is identified as a risk factor of distant metastases. 10.3389/fonc.2021.681961
    Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy. Kandikattu Hemanth Kumar,Manohar Murli,Verma Alok Kumar,Kumar Sandeep,Yadavalli Chandra Sekhar,Upparahalli Venkateshaiah Sathisha,Mishra Anil Life science alliance Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP. 10.26508/lsa.202000979
    Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights. Mas Léo,Lupinacci Renato M,Cros Jérôme,Bachet Jean-Baptiste,Coulet Florence,Svrcek Magali International journal of molecular sciences Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed. 10.3390/ijms22136756
    Pancreatic incidentalomas: Investigation and management. Del Chiaro Marco,Torphy Robert J,Schulick Richard D Journal of internal medicine The incidence of pancreatic incidentalomas (PIs) detected in otherwise asymptomatic patients is growing with the increasing quality and use of advanced imaging techniques. PI can present as isolated main pancreatic duct dilation or as a solid or cystic lesion. Although historically thought to be relatively rare, PIs are rather common, particularly cystic lesions of the pancreas, which can be detected in up to 49% of the general population. With the poor prognosis of pancreatic cancer, PIs are an opportunity for prevention and early diagnosis, but when managed poorly, they can also lead to overtreatment and unnecessary morbidity. The management of PI should begin with a dedicated pancreas protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) to accurately characterize duct size, lesion characteristics and establish an accurate baseline for subsequent follow up. Diagnosis and subsequent management depends on the extent of main duct dilation and solid versus cystic appearance. Solid lesions are highly concerning for malignancy. Cystic lesions can be further categorized as intraductal papillary mucinous neoplasms of the pancreas (IPMNs) or mucinous cystic neoplasms (MCNs), both of which harbour malignant potential, or as serous cystic neoplasms (SCNs) that are benign. In this paper, we summarize the major challenges related to PI and present pragmatic suggestions for management. 10.1111/joim.13359
    Single-cell transcriptomics reveals heterogeneous progression and EGFR activation in pancreatic adenosquamous carcinoma. Zhao Xin,Li Han,Lyu Shaocheng,Zhai Jialei,Ji Zhiwei,Zhang Zhigang,Zhang Xinxue,Liu Zhe,Wang Huaguang,Xu Junming,Fan Hua,Kou Jiantao,Li Lixin,Lang Ren,He Qiang International journal of biological sciences Pancreatic adenosquamous carcinoma (PASC) - a rare pathological pancreatic cancer (PC) type - has a poor prognosis due to high malignancy. To examine the heterogeneity of PASC, we performed single-cell RNA sequencing (scRNA-seq) profiling with sample tissues from a healthy donor pancreas, an intraductal papillary mucinous neoplasm, and a patient with PASC. Of 9,887 individual cells, ten cell subpopulations were identified, including myeloid, immune, ductal, fibroblast, acinar, stellate, endothelial, and cancer cells. Cancer cells were divided into five clusters. Notably, cluster 1 exhibited stem-like phenotypes expressing UBE2C, ASPM, and TOP2A. We found that S100A2 is a potential biomarker for cancer cells. LGALS1, NPM1, RACK1, and PERP were upregulated from ductal to cancer cells. Furthermore, the copy number variations in ductal and cancer cells were greater than in the reference cells. The expression of EREG, FCGR2A, CCL4L2, and CTSC increased in myeloid cells from the normal pancreas to PASC. The gene sets expressed by cancer-associated fibroblasts were enriched in the immunosuppressive pathways. We demonstrate that EGFR-associated ligand-receptor pairs are activated in ductal-stromal cell communications. Hence, this study revealed the heterogeneous variations of ductal and stromal cells, defined cancer-associated signaling pathways, and deciphered intercellular interactions following PASC progression. 10.7150/ijbs.58886
    Carbohydrate Antigen 19-9 Is an Invasive Malignancy Preoperative Prognostic Factor for Intraductal Papillary Mucinous Neoplasms. Suzuki Shuji,Shimoda Mitsugi,Shimazaki Jiro,Oshiro Yukio,Nishda Kiyotaka,Orimoto Naoki,Nagakawa Yuichi,Tsuchida Akihiko European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes INTRODUCTION:This study aimed to determine the preoperative clinicophysiological and postoperative clinicopathological predictors of malignancy in patients with intraductal papillary mucinous neoplasm (IPMN). METHODS:This was a retrospective observational study. We included 121 patients (73 men and 48 women; mean age: 68.7 years) who had undergone pancreatic resection for IPMN between 2007 and 2018. These patients were grouped into invasive carcinoma (IPMN-INV, N = 21) and low/high-grade IPMN (IPMN-LG/HG, N = 100) groups. Univariate and multivariate analyses of clinicophysiological parameters were carried out. These parameters were also compared between the IPMN-INV/HG (N = 53) and IPMN-LG (N = 68) groups. Survival analyses according to macroscopic type and IPMN subtypes were performed. RESULTS:On univariate analysis, age (p = 0.038), carbohydrate antigen (CA) 19-9 (p < 0.001), IPMN macroscopic type (p = 0.001), IPMN subtype (p < 0.001), pancreatic duct diameter (p < 0.001), and mural nodule (p = 0.042), between IPMN-INV and IPMN-LG/HG were found to be significant prognostic factors of malignancy. CA 19-9 was found to be an independent prognostic factor of IPMN malignancy on multivariate analysis (p = 0.035). The 1-, 3-, and 5-year overall survival (OS) rates of the IPMN-INV and IPMN-LG/HG groups were 94.4/100%, 94.4/100%, and 67.2/100%, respectively. The OS rate in the IPMN-LG/HG group was significantly higher than that in the IPMN-INV group (p < 0.001). On univariate analysis, platelet (p = 0.043), CA 19-9 (p = 0.039), prognostic nutritional index (p = 0.034), platelet/lymphocyte ratio (p = 0.01), IPMN macroscopic type (p < 0.001), IPMN subtype (p < 0.001), pancreatic duct diameter (p = 0.036), and mural nodule (p = 0.032) between IPMN-INV/HG and IPMN-LG were found to be significant prognostic factors of malignancy. On multivariate analysis, CA 19-9 was found to be an independent prognostic factor (p = 0.042) between IPMN-INV/HG and IPMN-LG of malignancy. The 1-, 3-, and 5-year OS rates of the IPMN-INV/HG and IPMN-LG groups were 97.9/100%, 97.9/100%, and 82.6/100%, respectively. The OS rate was significantly higher in the IPMN-LG group than in the IPMN-INV/HG group (p = 0.03). No significant differences in survival were observed in patients with macroscopic tumors (p= 0.544). CONCLUSION:CA 19-9 is an independent invasive malignancy predictor of IPMN. 10.1159/000517558
    The Landscape of Genetic Alterations Stratified Prognosis in Oriental Pancreatic Cancer Patients. Guo Shiwei,Shi Xiaohan,Gao Suizhi,Hou Qunxing,Jiang Lisha,Li Bo,Shen Jing,Wang Huan,Shen Shuo,Zhang GuoXiao,Pan Yaqi,Liu Wuchao,Xu Xiongfei,Zheng Kailian,Shao Zhuo,Jing Wei,Lin Ling,Li Gang,Jin Gang Frontiers in oncology Background:Pancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated. Methods:A total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples. Results:We profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis. Conclusions:In this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival. 10.3389/fonc.2021.717989
    Narrative review of intraductal papillary mucinous neoplasms: pathogenesis, diagnosis, and treatment of a true precancerous lesion. Ma Gang,Li Guichen,Xiao Zhihuan,Gou Anjiang,Xu Yuanhong,Song Shaowei,Guo Kejian,Liu Zhe Gland surgery Objective:Although considerable progress has been made in our understanding of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, there are still some problems to be solved. Background:IPMN is one of the most important precancerous lesions of pancreatic cancer, but the relationship between IPMN and pancreatic cancer, and the specific mechanism of the development from IPMN to invasive carcinoma, remain to be explored in depth. With the development of imaging, the detection rate of IPMN has been greatly improved. However, the degree of malignancy of IPMN is difficult to assess, and its classification criteria and surgical treatment strategies are still controversial. Therefore, there is an urgent need for the best treatment plan for IPMN and research that can better predict IPMN recurrence and tumor malignancy. Methods:From the online database Web of Science (https://webofknowledge.com/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/), we use specific retrieval strategies to retrieve relevant articles based on the topics we discussed, and we review and discuss them. Conclusions:This paper discusses the related research and progress of IPMN in recent years to improve the understanding of the incidence, diagnosis, treatment, and prognosis of this disease. The follow-up and monitoring of IPMN is particularly important, but the specific strategy also remains controversial. 10.21037/gs-21-450
    Outcome after resection for invasive intraductal papillary mucinous neoplasia is similar to conventional pancreatic ductal adenocarcinoma. Holmberg Marcus,Ghorbani Poya,Gilg Stefan,Del Chiaro Marco,Arnelo Urban,Löhr J-Matthias,Sparrelid Ernesto Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] BACKGROUND/OBJECTIVES:Resections for intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Overall survival (OS) for conventional pancreatic ductal adenocarcinoma (PDAC) is well known but OS for invasive IPMN (inv-IPMN) is not as conclusive. This study aims to elucidate potential differences in clinicopathology and OS between these tumor types and to investigate if the raised number of resections have affected outcome. METHODS:Consecutive patients ≥18 years of age resected for inv-IPMN and PDAC at Karolinska University Hospital between 2009 and 2018 were included. Clinicopathological variables were analyzed in multivariable regression models. Outcome was assessed calculating two-year OS, estimating OS using the Kaplan-Meier model and comparing survival functions with log-rank test. RESULTS:513 patients were included, 122 with inv-IPMN and 391 with PDAC. During the study period both the proportion resected inv-IPMN and two-year OS, irrespective of tumor type, increased (2.5%-45%; p < 0.001 and 44%-57%; p = 0.005 respectively). In Kaplan-Meier survival analysis inv-IPMN had more favorable median OS (mOS) compared to PDAC (33.6 months vs 19.3 months, p = 0.001). However, in multivariable Cox Regression analysis, tumor type was not a predictor for death, but so were resection period, tumor subtype and N-stage (all p < 0.001). CONCLUSION:In this large single center observational cohort study, inv-IPMN seemed to have favorable survival outcome compared to PDAC, but after adjusting for predictors for death this benefit vanished. The combination of a pronounced increase in resected inv-IPMN and a concurrent hazard abatement for death within 2 years during the study period proved to be a principal factor. 10.1016/j.pan.2021.07.009
    Detection of Hot-Spot Mutations in Circulating Cell-Free DNA From Patients With Intraductal Papillary Mucinous Neoplasms of the Pancreas. Berger Andreas W,Schwerdel Daniel,Costa Ivan G,Hackert Thilo,Strobel Oliver,Lam Sandra,Barth Thomas F,Schröppel Bernd,Meining Alexander,Büchler Markus W,Zenke Martin,Hermann Patrick C,Seufferlein Thomas,Kleger Alexander Gastroenterology Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic tumors. Little is known about their molecular alterations, but mutations in GNAS have been reported to promote IPMN formation. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, contains many of the same mutations as the primary tumor, and could be a tool for noninvasive disease monitoring. We found that the total amount of cfDNA can discriminate between individuals without pancreatic lesions (controls) and patients with Fukuoka-negative branch-duct IPMN or pancreatic cancer. Furthermore, we detected GNAS mutations in cfDNA from patients with IPMN, but not in patients with serous cystadenoma or controls. Analyses of cfDNA might therefore be used in the diagnosis of patients with IPMN or in monitoring disease progression. 10.1053/j.gastro.2016.04.034
    Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms. Skaro Michael,Nanda Neha,Gauthier Christian,Felsenstein Matthäus,Jiang Zhengdong,Qiu Miaozhen,Shindo Koji,Yu Jun,Hutchings Danielle,Javed Ammar A,Beckman Ross,He Jin,Wolfgang Christopher L,Thompson Elizabeth,Hruban Ralph H,Klein Alison P,Goggins Michael,Wood Laura D,Roberts Nicholas J Gastroenterology BACKGROUND & AIMS:Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS:We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS:We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS:In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer. 10.1053/j.gastro.2019.01.254
    Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. Fischer Catherine G,Beleva Guthrie Violeta,Braxton Alicia M,Zheng Lily,Wang Pei,Song Qianqian,Griffin James F,Chianchiano Peter E,Hosoda Waki,Niknafs Noushin,Springer Simeon,Dal Molin Marco,Masica David,Scharpf Robert B,Thompson Elizabeth D,He Jin,Wolfgang Christopher L,Hruban Ralph H,Roberts Nicholas J,Lennon Anne Marie,Jiao Yuchen,Karchin Rachel,Wood Laura D Gastroenterology BACKGROUND & AIMS:Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS:We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS:We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS:In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer. 10.1053/j.gastro.2019.06.001
    Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features. Omori Yuko,Ono Yusuke,Tanino Mishie,Karasaki Hidenori,Yamaguchi Hiroshi,Furukawa Toru,Enomoto Katsuro,Ueda Jun,Sumi Atsuko,Katayama Jin,Muraki Miho,Taniue Kenzui,Takahashi Kuniyuki,Ambo Yoshiyasu,Shinohara Toshiya,Nishihara Hiroshi,Sasajima Junpei,Maguchi Hiroyuki,Mizukami Yusuke,Okumura Toshikatsu,Tanaka Shinya Gastroenterology 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. 10.1053/j.gastro.2018.10.029
    Pancreatic Fluid Interleukin-1β Complements Prostaglandin E2 and Serum Carbohydrate Antigen 19-9 in Prediction of Intraductal Papillary Mucinous Neoplasm Dysplasia. Simpson Rachel E,Yip-Schneider Michele T,Flick Katelyn F,Wu Huangbing,Colgate Cameron L,Schmidt C Max Pancreas OBJECTIVES:We sought to determine if interleukin (IL)-1β and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone. METHODS:Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1β (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1β [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined. RESULTS:Levels of IL-1β were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1β (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN. CONCLUSIONS:Cyst fluid PGE2, IL-1β, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia. 10.1097/MPA.0000000000001377
    Intraductal papillary mucinous neoplasm of the pancreas - epidemiology, risk factors, diagnosis, and management. Aronsson Linus,Andersson Roland,Ansari Daniel Scandinavian journal of gastroenterology Intraductal papillary mucinous neoplasm (IPMN) is one of the most common cystic neoplasms of the pancreas. It is a heterogeneous disease and can be divided into ductal types and morphological subtypes. The incidence of IPMN is increasing, likely due to the widespread use of cross-sectional imaging and a growing elderly population. IPMN poses an increasing demand on the health care system. Current guidelines provide indications for surgery and recommendations for surveillance, but management of IPMN is still challenging in routine clinical practice. In this article, we review current knowledge about IPMN and provide future directions for improving diagnosis and management. 10.1080/00365521.2017.1318948
    hsa-miR-96 and hsa-miR-217 Expression Down-Regulates with Increasing Dysplasia in Pancreatic Intraepithelial Neoplasias and Intraductal Papillary Mucinous Neoplasms. Chang XiaoYan,Yu ChunKai,Li Ji,Yu Shuangni,Chen Jie International journal of medical sciences To compare the clinicopathological features of pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), and to investigate the role of hsa-miR-96 and hsa-miR-217 in these two lesions. Formalin-fixed paraffin-embedded pancreatic specimens were selected in this study, including 58 cases of pancreatic intraepithelial neoplasias (PanINs), 45 cases of pancreatic ductal adenocarcinomas (PDAs), and 57 cases of intraductal papillary mucinous neoplasms (IPMNs). MiRNAs hsa-miR-96 and hsa-miR-217 were detected using locked nucleic acid hybridization (LNA-ISH) with the NBT/BCIP staining system. The differences in miRNA expression among sample sets were analyzed with the Chi-squared test. PanIN-PDAs were inclined to present with higher rate of invasion (p=0.033), lymph node metastasis (p=0.0004) and poorer differentiation (p<0.001). Of the 45 PDAs, only 2 cases were within AJCC Ⅰstage, while there were 11 cases of IPMN associated carcinomas (p=0.0018). In PanIN-1, PanIN-2 and PanIN-3, the expression of hsa-miR-96 was 91.3% (22/23), 78.6%(12/17) and 22.2%(4/18) respectively, while the expression of hsa-miR-217 was 95.7%(22/23) , 70.6% (12/17) and 27.8% (5/18). In IPMN with low-grade, intermediate-grade, high-grade dysplasia, associated carcinoma, the expression of hsa-miR-96 was 67%(9/13), 64%(7/11), 43%(3/7) and 27%(7/26) respectively, while the expression of hsa-miR-217 was 77%(10/13), 64%(7/11), 29%(2/7) and 38%(10/26). The expression of hsa-miR-96 and hsa-miR-217 in PanIN-1 lesions was not significantly different from that in the normal pancreatic ductal epithelium. However, their expression in PanIN-2/3 lesions was significantly different from that in normal pancreatic ductal epithelium (P<0.01). No difference was observed between PanIN derived adenocarcinomas and IPMN-associated carcinomas. IPMN associated carcinomas were in a statistically earlier stage than PanIN- PDAs at the time of operation. Abnormal expression of hsa-miR-96 and of hsa-miR-217 was observed in premalignant lesions (PanINs and IPMNs) of pancreatic carcinoma and down-regulated with increasing grades of PanINs and IPMNs. These microRNAs may serve as potentially early biomarker and act as tumor suppressor genes. 10.7150/ijms.18641
    High-density and targeted glycoproteomic profiling of serum proteins in pancreatic cancer and intraductal papillary mucinous neoplasm. Aronsson Linus,Andersson Roland,Bauden Monika,Andersson Bodil,Bygott Thomas,Ansari Daniel Scandinavian journal of gastroenterology OBJECTIVE:Glycoproteomics is an emerging subfield of proteomics. Tumor-specific variations in protein glycosylation might be potential targets for the development of new cancer diagnostics. Here, we performed high-throughput screening and targeted verification of glycome alterations in serum samples from patients with pancreatic cancer and the precancerous lesion intraductal papillary mucinous neoplasm (IPMN). MATERIAL AND METHODS:The glycosylation profile of 1000 proteins was mapped in a discovery cohort comprising serum samples from 16 individuals, including 8 patients with pancreatic cancer and 8 healthy controls. The top 10 glycoprotein biomarker candidates with the highest signal intensity difference in glycosylation levels were evaluated in a cohort consisting of 109 serum samples, including 49 patients with resectable pancreatic cancer, 13 patients with resectable noninvasive IPMN and 47 healthy controls, using a targeted assay. RESULTS:Multivariable analysis defined sets of panels comprising CA19-9 and distinctively glycosylated proteins for discrimination between pancreatic cancer, IPMN and healthy controls. A panel including CA 19-9, IL.17E, B7.1 and DR6 gave an AUC of 0.988 at 100% sensitivity at 90% specificity for the discrimination of stage 1 pancreatic cancer and healthy controls. B7.1 was found to be a valuable biomarker for differentiating between IPMN and healthy controls, with better performance alone than CA 19-9. CONCLUSIONS:Measurement of protein glycosylation profiles in serum may aid in the early detection of pancreatic cancer and precursor lesions. 10.1080/00365521.2018.1532020
    Circulating Thrombospondin-2 enhances prediction of malignant intraductal papillary mucinous neoplasm. Simpson Rachel E,Yip-Schneider Michele T,Wu Huangbing,Fan Hao,Liu Ziyue,Korc Murray,Zhang Jianjun,Schmidt C Max American journal of surgery BACKGROUND:IPMNs are cystic pancreatic lesions with variable malignant potential. Thrombospondin-2 (THBS2)-an endogenous, anti-angiogenic matrix glycoprotein-may modulate tumor progression. We hypothesized that circulating levels of THBS2 could aid in preoperative prediction of malignant IPMN. METHODS:Preoperative serum/plasma samples were procured from patients undergoing surgery. Circulating levels of THBS2 were measured (enzyme-linked immunosorbent assay) and compared to surgical pathology IPMN dysplastic grade. RESULTS:164 patients underwent THBS2 testing (100 Low/Moderate-IPMN; 64 High-Grade/Invasive-IPMN). Circulating THBS2 (mean ± SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6 ± 12.7 ng/mL vs. 20.4 ± 8.2 ng/mL; P < 0.001). THBS2 (AUC = 0.65) out-performed CA19-9 (n = 144; AUC = 0.59) in predicting IPMN grade. The combination of THBS2, CA19-9, radiographic main-duct involvement, main-duct diameter, age, sex, and BMI (AUC 0.82; n = 137) provided a good prediction model for IPMN grade. CONCLUSION:Circulating THBS2 is correlated with IPMN dysplasia grade. THBS2 alone did not strongly predict IPMN grade but rather strengthened prediction models for High-Grade/Invasive IPMN when combined with other clinical/biomarker data. 10.1016/j.amjsurg.2018.08.026
    Clinicopathological and prognostic significance of MUC13 and AGR2 expression in intraductal papillary mucinous neoplasms of the pancreas. Mito Kumiko,Saito Michihiro,Morita Kohei,Maetani Iruru,Sata Naohiro,Mieno Makiko,Fukushima Noriyoshi Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a primary pancreatic ductal epithelial neoplasm with the potential to develop into an invasive adenocarcinoma. This study aimed to investigate the clinicopathologic and prognostic significance of four potential biomarkers for the preoperative evaluation of patients with IPMN. MATERIALS AND METHODS:Clinicopathologic materials from 104 patients with IPMN who underwent surgical resection at Jichi Medical University Hospital were analyzed. IPMNs (110 lesions in total) were histologically classified into low-grade IPMN (Group 1; n = 68), high-grade IPMN (Group 2; n = 16), or IPMN with an associated invasive carcinoma (Group 3; n = 26). We evaluated the immunohistochemical expression of MUC13, AGR2, FUT8, and FXYD3, which were previously reported to be overexpressed in pancreatic ductal adenocarcinoma. RESULTS:The expression of MUC13 was more common in Group 3 compared with groups 1 and 2 (p < 0.001) and was associated with poor prognosis (p = 0.004). The expression of MUC13 was not associated with age, sex, tumor location, histological subtype, lymphatic or vascular invasion, or neural invasion. In most cases of IPMN, the loss of expression of AGR2 appeared to show an association with tumor recurrence and poorly differentiated histology of invasive carcinoma; however, this association was not statistically significant. The expressions of FUT8 and FXYD3were not associated with the clinicopathological features of IPMNs. CONCLUSIONS:The results suggest that MUC13 overexpression and loss of expression of AGR2 may predict the progression of IPMN and an unfavorable prognosis in patients with IPMN. 10.1016/j.pan.2018.04.003
    Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium. Attiyeh Marc A,Fernández-Del Castillo Carlos,Al Efishat Mohammad,Eaton Anne A,Gönen Mithat,Batts Ruqayyah,Pergolini Ilaria,Rezaee Neda,Lillemoe Keith D,Ferrone Cristina R,Mino-Kenudson Mari,Weiss Matthew J,Cameron John L,Hruban Ralph H,D'Angelica Michael I,DeMatteo Ronald P,Kingham T Peter,Jarnagin William R,Wolfgang Christopher L,Allen Peter J Annals of surgery OBJECTIVE:Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA:IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS:Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS:We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS:For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease. 10.1097/SLA.0000000000002015
    Significance of microcystic, elongated, and fragmented glandular-like features in intraductal papillary mucinous neoplasm of the pancreas. Park Ji Y,Lee Jae Hoon,Song Ki-Byung,Hwang Dae Wook,Kim Kyu-Rae,Kim Song Cheol,Hong Seung-Mo Human pathology Microcystic, elongated, and fragmented (MELF) glandular features are associated with epithelial-mesenchymal transition, invasion, and progression in endometrioid adenocarcinoma of the uterus. Similar histological features are also observed at the periphery of pancreatic intraductal papillary mucinous neoplasms (IPMNs). However, the clinicopathological significance of MELF-like features-particularly whether they represent regenerative or truly neoplastic conditions-in IPMNs remains unclear. We assessed a total of 152 surgically resected IPMNs. Fifty cases exhibited MELF-like features, including 26 cases of IPMNs with accompanying adenocarcinomas and 24 cases of IPMNs without accompanying adenocarcinomas. MELF-like features were more frequently observed in IPMN cases with accompanying adenocarcinomas, larger tumors, main-duct type, and non-gastric histologic subtype. A positive correlation between the presence of MELF-like features and high-grade dysplasia was observed in IPMNs without accompanying adenocarcinomas. Moreover, DPC4 loss and p53 overexpression in MELF-like glands were more commonly observed in IPMNs with high-grade dysplasia. IPMN patients with MELF-like features had worse overall and disease-specific survival by univariate analyses. Our observations suggest that MELF-like features in some IPMNs with high-grade dysplasia could be related to stromal invasion. Hence, when MELF-like features are observed in IPMNs, pathologists should carefully evaluate the results of microscopic examinations to identify the invasive components; and, immunohistochemical staining for DPC4 and p53 could help clarify its clinicopathological significance. 10.1016/j.humpath.2018.01.020
    Expression of Matrix Metalloproteinases in Intraductal Papillary Mucinous Neoplasm of the Pancreas. Akashi Masanori,Hisaka Toru,Sakai Hisamune,Ishikawa Hiroto,Kawahara Ryuichi,Goto Yuichi,Nomura Yoriko,Yasunaga Masafumi,Fujita Fumihiko,Tanigawa Masahiko,Naito Yoshiki,Akiba Jun,Yano Hirohisa,Tanaka Hiroyuki,Akagi Yoshito,Okuda Koji Anticancer research BACKGROUND/AIM:Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions. MATERIALS AND METHODS:The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining. RESULTS:MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups. CONCLUSION:MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN. 10.21873/anticanres.13623
    Plasma protein profiling of patients with intraductal papillary mucinous neoplasm of the pancreas as potential precursor lesions of pancreatic cancer. Ilies Maria,Sappa Praveen Kumar,Iuga Cristina Adela,Loghin Felicia,Gesell Salazar Manuela,Weiss Frank Ulrich,Beyer Georg,Lerch Markus M,Völker Uwe,Mayerle Julia,Hammer Elke Clinica chimica acta; international journal of clinical chemistry Efforts for the early diagnosis of the pancreatic ductal adenocarcinoma (PDAC) have recently been driven to one of the precursor lesions, namely intraductal papillary mucinous neoplasm of the pancreas (IPMN). Only a few studies have focused on IPMN molecular biology and its overall progression to cancer. Therefore, IPMN lacks comprehensive characterization which makes its clinical management controversial. In this study, we characterized plasma proteins in the presence of IPMNs in comparison to healthy controls, chronic pancreatitis, and PDAC by a proteomics approach using data-independent acquisition based mass spectrometry. We describe several protein sets that could aid IPMN diagnosis, but also differentiation of IPMN from healthy controls, as well as from benign and malignant diseases. Among all, high levels of carbonic anhydrases and hemoglobins were characteristic for the IPMN group. By employing ELISA based quantification we validated our results for human tissue inhibitor of metalloproteinase inhibitor 1 (TIMP-1). We consider IPMN management directed towards an early potential cancer development a crucial opportunity before PDAC initiation and thus its early detection and cure. 10.1016/j.cca.2017.12.008
    SLC2A1/GLUT1 expression in mural nodules of intraductal papillary mucinous neoplasm of the pancreas. Oda Yasunori,Aishima Shinichi,Shindo Koji,Fujino Minoru,Mizuuchi Yusuke,Hattori Masami,Miyazaki Tetsuyuki,Tanaka Masao,Oda Yoshinao Human pathology In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased F-fluorodeoxyglucose (F-FDG) uptake. We examined SLC2A1/GLUT1 expression in the mural nodules of 180 IPMN specimens to distinguish malignant/benign tumors. A mural nodule was detected in 80 (44.4%) of the IPMNs, and was detected in 18.6% (13/70) of the IPMN-low (dysplasia) specimens, 36.1% (13/36) of the IPMN-int, 93.3% (28/30) of the IPMN-high, and 59.1% (26/44) of the IPMN-inv (with an associated invasive carcinoma) specimens. The sensitivity for detecting mural nodules was 81.7% by endoscopic ultrasonography, 70% by contrast-enhanced computed tomography and 54% by endoscopic retrograde cholangiopancreatography. SLC2A1/GLUT1 expression in the mural nodules was recognized in the basal and basolateral cytomembrane of tumor cells and was expressed in 15.4% (2/13) of the IPMN-low, 15.4% (2/13) of the IPMN-int, 71.4% (20/28) of the IPMN-high and 84.6% (22/26) of the IPMN-inv groups. The SLC2A1/GLUT1 expression was significantly higher in the IPMN-high and IPMN-inv mural nodules than in those of the IPMN-low and IPMN-int groups. Our findings suggest that SLC2A1/GLUT1 is expressed late in the adenoma-carcinoma sequence during carcinogenesis in IPMN, and SLC2A1/GLUT1 act as therapeutic target for malignant IPMN. 10.1016/j.humpath.2017.03.008
    Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: clinicopathological features and long-term outcomes following a pancreatectomy. Antoñanzas Javier,Cienfuegos Javier A,Hurtado-Pardo Luis,Panadero Pablo,Benito Alberto,Pardo Fernando,Rotellar Fernando,Martí-Cruchaga Pablo,Zozaya Gabriel,Valentí Víctor,Hernández Lizoain José Luis Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva OBJECTIVE:the objective of this study was to analyze the anatomical and clinical features and long-term oncologic outcomes of 25 patients that underwent surgery due to intraductal papillary mucinous neoplasm of the pancreas. MATERIAL AND METHODS:patients undergoing surgery for intraductal papillary mucinous neoplasm of the pancreas were identified from a prospective database of pancreatic resections. Demographic data, symptoms, type of surgery and type of lesion (branch type, main duct or mixed) were recorded. The lesions were classified into invasive (high grade dysplasia and carcinoma) and noninvasive (low- or intermediate-grade dysplasia). Postoperative complications were analyzed as well as the pattern of recurrence and disease-free survival at five and ten years. RESULTS:the most common symptoms in the 25 patients (14 males and eleven females) were abdominal pain and weight loss. Eight (32%) cases were diagnosed incidentally. Twelve (48%) of the lesions were of the branch type, three affected the main duct and ten (40%) were mixed. Twelve cephalic duodenopancreatectomies and seven total pancreatectomies were performed; three were central; two, distal; and one, enucleation. Seven cases (32%) had an invasive phenotype. Three patients had locoregional and distant recurrence at six, 16 and 46 months after surgery with a median follow-up of 7.7 years. Disease-free survival at five and ten years for the noninvasive type was 94% and 57% for invasive phenotypes (p < 0.05). CONCLUSIONS:intraductal papillary mucinous neoplasm is a heterogeneous entity with well differentiated phenotypes, which requires a tailored strategy and treatment, as established in the current consensus guidelines due to its malignant potential. 10.17235/reed.2018.5646/2018
    and mutations synergistically induce intraductal papillary mucinous neoplasm derived from pancreatic duct cells. Collet Louis,Ghurburrun Elsa,Meyers Nora,Assi Mohamad,Pirlot Boris,Leclercq Isabelle A,Couvelard Anne,Komuta Mina,Cros Jérôme,Demetter Pieter,Lemaigre Frédéric P,Borbath Ivan,Jacquemin Patrick Gut OBJECTIVE:Pancreatic cancer can arise from precursor lesions called intraductal papillary mucinous neoplasms (IPMN), which are characterised by cysts containing papillae and mucus-producing cells. The high frequency of mutations in IPMN and histological analyses suggest that oncogenic KRAS drives IPMN development from pancreatic duct cells. However, induction of mutation in ductal cells is not sufficient to generate IPMN, and formal proof of a ductal origin of IPMN is still missing. Here we explore whether combining oncogenic mutation with an additional gene mutation known to occur in human IPMN can induce IPMN from pancreatic duct cells. DESIGN:We created and phenotyped mouse models in which mutations in and in the tumour suppressor gene liver kinase B1 (/) are conditionally induced in pancreatic ducts using Cre-mediated gene recombination. We also tested the effect of β-catenin inhibition during formation of the lesions. RESULTS:Activating mutation and inactivation synergised to induce IPMN, mainly of gastric type and with malignant potential. The mouse lesions shared several features with human IPMN. Time course analysis suggested that IPMN developed from intraductal papillae and glandular neoplasms, which both derived from the epithelium lining large pancreatic ducts. β-catenin was required for the development of glandular neoplasms and subsequent development of the mucinous cells in IPMN. Instead, the lack of β-catenin did not impede formation of intraductal papillae and their progression to papillary lesions in IPMN. CONCLUSION:Our work demonstrates that IPMN can result from synergy between mutation and inactivation of a tumour suppressor gene. The ductal epithelium can give rise to glandular neoplasms and papillary lesions, which probably both contribute to IPMN formation. 10.1136/gutjnl-2018-318059
    Can we better predict the biologic behavior of incidental IPMN? A comprehensive analysis of molecular diagnostics and biomarkers in intraductal papillary mucinous neoplasms of the pancreas. Tulla Kiara A,Maker Ajay V Langenbeck's archives of surgery PURPOSE:Predicting the biologic behavior of intraductal papillary mucinous neoplasm (IPMN) remains challenging. Current guidelines utilize patient symptoms and imaging characteristics to determine appropriate surgical candidates. However, the majority of resected cysts remain low-risk lesions, many of which may be feasible to have under surveillance. We herein characterize the most promising and up-to-date molecular diagnostics in order to identify optimal components of a molecular signature to distinguish levels of IPMN dysplasia. METHODS:A comprehensive systematic review of pertinent literature, including our own experience, was conducted based on the PRISMA guidelines. RESULTS:Molecular diagnostics in IPMN patient tissue, duodenal secretions, cyst fluid, saliva, and serum were evaluated and organized into the following categories: oncogenes, tumor suppressor genes, glycoproteins, markers of the immune response, proteomics, DNA/RNA mutations, and next-generation sequencing/microRNA. Specific targets in each of these categories, and in aggregate, were identified by their ability to both characterize a cyst as an IPMN and determine the level of cyst dysplasia. CONCLUSIONS:Combining molecular signatures with clinical and imaging features in this era of next-generation sequencing and advanced computational analysis will enable enhanced sensitivity and specificity of current models to predict the biologic behavior of IPMN. 10.1007/s00423-017-1644-z
    Intraductal papillary mucinous neoplasms of the pancreas: a clinical challenge. Rossi Roberta Elisa,Massironi Sara Expert review of gastroenterology & hepatology INTRODUCTION:The incidental detection rate of intraductal papillary mucinous neoplasms (IPMNs) has significantly increased. However, little is known about the natural history of these tumors. Their optimal management and appropriate follow-up are still unclear. We have, therefore, reviewed the available literature on IPMN focusing on their diagnosis, treatment according to the risk of malignant transformation, and follow-up. Areas covered: Bibliographical searches were performed in PubMed for the terms 'intraductal papillary mucinous neoplasm' and 'natural history' and 'diagnosis' and 'treatment' and 'surgery' and 'follow-up' and 'prognosis.' PubMed was used to search for all the relevant articles published over the last 10 years. A total of 7244 records were identified. After filtering for year range, English language, human studies, article types, and removing duplicates, 74 articles were left with the strongest level of evidence. Expert commentary: Available guidelines for IPMN management are mainly based on expert opinions and may lack strong evidence. Further studies are warranted to better predict the risk of recurrence/future malignancy and to establish standardized guidelines. IPMNs management should be based on multidisciplinary discussion and treatment should be tailored to an individual patient according to patient and tumor characteristics. 10.1080/17474124.2018.1530111
    Intraductal Papillary Mucinous Neoplasms of The Pancreas: A Nationwide Registry-Based Study. Aronsson L,Andersson B,Andersson R,Tingstedt B,Bratlie S O,Ansari D Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society BACKGROUND AND AIMS::To investigate the paraclinical and pathological features of surgically resected intraductal papillary mucinous neoplasms in Sweden. MATERIALS AND METHODS::A review of prospectively collected data on patients undergoing pancreatic resection for a histopathologically verified intraductal papillary mucinous neoplasm between 2010 and 2016 was performed using the Swedish National Registry for Pancreatic and Periampullary Cancer. RESULTS::A total of 3038 pancreatic resections were performed during the study period, of which 251 (8.3%) were due to intraductal papillary mucinous neoplasms. The intraductal papillary mucinous neoplasm cases comprised 227 noninvasive and 24 invasive lesions. There was an annual increase in the number of resected intraductal papillary mucinous neoplasms, from 13 in 2010 to 56 in 2016, and an increase in the proportion of intraductal papillary mucinous neoplasm to the total number of pancreatic resections (4.7%-11%). Biliary obstruction was the only independent predictor of invasive disease, with odds ratio 3.106 (p = 0.030). There was no difference in survival between low-, intermediate-, and high-grade dysplastic lesions (p = 0.417). However, once invasive, the prognosis was severely impacted (p < 0.001). Three-year survival was 90% for noninvasive intraductal papillary mucinous neoplasm and 39% for invasive intraductal papillary mucinous neoplasm. Survival was better in lymph node negative invasive intraductal papillary mucinous neoplasm (p = 0.021), but still dismal compared to noninvasive lesions (p < 0.001). CONCLUSION::The number of surgically resected intraductal papillary mucinous neoplasms is increasing in Sweden. Biliary obstruction is associated with invasive disease. Low-to-high-grade dysplastic intraductal papillary mucinous neoplasm has an excellent prognosis, while invasive intraductal papillary mucinous neoplasm has a poor survival rate. 10.1177/1457496918766727