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Pancreatic Neoplasms: HELP
Articles by Huamin Wang
Based on 116 articles published since 2010
(Why 116 articles?)
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Between 2010 and 2020, Huamin Wang wrote the following 116 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Review Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. 2017

Wang, Hanlin L / Kim, Christopher J / Koo, Jamie / Zhou, Wendi / Choi, Eunice K / Arcega, Ramir / Chen, Zongming Eric / Wang, Huamin / Zhang, Lanjing / Lin, Fan. · ·Arch Pathol Lab Med · Pubmed #28854347.

ABSTRACT: CONTEXT: - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES: - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES: - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS: - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.

2 Review The emerging roles of F-box proteins in pancreatic tumorigenesis. 2016

Wang, Hua / Maitra, Anirban / Wang, Huamin. ·Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, United States. · Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, United States; Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, United States. · Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, United States; Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, United States. Electronic address: hmwang@mdanderson.org. ·Semin Cancer Biol · Pubmed #26384530.

ABSTRACT: The role of F-box proteins in pancreatic tumorigenesis is emerging owing to their pivotal and indispensable roles in cell differentiation, cell cycle regulation and proliferation. In this review, we will focus on β-TrCP (β-transducin repeat-containing protein) and two other prototypical mammalian F-box proteins, Fbxw7 and Fbxw8, in pancreatic tumorigenesis and progression. We will highlight the functions and regulation of these F-box proteins, their respective substrates and cross-talks with other key signaling pathways, such as the Ras-Raf-Mek-Erk, Hedgehog, NFκB, TGF-β, Myc and HPK1 signaling pathways in pancreatic cancer.

3 Clinical Trial Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer. 2016

Chadha, Awalpreet S / Skinner, Heath D / Gunther, Jillian R / Munsell, Mark F / Das, Prajnan / Minsky, Bruce D / Delclos, Marc E / Chatterjee, Deyali / Wang, Huamin / Clemons, Marilyn / George, Geena / Singh, Pankaj K / Katz, Matthew H / Fleming, Jason B / Javle, Milind M / Wolff, Robert A / Varadhachary, Gauri R / Crane, Christopher H / Krishnan, Sunil. ·Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. ·PLoS One · Pubmed #27336466.

ABSTRACT: PURPOSE: To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer. METHODS: Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. RESULTS: Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures. CONCLUSIONS: This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.

4 Clinical Trial Neoadjuvant therapy is associated with a reduced lymph node ratio in patients with potentially resectable pancreatic cancer. 2015

Roland, Christina L / Yang, Anthony D / Katz, Matthew H G / Chatterjee, Deyali / Wang, Huamin / Lin, Heather / Vauthey, Jean N / Pisters, Peter W / Varadhachary, Gauri R / Wolff, Robert A / Crane, Christopher H / Lee, Jeffrey E / Fleming, Jason B. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ·Ann Surg Oncol · Pubmed #25352267.

ABSTRACT: BACKGROUND: The use of neoadjuvant therapy (NAC) for the treatment of potentially resectable pancreatic cancer remains controversial. In this study, we sought to evaluate cancer-specific endpoints in patients undergoing a NAC versus a surgery-first (SF) approach with specific emphasis on lymph node metastases. METHODS: A total of 222 patients who underwent NAC and 85 patients who underwent SF were identified from 1990 to 2008 and compared for cancer-related endpoints. Peripancreatic lymph nodes from 135 neoadjuvant therapy patients were evaluated for histologic tumor regression. RESULTS: Patients who underwent NAC followed by surgery had improved overall survival and time to local recurrence compared with the SF approach. NAC patients were less likely to have lymph node metastases (p = 0.001), lymphovascular invasion (LVI), and had smaller tumors. On multivariate analysis, lymph node positivity was associated with SF, tumor size, and the presence of LVI. NAC patients with N0 disease had equivalent outcomes to patients with a low-LNR (0.01-0.15), whereas patients with a LNR >0.15 had reduced survival, and time to local and distant recurrence. Ten of 135 (7.4 %) NAC patients had evidence of tumor regression in at least one lymph node. CONCLUSIONS: Patients with potentially resectable PDAC selected to undergo NAC had improved survival and longer time to recurrence. Although some of these differences may be related to improvements in multimodality therapy completion rates, tumor regression in lymph node metastases exists and may demonstrate a biologic benefit of NAC compared with a SF approach.

5 Clinical Trial Transport properties of pancreatic cancer describe gemcitabine delivery and response. 2014

Koay, Eugene J / Truty, Mark J / Cristini, Vittorio / Thomas, Ryan M / Chen, Rong / Chatterjee, Deyali / Kang, Ya'an / Bhosale, Priya R / Tamm, Eric P / Crane, Christopher H / Javle, Milind / Katz, Matthew H / Gottumukkala, Vijaya N / Rozner, Marc A / Shen, Haifa / Lee, Jeffery E / Wang, Huamin / Chen, Yuling / Plunkett, William / Abbruzzese, James L / Wolff, Robert A / Varadhachary, Gauri R / Ferrari, Mauro / Fleming, Jason B. · ·J Clin Invest · Pubmed #24614108.

ABSTRACT: BACKGROUND: The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. METHODS: We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. RESULTS: Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. CONCLUSION: Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. TRIAL REGISTRATION: Clinicaltrials.gov NCT01276613. FUNDING: Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

6 Article Hematopoietic progenitor kinase 1 down-regulates the oncogenic receptor tyrosine kinase AXL in pancreatic cancer. 2020

Song, Xianzhou / Akasaka, Hironari / Wang, Hua / Abbasgholizadeh, Reza / Shin, Ji-Hyun / Zang, Fenglin / Chen, Jiayi / Logsdon, Craig D / Maitra, Anirban / Bean, Andrew J / Wang, Huamin. ·Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030. · Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030. · Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030. · Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Houston, Texas 77030. · Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 hmwang@mdanderson.org. ·J Biol Chem · Pubmed #31959629.

ABSTRACT: The oncogenic receptor tyrosine kinase AXL is overexpressed in cancer and plays an important role in carcinomas of multiple organs. However, the mechanisms of AXL overexpression in cancer remain unclear. In this study, using HEK293T, Panc-1, and Panc-28 cells and samples of human pancreatic intraepithelial neoplasia (PanIN), along with several biochemical approaches and immunofluorescence microscopy analyses, we sought to investigate the mechanisms that regulate AXL over-expression in pancreatic ductal adenocarcinoma (PDAC). We found that AXL interacts with hematopoietic progenitor kinase 1 (HPK1) and demonstrate that HPK1 down-regulates AXL and decreases its half-life. The HPK1-mediated AXL degradation was inhibited by the endocytic pathway inhibitors leupeptin, bafilomycin A1, and monensin. HPK1 accelerated the movement of AXL from the plasma membrane to endosomes in pancreatic cancer cells treated with the AXL ligand growth arrest-specific 6 (GAS6). Moreover, HPK1 increased the binding of AXL to the Cbl proto-oncogene (c-Cbl); promoted AXL ubiquitination; decreased AXL-mediated signaling, including phospho-AKT and phospho-ERK signaling; and decreased the invasion capability of PDAC cells. Importantly, we show that AXL expression inversely correlates with HPK1 expression in human PanINs and that patients whose tumors have low HPK1 and high AXL expression levels have shorter survival than those with low AXL or high HPK1 expression (

7 Article Significance of Cancer Cells at the Vein Edge in Patients with Pancreatic Adenocarcinoma Following Pancreatectomy with Vein Resection. 2020

Prakash, Laura R / Wang, Huamin / Zhao, Jun / Nogueras-Gonzalez, Graciela M / Cloyd, Jordan M / Tzeng, Ching-Wei D / Kim, Michael P / Lee, Jeffrey E / Katz, Matthew H G. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1484, Houston, TX, 77030, USA. · Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1484, Houston, TX, 77030, USA. mhgkatz@mdanderson.org. ·J Gastrointest Surg · Pubmed #30820801.

ABSTRACT: BACKGROUND: Resection of the superior mesenteric and/or portal vein (SMV-PV) is increasingly performed with pancreatectomy for adenocarcinoma. We sought to analyze the impact of cancer at the transected edge(s) of the vein wall. METHODS: Patients who underwent pancreatectomy with vein resection between 2003 and 2015 at a single center were evaluated. R1 resection was defined per guidelines from the American Joint Commission on Cancer and the College of American Pathologists. Specimens were also evaluated for the presence (V+) or absence (V-) of cancer cells at the transected edge(s) and depth of vein invasion. RESULTS: Among 127 evaluated patients, 114 (90%) received preoperative therapy. R-status was categorized as margin-negative (R0)/V- (n = 72, 57%), R0/V+ (n = 19, 15%), margin-positive (R1)/V- (n = 24, 19%), and R1/V+ (n = 12, 9%). Patients with V- specimens had similar median durations of recurrence-free survival (RFS) (12 vs 9 months) and overall survival (OS) (30 vs 28 months) as did patients with V+ specimens (P > 0.05). In contrast, cancer invasion into the lumen was associated with RFS and OS (P < 0.05). Among patients who underwent R0 resection, V-status had no association with OS, RFS, or local control (P > 0.05). CONCLUSION: Cancer invasion into the superior mesenteric and/or portal vein was adversely associated with survival, but cancer at the vein edge(s) was not. Transection of the SMV-PV through macroscopically normal vein may be performed to minimize resected vein length without fear of negatively affecting oncologic outcomes.

8 Article USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. 2019

Hou, Pingping / Ma, Xingdi / Zhang, Qiang / Wu, Chang-Jiun / Liao, Wenting / Li, Jun / Wang, Huamin / Zhao, Jun / Zhou, Xin / Guan, Carolyn / Ackroyd, Jeffery / Jiang, Shan / Zhang, Jianhua / Spring, Denise J / Wang, Y Alan / DePinho, Ronald A. ·Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. · Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. · Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. · Princeton University, Princeton, New Jersey 08544, USA. · Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. · Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ·Genes Dev · Pubmed #31488580.

ABSTRACT: The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of

9 Article Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. 2019

Yao, Wantong / Rose, Johnathon L / Wang, Wei / Seth, Sahil / Jiang, Hong / Taguchi, Ayumu / Liu, Jintan / Yan, Liang / Kapoor, Avnish / Hou, Pingping / Chen, Ziheng / Wang, Qiuyun / Nezi, Luigi / Xu, Zhaohui / Yao, Jun / Hu, Baoli / Pettazzoni, Piergiorgio F / Ho, I Lin / Feng, Ningping / Ramamoorthy, Vandhana / Jiang, Shan / Deng, Pingna / Ma, Grace J / Den, Peter / Tan, Zhi / Zhang, Shu Xing / Wang, Huamin / Wang, Y Alan / Deem, Angela K / Fleming, Jason B / Carugo, Alessandro / Heffernan, Timothy P / Maitra, Anirban / Viale, Andrea / Ying, Haoqiang / Hanash, Samir / DePinho, Ronald A / Draetta, Giulio F. ·Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA. · Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. gdraetta@mdanderson.org. · Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. gdraetta@mdanderson.org. ·Nature · Pubmed #30918400.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%

10 Article Expression and Clinical Significance of Protein Kinase RNA-Like Endoplasmic Reticulum Kinase and Phosphorylated Eukaryotic Initiation Factor 2α in Pancreatic Ductal Adenocarcinoma. 2019

Wang, Eric M / Akasaka, Hironari / Zhao, Jun / Varadhachary, Gauri R / Lee, Jeffrey E / Maitra, Anirban / Fleming, Jason B / Hung, Mien-Chie / Wang, Huamin / Katz, Matthew H G. ·Anatomic Pathology. · Gastrointestinal Medical Oncology. · From the Departments of Surgical Oncology. · Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #30747823.

ABSTRACT: OBJECTIVES: Endoplasmic reticulum stress and subsequent phosphorylation of eukaryotic initiation factor 2α (eIF2α) by protein kinase R-like endoplasmic reticulum kinase (PERK) plays an important role in the development and chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the expression and significance of phosphorylated eIF2α (p-eIF2α) and PERK in PDAC have not been examined. METHODS: We examined p-eIF2α and PERK expression in 84 PDAC and paired normal pancreas samples by immunohistochemistry and Western blotting and correlated the results with clinicopathologic parameters and survival. RESULTS: Mean PERK H score was 140.8 in PDAC compared with 82.1 in normal pancreas (P < 0.001). High p-eIF2α expression was present in 56% of PDACs versus 7.6% of normal pancreases (P < 0.001). High PERK and p-eIF2α expression correlated with shorter overall survival (P = 0.048 and P = 0.03, respectively). By multivariate analysis, high p-eIF2α (P = 0.01), positive margin (P = 0.002), and lymph node metastasis (P = 0.01) were independent prognosticators for survival. CONCLUSIONS: The expression levels of PERK and p-eIF2α are higher in PDAC than those in normal pancreas. High levels of PERK and p-eIF2α are predictors of shorter survival in PDAC patients, suggesting that PERK and eIF2α could be promising targets in PDAC.

11 Article Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. 2019

Blando, Jorge / Sharma, Anu / Higa, Maria Gisela / Zhao, Hao / Vence, Luis / Yadav, Shalini S / Kim, Jiseong / Sepulveda, Alejandro M / Sharp, Michael / Maitra, Anirban / Wargo, Jennifer / Tetzlaff, Michael / Broaddus, Russell / Katz, Matthew H G / Varadhachary, Gauri R / Overman, Michael / Wang, Huamin / Yee, Cassian / Bernatchez, Chantale / Iacobuzio-Donahue, Christine / Basu, Sreyashi / Allison, James P / Sharma, Padmanee. ·The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054. · Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Janssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065. · The Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054; jallison@mdanderson.org padsharma@mdanderson.org. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. ·Proc Natl Acad Sci U S A · Pubmed #30635425.

ABSTRACT: Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma,

12 Article METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis. 2019

Liu, Shuo / Hausmann, Simone / Carlson, Scott Moore / Fuentes, Mary Esmeralda / Francis, Joel William / Pillai, Renjitha / Lofgren, Shane Michael / Hulea, Laura / Tandoc, Kristofferson / Lu, Jiuwei / Li, Ami / Nguyen, Nicholas Dang / Caporicci, Marcello / Kim, Michael Paul / Maitra, Anirban / Wang, Huamin / Wistuba, Ignacio Ivan / Porco, John Anthony / Bassik, Michael Cory / Elias, Joshua Eric / Song, Jikui / Topisirovic, Ivan / Van Rechem, Capucine / Mazur, Pawel Karol / Gozani, Or. ·Department of Biology, Stanford University, Stanford, CA 94305, USA. · Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. · Lady Davis Institute and Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada. · Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Chemistry, Boston University, Boston, MA 02215, USA. · Deparment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. · Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org. · Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu. ·Cell · Pubmed #30612740.

ABSTRACT: Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.

13 Article Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis. 2019

Huang, Haojie / Chen, Jiaxiang / Peng, Lisi / Yao, Yao / Deng, Defeng / Zhang, Yang / Liu, Yan / Wang, Huamin / Li, Zhaoshen / Bi, Yan / Haddock, Ashley N / Zhan, Xianbao / Lu, Weiqin / Logsdon, Craig D / Ji, Baoan. ·Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China. · Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas. · Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida. · Departments of Anatomic Pathology and Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center , Houston, Texas. · Department of Gastroenterology, Mayo Clinic , Jacksonville, Florida. · Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China. · Department of Medicine, Stony Brook University , Stony Brook, New York. · Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center , Houston, Texas. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #30431318.

ABSTRACT: Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

14 Article First-Line Gemcitabine and Nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma. 2019

Gulhati, Pat / Prakash, Laura / Katz, Matthew H G / Wang, Xuemei / Javle, Milind / Shroff, Rachna / Fogelman, David / Lee, Jeffrey E / Tzeng, Ching-Wei D / Lee, Jeffrey H / Weston, Brian / Tamm, Eric / Bhosale, Priya / Koay, Eugene J / Maitra, Anirban / Wang, Huamin / Wolff, Robert A / Varadhachary, Gauri R. ·Hematology/Oncology Fellowship Program, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Surgery, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX, 77030, USA. · Division of Internal Medicine, Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Pathology/Lab Medicine, Department of Anatomic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 426, Houston, TX, 77030, USA. gvaradha@mdanderson.org. ·Ann Surg Oncol · Pubmed #30324485.

ABSTRACT: BACKGROUND: Preoperative chemotherapy provides early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy for localized pancreatic ductal adenocarcinoma (PDAC). For locally advanced (LA) PDAC, induction chemotherapy is the standard of care. This study evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy for localized PDAC. METHODS: Clinicopathologic features, treatment, and outcomes were evaluated for 99 patients with localized PDAC. The patients were staged using previously published criteria as follows: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (comorbidities requiring medical optimization), and LA. RESULTS: The 99 patients (PR/BR/LA: 45/14/40) were treated with Gem/nab-P. Clinical staging showed that 20 patients had PR or BR-A disease, whereas 39 patients had BR-B or BR-C disease. The BR-B+C cases included one or more of the following: age of 80 years or older (13%), Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 or more (13%), moderate to severe comorbidities (55%), CA19-9 of 1000 or higher (28%), and suspicion for metastases (21%). The majority of the patients received biweekly Gem/nab-P dosing, which was well tolerated. Pancreatectomy was performed for 12 (60%) of 20 patients with PR+BR-A, 2 (5%) of 39 patients with BR-B+C, and 1 (3%) of 40 patients with LA disease. During a median follow-up period of 26 months, the median overall survival (OS) period was 18 months (95% confidence interval [CI], 15.6-20.5 months) for all the patients, 17 months (95% CI, 14.6-19.5 months) for the unresected patients, and not reached for the resected patients (p = 0.028 for resected vs unresected patients). CONCLUSIONS: A significant number of patients with radiographically resectable PDAC albeit aggressive biology (BR-B), medically inoperable conditions (BR-C), or both received biweekly first-line Gem/nab-P. The resection rates were lower for the BR-B/BR-C patients than for the PR/BR-A patients (hazard ratio [HR], 0.43; 95% CI, 0.19-1.00; p = 0.05).

15 Article Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma. 2018

Zhou, Liran / Husted, Hongmei / Moore, Todd / Lu, Mason / Deng, Defeng / Liu, Yan / Ramachandran, Vijaya / Arumugam, Thiruvengadam / Niehrs, Christof / Wang, Huamin / Chiao, Paul / Ling, Jianhua / Curran, Michael A / Maitra, Anirban / Hung, Mien-Chie / Lee, Jeffrey E / Logsdon, Craig D / Hwang, Rosa F. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany. · Institute of Molecular Biology (IMB), 55128 Mainz, Germany. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. rhwang@mdanderson.org. · Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ·Sci Transl Med · Pubmed #30355799.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-κB activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8

16 Article Surgical overtreatment of pancreatic intraductal papillary mucinous neoplasms: Do the 2017 International Consensus Guidelines improve clinical decision making? 2018

Sharib, Jeremy M / Fonseca, Annabelle L / Swords, Douglas S / Jaradeh, Katrin / Bracci, Paige M / Firpo, Matthew A / Hatcher, Stacy / Scaife, Courtney L / Wang, Huamin / Kim, Grace E / Mulvihill, Sean J / Maitra, Anirban / Koay, Eugene J / Kirkwood, Kimberly S. ·Department of Surgery, Division of Surgical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, CA. · Department of Surgery, Division of Surgical Oncology, University of Texas MD Anderson Comprehensive Cancer Center, Houston, TX. · Department of Surgery, University of Utah Huntsman Cancer Institute, Salt Lake City, UT. · Department of Epidemiology and Biostatistics, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, CA. · Department of Pathology, University of Texas MD Anderson Comprehensive Cancer Center, Houston, TX. · Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, CA. · Department of Radiation Oncology, University of Texas MD Anderson Comprehensive Cancer Center, Houston, TX. · Department of Surgery, Division of Surgical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, CA. Electronic address: Kim.Kirkwood@ucsf.edu. ·Surgery · Pubmed #30170819.

ABSTRACT: BACKGROUND: Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. METHODS: Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. RESULTS: Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12-40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08-5.62), fine-needle aspiration without epithelial cells (2.6; 1.43-4.72), and normal duct diameter (3.07; 1.99-4.75). Diabetes developed in 30% of patients after resection. CONCLUSION: Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.

17 Article A Visually Apparent and Quantifiable CT Imaging Feature Identifies Biophysical Subtypes of Pancreatic Ductal Adenocarcinoma. 2018

Koay, Eugene J / Lee, Yeonju / Cristini, Vittorio / Lowengrub, John S / Kang, Ya'an / Lucas, F Anthony San / Hobbs, Brian P / Ye, Rong / Elganainy, Dalia / Almahariq, Muayad / Amer, Ahmed M / Chatterjee, Deyali / Yan, Huaming / Park, Peter C / Rios Perez, Mayrim V / Li, Dali / Garg, Naveen / Reiss, Kim A / Yu, Shun / Chauhan, Anil / Zaid, Mohamed / Nikzad, Newsha / Wolff, Robert A / Javle, Milind / Varadhachary, Gauri R / Shroff, Rachna T / Das, Prajnan / Lee, Jeffrey E / Ferrari, Mauro / Maitra, Anirban / Taniguchi, Cullen M / Kim, Michael P / Crane, Christopher H / Katz, Matthew H / Wang, Huamin / Bhosale, Priya / Tamm, Eric P / Fleming, Jason B. ·Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ekoay@mdanderson.org. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Center for Precision Biomedicine, The University of Texas Health Science Center, Houston, Texas. · Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas. · Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Mathematics, University of California, Irvine, California. · Department of Biomedical Engineering, University of California, Irvine, California. · Chao Family Comprehensive Cancer Center, University of California, Irvine, California. · Center for Complex Biological Systems, University of California, Irvine, California. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Deparment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Medical Oncology, The University of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania. · Department of Internal Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Radiology, The University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. ·Clin Cancer Res · Pubmed #30082477.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. EXPERIMENTAL DESIGN: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. RESULTS: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. CONCLUSIONS: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

18 Article Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer. 2018

Wang, Ying-Nai / Lee, Heng-Huan / Chou, Chao-Kai / Yang, Wen-Hao / Wei, Yongkun / Chen, Chun-Te / Yao, Jun / Hsu, Jennifer L / Zhu, Cihui / Ying, Haoqiang / Ye, Yuanqing / Wang, Wei-Jan / Lim, Seung-Oe / Xia, Weiya / Ko, How-Wen / Liu, Xiuping / Liu, Chang-Gong / Wu, Xifeng / Wang, Huamin / Li, Donghui / Prakash, Laura R / Katz, Matthew H / Kang, Yaan / Kim, Michael / Fleming, Jason B / Fogelman, David / Javle, Milind / Maitra, Anirban / Hung, Mien-Chie. ·Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: mhung@mdanderson.org. ·Cancer Cell · Pubmed #29606349.

ABSTRACT: Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families.

19 Article Immune Cell Production of Interleukin 17 Induces Stem Cell Features of Pancreatic Intraepithelial Neoplasia Cells. 2018

Zhang, Yu / Zoltan, Michelle / Riquelme, Erick / Xu, Hanwen / Sahin, Ismet / Castro-Pando, Susana / Montiel, Maria Fernanda / Chang, Kyle / Jiang, Zhengyu / Ling, Jianhua / Gupta, Sonal / Horne, William / Pruski, Melissa / Wang, Huamin / Sun, Shao-Cong / Lozano, Guillermina / Chiao, Paul / Maitra, Anirban / Leach, Steven D / Kolls, Jay K / Vilar, Eduardo / Wang, Timothy C / Bailey, Jennifer M / McAllister, Florencia. ·Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Engineering, Texas Southern University, Houston, Texas. · Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas. · Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. · Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas. · Department of Immunology, University of Texas Health Sciences Center, Houston, Texas. · Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: fmcallister@mdanderson.org. ·Gastroenterology · Pubmed #29604293.

ABSTRACT: BACKGROUND & AIMS: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to pancreatic interepithelial neoplasia (PanIN) initiation and progression. We investigated the effects that IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena. METHODS: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KC RESULTS: PanIN cells from KC CONCLUSIONS: In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.

20 Article Significance of T1a and T1b Carcinoma Arising in Mucinous Cystic Neoplasm of Pancreas. 2018

Hui, Ling / Rashid, Asif / Foo, Wai Chin / Katz, Matthew H / Chatterjee, Deyali / Wang, Hua / Fleming, Jason B / Tamm, Eric P / Wang, Huamin. ·Departments of Pathology. · Surgical Oncology. · Gastrointestinal Medical Oncology. · Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX. ·Am J Surg Pathol · Pubmed #29462092.

ABSTRACT: Mucinous cystic neoplasm (MCN) of pancreas is one of the precursor lesions of pancreatic ductal adenocarcinoma. The 5-year disease-specific survival for noninvasive MCNs was 100% and 20% to 60% for those with pancreatic ductal adenocarcinoma arising in a MCN. However, the significance of T1a (≤0.5 cm) and T1b (>0.5 and <1.0 cm) carcinoma arising in MCN as defined by the upcoming American Joint Committee on Cancer, eighth edition is unclear. In this study, we examined 3 cases of MCN with T1a or T1b carcinoma and compared their clinicopathologic characteristics and survival to 46 cases of MCN with low-grade dysplasia (MCN-LGD), 7 cases of MCN with high-grade dysplasia (MCN-HGD), and 7 cases of MCN with advanced invasive carcinoma (T2 or higher T stage). The tumors from all 3 cases were submitted in their entirety in 123, 296, and 200 blocks, respectively. All 3 patients were alive with no recurrence during the follow-up of 20.0, 113.8, and 137.2 months, respectively. Similarly, none of the patients who had MCN with either LGD or HGD had recurrence or died of disease. In contrast, 5 of 7 patients who had MCN with advanced invasive carcinoma had recurrence and later died of disease with a median survival of 22.9 months (P<0.001). Our study showed that MCN with T1a and T1b carcinoma had an excellent prognosis similar to MCNs with LGD or HGD after complete tumor sampling for histologic examination. Our results along with the previous studies suggest that close follow-up, rather than aggressive systemic therapy, may be a better approach for these patients.

21 Article Imaging-based biomarkers: Changes in the tumor interface of pancreatic ductal adenocarcinoma on computed tomography scans indicate response to cytotoxic therapy. 2018

Amer, Ahmed M / Zaid, Mohamed / Chaudhury, Baishali / Elganainy, Dalia / Lee, Yeonju / Wilke, Christopher T / Cloyd, Jordan / Wang, Huamin / Maitra, Anirban / Wolff, Robert A / Varadhachary, Gauri / Overman, Michael J / Lee, Jeffery E / Fleming, Jason B / Tzeng, Ching Wei / Katz, Matthew H / Holliday, Emma B / Krishnan, Sunil / Minsky, Bruce D / Herman, Joseph M / Taniguchi, Cullen M / Das, Prajnan / Crane, Christopher H / Le, Ott / Bhosale, Priya / Tamm, Eric P / Koay, Eugene J. ·Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa Bay, Florida. · Department of Radiation Oncology, Memorial Sloan Cancer Center, New York, New York. · Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Cancer · Pubmed #29370450.

ABSTRACT: BACKGROUND: The assessment of pancreatic ductal adenocarcinoma (PDAC) response to therapy remains challenging. The objective of this study was to investigate whether changes in the tumor/parenchyma interface are associated with response. METHODS: Computed tomography (CT) scans before and after therapy were reviewed in 4 cohorts: cohort 1 (99 patients with stage I/II PDAC who received neoadjuvant chemoradiation and surgery); cohort 2 (86 patients with stage IV PDAC who received chemotherapy), cohort 3 (94 patients with stage I/II PDAC who received protocol-based neoadjuvant gemcitabine chemoradiation), and cohort 4 (47 patients with stage I/II PDAC who received neoadjuvant chemoradiation and were prospectively followed in a registry). The tumor/parenchyma interface was visually classified as either a type I response (the interface remained or became well defined) or a type II response (the interface became poorly defined) after therapy. Consensus (cohorts 1-3) and individual (cohort 4) visual scoring was performed. Changes in enhancement at the interface were quantified using a proprietary platform. RESULTS: In cohort 1, type I responders had a greater probability of achieving a complete or near-complete pathologic response (21% vs 0%; P = .01). For cohorts 1, 2, and 3, type I responders had significantly longer disease-free and overall survival, independent of traditional covariates of outcomes and of baseline and normalized cancer antigen 19-9 levels. In cohort 4, 2 senior radiologists achieved a κ value of 0.8, and the interface score was associated with overall survival. The quantitative method revealed high specificity and sensitivity in classifying patients as type I or type II responders (with an area under the receiver operating curve of 0.92 in cohort 1, 0.96 in cohort 2, and 0.89 in cohort 3). CONCLUSIONS: Changes at the PDAC/parenchyma interface may serve as an early predictor of response to therapy. Cancer 2018;124:1701-9. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

22 Article Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. 2018

Zhao, Jun / Wang, Huamin / Hsiao, Cheng-Hui / Chow, Diana S-L / Koay, Eugene J / Kang, Yaan / Wen, Xiaoxia / Huang, Qian / Ma, Ying / Bankson, James A / Ullrich, Stephen E / Overwijk, Willem / Maitra, Anirban / Piwnica-Worms, David / Fleming, Jason B / Li, Chun. ·Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: cli@mdanderson.org. ·Biomaterials · Pubmed #29331808.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It has an excessive desmoplastic stroma that can limit the intratumoral delivery of chemotherapy drugs, and protect tumor cells against radiotherapy. Therefore, both stromal and tumor compartments need to be addressed in order to effectively treat PDAC. We hereby co-deliver a sonic hedgehog inhibitor, cyclopamine (CPA), and a cytotoxic chemotherapy drug paclitaxel (PTX) with a polymeric micelle formulation (M-CPA/PTX). CPA can deplete the stroma-producing cancer-associated fibroblasts (CAFs), while PTX can inhibit tumor proliferation. Here we show that in clinically relevant PDAC models, M-CPA effectively modulates stroma by increasing microvessel density, alleviating hypoxia, reducing matrix stiffness while maintaining the tumor-restraining function of extracellular matrix. M-CPA/PTX also significantly extends animal survival by suppressing tumor growth and lowering the percentages of poorly to moderately differentiated tumor phenotypes. Our study suggests that using multifunctional nanoparticles to simultaneously target stromal and tumor compartments is a promising strategy for PDAC therapy.

23 Article Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Chemotherapy. 2017

Nejati, Reza / Goldstein, Jennifer B / Halperin, Daniel M / Wang, Hua / Hejazi, Nazila / Rashid, Asif / Katz, Matthew H / Lee, Jeffrey E / Fleming, Jason B / Rodriguez-Canales, Jaime / Blando, Jorge / Wistuba, Ignacio I / Maitra, Anirban / Wolff, Robert A / Varadhachary, Gauri R / Wang, Huamin. ·From the Departments of *Pathology, †Gastrointestinal Medical Oncology, ‡Surgical Oncology, and §Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #28902789.

ABSTRACT: OBJECTIVES: The aim of this study was to examine tumor-infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. METHODS: Intratumoral CD4, CD8, and FOXP3 lymphocytes were examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathological parameters and survival. RESULTS: High CD4 TILs in treated PDAC were associated with high CD8 TILs (P = 0.003), differentiation (P = 0.04), and a lower frequency of recurrence (P = 0.02). Patients with high CD4 TILs had longer disease-free survival and overall survival (OS) than did patients with low CD4 TILs (P < 0.01). The median OS of patients with a high CD8/FOXP3 lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8/FOXP3 lymphocyte ratio (28.3 [standard deviation, 2.3] months; P = 0.01). In multivariate analysis, high CD4 TILs were an independent prognostic factor for disease-free survival (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81; P = 0.005) and OS (hazard ratio, 0.54; 95% confidence interval, 0.33-0.89; P = 0.02). CONCLUSIONS: High level of CD4 lymphocytes is associated with tumor differentiation and lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy.

24 Article Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma. 2017

Aguilera, Kristina Y / Huang, Huocong / Du, Wenting / Hagopian, Moriah M / Wang, Zhen / Hinz, Stefan / Hwang, Tae Hyun / Wang, Huamin / Fleming, Jason B / Castrillon, Diego H / Ren, Xiaomei / Ding, Ke / Brekken, Rolf A. ·Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. · School of Pharmacy, Jinan University, Guangzhou, China. · Department of Pathology, UT Southwestern Medical Center, Dallas, Texas. · Department of Pathology, UT MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, UT MD Anderson Cancer Center, Houston, Texas. · Department of Clinical Science, UT Southwestern Medical Center, Dallas, Texas. · Division of Surgical Oncology, Department of Surgery and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. Rolf.Brekken@utsouthwestern.edu. · Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas. ·Mol Cancer Ther · Pubmed #28864681.

ABSTRACT: The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients.

25 Article Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Patients With Pancreatic Ductal Adenocarcinoma. 2017

Cloyd, Jordan M / Katz, Matthew H G / Wang, Huamin / Cuddy, Amanda / You, Y Nancy. ·Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston. ·JAMA Surg · Pubmed #28793134.

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