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Pancreatic Neoplasms: HELP
Articles by Stephen W. Behrman
Based on 20 articles published since 2009
(Why 20 articles?)
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Between 2009 and 2019, S. W. Behrman wrote the following 20 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Guideline Pancreatic Adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines. 2012

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen W / Ben-Josef, Edgar / Benson, Al B / Casper, Ephraim S / Cohen, Steven J / Czito, Brian / Ellenhorn, Joshua D I / Hawkins, William G / Herman, Joseph / Hoffman, John P / Ko, Andrew / Komanduri, Srinadh / Koong, Albert / Ma, Wen Wee / Malafa, Mokenge P / Merchant, Nipun B / Mulvihill, Sean J / Muscarella, Peter / Nakakura, Eric K / Obando, Jorge / Pitman, Martha B / Sasson, Aaron R / Tally, Anitra / Thayer, Sarah P / Whiting, Samuel / Wolff, Robert A / Wolpin, Brian M / Freedman-Cass, Deborah A / Shead, Dorothy A / Anonymous1061005. ·UCSF Helen Diller Family Comprehensive Cancer Center. ·J Natl Compr Canc Netw · Pubmed #22679115.

ABSTRACT: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.

3 Guideline Pancreatic adenocarcinoma. 2010

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen / Ben-Josef, Edgar / Benson, Al B / Berlin, Jordan D / Cameron, John L / Casper, Ephraim S / Cohen, Steven J / Duff, Michelle / Ellenhorn, Joshua D I / Hawkins, William G / Hoffman, John P / Kuvshinoff, Boris W / Malafa, Mokenge P / Muscarella, Peter / Nakakura, Eric K / Sasson, Aaron R / Thayer, Sarah P / Tyler, Douglas S / Warren, Robert S / Whiting, Samuel / Willett, Christopher / Wolff, Robert A / Anonymous3820673. · ·J Natl Compr Canc Netw · Pubmed #20876541.

ABSTRACT: -- No abstract --

4 Editorial Role of miRNA and cancer stem cells in chemoresistance and pancreatic cancer treatment. 2012

Danquah, Michael / Singh, Saurabh / Behrman, Stephen W / Mahato, Ram I. · ·Expert Opin Drug Deliv · Pubmed #22954290.

ABSTRACT: -- No abstract --

5 Review Management of pancreatic neuroendocrine tumors. 2013

Dickson, Paxton V / Behrman, Stephen W. ·Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, 910 Madison Avenue, Suite 208, Memphis, TN 38163, USA. ·Surg Clin North Am · Pubmed #23632152.

ABSTRACT: Pancreatic neuroendocrine tumors account for 1% to 2% of pancreatic neoplasms and may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Asymptomatic pancreatic neuroendocrine tumors are increasingly detected incidentally during abdominal imaging performed for other reasons. The management of localized pancreatic neuroendocrine tumors is surgical resection. Hepatic metastases are common and their management involves a variety of liver-directed therapies, which should be tailored according to extent of disease, symptoms, presence of extrahepatic metastases, and patient performance status.

6 Article The impact of unplanned conversion to an open procedure during minimally invasive pancreatectomy. 2018

Stiles, Zachary E / Dickson, Paxton V / Deneve, Jeremiah L / Glazer, Evan S / Dong, Lei / Wan, Jim Y / Behrman, Stephen W. ·Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee. · Division of Biostatistics, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. · Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: sbehrman@uthsc.edu. ·J Surg Res · Pubmed #29804849.

ABSTRACT: BACKGROUND: Minimally invasive pancreatic resection (MIPR) is being increasingly utilized. Outcomes for patients experiencing unplanned conversion to an open procedure during MIPR have been incompletely assessed. We sought to determine the short-term outcomes and factors associated with unplanned conversion during MIPR. METHODS: A retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program pancreatectomy-targeted data set was conducted. Successful MIPR was compared with unplanned conversion. Propensity matching was used to separately compare unplanned conversion during MIPR with planned open pancreatectomy. RESULTS: Unplanned conversion occurred in 24.6% of 350 attempted minimally invasive pancreatoduodenectomy (MIPD) and 19.6% of 1174 attempted minimally invasive distal pancreatectomy (MIDP). Conversion was associated with greater overall morbidity and 30-day mortality compared with successful MIPR for both MIPD and MIDP. After matching, unplanned conversion resulted in outcomes equivalent or inferior to open pancreatectomy. Factors significantly associated with unplanned conversion during MIPD included intermediate gland texture, vascular resection, hypertension, disseminated cancer, and chronic steroid use. For MIDP, male sex, hard gland texture, vascular resection, smoking, and recent weight loss were independently associated with conversion. A robotic approach was inversely associated with conversion for MIPD and MIDP. CONCLUSIONS: Unplanned conversion during MIPR is associated with greater morbidity and 30-day mortality. Conversion resulted in outcomes that, at best, mimicked those of open pancreatectomy. Several risk factors including the need for vascular resection are associated with unplanned conversion and should be acknowledged when planning an operative approach.

7 Article Clinical significance of MUC13 in pancreatic ductal adenocarcinoma. 2018

Khan, Sheema / Zafar, Nadeem / Khan, Shabia S / Setua, Saini / Behrman, Stephen W / Stiles, Zachary E / Yallapu, Murali M / Sahay, Peeyush / Ghimire, Hemendra / Ise, Tomoko / Nagata, Satoshi / Wang, Lei / Wan, Jim Y / Pradhan, Prabhakar / Jaggi, Meena / Chauhan, Subhash C. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Computer Science, University of Kashmir, Srinagar, India. · Department of Surgery, Baptist Memorial Hospital and the University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Physics, University of Memphis, Memphis, TN, USA. · Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-City, Osaka, Japan. · Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: schauha1@uthsc.edu. ·HPB (Oxford) · Pubmed #29352660.

ABSTRACT: BACKGROUND: Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS: MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS: MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION: This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.

8 Article Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy. 2017

Setua, Saini / Khan, Sheema / Yallapu, Murali M / Behrman, Stephen W / Sikander, Mohammed / Khan, Shabia Shabir / Jaggi, Meena / Chauhan, Subhash C. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, 19 South Manassas, Cancer Research Building, Memphis, TN, USA. · Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Computer Science, University of Kashmir, Srinagar, Jammu and Kashmir, India. · Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, 19 South Manassas, Cancer Research Building, Memphis, TN, USA. schauha1@uthsc.edu. ·J Gastrointest Surg · Pubmed #27507554.

ABSTRACT: INTRODUCTION: The functional significance of lost microRNAs has been reported in several human malignancies, including pancreatic cancer (PC). Our prior work has identified microRNA-145 (miR-145) as a tumor suppressor microRNA (miRNA) in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a transmembrane glycoprotein that is aberrantly expressed in pancreatic cancer, thus efficiently inhibiting tumor growth in mice. However, lack of an effective tumor-specific delivery system remains an unmet clinical challenge for successful translation of microRNAs. METHODS: We developed a miRNA-145-based magnetic nanoparticle formulation (miR-145-MNPF) and assessed its anti-cancer efficacy. Physico-chemical characterization (dynamic light scattering (DLS), transmission electron microscopy (TEM) and miR-binding efficiency), cellular internalization (Prussian blue and confocal microscopy), miR-145 restitution potential (quantitative reverse-transcription PCR (qRT-PCR), and anti-cancer efficacy (proliferation, colony formation, cell migration, cell invasion assays) of this formulation were performed using clinically relevant pancreatic cancer cell lines (HPAF-II, AsPC-1). RESULTS: miR-145-MNPF exhibited optimal particle size and zeta potential which effectively internalized and restituted miR-145 in pancreatic cancer cells. miR-145 re-expression resulted in downregulation of MUC13, HER2, pAKT, and inhibition of cell proliferation, clonogenicity, migration, and invasion of pancreatic cancer cells. CONCLUSIONS: miR-145-MNPF is an efficient system for miR-145 delivery and restitution in pancreas cancer that may offer a potential therapeutic treatment for PC either alone or in conjunction with conventional treatment.

9 Article MUC13 interaction with receptor tyrosine kinase HER2 drives pancreatic ductal adenocarcinoma progression. 2017

Khan, S / Sikander, M / Ebeling, M C / Ganju, A / Kumari, S / Yallapu, M M / Hafeez, B B / Ise, T / Nagata, S / Zafar, N / Behrman, S W / Wan, J Y / Ghimire, H M / Sahay, P / Pradhan, P / Chauhan, S C / Jaggi, M. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. · Cancer Biology Research Center, Sanford Research, Sioux Falls, SD, USA. · Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki City, Osaka, Japan. · Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Biostatistics & Epidemiology, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Physics, University of Memphis, Memphis, TN, USA. ·Oncogene · Pubmed #27321183.

ABSTRACT: Although MUC13, a transmembrane mucin, is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and generally correlates with increased expression of HER2, the underlying mechanism remains poorly understood. Herein, we found that MUC13 co-localizes and interacts with HER2 in PDAC cells (reciprocal co-immunoprecipitation, immunofluorescence, proximity ligation, co-capping assays) and tissues (immunohistofluorescence). The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at p1248 in PDAC cells, leading to stimulation of HER2 signaling cascade, including ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling and motility, invasion of PDAC cells-all collectively contributing to PDAC progression. Interestingly, all of these phenotypic effects of MUC13-HER2 co-localization could be effectively compromised by depleting MUC13 and mediated by the first and second EGF-like domains of MUC13. Further, MUC13-HER2 co-localization also holds true in PDAC tissues with a strong functional correlation with events contributing to increased degree of disorder and cancer aggressiveness. In brief, findings presented here provide compelling evidence of a functional ramification of MUC13-HER2: this interaction could be potentially exploited for targeted therapeutics in a subset of patients harboring an aggressive form of PDAC.

10 Article Risk-adjusted Outcomes of Clinically Relevant Pancreatic Fistula Following Pancreatoduodenectomy: A Model for Performance Evaluation. 2016

McMillan, Matthew T / Soi, Sameer / Asbun, Horacio J / Ball, Chad G / Bassi, Claudio / Beane, Joal D / Behrman, Stephen W / Berger, Adam C / Bloomston, Mark / Callery, Mark P / Christein, John D / Dixon, Elijah / Drebin, Jeffrey A / Castillo, Carlos Fernandez-Del / Fisher, William E / Fong, Zhi Ven / House, Michael G / Hughes, Steven J / Kent, Tara S / Kunstman, John W / Malleo, Giuseppe / Miller, Benjamin C / Salem, Ronald R / Soares, Kevin / Valero, Vicente / Wolfgang, Christopher L / Vollmer, Charles M. ·*Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania†Department of Surgery, Mayo Clinic, Jacksonville, Florida‡Department of Surgery, University of Calgary, Calgary, Canada§Department of Surgery, University of Verona, Verona, Italy¶Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana||Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee**Department of Surgery, Jefferson Medical College, Philadelphia, Pennsylvania††Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio‡‡Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts§§Department of Surgery, University of Alabama School of Medicine, Birmingham, Alabama¶¶Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts||||Department of Surgery, Baylor College of Medicine, Houston, Texas***Department of Surgery, University of Florida College of Medicine, Gainesville, Florida†††Department of Surgery, Yale School of Medicine, New Haven, Connecticut‡‡‡Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland. ·Ann Surg · Pubmed #26727086.

ABSTRACT: OBJECTIVE: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator. BACKGROUND: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk. METHODS: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance. RESULTS: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment. CONCLUSIONS: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.

11 Article Follicular pancreatitis: a distinct form of chronic pancreatitis-an additional mimic of pancreatic neoplasms. 2016

Gupta, Rajib K / Xie, Bill H / Patton, Kurt T / Lisovsky, Mikhail / Burks, Eric / Behrman, Stephen W / Klimstra, David / Deshpande, Vikram. ·Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163. Electronic address: rajibgupta2011@gmail.com. · Pathology Group of Midsouth (Trumbull Laboratories), Germantown, TN, 38138; Department of Pathology, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: hbup@yahoo.com. · Pathology Group of Midsouth (Trumbull Laboratories), Germantown, TN, 38138; Department of Pathology, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: kurt_patton@yahoo.com. · Department of Pathology, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH. Electronic address: mikhail.lisovsky@hitchcock.org. · Department of Pathology, Lahey Hospital, Burlington, MA, 01805. Electronic address: eric.burks@lahey.org. · Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163; Department of Surgery, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: sbehrman@uthsc.edu. · Department of Pathology, Memorial Sloan-Kettering Cancer Center and Memorial Hospital for Cancer and Allied Diseases, New York, NY, 10065. Electronic address: klimstrd@mskcc.org. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114. Electronic address: Vikramdirdeshpande@gmail.com. ·Hum Pathol · Pubmed #26563969.

ABSTRACT: Follicular pancreatitis is a recently described variant of chronic pancreatitis characterized clinically by the formation of a discrete pancreatic mass and histologically by the presence of florid lymphoid aggregates with reactive germinal centers. Our aim was to study the clinical and histologic features of follicular pancreatitis, as well as to critically examine potential overlap with autoimmune pancreatitis. Immunohistochemistry for Bcl-2, CD21, κ and λ light chains as well as IgG4 and IgG were performed. We found a total of 6 patients (male-female ratio, 2:1; mean age, 57 years) who fulfilled the diagnosis of follicular pancreatitis in our institutions. Four had an incidental diagnosis, while two presented with abdominal pain, fatigue, and elevated liver enzymes. On imaging, 3 patients had a discrete solid mass, whereas 2 cases showed a dilated main pancreatic duct, mimicking an intraductal pancreatic mucinous neoplasm on imaging. One patient had a lesion in the intra-pancreatic portion of the common bile duct. On histopathology, all cases showed numerous lymphoid follicles with Bcl-2-negative germinal centers either in a periductal or in a more diffuse (periductal and intra-parenchymal) fashion, but without attendant storiform fibrosis, obliterative phlebitis, or granulocytic epithelial lesions. IgG4-to-IgG ratio was <40% in 5 cases. A comparison cohort revealed germinal centers in 25% of type 1 autoimmune pancreatitis and 2% of type 2 autoimmune pancreatitis cases, but none were periductal in location. In conclusion, follicular pancreatitis, an under-recognized mimic of pancreatic neoplasms is characterized by intrapancreatic lymphoid follicles with reactive germinal centers.

12 Article Nanoparticle formulation of ormeloxifene for pancreatic cancer. 2015

Khan, Sheema / Chauhan, Neeraj / Yallapu, Murali M / Ebeling, Mara C / Balakrishna, Swathi / Ellis, Robert T / Thompson, Paul A / Balabathula, Pavan / Behrman, Stephen W / Zafar, Nadeem / Singh, Man M / Halaweish, Fathi T / Jaggi, Meena / Chauhan, Subhash C. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. · Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA. · College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. · Methodology and Data Analysis Center, Sanford Research, Sioux Falls, SD, USA. · Department of Pharmaceutical Sciences and Plough Center for Sterile Drug Delivery Systems, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Pathology, University of Tennessee at Memphis, Memphis, TN, USA. · Saraswati Dental College, Lucknow, Uttar Pradesh, India. · Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD, 57007, USA. · Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: schauha1@uthsc.edu. ·Biomaterials · Pubmed #25890768.

ABSTRACT: Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulation, which will also offer tumor specific targeted delivery. Therefore, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) nanoparticle (NP) formulation (PLGA-ORM NP). This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). Because of its facile composition, this novel formulation is compatible with antibody/aptamer conjugation to achieve tumor specific targeting. The particle size analysis of this PLGA-ORM formulation (∼100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeability and Retention (EPR) effect. Cellular uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation, providing efficient endosomal release to cytosol. PLGA-ORM NPs showed remarkable anti-cancer potential in various pancreatic cancer cells (HPAF-II, AsPC-1, BxPC-3, Panc-1, and MiaPaca) and a BxPC-3 xenograft mice model resulting in increased animal survival. PLGA-ORM NPs suppressed pancreatic tumor growth via suppression of Akt phosphorylation and expression of MUC1, HER2, PCNA, CK19 and CD31. This study suggests that the PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and thus can be valuable for the treatment of pancreatic cancer in the future.

13 Article Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. 2015

Khan, Sheema / Ebeling, Mara C / Chauhan, Neeraj / Thompson, Paul A / Gara, Rishi K / Ganju, Aditya / Yallapu, Murali M / Behrman, Stephen W / Zhao, Haotian / Zafar, Nadeem / Singh, Man Mohan / Jaggi, Meena / Chauhan, Subhash C. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee. · Cancer Biology and Sanford Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota. · Methodology and Data Analysis Center, Sanford Research, Sioux Falls, South Dakota. · Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee. · Department of Pathology, University of Tennessee at Memphis, Memphis, Tennessee. · Saraswati Dental College, Lucknow, Uttar Pradesh, India. · Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee. schauha1@uthsc.edu. ·Cancer Res · Pubmed #25840985.

ABSTRACT: The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine. Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NF-κB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFβ-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.

14 Article Routine drainage of the operative bed following elective distal pancreatectomy does not reduce the occurrence of complications. 2015

Behrman, Stephen W / Zarzaur, Ben L / Parmar, Abhishek / Riall, Taylor S / Hall, Bruce L / Pitt, Henry A. ·Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA, sbehrman@uthsc.edu. ·J Gastrointest Surg · Pubmed #25115324.

ABSTRACT: BACKGROUND: Routine drainage of the operative bed following elective pancreatectomy remains controversial. Data specific to distal pancreatectomy (DP) have not been examined in a multi-institutional collaborative. METHODS: Data from the American College of Surgeons-National Surgical Quality Improvement Program Pancreatectomy Demonstration Project were utilized. The impact of drain placement on development of pancreatectomy-related and overall morbidity were analyzed. Propensity scores for drain placement were calculated, and nearest neighbor matching was used to create a matched cohort. Groups were compared using bivariate and logistic regression analyses. RESULTS: Over 14 months, 761 patients undergoing DP were accrued; 606 were drained. Propensity score matching was possible in 116 patients. Drain and no drain groups were not different with respect to multiple preoperative and operative variables. All pancreatic fistulas (p < 0.01) and overall morbidity (p < 0.05) were more common in patients who received a drain. The placement of a drain did not reduce the incidence of clinically relevant pancreatic fistula nor the need for postoperative procedures. CONCLUSIONS: Placement of drains following elective distal pancreatectomy was associated with a higher overall morbidity and pancreatic fistulas. Drains did not reduce intra-abdominal septic morbidity, clinically relevant pancreatic fistulas, nor the need for postoperative therapeutic intervention.

15 Article MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. 2014

Khan, Sheema / Ebeling, Mara C / Zaman, Mohd S / Sikander, Mohammed / Yallapu, Murali M / Chauhan, Neeraj / Yacoubian, Ashley M / Behrman, Stephen W / Zafar, Nadeem / Kumar, Deepak / Thompson, Paul A / Jaggi, Meena / Chauhan, Subhash C. ·Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA. · Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA. · Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee , USA. · Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee , USA. · Department of Biological and Environmental Sciences, University of the District of Columbia, Washington, District of Columbia. · Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA. Methodology and Data Analysis Center, Sanford Research, Sioux Falls, South Dakota, USA. ·Oncotarget · Pubmed #25277192.

ABSTRACT: Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3' untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.

16 Article Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. 2014

Tempero, Margaret A / Malafa, Mokenge P / Behrman, Stephen W / Benson, Al B / Casper, Ephraim S / Chiorean, E Gabriela / Chung, Vincent / Cohen, Steven J / Czito, Brian / Engebretson, Anitra / Feng, Mary / Hawkins, William G / Herman, Joseph / Hoffman, John P / Ko, Andrew / Komanduri, Srinadh / Koong, Albert / Lowy, Andrew M / Ma, Wen Wee / Merchant, Nipun B / Mulvihill, Sean J / Muscarella, Peter / Nakakura, Eric K / Obando, Jorge / Pitman, Martha B / Reddy, Sushanth / Sasson, Aaron R / Thayer, Sarah P / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer L / Freedman-Cass, Deborah A. ·From UCSF Helen Diller Family Comprehensive Cancer Center; Moffitt Cancer Center; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; City of Hope Comprehensive Cancer Center; Fox Chase Cancer Center; Duke Cancer Institute; Pancreatic Cancer Action Network (PanCAN); University of Michigan Comprehensive Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Stanford Cancer Institute; UC San Diego Moores Cancer Center; Roswell Park Cancer Institute; Vanderbilt-Ingram Cancer Center; Huntsman Cancer Institute at the University of Utah; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; Massachusetts General Hospital Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center; University of Colorado Cancer Center; The University of Texas MD Anderson Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #25099441.

ABSTRACT: The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCN Pancreatic Adenocarcinoma Panel meeting. The panel discussion focused mainly on the management of borderline resectable and locally advanced disease. In particular, the panel discussed the definition of borderline resectable disease, role of neoadjuvant therapy in borderline disease, role of chemoradiation in locally advanced disease, and potential role of newer, more active chemotherapy regimens in both settings.

17 Article Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer. 2014

Mittal, Anupama / Chitkara, Deepak / Behrman, Stephan W / Mahato, Ram I. ·Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. · Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA. · Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: ram.mahato@unmc.edu. ·Biomaterials · Pubmed #24836307.

ABSTRACT: Clinical effectiveness of gemcitabine in pancreatic cancer is hindered due to its rapid plasma metabolism and development of chemo-resistance. We have previously delineated the significant role of miRNAs in mediating the growth and proliferation of cancer stem cells (CSCs) which in turn result in chemo-resistance, invasion and metastasis. Here, we designed self-assembling, gemcitabine conjugated cationic copolymers for co-delivery of a tumor suppressor miRNA-205 (miR-205) and evaluated their in vivo efficacy in a pancreatic cancer ectopic tumor model developed using gemcitabine resistant MIA PaCa-2(R) cells. Combination formulations showed mean a particle size of <100 nm and gemcitabine payload of >10% w/w, exhibited miRNA complexation at N/P ratio of 4/1, sustained release of gemcitabine for >10 days, transfection efficiency of >90%, extended miRNA and drug stability in serum. Functional assays in gemcitabine resistant MIA PaCa-2(R) and CAPAN-1(R) pancreatic cancer cells revealed that the combination formulations effectively reversed chemo-resistance, invasion and migration. In pancreatic tumor model, the combination formulation treated group showed significant inhibition of tumor growth. Immuno-hiostochemical analysis revealed decreased tumor cell proliferation with increased apoptosis in the animals treated with miR-205 and gemcitabine combination.

18 Article Self-assembling, amphiphilic polymer-gemcitabine conjugate shows enhanced antitumor efficacy against human pancreatic adenocarcinoma. 2013

Chitkara, Deepak / Mittal, Anupama / Behrman, Stephan W / Kumar, Neeraj / Mahato, Ram I. ·Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA. ·Bioconjug Chem · Pubmed #23758084.

ABSTRACT: The therapeutic efficacy of gemcitabine is severely compromised due to its rapid plasma metabolism. Moreover, its hydrophilicity poses a challenge for its efficient entrapment in nanosized delivery systems and to provide a sustained release profile. In this study, gemcitabine was covalently conjugated to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (PEG-PCC) which could self-assemble into micelles of 23.6 nm. These micelles afforded protection to gemcitabine from plasma metabolism as evident by negligible amount of gemcitabine and its metabolite dFdU detected in the plasma after 24 h. A controlled release of gemcitabine from the micelles was observed with 53.89% drug release in 10 days in the presence of protease enzyme Cathepsin B. Gemcitabine conjugated micelles were cytotoxic, showed internalization, and induced cell apoptosis in MIA PaCa-2 and L3.6pl pancreatic cancer cell lines. These micelles efficiently inhibited tumor growth when injected intravenously into MIA PaCa-2 cell derived xenograft tumor bearing NSG mice at a dose of 40 mg/kg in terms of reduced tumor volume and tumor weight (0.38 g vs 0.58 g). TUNEL assay revealed that gemcitabine conjugated micelles induced a much higher extent of apoptosis in the tumor tissues compared to free gemcitabine. In conclusion, gemcitabine conjugated micelles were able to enhance the drug payload, protect it from rapid plasma metabolism, and provide a sustained release and showed enhanced antitumor activity, and thus have the potential to provide a better therapeutic alternative for treating pancreatic cancer.

19 Article miRNA profiling in pancreatic cancer and restoration of chemosensitivity. 2013

Singh, Saurabh / Chitkara, Deepak / Kumar, Virender / Behrman, Stephen W / Mahato, Ram I. ·Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States. ·Cancer Lett · Pubmed #23073476.

ABSTRACT: Pancreatic cancers relapse due to small but distinct population of cancer stem cells (CSCs) which are in turn regulated by miRNAs. The present study identifies a series of miRNAs which were either upregulated (e.g. miR-146) or downregulated (e.g. miRNA-205, miRNA-7) in gemcitabine resistant MIA PaCa-2 cancer cells and clinical metastatic pancreatic cancer tissues. Gemcitabine resistant MIA PaCa-2 cells possessed distinct ALDH-positive CSC fraction expressing stem cell markers OCT3/4 and CD44 and chemoresistance marker class IIIβ-tubulin (TUBB3) which decreases on transfection with miR-205 resulting in the restoration of chemosensitivity to gemcitabine.

20 Article Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. 2012

Chitkara, Deepak / Singh, Saurabh / Kumar, Virender / Danquah, Michael / Behrman, Stephen W / Kumar, Neeraj / Mahato, Ram I. ·Department of Pharmaceutical Sciences, and ‡Department of Surgery, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States. ·Mol Pharm · Pubmed #22780906.

ABSTRACT: Hedgehog (Hh) and epidermal growth factor receptor (EGFR) signaling are involved in pancreatic cancer progression. Targeting these pathways simultaneously with cyclopamine (Hh inhibitor) and gefitinib (EGFR inhibitor) is a promising approach for treating pancreatic cancer. However, the major limitation for effective clinical translation of these molecules is their low aqueous solubility. We have previously demonstrated that methoxy polyethyleneglycol-b-poly(carbonate-co-lactic acid) {mPEG-b-P(CB-co-LA)} copolymer solubilizes hydrophobic anticancer drugs and has the potential to deliver to tumors by an enhanced permeability and retention (EPR) effect. In this study, using the nanoprecipitation method, cyclopamine and gefitinib were efficiently loaded into mPEG-b-P(CB-co-LA) micelles with encapsulation efficiencies of 94.4 and 88.6%, respectively. These micelles had a narrow particle size distribution with a mean particle size of 54.3 nm and a PDI of 0.14. Combination therapy showed a synergistic effect against L3.6pl cells but an additive effect against MIA PaCa-2 cells. Caspase 3/7 activity was also increased when this combination therapy was used, indicating apoptotic cell death. Gene and protein expression analysis indicated cross-talk between Hh and EGFR signaling. Furthermore, the combination decreased tumor growth rate in L3.6pl-derived xenograft mouse tumors. These data suggest the applicability of our micellar system to effectively load and deliver cyclopamine and gefitinib for combination chemotherapy.