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Pancreatic Neoplasms: HELP
Articles by Courtney L. Scaife
Based on 20 articles published since 2008

Between 2008 and 2019, C. Scaife 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 Review The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. 2013

Poruk, Katherine E / Gay, D Z / Brown, K / Mulvihill, J D / Boucher, K M / Scaife, C L / Firpo, M A / Mulvihill, S J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. ·Curr Mol Med · Pubmed #23331006.

ABSTRACT: CA 19-9 and CEA are the most commonly used biomarkers for diagnosis and management of patients with pancreatic cancer. Since the original compendium by Steinberg in 1990, numerous studies have reported the use of CA 19-9 and, to a lesser extent, CEA in the diagnosis of pancreatic cancer. Here we update an evaluation of the accuracy of CA 19-9 and CEA, and, unlike previous reviews, focus on discrimination between malignant and benign disease instead of normal controls. In 57 studies involving 3,285 pancreatic carcinoma cases, the combined sensitivity of CA 19-9 was 78.2% and in 37 studies involving 1,882 cases with benign pancreatic disease the specificity of CA 19-9 was 82.8%. From the combined analysis of studies reporting CEA, the sensitivity was 44.2% (1,324 cases) and the specificity was 84.8% (656 cases). These measurements more appropriately reflect the expected biomarker accuracy in the differential diagnosis of patients with periampullary diseases. We also present a summary of the use of CA 19-9 as a prognostic tool and evaluate CA 19-9 diagnostic and prognostic utility in a 10-year, single institution experience.

3 Review Phenotype and genotype of pancreatic cancer cell lines. 2010

Deer, Emily L / González-Hernández, Jessica / Coursen, Jill D / Shea, Jill E / Ngatia, Josephat / Scaife, Courtney L / Firpo, Matthew A / Mulvihill, Sean J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. ·Pancreas · Pubmed #20418756.

ABSTRACT: The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

4 Clinical Trial Prospective phase I study of capecitabine and oxaliplatin concurrent with radiation therapy for the treatment of locally advanced pancreatic adenocarcinoma, and retrospective comparison to concurrent 5-fluorouracil/radiation and gemcitabine/radiation. 2012

Hazard, Lisa / Jones, Kimberly / Shaban, Akram / Anker, Christopher / Scaife, Courtney / Weis, John / Mulvihill, Sean. ·Department of Radiation Oncology, University of Arizona, Tucson, AZ 85724-5081, USA. lhazard@email.arizona.edu ·J Gastrointest Cancer · Pubmed #21243531.

ABSTRACT: PURPOSE: The aims of this study is to determine the maximum tolerated dose of capecitabine and oxaliplatin (CAPOX) delivered concurrent with radiation therapy (RT) in the treatment of locally advanced pancreatic adenocarcinoma and to retrospectively compare outcomes with this regimen to concurrent 5-fluorouracil or capecitabine with RT (5FU-RT) or concurrent gemcitabine-based chemotherapy with RT (GEM-RT). MATERIALS AND METHODS: Twelve patients were enrolled in a phase I study using 50.4 Gy RT concurrent with capecitabine chemotherapy (twice daily, 7 days per week) and oxaliplatin (once weekly during weeks 1, 2, 4, and 5). Capecitabine and oxaliplatin doses were 400 mg/m(2) and 50 mg/m(2), respectively, at dose level 1; 600 mg/m(2) and 50 mg/m(2) at level 2; and 600 mg/m(2) and 60 mg/m(2) at level 3. A standard dose of gemcitabine was recommended following RT or following surgery (if done). The outcomes of patients treated with this regimen were retrospectively compared to 20 patients treated with 5FU-RT and 30 patients treated with GEM-RT. RESULTS: Dose level 3 was tolerated with acceptable toxicity. Survival in patients receiving CAPOX-RT did not differ from GEM-RT or 5FU-RT. Response of the primary tumor was observed in 38% of patients treated with CAPOX-RT, 31% of patients treated with 5FU-RT, and 66% of patients treated with GEM-RT (p = 0.03 GEM-RT versus 5FU-RT). CONCLUSIONS: CAPOX-RT has acceptable toxicity. A retrospective comparison shows higher response rate with GEM-RT versus 5FU-RT, but this difference did not translate into improvement in overall survival.

5 Article Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery. 2018

Swords, Douglas S / Zhang, Chong / Presson, Angela P / Firpo, Matthew A / Mulvihill, Sean J / Scaife, Courtney L. ·Department of Surgery, University of Utah, Salt Lake City, UT. Electronic address: douglas.swords@hsc.utah.edu. · Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. · Department of Surgery, University of Utah, Salt Lake City, UT. ·Surgery · Pubmed #29248179.

ABSTRACT: BACKGROUND: Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. METHODS: The 2004-2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I-II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1-14 days), medium (15-42), and long (43-120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. RESULTS: Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. CONCLUSION: In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe.

6 Article Implications of inaccurate clinical nodal staging in pancreatic adenocarcinoma. 2017

Swords, Douglas S / Firpo, Matthew A / Johnson, Kirsten M / Boucher, Kenneth M / Scaife, Courtney L / Mulvihill, Sean J. ·Department of Surgery, University of Utah, Salt Lake City, UT. Electronic address: douglas.swords@hsc.utah.edu. · Department of Surgery, University of Utah, Salt Lake City, UT. ·Surgery · Pubmed #28238344.

ABSTRACT: BACKGROUND: Many patients with stage I-II pancreatic adenocarcinoma do not undergo resection. We hypothesized that (1) clinical staging underestimates nodal involvement, causing stage IIB to have a greater percent of resected patients and (2) this stage-shift causes discrepancies in observed survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) research database was used to evaluate cause-specific survival in patients with pancreatic adenocarcinoma from 2004-2012. Survival was compared using the log-rank test. Single-center data on 105 patients who underwent resection of pancreatic adenocarcinoma without neoadjuvant treatment were used to compare clinical and pathologic nodal staging. RESULTS: In SEER data, medium-term survival in stage IIB was superior to IB and IIA, with median cause-specific survival of 14, 9, and 11 months, respectively (P < .001). Seventy-two percent of stage IIB patients underwent resection vs 28% in IB and 36% in IIA (P < .001). In our institutional data, 12.4% of patients had clinical evidence of nodal involvement vs 69.5% by pathologic staging (P < .001). Among clinical stage IA-IIA patients, 71.6% had nodal involvement by pathologic staging. CONCLUSION: Both SEER and institutional data support substantial underestimation of nodal involvement by clinical staging. This finding has implications in decisions regarding neoadjuvant therapy and analysis of outcomes in the absence of pathologic staging.

7 Article Initial Misdiagnosis of Proximal Pancreatic Adenocarcinoma Is Associated with Delay in Diagnosis and Advanced Stage at Presentation. 2015

Swords, Douglas S / Mone, Mary C / Zhang, Chong / Presson, Angela P / Mulvihill, Sean J / Scaife, Courtney L. ·Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA. douglas.swords@hsc.utah.edu. · Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA. ·J Gastrointest Surg · Pubmed #26286368.

ABSTRACT: INTRODUCTION: Delay in diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with decreased survival. The effect of an initial misdiagnosis on delay in diagnosis and stage of PDAC is unknown. METHODS: This study is a retrospective review (2000-2010) from a University-based cancer center of new diagnoses of proximal PDAC. RESULTS: Of 313 patients, 98 (31.3 %) had an initial misdiagnosis. Misdiagnosed patients were younger, 62.8 ± 12.6 vs. 68.0 ± 10.1 (p < 0.001). The most common initial misdiagnoses were: gallbladder disease, gastroesophageal reflux disease, and peptic ulcer disease. After excluding patients with prior cholecystectomy, 14.2 % were misdiagnosed with gallbladder disease and underwent cholecystectomy before PDAC diagnosis. Misdiagnosed patients had higher rates of abdominal pain (p < 0.001), weight loss (p = 0.04), and acute pancreatitis (p < 0.001) and lower rate of jaundice (p < 0.001). Median time between symptoms to PDAC diagnosis was longer in misdiagnosed: 4.2 months vs. 1.4 (p < 0.001). Median time from contact with medical provider to axial imaging was longer in misdiagnosed (p < 0.001). Rate of stages III-IV disease at diagnosis was higher in misdiagnosed: 61.2 vs. 43.7 % (p = 0.004), with a 1.4 (95 % confidence interval (CI), 1.12-1.74) higher risk of stages III-IV disease at diagnosis; however, there was no difference in median overall survival in misdiagnosed patients (9.6 months in misdiagnosed vs. 10.3 months in correctly diagnosed, p = 0.69). CONCLUSIONS: Initial misdiagnosis of patients with proximal PDAC is associated with delay in diagnosis and higher risk of locally advanced or advanced disease at time of PDAC diagnosis.

8 Article Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread. 2015

Shen, Yi / Zificsak, Craig A / Shea, Jill E / Lao, Xuegang / Bollt, Oana / Li, Xiufen / Lisko, Joseph G / Theroff, Jay P / Scaife, Courtney L / Ator, Mark A / Ruggeri, Bruce A / Dorsey, Bruce D / Kuwada, Scott K. ·John A. Burns School of Medicine, University of Hawaii , 651 Ilalo Street, Honolulu, Hawaii 96813, United States. ·J Med Chem · Pubmed #25581261.

ABSTRACT: The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.

9 Article Serum IGFBP2 and MSLN as diagnostic and prognostic biomarkers for pancreatic cancer. 2014

Kendrick, Zachary W / Firpo, Matthew A / Repko, Robert C / Scaife, Courtney L / Adler, Douglas G / Boucher, Kenneth M / Mulvihill, Sean J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA. ·HPB (Oxford) · Pubmed #24308545.

ABSTRACT: BACKGROUND: Identification of diagnostic and prognostic biomarkers is a research priority for the improved management of pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor binding protein 2 (IGFBP2) and mesothelin (MSLN) have shown potential as serum biomarkers in other cancers, but have not been adequately studied in PDAC. METHODS: Serum IGFBP2 and MSLN levels were quantified by enzyme-linked immunosorbent assay (ELISA) in a cohort of 84 PDAC patients, 84 healthy control subjects and 40 chronic pancreatitis (ChPT) patients. Regression models related IGFBP2 and MSLN levels to diagnosis, gender, age, stage and survival. RESULTS: IGFPB2 and MSLN serum levels were diagnostic for PDAC in age-adjusted models (P = 0.032 and P = 0.002, respectively) when compared with ChPT and healthy control samples. At a 95% specificity threshold, the sensitivity for IGFBP2 was 22% and the sensitivity for MSLN was 17%. Neither protein approached the diagnostic accuracy of CA 19-9. However, IGFBP2 or MSLN or both correctly identified 18 of the 28 samples misidentified by CA 19-9. In age-adjusted models, neither serum IGFBP2 (P = 0.36) nor MSLN (P = 0.29) were significant predictors of survival. DISCUSSION: Serum IGFBP2 and MSLN are weak diagnostic classifiers individually, but may be useful in a diagnostic biomarker panel.

10 Article Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. 2013

Poruk, Katherine E / Firpo, Matthew A / Scaife, Courtney L / Adler, Douglas G / Emerson, Lyska L / Boucher, Kenneth M / Mulvihill, Sean J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. ·Pancreas · Pubmed #23407481.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 5%. There is an urgent need for early detection while the tumors are small and surgically resectable. We assessed serum osteopontin (OPN) and tissue inhibitor of metalloproteinase 1 (TIMP-1) as possible diagnostic and prognostic biomarkers in a novel cohort of patients with pancreatic cancer. METHODS: Osteopontin and TIMP-1 levels were determined in sera from 86 patients with PDAC, 86 healthy control subjects, and 48 patients with chronic pancreatitis. Regression models were used to relate OPN and TIMP-1 to sex, age, stage, class, and treatment. Survival analyses were performed using univariate and multivariate Cox models. RESULTS: The serum levels of both OPN and TIMP-1 distinguished PDAC from chronic pancreatitis (P ≤ 0.0001) and healthy control subjects (P < 0.0001). The serum levels of both OPN and TIMP-1 also distinguished early-stage resectable PDAC cases from chronic pancreatitis (P < 0.04) and healthy control subjects (P < 0.01). High serum levels of OPN were significantly correlated with reduced patient survival. CONCLUSIONS: Serum OPN and TIMP-1 have use as diagnostic biomarkers in PDAC. Our data suggest a potential benefit of using OPN, TIMP-1, and CA 19-9 in a panel to improve diagnostic accuracy in PDAC.

11 Article Identification of factors predictive of malignancy in patients with atypical biliary brushing results obtained via ERCP. 2013

Witt, Benjamin L / Kristen Hilden, R N / Scaife, Courtney / Chadwick, Barbara / Layfield, Lester / Cory Johnston, W / Safaee, Maryam / Siddiqui, Ali / Adler, Douglas G. ·Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. ·Diagn Cytopathol · Pubmed #23008113.

ABSTRACT: Biliary brushings obtained during ERCP can have one of three cellular interpretations: benign, malignant, or "atypical." Atypical interpretations usually result in further testing, and may cause controversy over management and increases in cost. We evaluated a large cohort of patients with atypical biliary brushings for analysis and risk stratification. All biliary brushing specimens collected between January 1, 2001 and December 31, 2010 that had an atypical result were included. Hospital electronic records were reviewed for these patients to include: demographics, indication for ERCP, endoscopist/pathologist impressions, serologic testing, stricture site, and information relating to the final clinical diagnosis. Eighty-six patients were included. Totally, 60/86 patients (70%) had malignancies while 26/86 (30%) had no evidence of malignancy during long term follow up. Univariate analysis showed that the risk of malignant outcomes was significantly associated with older age, suspicious/malignant endoscopic impression, pancreatic mass, indications including jaundice and/or dilated bile ducts, stricture location within the common bile duct, PSC, and CA 19-9 levels >300 U/mL. We created a novel scoring system for prediction of malignancy based on clinical and endoscopic factors. We identified parameters that are typically available to the clinician to categorize patients with an "atypical" bile duct brushing results into "high risk" and "lower risk" classifications. Our proposed scoring system would allow such risk stratification to take place.

12 Article Genexol inhibits primary tumour growth and metastases in gemcitabine-resistant pancreatic ductal adenocarcinoma. 2011

Shea, Jill E / Nam, Kweon-Ho / Rapoport, Natalya / Scaife, Courtney L. ·Department of Surgery, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA. ·HPB (Oxford) · Pubmed #21309930.

ABSTRACT: INTRODUCTION: Gemcitabine, the current standard of care for pancreatic ductal adenocarcinoma (PDA), has a less than 10% partial response rate. Genexol-PM, a modified form of paclitaxel, has been shown to have antitumour effects in clinical trials of metastatic breast and small-lung-cell carcinoma. The aim of the present study was to determine if Genexol would be a beneficial treatment for gemcitabine-resistant PDA. MATERIALS AND METHODS: We measured the in vitro IC50s of gemcitabine and genexol in cell lines sensitive and resistant to gemcitabine. In vivo, animals with orthotopic pancreatic tumours, resistant to gemcitabine, were treated with phosphate-buffered saline (PBS), gemcitabine, Genexol or gemcitabine+Genexol. Tumour progression was monitored using red fluorescent protein imaging. RESULTS: We showed equivalent IC50s for gemcitabine-sensitive and gemcitabine-resistant cell lines when treated with genexol. In vivo treatment with genexol resulted in a greater per cent reduction in tumour size, less metastatic spread and longer survival compared with treatment with gemcitabine. DISCUSSION: Genexol proved to be an effective treatment for gemcitabine-resistant PDA. These data combined with the successful clinical use of genexol in Phase II trials of other malignancies suggests it maybe an effective treatment for pancreatic cancer, specifically for those patients resistant to gemcitabine.

13 Article Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. 2011

Rapoport, Natalya / Nam, Kweon-Ho / Gupta, Roohi / Gao, Zhongao / Mohan, Praveena / Payne, Allison / Todd, Nick / Liu, Xin / Kim, Taeho / Shea, Jill / Scaife, Courtney / Parker, Dennis L / Jeong, Eun-Kee / Kennedy, Anne M. ·Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. natasha.rapoport@utah.edu ·J Control Release · Pubmed #21277919.

ABSTRACT: Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.

14 Article Serum platelet factor 4 is an independent predictor of survival and venous thromboembolism in patients with pancreatic adenocarcinoma. 2010

Poruk, Katherine E / Firpo, Matthew A / Huerter, Luke M / Scaife, Courtney L / Emerson, Lyska L / Boucher, Kenneth M / Jones, Kimberly A / Mulvihill, Sean J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, USA. ·Cancer Epidemiol Biomarkers Prev · Pubmed #20729288.

ABSTRACT: BACKGROUND: Improved diagnostic, predictive, and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Platelet factor 4 (PF4) has been proposed as a diagnostic biomarker for PDAC. We assessed the diagnostic and prognostic potential of serum PF4 levels in PDAC patients. METHODS: Serum PF4 levels were determined by enzyme-linked immunosorbent assay in an initial cohort of 62 PDAC patients, 62 healthy control subjects, and 34 chronic pancreatitis patients. A second validation set consisted of 71 PDAC patients. Linear regression models were used to relate PF4 to class, gender, age, stage, platelet count, and diagnosis. Survival analyses were done using univariate and multivariate Cox models. RESULTS: In the initial cohort, serum PF4 levels distinguished PDAC from chronic pancreatitis patients (P = 0.011), but not from healthy control subjects (P = 0.624). In PDAC patients, high serum PF4 level significantly predicted decreased survival independent of all covariates examined (P < 0.01). The prognostic relationship of serum PF4 levels remained significant in the validation set. Venous thromboembolism (VTE) occurred in 20% of the 133 PDAC patients. The VTE risk was higher in subjects with elevated PF4 levels (P = 0.009). CONCLUSIONS: Serum PF4 is shown for the first time to be prognostic for survival in PDAC patients. High PF4 is associated with an increased risk for the development of VTE. IMPACT: Serum PF4 levels may be useful for patient stratification and for directing treatment options in patients with pancreatic cancer including anticoagulation prophylaxis. The relationship between high PF4 levels and poorer outcomes requires further study.

15 Article Prognostic significance of PINCH signalling in human pancreatic ductal adenocarcinoma. 2010

Scaife, Courtney L / Shea, Jill / Emerson, Lyska / Boucher, Kenneth / Firpo, Matthew A / Beckerle, Mary C / Mulvihill, Sean J. ·Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA. courtney.scaife@hci.utah.edu ·HPB (Oxford) · Pubmed #20590912.

ABSTRACT: OBJECTIVE: Prognostic markers for pancreatic ductal adenocarcinoma (PDA) have failed to accurately predict patient prognosis. Recently, interest has developed in the accuracy of integrin-associated PINCH protein expression in human cancers as a predictive marker of tumour status. The goal of this study was to define the expression of PINCH protein in PDA. METHODS: Human PDA samples and orthotopic tumours from a murine model were analysed by immunohistochemistry for PINCH expression. In the animal model, PINCH expression was compared between primary and metastatic tumours. In the human samples, PINCH expression was correlated with stage, nodal involvement, margin status and overall survival. RESULTS: In the murine model, there was greater PINCH expression in metastatic tumours than in primary tumours. In the human PDA samples, greater staining for PINCH in the tumour cells was correlated with higher T status. Additionally, high PINCH expression in the stroma was associated with decreased overall survival. CONCLUSIONS: Findings of increased PINCH protein in more advanced stages of human PDA, as well as in metastatic tumours in the animal model, support the hypothesis that PINCH is an important controller of cell survival and migration. Additionally, the importance of the differential expression of PINCH in the human tumour and stroma warrants further evaluation.

16 Article Ultrasonic nanotherapy of pancreatic cancer: lessons from ultrasound imaging. 2010

Rapoport, Natalya / Kennedy, Anne M / Shea, Jill E / Scaife, Courtney L / Nam, Kweon-Ho. ·Department of Bioengineering, University of Utah, and Departments of Clinical Radiology and Surgery, School of Medicine, University of Utah, Salt Lake City, Utah 84112, USA. natasha.rapoport@utah.edu ·Mol Pharm · Pubmed #19899813.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States, with a median survival time of only 3-6 months for forty percent of patients. Current treatments are ineffective, and new PDA therapies are urgently needed. In this context, ultrasound-mediated chemotherapy by polymeric micelles and/or nanoemulsion/microbubble encapsulated drugs may offer an innovative approach to PDA treatment. PDA xenografts were orthotopically grown in the pancreas tails of nu/nu mice by surgical insertion of red fluorescence protein (RFP)-transfected MiaPaCa-2 cells. Tumor growth was controlled by fluorescence imaging. Occasional sonographic measurements correlated well with the formal tumor tracking by red fluorescence. Tumor accumulation of paclitaxel-loaded nanoemulsion droplets and droplet-to-bubble transition under therapeutic ultrasound was monitored by diagnostic ultrasound imaging. MiaPaCa-2 tumors manifested resistance to treatment by gemcitabine (GEM). This drug is the gold standard for PDA therapy. The GEM-resistant tumors proved sensitive to paclitaxel. Among six experimental groups studied, the strongest therapeutic effect was exerted by the following drug formulation: GEM + nanodroplet-encapsulated paclitaxel (nbGEN) combined with tumor-directed 1-MHz ultrasound that was applied for 30 s four to five hours after the systemic drug injection. Ultrasound-mediated PDA therapy by either micellar or nanoemulsion encapsulated paclitaxel resulted in substantial suppression of metastases and ascites, suggesting ultrasound-enhanced killing of invasive cancerous cells. However, tumors relapsed after the completion of therapy, indicating survival of some tumor cells. The recurrent tumors manifested development of paclitaxel resistance. Ultrasound imaging suggested nonuniform distribution of nanodroplets in the tumor volume due to irregular vascularization, which may result in the development of zones with subtherapeutic drug concentration. This is implicated as a possible cause of the resistance development, which may be pertinent to various modes of tumor nanotherapy.

17 Article Adenocarcinoma of the pancreas undetected by multidetector CT, endoscopic ultrasound, or intraoperative ultrasound. 2009

Chan, Melissa / Scaife, Courtney / Thaker, Harshwardhan M / Adler, Douglas G. ·Division of Gastroenterology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA. ·JOP · Pubmed #19734637.

ABSTRACT: CONTEXT: Patients with known or suspected pancreatic adenocarcinoma are typically evaluated with noninvasive imaging studies and endoscopic ultrasound. Rarely, patients require intraoperative evaluation with intraoperative ultrasound to identify mass lesions. Some patients have pancreatic adenocarcinomas that cannot be detected using any of these methods. CASE REPORT: A-58-year old female presented with a distal common bile duct stricture seen on ERCP with negative brushings. Multiple endoscopic ultrasound and triple phase pancreatic protocol CT exams were negative for a mass lesion and revealed a normal pancreas. Intraoperative ultrasound of the pancreas was also felt to be normal. Intraoperative biopsy of the head of the pancreas revealed a small, moderately to poorly differentiated adenocarcinoma, not visible on any of her imaging studies. CONCLUSION: Some pancreatic adenocarcinomas may defy detection using modern imaging modalities. This case illustrates how extensive imaging failed to detect a malignancy prior to surgery. Patients with a high clinical suspicion for malignancy but no visualized mass should undergo operative evaluation with definitive tissue sampling.

18 Article Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. 2009

Rapoport, Natalya Y / Kennedy, Anne M / Shea, Jill E / Scaife, Courtney L / Nam, Kweon-Ho. ·Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA. natasha.rapoport@utah.edu ·J Control Release · Pubmed #19477208.

ABSTRACT: The paper reports the results of nanotherapy of ovarian, breast, and pancreatic cancerous tumors by paclitaxel-loaded nanoemulsions that convert into microbubbles locally in tumor tissue under the action of tumor-directed therapeutic ultrasound. Tumor accumulation of nanoemulsions was confirmed by ultrasound imaging. Dramatic regression of ovarian, breast, and orthotopic pancreatic tumors was observed in tumor therapy through systemic injections of drug-loaded nanoemulsions combined with therapeutic ultrasound, signifying efficient ultrasound-triggered drug release from tumor-accumulated nanodroplets. The mechanism of drug release in the process of droplet-to-bubble conversion is discussed. No therapeutic effect from the nanodroplet/ultrasound combination was observed without the drug, indicating that therapeutic effect was caused by the ultrasound-enhanced chemotherapeutic action of the tumor-targeted drug, rather than the mechanical or thermal action of ultrasound itself. Tumor recurrence was observed after the completion of the first treatment round; a second treatment round with the same regimen proved less effective, suggesting that drug-resistant cells were either developed or selected during the first treatment round.

19 Article Improved diagnosis of pancreatic adenocarcinoma using haptoglobin and serum amyloid A in a panel screen. 2009

Firpo, Matthew A / Gay, David Z / Granger, Steven R / Scaife, Courtney L / DiSario, James A / Boucher, Kenneth M / Mulvihill, Sean J. ·Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. matt.firpo@hsc.utah.edu ·World J Surg · Pubmed #19082654.

ABSTRACT: BACKGROUND: Timely, accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker cancer antigen 19-9 (CA 19-9) to discriminate PA from benign conditions effectively. The goals of this study were to validate two acute-phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA, and CA 19-9 would improve PA diagnosis over CA 19-9 alone. METHODS: Levels of haptoglobin, SAA, and CA 19-9 were measured in pretreatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture, and 150 healthy control subjects by enzyme-linked immunosorbent assay or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using analysis of variance. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics (ROC) analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel. RESULTS: Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (p<0.0001) and patients with chronic pancreatitis (p=0.01). Haptoglobin was significantly elevated in sera from PA patients relative to patients with other benign diseases (p=0.0015), whereas SAA fell short of significance in the same comparison (p=0.0508). ROC analysis indicated that haptoglobin [area under the curve (AUC)=0.792] was a better diagnostic marker than SAA (AUC=0.691) over multiple threshold cutoffs. Using specific cutoffs that minimized overall misclassification, haptoglobin yielded a sensitivity of 82.7% and a specificity of 71.1%, and SAA yielded a sensitivity of 34.7% and a specificity of 90.2% when discriminating PA cases from all non-PA controls. In the same sample set, CA 19-9 yielded a sensitivity of 77.3% and a specificity of 91.1%. Combining data from haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel improved the overall accuracy when compared to CA 19-9 alone, yielding a sensitivity of 81.3% and a specificity of 95.5%. CONCLUSIONS: These data demonstrate that haptoglobin and SAA are useful for discriminating PA from benign conditions as well as healthy controls when used in a diagnostic screening panel. This study supports the use of combined biomarkers for improved accuracy in the diagnosis of PA.

20 Article Natural history of pancreatic cancer recurrence following "curative" resection in athymic mice. 2008

Torgenson, Marcus J / Shea, Jill E / Firpo, Matthew A / Dai, Qiang / Mulvihill, Sean J / Scaife, Courtney L. ·Department of Surgery, University of Utah, Salt Lake City, Utah 84132, USA. marcus.torgenson@hsc.utah.edu ·J Surg Res · Pubmed #18222475.

ABSTRACT: OBJECTIVE: We present a mouse model of pancreatic cancer recurrence following "curative" resection using a novel technique of implanting red fluorescent protein transfected tumor cells within a hyaluronan-based synthetic extracellular matrix into the distal pancreas of nude mice. Following "curative" pancreatic resection, we demonstrate postoperative disease recurrence by fluorescence imaging. METHODS: Forty athymic nude mice underwent pancreatic injection with red fluorescent protein transfected MiaPaCa-2 or AsPc-1 cells suspended in a synthetic extracellular matrix. In 20 animals, the distal pancreas and primary tumor were resected at 2 or 5 wk following injection. The remaining 20 mice underwent sham resection. Eight weeks following resection, necropsy and fluorescence imaging were performed to assess disease recurrence. RESULTS: At exploration, 39 of 40 mice had primary tumors. Eighteen of 20 mice were eligible for curative resection. Eight weeks following "curative" resection, 10 of 18 mice had recurrent disease. Of these, six developed local recurrence, two had distant metastases, and two had both. CONCLUSIONS: Using an orthotopic animal model, we are able to reliably develop primary tumors, safely perform "curative" resection, and demonstrate a 56% recurrence rate 8 wk following resection. We confirmed disease-free resection using fluorescence imaging. This model may prove useful for preclinical adjuvant therapeutic trials.