Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by James S. Tomlinson
Based on 24 articles published since 2010
(Why 24 articles?)
||||

Between 2010 and 2020, J. S. Tomlinson wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pancreatic cancer circulating tumor cells: applications for personalized oncology. 2018

DiPardo, Benjamin J / Winograd, Paul / Court, Colin M / Tomlinson, James S. ·a Department of Surgery , University of California Los Angeles , Los Angeles , CA , USA. · b Department of Surgery , Greater Los Angeles Veterans Health Administration , Los Angeles , CA , USA. ·Expert Rev Mol Diagn · Pubmed #30099926.

ABSTRACT: INTRODUCTION: Pancreatic cancer (PC) is a highly lethal disease, in part because of early metastasis, late diagnosis, and limited treatment options. Circulating tumor cells (CTCs) are cancer cells that have achieved the metastatic step of intravasation, and are thus a unique source of biomarkers with potential applications in the staging, prognostication, and treatment of PC. Areas covered: This review describes the use of CTCs in PC, including isolation methods, the significance of CTC enumeration, and studies examining phenotypic and molecular characteristics of CTCs. We also speculate on future directions for PC CTC research such as single-cell analysis and CTC culture. Expert commentary: CTCs represent a potential unique serial source of cancer tissue via a convenient and minimally invasive blood draw. Recent development of isolation methods that allow for the release of viable CTCs with unaltered molecular characteristics has set the stage for single-cell analysis and ex vivo culture. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC.

2 Review Circulating Tumor Cells in Gastrointestinal Cancer: Current Practices and Future Directions. 2016

Court, Colin M / Ankeny, Jacob S / Sho, Shonan / Tomlinson, James S. · ·Cancer Treat Res · Pubmed #29206383.

ABSTRACT: GI cancers are the leading cause of cancer-related death worldwide primarily due to a combination of late presentation and aggressive biology. The lack of adequate biomarkers for screening, diagnosis, staging, and prognosis confounds clinical decision-making and delays potentially effective therapies. Circulating tumor cells (CTCs) are a new biomarker with particular promise in GI cancers, potentially offering clinicians and researchers real-time access to tumor tissue in a reliable, safe, and cost-effective manner. Preliminary studies have investigated the potential clinical utility of CTCs for all GI cancer types with promising results. Furthermore, advances in single cell analytics have been successfully applied to CTCs, allowing for exciting new clinical and research applications. In this chapter, we will review the current state of CTC research in GI cancers as well as the potential future applications that are currently being developed.

3 Review Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis. 2015

Court, Colin M / Ankeny, Jacob S / Hou, Shuang / Tseng, Hsian-Rong / Tomlinson, James S. ·a 1 Department of Surgery, University of California , Los Angeles, USA. · b 2 VA Greater, Healthcare System , Los Angeles, USA. · c 3 Department of Molecular and Medical Pharmacology, University of California , Los Angeles, USA. · d 4 Center for Pancreatic Diseases, University of California , Los Angeles, USA. ·Expert Rev Mol Diagn · Pubmed #26390158.

ABSTRACT: Pancreatic cancer (PC) is the fourth most common cause of cancer-related death in the USA, primarily due to late presentation coupled with an aggressive biology. The lack of adequate biomarkers for diagnosis and staging confound clinical decision-making and delay potentially effective therapies. Circulating tumor cells (CTCs) are a promising new biomarker in PC. Preliminary studies have demonstrated their potential clinical utility, and newer CTC isolation platforms have the potential to provide clinicians access to tumor tissue in a reliable, real-time manner. Such a 'liquid biopsy' has been demonstrated in several cancers, and small studies have demonstrated its potential applications in PC. This article reviews the available literature on CTCs as a biomarker in PC and presents the latest innovations in CTC research as well as their potential applications in PC.

4 Clinical Trial Pancreatic cancer patients with lymph node involvement by direct tumor extension have similar survival to those with node-negative disease. 2015

Williams, Jennifer L / Nguyen, Andrew H / Rochefort, Matthew / Muthusamy, V Raman / Wainberg, Zev A / Dawson, David W / Tomlinson, James S / Hines, O Joe / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, Harbor-UCLA Medical Center, Torrance, California. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California. ·J Surg Oncol · Pubmed #26303811.

ABSTRACT: BACKGROUND: Lymph node (LN) involvement is a well-known poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). However, there have been conflicting results on the significance of the mechanism of LN involvement, "direct" tumor invasion versus "metastatic," disease on patient survival. METHODS: Clinicopathologic records from all patients who underwent resection for PDAC from 1990 to 2014 at a single-institution were reviewed. RESULTS: Of the 385 total patients, there was tumor invasion outside of the pancreas in 289 (75.1%) patients. Overall, 239 (62.1%) had node-positive disease: 220 (92.0%) by "metastatic" involvement, 14 (5.9%) by "direct" tumor extension, and five (2.1%) by a mix of "metastatic" and "direct". There were no significant differences in clinicopathologic factors associated with PDAC survival between "metastatic" and "direct" LN patients. The median overall survival for the whole cohort was 31.1 months. Compared to overall survival in patients with LN-negative disease (median 40.7 months), those with LNs involved by "metastatic" spread was significantly shorter (median 25.7 months, P < 0.001), yet "direct" LN extension was similar (median 48.1 months, P = 0.719). CONCLUSIONS: The mechanism of LN involvement affects PDAC prognosis. Patients with LNs involved by direct extension have similar survival to those with node-negative disease.

5 Article Circulating Tumor Cells Predict Occult Metastatic Disease and Prognosis in Pancreatic Cancer. 2018

Court, Colin M / Ankeny, Jacob S / Sho, Shonan / Winograd, Paul / Hou, Shuang / Song, Min / Wainberg, Zev A / Girgis, Mark D / Graeber, Thomas G / Agopian, Vatche G / Tseng, Hsian-Rong / Tomlinson, James S. ·Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. · Department of Surgery, Veteran's Health Administration, Los Angeles, CA, USA. · Department of Molecular, Cellular, and Integrative Physiology, University of California Los Angeles, Los Angeles, CA, USA. · Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. · Department of Hematology/Oncology, University of California Los Angeles, Los Angeles, CA, USA. · Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA. jtomlinson@mednet.ucla.edu. · Department of Surgery, Veteran's Health Administration, Los Angeles, CA, USA. jtomlinson@mednet.ucla.edu. · California NanoSystems Institute (CNSI), University of California Los Angeles, Los Angeles, CA, USA. jtomlinson@mednet.ucla.edu. ·Ann Surg Oncol · Pubmed #29442211.

ABSTRACT: BACKGROUND: Occult metastatic tumors, below imaging thresholds, are a limitation of staging systems that rely on cross-sectional imaging alone and are a cause of the routine understaging of pancreatic ductal adenocarcinomas (PDACs). We investigated circulating tumor cells (CTCs) as a preoperative predictor of occult metastatic disease and as a prognostic biomarker for PDAC patients. EXPERIMENTAL DESIGN: A total of 126 patients (100 with cancer, 26 with benign disease) were enrolled in our study and CTCs were identified and enumerated from 4 mL of venous blood using the microfluidic NanoVelcro assay. CTC enumeration was correlated with clinicopathologic variables and outcomes following both surgical and systemic therapies. RESULTS: CTCs were identified in 78% of PDAC patients and CTC counts correlated with increasing stage (ρ = 0.42, p < 0.001). Of the 53 patients taken for potentially curative surgery, 13 (24.5%) had occult metastatic disease intraoperatively. Patients with occult disease had significantly more CTCs than patients with local disease only (median 7 vs. 1 CTC, p < 0.0001). At a cut-off of three or more CTCs/4 mL, CTCs correctly identified patients with occult metastatic disease preoperatively (area under the receiver operating characteristic curve 0.82, 95% confidence interval (CI) 0.76-0.98, p < 0.0001). CTCs were a univariate predictor of recurrence-free survival following surgery [hazard ratio (HR) 2.36, 95% CI 1.17-4.78, p = 0.017], as well as an independent predictor of overall survival on multivariate analysis (HR 1.38, 95% CI 1.01-1.88, p = 0.040). CONCLUSIONS: CTCs show promise as a prognostic biomarker for PDAC patients at all stages of disease being treated both medically and surgically. Furthermore, CTCs demonstrate potential as a preoperative biomarker for identifying patients at high risk of occult metastatic disease.

6 Article Digital PCR Improves Mutation Analysis in Pancreas Fine Needle Aspiration Biopsy Specimens. 2017

Sho, Shonan / Court, Colin M / Kim, Stephen / Braxton, David R / Hou, Shuang / Muthusamy, V Raman / Watson, Rabindra R / Sedarat, Alireza / Tseng, Hsian-Rong / Tomlinson, James S. ·Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America. · Department of Surgery, Greater Los Angeles Veteran's Affairs Administration, Los Angeles, California, United States of America. · Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America. · UCLA Center for Pancreatic Diseases, University of California Los Angeles, Los Angeles, California, United States of America. · Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America. · Department of Pathology, University of California Los Angeles, Los Angeles, California, United States of America. ·PLoS One · Pubmed #28125707.

ABSTRACT: Applications of precision oncology strategies rely on accurate tumor genotyping from clinically available specimens. Fine needle aspirations (FNA) are frequently obtained in cancer management and often represent the only source of tumor tissues for patients with metastatic or locally advanced diseases. However, FNAs obtained from pancreas ductal adenocarcinoma (PDAC) are often limited in cellularity and/or tumor cell purity, precluding accurate tumor genotyping in many cases. Digital PCR (dPCR) is a technology with exceptional sensitivity and low DNA template requirement, characteristics that are necessary for analyzing PDAC FNA samples. In the current study, we sought to evaluate dPCR as a mutation analysis tool for pancreas FNA specimens. To this end, we analyzed alterations in the KRAS gene in pancreas FNAs using dPCR. The sensitivity of dPCR mutation analysis was first determined using serial dilution cell spiking studies. Single-cell laser-microdissection (LMD) was then utilized to identify the minimal number of tumor cells needed for mutation detection. Lastly, dPCR mutation analysis was performed on 44 pancreas FNAs (34 formalin-fixed paraffin-embedded (FFPE) and 10 fresh (non-fixed)), including samples highly limited in cellularity (100 cells) and tumor cell purity (1%). We found dPCR to detect mutations with allele frequencies as low as 0.17%. Additionally, a single tumor cell could be detected within an abundance of normal cells. Using clinical FNA samples, dPCR mutation analysis was successful in all preoperative FNA biopsies tested, and its accuracy was confirmed via comparison with resected tumor specimens. Moreover, dPCR revealed additional KRAS mutations representing minor subclones within a tumor that were not detected by the current clinical gold standard method of Sanger sequencing. In conclusion, dPCR performs sensitive and accurate mutation analysis in pancreas FNAs, detecting not only the dominant mutation subtype, but also the additional rare mutation subtypes representing tumor heterogeneity.

7 Article Reality of Single Circulating Tumor Cell Sequencing for Molecular Diagnostics in Pancreatic Cancer. 2016

Court, Colin M / Ankeny, Jacob S / Sho, Shonan / Hou, Shuang / Li, Qingyu / Hsieh, Carolyn / Song, Min / Liao, Xinfang / Rochefort, Matthew M / Wainberg, Zev A / Graeber, Thomas G / Tseng, Hsian-Rong / Tomlinson, James S. ·Department of Surgery, University of California Los Angeles, Los Angeles, California; Department of Surgery, Greater Los Angeles Veterans Affairs Administration, Los Angeles, California; Department of Molecular, Cellular, and Integrative Physiology, University of California Los Angeles, Los Angeles, California. · Department of Surgery, University of California Los Angeles, Los Angeles, California; Department of Surgery, Greater Los Angeles Veterans Affairs Administration, Los Angeles, California. · Department of Surgery, University of California Los Angeles, Los Angeles, California; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. · Department of Surgery, University of California Los Angeles, Los Angeles, California. · Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. · Center for Pancreatic Disease, University of California Los Angeles, Los Angeles, California. · Department of Molecular, Cellular, and Integrative Physiology, University of California Los Angeles, Los Angeles, California; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. · Department of Surgery, University of California Los Angeles, Los Angeles, California; Department of Surgery, Greater Los Angeles Veterans Affairs Administration, Los Angeles, California; Center for Pancreatic Disease, University of California Los Angeles, Los Angeles, California. Electronic address: jtomlinson@mednet.ucla.edu. ·J Mol Diagn · Pubmed #27375074.

ABSTRACT: To understand the potential and limitations of circulating tumor cell (CTC) sequencing for molecular diagnostics, we investigated the feasibility of identifying the ubiquitous KRAS mutation in single CTCs from pancreatic cancer (PC) patients. We used the NanoVelcro/laser capture microdissection CTC platform, combined with whole genome amplification and KRAS Sanger sequencing. We assessed both KRAS codon-12 coverage and the degree that allele dropout during whole genome amplification affected the detection of KRAS mutations from single CTCs. We isolated 385 single cells, 163 from PC cell lines and 222 from the blood of 12 PC patients, and obtained KRAS sequence coverage in 218 of 385 single cells (56.6%). For PC cell lines with known KRAS mutations, single mutations were detected in 67% of homozygous cells but only 37.4% of heterozygous single cells, demonstrating that both coverage and allele dropout are important causes of mutation detection failure from single cells. We could detect KRAS mutations in CTCs from 11 of 12 patients (92%) and 33 of 119 single CTCs sequenced, resulting in a KRAS mutation detection rate of 27.7%. Importantly, KRAS mutations were never found in the 103 white blood cells sequenced. Sequencing of groups of cells containing between 1 and 100 cells determined that at least 10 CTCs are likely required to reliably assess KRAS mutation status from CTCs.

8 Article Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. 2016

Ankeny, J S / Court, C M / Hou, S / Li, Q / Song, M / Wu, D / Chen, J F / Lee, T / Lin, M / Sho, S / Rochefort, M M / Girgis, M D / Yao, J / Wainberg, Z A / Muthusamy, V R / Watson, R R / Donahue, T R / Hines, O J / Reber, H A / Graeber, T G / Tseng, H R / Tomlinson, J S. ·Department of Surgery, University of California Los Angeles, 575 Westwood Plaza, Los Angeles, CA 90095, USA. · Veteran's Health Administration, Greater Los Angeles, Department of Surgery, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. · Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, California NanoSystems Institute, University of California, Los Angeles, 570 Westwood Plaza, Los Angeles, CA 90095-1770, USA. · California NanoSystems Institute, University of California, 570 Westwood Plaza, Los Angeles, CA 90095, USA. · UCLA Center for Pancreatic Diseases, 575 Westwood Plaza, Los Angeles, CA 90095, USA. · Department of Hematology/Oncology, University of California Los Angeles, 575 Westwood Plaza, Los Angeles, CA 90095, USA. · Department of Gastroenterology, University of California Los Angeles, 575 Westwood Plaza, Los Angeles, CA 90095, USA. ·Br J Cancer · Pubmed #27300108.

ABSTRACT: BACKGROUND: Current diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) has important limitations and better biomarkers are needed to guide initial therapy. We investigated the performance of circulating tumour cells (CTCs) as an adjunctive biomarker at the time of disease presentation. METHODS: Venous blood (VB) was collected prospectively from 100 consecutive, pre-treatment patients with PDAC. Utilising the microfluidic NanoVelcro CTC chip, samples were evaluated for the presence and number of CTCs. KRAS mutation analysis was used to compare the CTCs with primary tumour tissue. CTC enumeration data was then evaluated as a diagnostic and staging biomarker in the setting of PDAC. RESULTS: We found 100% concordance for KRAS mutation subtype between primary tumour and CTCs in all five patients tested. Evaluation of CTCs as a diagnostic revealed the presence of CTCs in 54/72 patients with confirmed PDAC (sensitivity=75.0%, specificity=96.4%, area under the curve (AUROC)=0.867, 95% CI=0.798-0.935, and P<0.001). Furthermore, a cut-off of ⩾3 CTCs in 4 ml VB was able to discriminate between local/regional and metastatic disease (AUROC=0.885; 95% CI=0.800-0.969; and P<0.001). CONCLUSION: CTCs appear to function well as a biomarker for diagnosis and staging in PDAC.

9 Article Long-term survival in patients with pancreatic ductal adenocarcinoma. 2016

Stark, Alexander P / Sacks, Greg D / Rochefort, Matthew M / Donahue, Timothy R / Reber, Howard A / Tomlinson, James S / Dawson, David W / Eibl, Guido / Hines, O Joe. ·Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Department of Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. · Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. Electronic address: joehines@mednet.ucla.edu. ·Surgery · Pubmed #26847803.

ABSTRACT: BACKGROUND: Long-term survival (LTS) is uncommon for patients with pancreatic ductal adenocarcinoma (PDAC). We sought to identify factors that predict 10-year, LTS after resection of PDAC. METHODS: We identified all patients with PDAC who underwent resection at UCLA after 1990 and included all patients eligible for observed LTS (1/1/1990-12/31/2004). An independent pathologist reconfirmed the diagnosis of PDAC in patients with LTS. Logistic regression was used to predict LTS on the basis of patient and tumor characteristics. RESULTS: Of 173 included patients, 53% were male, median age at diagnosis was 66 years, and median survival was 23 months. The rate of observed LTS was 12.1% (n = 21). Age, sex, number of lymph nodes evaluated, margin status, lymphovascular invasion, and adjuvant chemotherapy and radiation were not associated with LTS. The following were associated with LTS on bivariate analysis: low AJCC stage (Ia, Ib, IIa) (P = .034), negative lymph node status (P = .034), low grade (well-, moderately-differentiated) (P = .001), and absence of perineural invasion (P = .019). Only low grade (odds ratio 7.17, P = .012) and absent perineural invasion (odds ratio 3.28, P = .036) were independently associated with increased odds of LTS. Our multivariate model demonstrated good discriminatory power for LTS, as indicated by a c-statistic of 0.7856. CONCLUSION: Absence of perineural invasion and low tumor grade were associated with greater likelihood of LTS. Understanding the tumor biology of LTS may provide critical insight into a disease that is typically marked by aggressive behavior and limited survival.

10 Article The complex morphology of acute kidney injury with microangiopathic hemolytic anemia and hyposplenism. 2015

Erblich, Thomas / Hill, Peter D / Tomlinson, James / Bain, Barbara J. ·Departments of Haematology. · Departments of Nephrology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, W12 OHS, UK. · Department of Haematology, St Mary's Hospital Campus of Imperial College Faculty of Medicine, St Mary's Hospital, Praed Street, London, N1 1NY, UK. ·Am J Hematol · Pubmed #25820529.

ABSTRACT: -- No abstract --

11 Article Current recommendations for surveillance and surgery of intraductal papillary mucinous neoplasms may overlook some patients with cancer. 2015

Nguyen, Andrew H / Toste, Paul A / Farrell, James J / Clerkin, Barbara M / Williams, Jennifer / Muthusamy, V Raman / Watson, Rabindra R / Tomlinson, James S / Hines, O Joe / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, CHS 72-215, Los Angeles, CA, 90095, USA. ·J Gastrointest Surg · Pubmed #25373706.

ABSTRACT: BACKGROUND: The 2012 Sendai Criteria recommend that patients with 3 cm or larger branch duct intraductal papillary mucinous neoplasms (BD-IPMN) without any additional "worrisome features" or "high-risk stigmata" may undergo close observation. Furthermore, endoscopic ultrasound (EUS) is not recommended for BD-IPMN <2 cm. These changes have generated concern among physicians treating patients with pancreatic diseases. The purposes of this study were to (i) apply the new Sendai guidelines to our institution's surgically resected BD-IPMN and (ii) reevaluate cyst size cutoffs in identifying patients with lesions harboring high-grade dysplasia or invasive cancer. METHODS: We retrospectively reviewed 150 patients at a university medical center with preoperatively diagnosed and pathologically confirmed IPMNs. Sixty-six patients had BD-IPMN. Pathologic grade was dichotomized into low-grade (low or intermediate grade dysplasia) or high-grade/invasive (high-grade dysplasia or invasive cancers). Fisher's exact test, chi-square test, student's t test, linear regression, and receiver operating characteristic (ROC) analyses were performed. RESULTS: The median BD-IPMN size on imaging was 2.4 cm (interquartile range 1.5-3.0). Fifty-one (77 %) low-grade and 15 (23 %) high-grade/invasive BD-IPMN were identified. ROC analysis demonstrated that cyst size on preoperative imaging is a reasonable predictor of grade with an area under the curve of 0.691. Two-thirds of high-grade/invasive BD-IPMN were <3 cm (n = 10). Compared to a cutoff of 3, 2 cm was associated with higher sensitivity (73.3 vs. 33.3 %) and negative predictive value (83.3 vs. 80 %, NPV) for high-grade/invasive BD-IPMN. Mural nodules on endoscopic ultrasound (EUS) or atypical cells on endoscopic ultrasound-fine needle aspiration (EUS-FNA) were identified in all cysts <2 and only 50 % of those <3 cm. Forty percent of cysts >3 cm were removed based on size alone. DISCUSSION/CONCLUSIONS: Our results suggest that "larger" size on noninvasive imaging can indicate high-grade/invasive cysts, and EUS-FNA may help identify "smaller" cysts with high-grade/invasive pathology.

12 Article A mutated anti-CA19-9 scFv-Fc for positron emission tomography of human pancreatic cancer xenografts. 2014

Rochefort, Matthew M / Girgis, Mark D / Knowles, Scott M / Ankeny, Jacob S / Salazar, Felix / Wu, Anna M / Tomlinson, James S. ·Department of Surgery, UCLA, 570 Westwood Plaza, Bldg 114, CNSI, Rm4324E, Los Angeles, CA, 90095, USA, mrochefort@mednet.ucla.edu. ·Mol Imaging Biol · Pubmed #24691872.

ABSTRACT: PURPOSE: Intact antibodies have a long serum persistence resulting in high background signal that inhibits their direct translation as imaging agents. Engineering of antibody fragments through the introduction of mutations in the fragment crystallizable (Fc) region can dramatically reduce serum persistence. We sought to develop a Fc-mutated, anti-CA19-9 antibody fragment (anti-CA 19-9 scFv-Fc H310A) to provide micro-positron emission tomography (microPET) imaging of pancreatic cancer xenografts. PROCEDURES: The anti-CA19-9 scFv-Fc H310A was successfully expressed and purified. Biochemical characterization included size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and flow cytometry. The antibody fragment was labeled with iodine-124 ((124)I) and injected into mice containing human pancreatic cancer xenografts. MicroPET/CT images were then obtained. Blood, organ, and tumor radioactivity was measured and expressed as the percent of injected dose per gram of tissue (%ID/g). RESULTS: Biochemical characterization was consistent with the creation of a 105 kD dimer containing a human Fc region. Flow cytometry demonstrated antigen-specific binding, and cell-based ELISA further established a dissociation constant (K D) of 10.7 nM. (124)I-labeled scFv-Fc H310A localized to the antigen-positive tumor xenografts as detected by microPET. Objective confirmation of targeting was demonstrated by higher %ID/g in the antigen-positive tumor compared to the blood, antigen-negative tumor, and liver. CONCLUSIONS: We successfully engineered and produced an anti-CA19-9 scFv-Fc H310A antibody fragment that retains similar affinity when compared to the parental intact murine antibody. Additionally, our engineered and mutated fragment exhibited antigen-specific microPET imaging of both subcutaneous and orthotopic pancreatic cancer xenografts at early time points secondary to decreased serum half-life.

13 Article Postoperative complications reduce adjuvant chemotherapy use in resectable pancreatic cancer. 2014

Merkow, Ryan P / Bilimoria, Karl Y / Tomlinson, James S / Paruch, Jennifer L / Fleming, Jason B / Talamonti, Mark S / Ko, Clifford Y / Bentrem, David J. ·*Division of Research and Optimal Patient Care, American College of Surgeons, Chicago, IL; †Surgical Outcomes and Quality Improvement Center and the Northwestern Institute for Comparative Effectiveness Research (NICER) in Oncology, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL; ‡Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, IL; §Department of Surgery, University of California, Los Angeles and VA Greater Los Angeles Healthcare System, Los Angeles, CA; ¶Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX; ‖Department of Surgery, Northshore University Health System, Evanston, IL; and **Department of Surgery, Jesse Brown Veteran Affairs Medical Center, Chicago, IL. ·Ann Surg · Pubmed #24374509.

ABSTRACT: OBJECTIVE: To assess the impact of postoperative complications on the receipt of adjuvant chemotherapy. BACKGROUND: Randomized trials have demonstrated that adjuvant chemotherapy is associated with improved long-term survival. However, pancreatic surgery is associated with significant morbidity and the degree to which complications limit subsequent treatment options is unknown. METHODS: Patients from the American College of Surgeons National Surgical Quality Improvement Program and the National Cancer Data Base who underwent pancreatic resection for cancer were linked (2006-2009). The associations between complications and adjuvant chemotherapy use or treatment delay (≥ 70 days from surgery) were assessed using multivariable regression methods. RESULTS: From 149 hospitals, 2047 patients underwent resection for stage I-III pancreatic adenocarcinoma of which 23.2% had at least 1 serious complication. Overall adjuvant chemotherapy receipt was 57.7%: 61.8% among patients not experiencing any complication and 43.6% among those who had a serious complication. Serious complications increased the likelihood of not receiving adjuvant therapy over twofold [odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.73-2.80]. Specific complications associated with adjuvant chemotherapy omission were reintubation (OR = 7.79, 95% CI: 3.59-16.87), prolonged ventilation (OR = 5.92, 95% CI: 3.23-10.86), pneumonia (OR = 2.83, 95% CI: 1.63-4.90), sepsis/shock (OR = 2.76, 95% CI: 2.02-3.76), organ space/deep surgical site infection (OR = 2.19, 95% CI: 1.53-3.13), venous thromboembolism (OR = 1.92, 95% CI: 1.08-3.43), and urinary tract infection (OR = 1.61, 95% CI: 1.02-2.54). Serious complications also doubled the likelihood of delaying adjuvant treatment administration (OR = 2.08, 95% CI: 1.42-3.05). Sensitivity analysis in a younger, healthier patient cohort demonstrated similar associations. CONCLUSIONS: Postoperative complications are common following pancreatic surgery and are associated with adjuvant chemotherapy omission and treatment delays.

14 Article Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival. 2014

Kadera, Brian E / Sunjaya, Dharma B / Isacoff, William H / Li, Luyi / Hines, O Joe / Tomlinson, James S / Dawson, David W / Rochefort, Matthew M / Donald, Graham W / Clerkin, Barbara M / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles. · Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles6Institute for Molecular. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles4Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles5Jonsson. ·JAMA Surg · Pubmed #24306217.

ABSTRACT: IMPORTANCE: Treatment of patients with locally advanced/borderline resectable (LA/BR) pancreatic ductal adenocarcinoma (PDAC) is not standardized. OBJECTIVE: To (1) perform a detailed survival analysis of our institution's experience with patients with LA/BR PDAC who were downstaged and underwent surgical resection and (2) identify prognostic biomarkers that may help to guide a decision for the use of adjuvant therapy in this patient subgroup. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of 49 consecutive patients from a single institution during 1992-2011 with American Joint Committee on Cancer stage III LA/BR PDAC who were initially unresectable, as determined by staging computed tomography and/or surgical exploration, and who were treated and then surgically resected. MAIN OUTCOMES AND MEASURES: Clinicopathologic variables and prognostic biomarkers SMAD4, S100A2, and microRNA-21 were correlated with survival by univariate and multivariate Cox proportional hazard modeling. RESULTS: All 49 patients were deemed initially unresectable owing to vascular involvement. After completing preoperative chemotherapy for a median of 7.1 months (range, 5.4-9.6 months), most (75.5%) underwent a pylorus-preserving Whipple operation; 3 patients (6.1%) had a vascular resection. Strikingly, 37 of 49 patients were lymph-node (LN) negative (75.5%) and 42 (85.7%) had negative margins; 45.8% of evaluable patients achieved a complete histopathologic (HP) response. The median overall survival (OS) was 40.1 months (range, 22.7-65.9 months). A univariate analysis of HP prognostic biomarkers revealed that perineural invasion (hazard ratio, 5.5; P=.007) and HP treatment response (hazard ratio, 9.0; P=.009) were most significant. Lymph-node involvement, as a marker of systemic disease, was also significant on univariate analysis (P=.05). Patients with no LN involvement had longer OS (44.4 vs 23.2 months, P=.04) than LN-positive patients. The candidate prognostic biomarkers, SMAD4 protein loss (P=.01) in tumor cells and microRNA-21 expression in the stroma (P=.05), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P=.004). CONCLUSIONS AND RELEVANCE: Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.

15 Article Metabolic exploitation of the sialic acid biosynthetic pathway to generate site-specifically labeled antibodies. 2014

Rochefort, Matthew M / Girgis, Mark D / Ankeny, Jacob S / Tomlinson, James S. ·Department of Surgery, University of California Los Angeles. ·Glycobiology · Pubmed #24150277.

ABSTRACT: Lack of a universal site-specific conjugation methodology for antibodies limits their potential to be developed as tumor-specific imaging agents or targeted therapeutics. A potential mechanism for site-specific conjugation involves utilization of the conserved N-glycosylation site in the CH2 domain. We sought to develop an antibody with an altered azido-sugar at this site whereby site-specific label could be added. The HB8059 hybridoma was cultured with peracetylated N-azidoacetlymannosamine (Ac4ManNAz). The resulting azido-sugar antibody was conjugated to phosphine-polyethylene glycol (PEG3)-biotin via a modified Staudinger reaction. Biochemical and functional characterization of the biotinylated antibody was performed. The azido-sugar antibody was also labeled with DyLight-650-Phosphine and injected into mice harboring pancreatic cancer xenografts. The tumors were dissected and imaged utilizing an IVIS fluorescent camera. The antibody was successfully produced in 100 μM Ac4ManNAz. The biotinylated antibody demonstrated a 50 kDa heavy and 25 kDa light chain on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but demonstrated a single band at 50 kDa on western blot. Treatment with a N-linked glycosidase extinguished the band. Flow cytometry demonstrated antigen-specific binding of CA19-9-positive cells and the antibody localized to the antigen-positive tumor in vivo. We successfully produced an antibody with an azido-sugar at the conserved CH2 glycosylation site. We were able to utilize this azide to label the antibody with biotin or fluorescent label and demonstrate that the label is added in a site-specific manner to the heavy chain, N-linked glycosylation site. Finally, we demonstrated functionality of our antibody for in vitro and in vivo targeting of pancreatic cancer cells.

16 Article Nonfunctional pancreatic neuroendocrine tumors <2 cm on preoperative imaging are associated with a low incidence of nodal metastasis and an excellent overall survival. 2013

Toste, Paul A / Kadera, Brian E / Tatishchev, Sergei F / Dawson, David W / Clerkin, Barbara M / Muthusamy, Raman / Watson, Rabindra / Tomlinson, James S / Hines, Oscar J / Reber, Howard A / Donahue, Timothy R. ·Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA, ptoste@mednet.ucla.edu. ·J Gastrointest Surg · Pubmed #24101447.

ABSTRACT: BACKGROUND: The optimal surgical management of small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial. We sought to identify (1) clinicopathologic factors associated with survival in NF-PNETs and (2) preoperative tumor characteristics that can be used to determine which lesions require resection and lymph node (LN) harvest. METHODS: The records of all 116 patients who underwent resection for NF-PNETs between 1989 and 2012 were reviewed retrospectively. Preoperative factors, operative data, pathology, surgical morbidity, and survival were analyzed. RESULTS: The overall 5- and 10-year survival rates were 83.9 and 72.8 %, respectively. Negative LNs (p = 0.005), G1 or G2 histology (p = 0.033), and age <60 years (p = 0.002) correlated with better survival on multivariate analysis. The 10-year survival rate was 86.6 % for LN-negative patients (n = 73) and 34.1 % for LN-positive patients (n = 32). Tumor size ≥2 cm on preoperative imaging predicted nodal positivity with a sensitivity of 93.8 %. Positive LNs were found in 38.5 % of tumors ≥2 cm compared to only 7.4 % of tumors <2 cm. CONCLUSIONS: LN status, a marker of systemic disease, was a highly significant predictor of survival in this series. Tumor size on preoperative imaging was predictive of nodal disease. Thus, it is reasonable to consider parenchyma-sparing resection or even close observation for NF-PNETs <2 cm.

17 Article Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system. 2013

Rochefort, Matthew M / Ankeny, Jacob S / Kadera, Brian E / Donald, Graham W / Isacoff, William / Wainberg, Zev A / Hines, O Joe / Donahue, Timothy R / Reber, Howard A / Tomlinson, James S. ·Department of Surgery, Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA. ·Ann Surg Oncol · Pubmed #23943022.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data. METHODS: All patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system. RESULTS: We identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system. CONCLUSIONS: We were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system.

18 Article An engineered anti-CA19-9 cys-diabody for positron emission tomography imaging of pancreatic cancer and targeting of polymerized liposomal nanoparticles. 2013

Girgis, Mark D / Federman, Noah / Rochefort, Matthew M / McCabe, Katelyn E / Wu, Anna M / Nagy, Jon O / Denny, Christopher / Tomlinson, James S. ·Department of Surgery, Veterans Healthcare Affairs, Greater Los Angeles, Los Angeles, California; Department of Surgery, UCLA, Los Angeles, California. ·J Surg Res · Pubmed #23827791.

ABSTRACT: BACKGROUND: Antibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments demonstrate similar antigen affinity compared with the parental antibody but have a shorter serum half-life and possess the ability to be conjugated to nanoparticles. The goal of this study was to engineer an anti-carbohydrate antigen 19-9 (CA19-9) cys-diabody fragment in hopes of targeting nanoparticles to pancreatic cancer. METHODS: The anti-CA19-9 cys-diabody was created by engineering a C-terminal cysteine residue into the DNA single-chain Fv construct of the anti-CA19-9 diabody and expressed in NS0 cells. Maleimide chemistry was used to conjugate the cys-diabody to polymerized liposomal nanoparticles (PLNs) through the cysteine residues. Flow cytometry was used to evaluate targeting of cys-diabody and cys-diabody-PLN conjugate to human pancreatic cancer cell lines. The cys-diabody was radiolabeled with a positron emitter ((124)I) and evaluated in a mouse model of CA19-9-positive and CA19-9-negative xenografts with micro-positron emission tomography/micro-computed tomography at successive time intervals after injection. Percentage of injected dose per gram of radioactivity was measured in blood and tumor to provide objective confirmation of the micro-positron emission tomographic images. RESULTS: Tumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor-to-blood ratio of 3.0 and positive-to-negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by flow cytometry showing specific binding of cys-diabody-PLN conjugate to human pancreatic cancer cells in vitro. CONCLUSIONS: Our results show that the anti-CA19-9 cys-diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the cys-diabody-PLN conjugate demonstrates target-specific binding of human pancreatic cancer cells with the potential to deliver targeted treatment.

19 Article An engineered cysteine-modified diabody for imaging activated leukocyte cell adhesion molecule (ALCAM)-positive tumors. 2012

McCabe, Katelyn E / Liu, Bin / Marks, James D / Tomlinson, James S / Wu, Hong / Wu, Anna M. ·Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA. kmccabe@ucla.edu ·Mol Imaging Biol · Pubmed #21630083.

ABSTRACT: PURPOSE: The purpose of this study was to generate and evaluate a positron emission tomography (PET) radiotracer targeting activated leukocyte cell adhesion molecule (ALCAM). PROCEDURES: A human anti-ALCAM single chain variable fragment was reformatted to produce a covalent dimer, termed a cys-diabody (CysDb). Purified CysDb was characterized by gel electrophoresis and size exclusion chromatography, and immunoreactivity was assessed by flow cytometry and immunofluorescence. Targeting and imaging of ALCAM-positive tumors using (64)Cu-DOTA-CysDb were evaluated in mice bearing human pancreatic adenocarcinoma xenografts (HPAF-II or BxPC-3). RESULTS: CysDb binds specifically to ALCAM-positive cells in vitro with an apparent affinity in the range of 1-3 nM. MicroPET images at 4 h showed specific targeting of positive tumors in vivo, a finding confirmed by biodistribution analysis, with positive/negative tumor ratios of 1.9 ± 0.6 and 2.4 ± 0.6, and positive tumor/blood ratios of 2.5 ± 0.9 and 2.9 ± 0.6 (HPAF-II and BxPC-3, respectively). CONCLUSIONS: Successful imaging with (64)Cu-DOTA-CysDb in animal models suggests further investigation of ALCAM as an imaging biomarker is warranted.

20 Article Downstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery. 2011

Donahue, Timothy R / Isacoff, William H / Hines, O Joe / Tomlinson, James S / Farrell, James J / Bhat, Yasser M / Garon, Edward / Clerkin, Barbara / Reber, Howard A. ·Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095-6904, USA. tdonahue@mednet.ucla.edu ·Arch Surg · Pubmed #21768431.

ABSTRACT: OBJECTIVES: To determine whether computed tomography (CT)/magnetic resonance imaging (MRI) signs of vascular involvement are accurate after downstaging chemotherapy (DCTx) and to highlight factors associated with survival in patients who have undergone resection. DESIGN: Retrospective cohort study; prospective database. SETTING: University pancreatic disease center. PATIENTS: Patients with unresectable pancreaticobiliary cancer who underwent curative intent surgery after completing DCTx. INTERVENTIONS: Use of CT/MRI scan, pancreatic resection, and palliative bypass. MAIN OUTCOME MEASURES: Resectability after DCTx and disease-specific survival. RESULTS: We operated on 41 patients (1992-2009) with locally advanced periampullary malignant tumors after a median of 8.5 months of DCTx. Before DCTx, most patients (38 [93%]) were unresectable because of evidence of vascular contact on CT/MRI scan or operative exploration. Criteria for exploration after DCTx were CT/MRI evidence of tumor shrinkage and/or change in signs of vascular involvement, cancer antigen 19-9 decrease, and good functional status. None had progressive disease. At operation, we resected tumors in 34 of 41 patients (83%), and 6 had persistent vascular involvement. Surprisingly, CT/MRI scan was only 71% sensitive and 58% specific to detect vascular involvement after DCTx. "Involvement" on imaging was often from tumor fibrosis rather than viable cancer. Radiographic decrease in tumor size also did not predict resectability (P = .10). Patients with tumors that were resected had a median 87% decrease in cancer antigen 19-9 (P = .04) during DCTx. The median follow-up (all survivors) was 31 months, and disease-specific survival was 52 months for patients with resected tumors. CONCLUSIONS: In patients with initially unresectable periampullary malignant tumors, original CT/MRI signs of vascular involvement may persist after successful DCTx. Patients should be chosen for surgery on the basis of lack of disease progression, good functional status, and decrease in cancer antigen 19-9.

21 Article Anti-CA19-9 diabody as a PET imaging probe for pancreas cancer. 2011

Girgis, Mark D / Kenanova, Vania / Olafsen, Tove / McCabe, Katelyn E / Wu, Anna M / Tomlinson, James S. ·Department of Surgery, UCLA, Los Angeles, California 90095, USA. ·J Surg Res · Pubmed #21601881.

ABSTRACT: BACKGROUND: Intact antibodies are poor imaging agents due to a long serum half-life (10-20 d) preventing adequate contrast between the tumor and surrounding blood. Smaller engineered antibody fragments overcome this problem by exhibiting shorter serum half-lives (4-20 h).The diabody (55 kDa) is the smallest antibody fragment, which retains the bivalency of the intact antibody. Our goal was to develop and characterize the anti-CA19-9 diabody fragment and determine its ability to provide antigen specific imaging of pancreas cancer. METHODS: The diabody DNA construct was created by isolation of the variable region genes of the intact anti-CA19-9 antibody. Diabody expression was carried out in NS0 cells and purified using HPLC from supernatant. Specific antigen binding was confirmed with flow cytometry and immunofluorescence. Radiolabeled diabody was injected into mice harboring an antigen positive xenograft (BxPC3 or Capan-2) and a negative xenograft (MiaPaca-2). MicroCT and MicroPET were performed at successive time intervals after injection. Radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images. RESULTS: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 diabody. Pancreas xenograft imaging of BxPC3/MiaPaca-2 and Capan-2/MiaPaca-2 models with the anti-CA19-9 diabody demonstrated an average tumor:blood ratio of 5.0 and 2.0, respectively, and an average positive:negative tumor ratio of 11 and 6, respectively. With respect to the tumor:blood ratio, these data indicate five times and two times more radioactivity in the tumor than in the blood yielding adequate contrast between tumor tissue and background (i.e., blood) to create the representative microPET images. CONCLUSIONS: We successfully engineered a functional diabody against CA19-9, a tumor antigen present on the vast majority of pancreas cancers. Additionally, we demonstrate high contrast antigen specific microPET imaging of pancreas cancer in xenograft models.

22 Article Cystic neoplasms of the pancreas: results of 114 cases. 2010

Donahue, Timothy R / Hines, O Joe / Farrell, James J / Tomlinson, James S / Eibl, Guido / Reber, Howard A. ·Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095-6904, USA. ·Pancreas · Pubmed #20717069.

ABSTRACT: OBJECTIVES: To identify clinical, radiographic, and histopathologic characteristics associated with cancer in cystic pancreatic neoplasms and to evaluate our preoperative diagnostic accuracy to predict cancer in such cysts. METHODS: Retrospective case series of 114 patients with cystic lesions of the pancreas who underwent resection between 1992 and 2006. RESULTS: Eighty-nine patients (78%) had benign or premalignant cysts; 25 patients (22%) had malignant cysts (carcinoma in situ and/or an invasive cancer). The factors most predictive of malignancy were age (P = 0.03), presence of symptoms (P = 0.02), and a dilated pancreatic duct (P = 0.01). Of the symptoms recorded, weight loss (P = 0.01) and jaundice (P = 0.02) had the strongest correlation with malignancy. We correctly predicted the pathological diagnosis (benign vs malignant) for only 39 (67%) of the 58 patients where a preoperative diagnosis was clearly evident. Endoscopic ultrasound did not seem to improve our ability to preoperatively differentiate benign from malignant cysts (P > 0.05). CONCLUSIONS: This series confirms that age, the presence of symptoms, and a dilated pancreatic duct on imaging are significantly associated with cancer in pancreatic cysts, and it highlights our inability to consistently make the preoperative diagnosis of cancer. Until more accurate markers of malignancy are available, an aggressive approach to management seems justified.

23 Article Invasive intraductal papillary mucinous neoplasm versus sporadic pancreatic adenocarcinoma: a stage-matched comparison of outcomes. 2010

Wasif, Nabil / Bentrem, David J / Farrell, James J / Ko, Clifford Y / Hines, Oscar J / Reber, Howard A / Tomlinson, James S. ·John Wayne Cancer Institute at St. John's Health Center, Santa Monica, California, USA. ·Cancer · Pubmed #20564064.

ABSTRACT: BACKGROUND: Although invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas is thought to be more indolent than sporadic pancreatic adenocarcinoma (PAC), the natural history remains poorly defined. The authors compared survival and identify prognostic factors after resection for invasive IPMN versus stage-matched PAC. METHODS: The Surveillance, Epidemiology, and End Results database (1991-2005) was used to identify 729 patients with invasive IPMN and 8082 patients with PAC who underwent surgical resection. RESULTS: Patients with resected invasive IPMN experienced improved overall survival when compared with resected PAC (median survival, 21 vs 14 months; P<.001). Stratification by nodal status demonstrated no difference in survival among lymph node-positive patients; however, median survival of resected, lymph node-negative, invasive IPMN was significantly improved compared with lymph node-negative PAC (34 vs 18 months; P<.001). On multivariate analysis, PAC histology was an adverse predictor of overall survival (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.50) compared with invasive IPMN. For patients with invasive IPMN, positive lymph nodes (HR, 1.98; 95% CI, 1.50-2.60), high tumor grade (HR, 1.74; 95% CI, 1.31-2.31), tumor size>2 cm (HR, 1.50; 95% CI, 1.04-2.19), and age>66 years (HR, 1.33; 95% CI, 1.03-1.73) were adverse predictors of survival. CONCLUSIONS: Although lymph node-negative invasive IPMN showed improved survival after resection compared with lymph node-negative PAC, the natural history of lymph node-positive invasive IPMN mimicked that of lymph node-positive PAC. The authors also identified adverse predictors of survival in invasive IPMN to guide discussions regarding use of adjuvant therapies and prognosis after resection of invasive IPMN.

24 Article Impact of tumor grade on prognosis in pancreatic cancer: should we include grade in AJCC staging? 2010

Wasif, Nabil / Ko, Clifford Y / Farrell, James / Wainberg, Zev / Hines, Oscar J / Reber, Howard / Tomlinson, James S. ·John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA. ·Ann Surg Oncol · Pubmed #20422460.

ABSTRACT: BACKGROUND: AJCC staging of pancreatic cancer (PAC) is used to determine prognosis, yet survival within each stage shows wide variation and remains unpredictable. We hypothesized that tumor grade might be responsible for some of this variation and that the addition of grade to current AJCC staging would provide improved prognostication. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1991-2005) was used to identify 8082 patients with resected PAC. The impact of grade on overall and stage-specific survival was assessed using Cox regression analysis. Variables in the model were age, sex, tumor size, lymph node status, and tumor grade. RESULTS: For each AJCC stage, survival was significantly worse for high-grade versus low-grade tumors. On multivariate analysis, high tumor grade was an independent predictor of survival for the entire cohort (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.31-1.48) as well as for stage I (HR 1.28, 95% CI 1.07-1.54), stage IIA (HR 1.43, 95% CI 1.26-1.61), stage IIB (HR 1.38, 95% CI 1.27-1.50), stage III (HR 1.28, 95% CI 1.02-1.59), and stage IV (HR 1.58, 95% CI 1.21-2.05) patients. The addition of grade to staging results in a statistically significant survival discrimination between all stages. CONCLUSIONS: Tumor grade is an important prognostic variable of survival in PAC. We propose a novel staging system incorporating grade into current AJCC staging for pancreas cancer. The improved prognostication is more reflective of tumor biology and may impact therapy decisions and stratification of future clinical trials.