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Pancreatic Neoplasms: HELP
Articles by Brian E. Kadera
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, Brian E. Kadera wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer. 2016

Williams, Jennifer L / Kadera, Brian E / Nguyen, Andrew H / Muthusamy, V Raman / Wainberg, Zev A / Hines, O Joe / Reber, Howard A / Donahue, Timothy R. ·Department of Surgery, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. · Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. · Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. tdonahue@mednet.ucla.edu. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 72-215 CHS, Box 956904, Los Angeles, CA, 90095, USA. tdonahue@mednet.ucla.edu. ·J Gastrointest Surg · Pubmed #27114246.

ABSTRACT: BACKGROUND: Compared to the widely adopted 2-4 months of pre-operative therapy for patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC), our institution tends to administer a longer duration before considering surgical resection. Using this unique approach, the aim of this study was to determine pre-operative variables associated with survival. METHODS: Records from patients with BR/LA PDAC who underwent attempt at surgical resection from 1992-2014 were reviewed. RESULTS: After a median duration of 6 months of pre-operative treatment, 109 patients with BR/LA PDAC (BR 63, LA 46) were explored; 93 (85.3 %) underwent pancreatectomy. Those who received at least 6 months of pre-operative treatment had longer median overall survival (OS) than those who received less (52.8 vs. 32.1 months, P = 0.044). On multivariate analysis, pre-operative treatment duration was the strongest predictor of survival (hazard ratio (HR) 4.79, P = 0.043). However, OS was similar in those whose CA19-9 normalized regardless of whether they received more or less than 6 months of chemotherapy (71.4 vs. 101.8 months, P = 0.930). CONCLUSIONS: Pre-operative CA19-9 decline can guide treatment duration in patients with BR/LA PDAC. We endorse 6 months of therapy except in those patients whose values normalize, where surgery can be considered after a shorter course.

2 Article Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK. 2016

Toste, Paul A / Nguyen, Andrew H / Kadera, Brian E / Duong, Mindy / Wu, Nanping / Gawlas, Irmina / Tran, Linh M / Bikhchandani, Mihir / Li, Luyi / Patel, Sanjeet G / Dawson, David W / Donahue, Timothy R. ·Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. tdonahue@mednet.ucla.edu. ·Mol Cancer Res · Pubmed #26979711.

ABSTRACT: IMPLICATIONS: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.

3 Article p85α is a microRNA target and affects chemosensitivity in pancreatic cancer. 2015

Toste, Paul A / Li, Luyi / Kadera, Brian E / Nguyen, Andrew H / Tran, Linh M / Wu, Nanping / Madnick, David L / Patel, Sanjeet G / Dawson, David W / Donahue, Timothy R. ·Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA. ·J Surg Res · Pubmed #25846727.

ABSTRACT: BACKGROUND: We previously identified a correlation between increased expression of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85α and improved survival in human pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the impact of changes in p85α expression on response to chemotherapy and the regulation of p85α by microRNA-21 (miR-21). MATERIALS AND METHODS: PDAC tumor cells overexpressing p85α were generated by viral transduction, and the effect of p85α overexpression on sensitivity to gemcitabine was tested by MTT assay. Primary human PDAC tumors were stained for p85α and miR-21 via immunohistochemistry and in situ hybridization, respectively. Additionally, PDAC cells were treated with miR-21 mimic, and changes in p85α and phospho-AKT were assessed by Western blot. Finally, a luciferase reporter assay system was used to test direct regulation of p85α by miR-21. RESULTS: Higher p85α expression resulted in increased sensitivity to gemcitabine (P < 0.01), which correlated with decreased PI3K-AKT activation. Human tumors demonstrated an inverse correlation between miR-21 and p85α expression levels (r = -0.353, P < 0.001). In vitro, overexpression of miR-21 resulted in decreased levels of p85α and increased phosphorylation of AKT. Luciferase reporter assays confirmed the direct regulation of p85α by miR-21 (P < 0.01). CONCLUSIONS: Our results demonstrate that p85α expression is a determinant of chemosensitivity in PDAC. Additionally, we provide novel evidence that miR-21 can influence PI3K-AKT signaling via its direct regulation of p85α. These data provide insight into potential mechanisms for the known relationship between increased p85α expression and improved survival in PDAC.

4 Article Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition. 2015

Kadera, Brian E / Toste, Paul A / Wu, Nanping / Li, Luyi / Nguyen, Andrew H / Dawson, David W / Donahue, Timothy R. ·Department of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. · Department of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. tdonahue@mednet.ucla.edu. ·Clin Cancer Res · Pubmed #25348515.

ABSTRACT: PURPOSE: Expression of CBL, an ubiquitin ligase, is decreased in 60% of human pancreatic ductal adenocarcinomas (PDAC) and is associated with shorter overall survival. We sought to determine how low CBL directly contributes to clinically more aggressive PDAC. EXPERIMENTAL DESIGN: Human PDACs were stained for CBL, pEGFR, and EGFR. CBL-low was modeled in PDAC cells (Panc-1, L3.6pl, and AsPC-1) via transient transfection (siRNA) or stable knockdown (shRNA). Cell viability and apoptosis were measured by MTT assays and FACS. Immunoblot and a phospho-receptor tyrosine kinase (pRTK) array were used to probe signal transduction. NOD-scid-IL2Rγ(null) mice were subcutaneously implanted with PDAC or PDAC(CBL-low) cells on opposite flanks and treated with gemcitabine ± erlotinib for ≥4 weeks. RESULTS: There was an inverse correlation between CBL and pEGFR protein expression in 12 of 15 tumors. CBL knockdown increased PDAC resistance to gemcitabine and 5-fluorouracil (5-FU) by upregulating pEGFR (Y1068), pERK, and pAKT. A pRTK array of PDAC(CBL-low) cells revealed additional activated tyrosine kinases but all to a much lower magnitude than EGFR. Increased chemoresistance from low CBL was abrogated by the EGFR inhibitor erlotinib both in vitro and in vivo. Erlotinib+gemcitabine-treated PDAC(CBL-low) cells exhibited greater apoptosis by cleaved PARP, caspase-3, and Annexin V/PI. CONCLUSIONS: Low CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment.

5 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.

6 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.

7 Article MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis. 2013

Kadera, Brian E / Li, Luyi / Toste, Paul A / Wu, Nanping / Adams, Curtis / Dawson, David W / Donahue, Timothy R. ·Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America. ·PLoS One · Pubmed #23991015.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion. METHODS: In-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers. RESULTS: miR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing α-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21. CONCLUSIONS: miR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.

8 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.