PDA Patients Research Articles

Abstract B11: Development of orthotopically grafted organoid models to study pancreatic cancer progression

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. A subset of potential tumor suppressor (Ts) genes was identified by genome-wide analysis of human PDA and insertional mutagenesis in genetically engineered mouse models (GEMMs). Since the functional validation of these genes in GEMMs is time-consuming and labor-intensive, we have developed a rapid and efficient “orthotopically grafted organoid’ (OGO) models in conjunction with RNAi and CRISPR/Cas9 technology to study PDA progression. Previously, we showed that OGO model represents the full spectrum of PDA progression in vivo upon orthotopic engraftment. Here, as a proof-of-concept experiment, we demonstrate that ablation of Trp53 by shRNA or gRNA in PanIN-derived organoids accelerates PDA progression upon transplantation. Therefore, OGO models should provide an excellent platform to study the functional role of genes in PDA progression in vivo. Note: This abstract was not presented at the conference. Citation Format: Chang-Il Hwang, EunJung Lee, Tobiloba Oni, Youngkyu Park, David A. Tuveson.{Authors}. Development of orthotopically grafted organoid models to study pancreatic cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B11.

Robotic and open distal pancreatectomy with celiac axis resection for locally advanced pancreatic body tumors: a single institutional assessment of perioperative outcomes and survival

BackgroundDistal pancreatectomy with celiac axis resection (DP-CAR) is an option for T4 tumors of the pancreatic body. We examined the perioperative and oncologic outcomes of open and robotic DP-CAR at a high-volume pancreatic center. MethodsRetrospective review of all consecutive DP-CARs. Patient demographics, 90-day perioperative outcomes, and disease specific survival were collected. Results30 DP-CARs were performed (11 Robotic, 19 Open). Both groups had similar preoperative/tumor characteristics, and 27 of 28 PDA patients received neoadjuvant chemotherapy. Robotic DP-CAR was associated with decreased OT (316 vs. 476 min), reduced EBL (393 vs. 1736 ml) and lower rates of blood transfusion (0% vs. 54%) (all p < 0.05). No robotic DP-CAR required conversion. Both groups had similar rates of 90-day mortality, major morbidity, LOS, readmission, and receipt of adjuvant therapy. Similarly, both approaches were associated with high R0 resection rates (82% vs. 79%). At a median follow-up of 33 months, median overall survival for the PDA cohort was 35 months, with no difference in the robotic and open approach (33 and 40 months, p = 0.310). ConclusionsWith a median survival approaching 3 years, DP-CAR represents an effective treatment for select patients with locally advanced pancreatic body cancer, regardless of approach.

The surface alpha-enolase targeting as a novel immunotherapeutical strategy for pancreatic cancer

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is a very aggressive tumor for which effective therapeutical strategies are still lacking. The global five-years survival is of 5% and surgery is the only potentially curative treatment. The PDA-associated antigen α-enolase (ENO1), beside its glycolytic function, acts as a plasminogen receptor, promoting activation into plasmin, involved in extracellular matrix degradation. Antibodies against ENO1 are detected in more than 60% of PDA patients and correlate with a better prognosis. Furthermore, anti-ENO1 antibodies are induced in mice after ENO1-DNA vaccination. We observed an increased ENO1 expression on the cell surface of both PDA and myeloid cells (MDSC), suggesting a role in tumor progression and spreading. The immunotherapy represents a chance to selectively target PDA cells and MDSC. Mouse anti-human ENO1 monoclonal antibody (mAb) inhibits plasminogen-dependent invasion of human PDA cells and metastatic spreading in immunosuppressed mice, as well as MDSC adhesion to pancreatic endothelial cells and in vitro and in vivo migration. Similarly MDSC arginase activity and secretion of IL-6 decrease after ENO1 triggering, while anti-ENO1 treatment does not affect costimulatory molecule expression and MDSC suppression functions. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing an anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDA cells. In conclusion, the antibodies anti-ENO1 may inhibit PDA cell and myeloid cell invasion and modulate T cell response, making the immunotherapy more effective.

Multi-Omic profiling (MoP) for patients (pts) with pancreatic cancer (PDA): Initial results of the Know Your Tumor (KYT) initiative.

282 Background: Emerging insights into the molecular biology of tumors and recent developments in MoP have led to the identification of targets that can be used for selecting treatment (tx) regimens. Multiple testing platforms are available, though most studies to date have used only next generation DNA sequencing (NGS). Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have initiated an IRB-approved registry trial wherein we facilitate commercial MoP on tumor tissue from PDA patients. MoP includes NGS, immunohistochemistry (IHC), and phosphoproteomics (PHO). The results are reviewed by a team of PDA specialists in the context of the pt’s tx history. Tx options are prioritized based on the actionable molecular abnormalities. Pts are being followed longitudinally to assess physician acceptance of the tx options and track survival outcomes. Results: From 06/2014 to 09/2015, Perthera reports were delivered for 117 pts. 44% of the analyses were for second-line tx and 43% for ≥ third-line. Tumor based NGS and IHC were available for 75% and 90% of pts, respectively, and research use only PHO data was available for 20 pts. Actionable findings, defined based on a high response rate in pts with an identified molecular abnormality (in any cancer type), or based on a mechanism/pathway-defined implication of response to tx were identified in 43% of pts, primarily based on NGS. Incorporation of IHC refined and expanded chemotherapy tx options in all pts. PHO revealed pathway activation (e.g. mTOR, JAK-STAT, MET, RET, or EGFR) in 16/20 samples. Interestingly, only 45% of KRAS mutant samples had PHO-defined activation of the MEK-ERK pathway. Conclusions: MoP resulted in actionable findings in 43% of PDA pts using NGS and IHC. Incorporation of PHO data could have a significant impact on MoP-based therapy options. Analysis of the MoP in the context of patient history by a PDA specialist provided a service to treating oncologists in the community that was frequently incorporated into their treatment decisions. Survival outcomes will be presented. As additional testing platforms and results become available, the breadth and confidence of actionable markers is expected to increase.

The Know Your Tumor (KYT) initiative: A national program of multi-omic molecular profiling (MoP) for patients (Pts) with pancreatic cancer (PDA).

279 Background: There has been a significant increase in the utilization of MoP to facilitate the selection of therapies for pts with advanced cancers. However, coordinated efforts to perform uniform MoP and collect clinical outcomes data have only successfully been executed in limited academic settings. In an effort to “democratize” the availability of MoP for PDA patients in a broad spectrum of clinical settings, The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated the KYT initiative, an academic, industry, and advocacy group collaboration. Methods: PDA pts self-referred to the Patient Central call center at PanCAN. Pts interested in enrolling in an IRB-approved registry trial were then referred to Perthera to facilitate consent, tissue acquisition, and commercial MoP of the pt’s tumor. Test results were reviewed by a team of PDA specialists in the context of the pt’s treatment (tx) history. A report detailing tx options was delivered to the pt’s oncologist. Pts are being actively followed longitudinally to assess physician acceptance of the tx options and to track outcomes. Results: From 06/2014 to 09/2015, 382 pts were enrolled into KYT. Of these, 273 pts from 192 physicians (community and academic) in 38 states were enrolled. Reasons for non-enrollment were: pts no longer interested (67%); pts too ill or not appropriate for KYT (17%); the pt’s physician would not sanction MoP (16%). To date, 162 pt tumor samples have been obtained, and 117 reports delivered. 75% of samples had adequate tissue for genomic profiling (NGS), with 87% of samples harboring a KRAS mutation. Actionable findings (i.e. linked to a specific tx option) identified by NGS included mutations in BRCA2 (5%), PALB2 (1%), ATM (4%); BRAF (2%), PIK3C/PIK3R (7%), STK11 (5%), amplification of ERBB2 (3%), FGFR (2%), PDGFR (2%); and RET fusions (2%). Of the 117 profiles, 43% revealed actionable findings; 58% presented off-label therapy options; and 48% led towards high priority clinical trials. Conclusions: MoP of pts with PDA is feasible irrespective of their geographical location or access to an academic center. Updated information on tx selection and patient outcomes will be provided.

Anti-α-enolase antibody limits the invasion of myeloid-derived suppressor cells and attenuates their restraining effector T cell response

ABSTRACTPancreatic Ductal Adenocarcinoma (PDA) is a very aggressive tumor for which effective therapeutical strategies are still lacking. Globally, the 5 y survival rate is 5–7% and surgery is the only potentially curative treatment. Immunotherapy represents a novel possibility for treating PDA, and myeloid-derived suppressor cells (MDSC), which are increased in cancer patients and correlate with metastatic burden and cancer stage, offer a new target in cancer therapy. We have previously shown that antibodies against the PDA-associated antigen α-enolase (ENO1) are detected in more than 60% of PDA patients and correlate with a better prognosis. Furthermore, ENO1-DNA vaccination in mice induced anti-ENO1 antibodies that mediated antitumor activity. In this study, the effects of anti-ENO1 binding on MDSC functions and on the T cell response were evaluated. Here, we show that MDSC express ENO1 on their surface, which increased after LPS stimulation. Moreover, anti-ENO1 mAb inhibited adhesion to endothelial cells, as well as in vitro and in vivo migration. Similarly, after ENO1 mAb treatment of MDSC, arginase activity decreased, while the secretion of pro-inflammatory cytokines (particularly IL-6) increased, and co-stimulatory molecule expression and suppression functions were only partially affected. Finally, we found that activated T cells in the presence of anti-ENO1 mAb-treated MDSC increased IFNγ and IL-17 secretion and decreased IL-10 and TGFβ secretion compared to control MDSC. In conclusion, anti-ENO1 antibodies may inhibit in vivo the infiltration into the tumor microenvironment of MDSC, and attenuate their restraining of effector T cell response, opening a new perspective to render PDA immunotherapy more effective.

Abstract PL03-03: K-RAS dependency in pancreatic cancer

Abstract 2015 AACR-NCI-EORTC K-RAS dependency in Pancreatic Cancer David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory Efforts to inhibit the KRAS oncogene in pancreatic cancer have focused on classical downstream pathways and empirically identified dependencies. We have developed organoid models of mouse and human pancreatic cancer to expedite such translational approaches for this disease. We find that organoid models of PDA demonstrate ERBB pathway activation in response to dual MEK/AKT inhibition, and that this feature is absent in non-neoplastic organoids. Furthermore, organoid models predict the limited activity of EGFR specific inhibitors in PDA patients that are also receiving MEK or AKT inhibitors. These models have also been an invaluable resource for probing new dependencies in PDA, and will be discussed. Citation Format: David A. Tuveson. K-RAS dependency in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL03-03.

Abstract 3170: IL17 favours carcinogenesis and limits the anti-tumor responses in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is a fatal medical condition with few advances in therapy and patient survival. The role of IL17 and Th17 in cancer progression and anti-tumor immunity is still controversial. In this study we have investigated the role of IL17 and Th17 in PDA carcinogenesis and anti-tumor responses. IL-17 production and Th17 percentage in blood from PDA patients and control subjects as well from genetically engineered mice (GEM) that spontaneously develop PDA, were analysed by ELISA and FACS respectively. Survival of GEM mice crossed with IL-17 KO mice (GEM/IL17KO) was analysed by Kaplan-Meier analysis. WT or IL17KO mice that were prophylactically vaccinated with a plasmid coding for the PDA-associated antigen α-enolase (ENO1) (1-3), were subsequently injected with PDA cell line derived from GEM. Tumor growth and the induction of an antigen-specific immune response were monitored. We have found a statistically significant increase of peripheral Th17 cells and a decrease of Th1 in PDA patients compared to healthy subjects. GEM mice showed 3-fold more RORγT+ cells at the onset of duct transformation, which dropped to the level of control mice at 20 weeks and lasted until 35 weeks. Notably, GEM/IL17 KO mice survived significantly more than GEM mice, even if there were no changes in the tumor onset. In addition, in GEM/IL17 KO mice, we observed an increased fibrotic reaction compared to GEM mice starting from early stage of disease. Lastly, ENO-1 DNA vaccination in IL17KO mice significantly decreased PDA cells growth and enhanced the CD8 T cell response compared to that observed in WT mice. Our data suggest that the absence of IL17 does not affect the tumor onset but the progression, likely affecting the immune response, which seems to be able to better counteract tumor growth in the absence of this cytokine. Tomaino et al., J Proteome Res. 2007;6:4025-31; Cappello et al, Int. J. Cancer. 2009;125:639-48; Cappello P et al, Gastroenterology. 2013;144:1098-106. Citation Format: Paola Cappello, Roberta Curto, Gianluca Mucciolo, Simona Rolla, Elisabetta Tonoli, Francesco Novelli. IL17 favours carcinogenesis and limits the anti-tumor responses in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3170. doi:10.1158/1538-7445.AM2015-3170

The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy

BackgroundPancreatic ductal adenocarcinoma (PDA) is comprised of a prominent desmoplastic stromal compartment and only 10–40% of the tumour consists of PDA cells. However, how stromal components should be assessed and how the characteristics of the stromal compartment determine clinical outcomes in PDA patients remain unknown. MethodA cohort of 66 consecutive patients who underwent pancreaticoduodenectomy and were primarily followed at Johns Hopkins Hospital between 1998 and 2004, and treated with adjuvant therapy, were included in a retrospective analysis. Resected PDA blocks with good tissue preservation were available for all patients. A new, computer-aided, quantitative method was developed to assess the density and activity of stroma in PDAs and the associations of these characteristics with clinical outcomes. ResultsHigh stromal density in resected PDA was found to be significantly associated with longer disease-free [adjusted hazard ratio (aHR) 0.39; P = 0.001] and overall (aHR 0.44; P = 0.004) survival after adjusting for the use of pancreatic cancer vaccine therapy, as well as gender and resection margin positivity. Stromal activity, representing activated pancreatic stellate cells in PDAs, was not significantly associated with the prognosis of resected PDAs. ConclusionsThese results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.

Abstract 1434: Metformin-induced metabolic changes are k-ras-dependent in animal models of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy, that is very difficult to treat. To date, systemic treatment for PDA, either a single agent or combinations of agents, has shown only modest benefits. Numerous epidemiological studies have reported that metformin (MET), a widely used anti-diabetic drug, provides protective benefits in reducing PDA risk among the diabetic population. Using a stable isotope glucose (GLUC) tracer for dynamic metabolic profiling (SiDMAP), we recently reported that high cholesterol (CHOL) alters the cellular metabolism of MiaPaCa2 (a PDA cell line harboring mutant K-Ras) cells by redirecting glucose-derived acetyl-CoA toward fatty acid (FA) synthesis. This response to MET is depended on the level of intracellular CHOL synthesis. We now performed a SiDMAP study in the LSL-K-RasG12D/+, LSL-Trp53R172H/+, Pdx-1-Cre (KPC) and the LSL-K-RasG12D/+, Pdx-1-Cre (KC) mouse models for PDA, and their wild-type littermates (C57Bl6.129). The mice were treated (or not) with MET (250 mg/kg, i.p. Q5D) and subjected to an Intra Peritoneal GLUC Tolerance Test (IPGTT) pre- and post-MET treatment. The KPC mice with the average tumor volume of 80.83+8.57 mm3 and the KC mice with PanIN lesions (aver. 9 mo old) were put on study. K-Ras mutation, with the presence of the tumor (KPC mice), induced an increase in plasma GLUC production via de novo synthesis by the liver using futile cycling of GLUC derived lactate and pyruvate. MET treatment decreased this flux in mutated (KC) and tumor-bearing animals (KPC), but increased this flux in liver of control mice. MET treatment increased the complete GLUC oxidation into 13CO2 in the pancreas of KC and KPC animals. This indicates that the pancreas in MET-treated animals use less GLUC for RNA, DNA and FA synthesis. For 13CO2 production, we found that tumor growth has to be established; the mutation is not enough to induce changes in this flux. As in plasma, tumor growth increases pancreas lactate production from GLUC. MET treatment dramatically decreased the Warburg effect in the pancreas of mutated (KC) and mutated/tumor-bearing (KPC) mice. Finally, MET decreased GLUC-derived acetyl-CoA delivery to FAS and palmitate in control, mutated and tumor-bearing mice. Immunohistochemical analysis of the tumors from the KPC mice revealed that treatment with MET decreased the staining of phospho-Ser79-ACC by ∼54%, total FAS staining (mainly in the tumor stroma) by ∼43%, and the growth-associated transcription factor HMGA2 by ∼36.7%. These decreases correlated with a decrease in Ki67 staining by almost 80%, indicative of an inhibitory effect of MET on PDA growth. These results suggest that mutant K-Ras is responsible for the metabolic adaptation in both the tumor- (KPC) and non-tumor-bearing animals (KC). Our findings provide a strong rationale for targeting the metabolic changes induced by activated K-RAS in PDA patients which harbor mutations in K-RAS gene in &amp;gt;95% of cases. Citation Format: Mary Jo Cantoria, Laszlo G. Boros, Hitendra Patel, Haiyong Han, Natalia Ignatenko, Emmanuelle J. Meuillet. Metformin-induced metabolic changes are k-ras-dependent in animal models of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1434. doi:10.1158/1538-7445.AM2014-1434

Baseline Heartbeat Perception Accuracy and Short-Term Outcome of Brief Cognitive-Behaviour Therapy for Panic Disorder with Agoraphobia

Increased heartbeat perception accuracy (HBP-accuracy) may contribute to the pathogenesis of Panic Disorder (PD) without or with Agoraphobia (PDA). Extant research suggests that HBP-accuracy is a rather stable individual characteristic, moreover predictive of worse long-term outcome in PD/PDA patients. However, it remains still unexplored whether HBP-accuracy adversely affects patients' short-term outcome after structured cognitive behaviour therapy (CBT) for PD/PDA. To explore the potential association between HBP-accuracy and the short-term outcome of a structured brief-CBT for the acute treatment of PDA. We assessed baseline HBP-accuracy using the "mental tracking" paradigm in 25 consecutive medication-free, CBT-naive PDA patients. Patients then underwent a structured, protocol-based, 8-session CBT by the same therapist. Outcome measures included the number of panic attacks during the past week, the Agoraphobic Cognitions Questionnaire (ACQ), and the Mobility Inventory-Alone subscale (MI-alone). No association emerged between baseline HBP-accuracy and posttreatment changes concerning number of panic attacks. Moreover, higher baseline HBP-accuracy was associated with significantly larger reductions in the scores of the ACQ and the MI-alone scales. Our results suggest that in PDA patients undergoing structured brief-CBT for the acute treatment of their symptoms, higher baseline HBP-accuracy is not associated with worse short-term outcome concerning panic attacks. Furthermore, higher baseline HBP-accuracy may be associated with enhanced therapeutic gains in agoraphobic cognitions and behaviours.

Long-term outcome of percutaneous closure of left-to-right shunts in patients with systemic or near systemic pulmonary artery pressure

Background: The ESC 2010 guidelines recommend closure of left-to-right (L-R) shunts with Pulmonary Arterial Hypertension (PAH) when Pulmonary Arterial Pressure (PAP) is less than 2/3 of SAP. There is paucity of data on long-term outcome of percutaneous device closure in patients with L-R shunt and PAP >2/3 of SAP. Methods: Between August 2007 and December 2012, we attempted percutaneous closure of 20 ostium Secundum ASD,11 PDA and 3 perimembranous VSD with systemic or near systemic PAP. All patients received pretreatment with sildenafil for 3 weeks to 3 months prior to cath study and device closure. The baseline characteristics are shown in table1. Result: The device closure was successful in all ASD and PDA patients but was unsuccessful in all 3 VSDpatients. Two patient in VSD group died, both due to uncontrolled pulmonary hypertensive crisis, one after unsuccessful procedure and another after surgical closure. Third patient in VSD group had successful surgical closure and PASP was 34 mmHg at the time of discharge. The mean follow-up for ASD is 22.26±9.22 months and 17.89±8.76 months for PDA patients. All patients in ASD and PDA group improved from functional class III to asymptomatic level. In ASD subgroup, 13/19 patients (68.4%) have PASP between 30-45 mmHg and 6/19 (31.6%) have PASP between 45-70 mmHg. In PDA subgroup, 8/9 patient (88.9%) have PASP between 30-45 mmHg, and 1/9 (11.1%) have PASP between 40-60 mmHg. Sildenafil was stopped in all patients when PASP was less than 45 mmHg. No rebound PAH was noted in any patient. View this table: Table 1. Baseline characteristics Conclusion: Percutaneous closure in patients with left to right shunt with Qp/Qs>1.5:1, but systemic or near systemic PAP is safe with good outcomes in ASD and PDA patients.VSD patients probably behave differently from similar ASD and PDA population.

Abstract 3935: AnnexinA2 regulates invasion and metastasis of pancreatic ductal adenocarcinoma through Semaphorin3d.

Abstract Pancreatic ductal adenocarcinoma (PDA), a devastating disease with a median survival of less than six months, is characterized by its high metastatic ability and a lack of effective therapies. The mechanisms involved in promoting metastasis of PDA have yet to be elucidated. We recently identified AnnexinA2 (AnxA2) as a PDA-associated antigen. Tyr23 phosphorylated AnxA2 promotes metastasis of PDA cells, while shRNA knockdown, knockout or therapeutic inhibition of AnxA2 prevents metastasis to the liver in a mouse model. To identify downstream mediators of AnxA2 signaling, we evaluated gene expression differences in cell lines derived from the primary tumors of mice that express AnxA2 (KPC) and are metastatic or lack AnxA2 expression (KPCA) and are unable to metastasize. Using microarray analysis, we observed that expression of the ligand-receptor pair Semaphorin3d (Sema3d) and PlexinD1 (PlxnD1) was significantly down regulated in the non-metastatic KPCA cells. Sema3d and PlxnD1 were first identified as axon guidance genes. However, recently, axon guidance genes, including Sema3d and PlxnD1, were recently found by the International Cancer Genome Consortium to be among the cellular pathways that are most frequently altered by genetic mutations and amplification in human PDA (Biankin 2012). Therefore, we hypothesized that AnxA2 interacts with Sema3d and PlxnD1 in PDA to induce metastasis. We confirmed by RT-PCR and immunofluorescence analysis in multiple independent tumors from KPC and KPCA mice that Sema3d and PlxnD1 expression is down regulated in the absence of AnxA2 expression. AnxA2, Sema3d and PlxnD1 colocalize at the cell surface during pancreatic tumor development when AnxA2 is expressed. Interestingly, co-immunoprecipitation analysis demonstrated a direct interaction between Sema3d and AnxA2 in PDA cells supporting our hypothesis that AnxA2 regulates the secretion of Sema3d from PDA cells to enable its paracrine interaction with PlxnD1 resulting in invasion of PDA cells. Clinically, we have found that Sema3d expression correlates with increased lymphovascular invasion, increased perineural invasion, poor survival and increased metastatic potential in human PDA patients. Therefore, understanding the pathways that lead to metastasis of PDA will enable the development of more effective therapeutics and better clinical outcomes. Citation Format: Kelly Foley, Donger Zhou, Qian Xiao, Agnieszka Rucki, Guanglan Mo, Lanqing Huang, Anirban Maitra, Elizabeth Jaffee, Lei Zheng. AnnexinA2 regulates invasion and metastasis of pancreatic ductal adenocarcinoma through Semaphorin3d. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3935. doi:10.1158/1538-7445.AM2013-3935

Parkinsonism-Dementia-ALS Complex (PDA) Phenotype in an African-American Patient (P07.189)

Objective: To report a case of PDA phenotype in an African-American patient. Background Amyotrophic lateral sclerosis (ALS)/Parkinsonism dementia complex (PDC) is an endemic disorder described in patients from Guam and the Kii peninsula of Japan. Patients with this disorder exhibit features of Parkinsonism, akinesia, masked facies, dysarthria, mental slowness, apathy, depression and gait abnormalities and features of ALS. An environmental cause has been suggested. However, recently 4 patients from central Europe were reported to satisfy criteria for PDA, supporting the notion that this complex disorder may not be purely environmental in origin. Design/Methods: Case report. Results: A 59-year old previously healthy, functional African-American man developed progressive cognitive decline over a period of 2 years. The patient was initially found to have subtle memory disturbances, which quickly evolved to an inability to work. Within the next few months, the patient lost his ability to speak, eat and swallow. On neurological exam, the patient was awake and alert, but anarthric, able to follow simple commands. He had normal extra-ocular movements, bifacial diplegia, dysphagia, and positive Glabellar sign. Motor exam showed normal strength, diffuse muscular atrophy, rigidity and bradykinesia. Diffuse hyper-reflexia with sustained ankle clonus, positive jaw jerk reflex, primitive reflexes and frontal release signs were noted. Cerebrospinal fluid evaluation, including 14-3-3, was normal. Brain MRI showed fronto-temporal atrophy. Brain FDG-PET showed fronto-temporal hypometabolism. EMG/NCS revealed diffuse, ongoing denervation in 3 body segments. Conclusions: Here we describe an African-American patient with constellation of signs similar to what has been previously described in PDA patients from Guam/Kii. To our knowledge, this is the first report of a non-Guamanian, non-caucasian patient from the American continent, with PDA, supporting a possible non-environmental, genetic cause. Additional neuropathological and molecular studies will be helpful in analyzing this disease further. Disclosure: Dr. Kassar has nothing to disclose. Dr. Iyadurai has nothing to disclose.

Abstract 2628: Genome-wide sequencing identifies ATM as a pancreatic cancer susceptibility gene

Abstract Pancreatic ductal adenocarcinoma (PDA) affects over 44,000 people in the United States every year and carries a dismal prognosis, with a 5-year survival rate of just 5%. A subset of these patients (5-10%) report a familial history of the disease. The genetic etiology in these familial cases is poorly defined, with known susceptibility genes, such as: BRCA2, PALB2, CDKN2A, BRCA1, PRSS1 and STK11, accounting for only 10-15% of familial pancreatic cancer. In an effort to identify previously unappreciated pancreatic cancer susceptibility genes, we used next generation sequencing technology to evaluate the whole genome and whole exome sequences of 16 (6 families) and 22 individuals (10 families) respectively. All of these families enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology (PacGene) Consortium, all had at least three members with PDA, and DNA was available from at least two affected members in each kindred. Using this approach, we identified heterozygous, inactivating, ATM mutations in two kindreds with familial pancreatic cancer (c.8266A&amp;gt;AT; p.K2756X and c.170G&amp;gt;GA; p.W57X). These mutations were previously reported as disease causing variants in patients with ataxia-telangiectasia, an autosomal recessive condition resulting from bi-allelic deleterious mutations of ATM. Interestingly, heterozygotes of deleterious ATM mutations have an increased risk of breast cancer. However, there have been no previous reports of deleterious ATM mutations in the germline of familial PDA patients. In our study, mutations segregated with disease in both kindreds and tumor analysis demonstrated Loss of heterozygosity (LOH) of the wild-type allele. Sequence analysis of the entire ATM gene in an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene (c.3214G&amp;gt;GT; p.E1072X, c.6095G&amp;gt;GA; p.R2032K, IVS41-1G&amp;gt;GT and c.3801delG), while no deleterious mutations were identified in 190 spouse controls (p=0.046). When considering only the mostly severely affected families, those with three or more pancreatic cancer cases, four deleterious mutations were found in 87 families (P=0.009). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition and have significant implications in the management of affected individuals and the risk assessment of family members. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2628. doi:1538-7445.AM2012-2628

P029 * Brain natriuretic peptide as a predictor of volume overload in childrenwith congenital cardiac shunt lesion

P029 * Brain natriuretic peptide as a predictor of volume overload in childrenwith congenital cardiac shunt lesion

Perfectionism in Anxiety and Depression: Comparisons across Disorders, Relations with Symptom Severity, and Role of Comorbidity

We investigated perfectionism in clinical samples using new measures of maladaptive cognitive-personality dimensions—the Evaluative Concerns Perfectionism Scale (ECPS) and Self-Critical Perfectionism Scale (SCPS), as well as the Frost (FMPS) and the Hewitt and Flett (HMPS) Multidimensional Perfectionism Scales. Outpatients (N = 190) with a principal diagnosis of social anxiety disorder (SAD), panic disorder with or without agoraphobia (PDA), obsessive-compulsive disorder (OCD), or predominantly major depressive disorder were compared to non-psychiatric controls. Patients with depression and SAD had similar or significantly higher scores than the controls, and patients with PDA and/or OCD on many perfectionism measures. OCD patients were also higher than controls and those with PDA on many scales. PDA patients were similar to controls on all but a few measures. The SCPS was the only consistent unique positive predictor of variance on the Depression Anxiety Stress Scale (DASS) in a combined patient group.

A Combination of DR5 Agonistic Monoclonal Antibody with Gemcitabine Targets Pancreatic Cancer Stem Cells and Results in Long-term Disease Control in Human Pancreatic Cancer Model

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with one of the worst outcomes among all cancers. PDA often recurs after initial treatment to result in patient death despite the use of chemotherapy or radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSC), which may contribute to therapeutic resistance and metastasis. At present, conventional chemotherapy and radiotherapy are largely ineffective in depleting CSC pool, suggesting the need for novel therapies that specifically target the cancer-sustaining stem cells for tumor eradication and to improve the poor prognosis of PDA patients. In this study, we report that death receptor 5 (DR5) is enriched in pancreatic CSCs compared with the bulk of the tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with gemcitabine, the first-line chemotherapeutic agent for PDA, is initially effective in reducing tumor size, but largely ineffective in diminishing the CSC populations, and eventually culminated in tumor relapse. However, a combination of tigatuzumab, a fully humanized DR5 agonist monoclonal antibody, with gemcitabine proved to be more efficacious by providing a double hit to kill both CSCs and bulk tumor cells. The combination therapy produced remarkable reduction in pancreatic CSCs, tumor remissions, and significant improvements in time to tumor progression in a model that is considered more difficult to treat. These data provide the rationale to explore the DR5-directed therapies in combination with chemotherapy as a therapeutic option to improve the current standard of care for pancreatic cancer patients.

Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease.

This study was designed to explore whether it was possible to evaluate the severity of VSD, PDA, and ASD by measuring brain natriuretic peptide (BNP) levels. We also investigated normal BNP levels in children to provide a baseline for our study. We measured BNP levels in 253 normal children, including 11 normal neonates, and in 91 VSD patients, 29 PDA patients, and 34 ASD patients. BNP levels showed no age-related differences in normal children (the mean value: 5.3 +/- 3.8 pg/ml). In the healthy neonates, BNP levels rose from 10.4 +/- 11.9 pg/ml in cord blood to 118.8 +/- 83.2 pg/ml on day 0, then fell to 15.3 +/- 7.8 pg/ml by day 7. In VSD and PDA patients, BNP levels correlated significantly with Qp/Qs, LVEDV, and peak RVP/LVP. In ASD patients, BNP levels correlated with Qp/Qs and RVEDV. Especially, in VSD patients, as an index corresponding to 1.5-2.0 of the Qp/Qs ratio, BNP levels of 20-35 pg/ml were found to be best with regard to both sensitivity and specificity. In the healthy neonates, BNP levels changed rapidly after birth. In VSD, PDA, and ASD patients, BNP levels were well-correlated with the severity of the disease. Especially, in VSD patients, it that appears BNP levels may be useful in evaluating surgical indications, with 20-35 pg/ml levels being the appropriate cut-off value.

Emotional responding to hyperventilation as a predictor of agoraphobia status among individuals suffering from panic disorder

Some data suggest that panic patients with extensive agoraphobia (PDA) display more intense respiratory distress during their panic attacks than Panic disorder (PD) patients. However, no studies have determined if PDA patients also show heightened sensitivity to a respiratory challenge compared to PD patients. The current study examined the differential emotional responding to hyperventilation among PDA patients, PD patients, and a non-clinical group with a history of panic attacks. Response to hyperventilation challenge did not distinguish non-clinical panickers from panic patients; however, behavioral tolerance to hyperventilation challenge significantly predicted agoraphobia status among panic disorder patients, even after controlling for demographic and clinical status variables.