Metastatic Pancreatic Carcinoma Research Articles

Expression of mesothelin, fascin, and prostate stem cell antigen in primary ovarian mucinous tumors and their utility in differentiating primary ovarian mucinous tumors from metastatic pancreatic mucinous carcinomas in the ovary.

Metastatic pancreatic mucinous adenocarcinomas in the ovaries can be difficult to distinguish from primary ovarian mucinous neoplasms because the former can simulate the latter grossly and histologically and both tumor types share the same cytokeratin 7/cytokeratin 20 immunoprofile. We previously reported the utility of loss of Dpc4 expression in distinguishing metastatic pancreatic carcinomas from primary ovarian mucinous tumors. Recently several new pancreatic carcinoma markers have been identified, including mesothelin, fascin, and prostate stem cell antigen (PSCA). In this study we investigate the expression patterns of these markers in 35 primary ovarian mucinous tumors (28 atypical proliferative [borderline] tumors and 7 invasive carcinomas) and 11 metastatic pancreatic mucinous carcinomas in the ovary. Primary ovarian mucinous tumors expressed mesothelin (17%), fascin (26%), and PSCA (43%) less frequently than metastatic pancreatic adenocarcinomas (73%, 73%, and 82%, respectively). Expression of all three markers was seen only in metastatic pancreatic adenocarcinomas (45%), and coexpression of at least two markers was observed significantly more frequently in metastatic (82%) than primary ovarian mucinous tumors (17%). Our results indicate that an immunohistochemical panel including Dpc4, mesothelin, fascin, and PSCA is useful for evaluating difficult mucinous tumors in the ovary when the differential diagnosis includes metastatic pancreatic adenocarcinoma.

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma.

Objectives:There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.Methods:The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan–Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.Results:A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7–12.3) and the wild-type (9 months; 95% CI: 8.7–12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4–9.7) compared with the other patients (OS: 9 months; 95% CI: 10–13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).Conclusions:The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.

Inducible MyD88/CD40 to allow rimiducid-dependent activation for control of proliferation and survival of chimeric antigen receptor (CAR) T cells targeting prostate stem cell antigen (PSCA).

206 Background: PSCA is a cell surface antigen that is overexpressed in a majority of metastatic prostate, transitional cell and pancreatic carcinomas. We describe a novel T cell costimulation switch, inducible MyD88/CD40 (iMC), activated by a small molecule, rimiducid, to enhance survival, proliferation and anti-tumor activity of CAR-T cells targeting PSCA. Methods: T cells were transduced with a retrovirus encoding tandem rimiducid-binding domains,cloned in-frame with MyD88 and CD40 signaling elements and first generation CARs (CAR.ζ) targeting PSCA (SFG-iMC-2A-PSCA.ζ). iMC activation was assessed with and without rimiducid treatment of T cells. Coactivation via iMC and CAR was tested in coculture assays with or without rimiducid using various PSCA+tumor cells, e.g. Capan-1 and HPAC pancreatic adenocarcinoma. Efficacy of iMC-modified CAR-T cells in vivo was assessed using an NSG mouse tumor model. Results: T cells transduced with iMC-PSCA.ζ produced cytokines (e.g., IFN-γ and IL-6) in response to rimiducid; however, IL-2 was only produced when both iMC and CAR were activated simultaneously by rimiducid and tumor antigen. Treatment of NSG mice bearing large (> 200 mm3) HPAC tumors with a single i.v. dose of 1x107 iMC-PSCA.ζ cells resulted in complete tumor elimination in 10/10 mice including both rimiducid-treated and untreated animals, compared to mice receiving non-transduced T cells (p = 0.0003). Weekly rimiducid administration dramatically increased CAR-T cell numbers, resulting in a 23-fold expansion of iMC-PSCA.ζ-modified T cells in the spleen compared to mice not receiving rimiducid four weeks after infusion (p = 0.02). In a dose-titration study, rimiducid administration was required for tumor control, and led to 565- and 948-fold T cell expansion at the tumor site, respectively, when lower numbers (1.25x106 or 6.25x105, respectively) of iMC-PSCA.ζ-modified T cells were given. Conclusions: GoCAR-T cells targeting PSCA, which contain an inducible MyD88/CD40 activation switch, may be an effective adoptive cell therapy for patients with pancreatic, prostate, bladder, and other cancers that overexpress PSCA.

Cotton Wool Spots in Trousseau’s Syndrome

Trousseau’s syndrome is a paraneoplastic disorder characterized by a hypercoagulable state inducing either migratory superficial thrombophlebitis or arterial emboli from a nonbacterial thrombotic endocarditis. Cotton wool spots (CWS) are usually asymptomatic and represent small areas of retinal infarction. A 69 year-old man was investigated for multiple cerebral and cerebellar thromboembolic events and was found to harbour a metastatic pancreatic carcinoma.

Metastatic Pancreatic Carcinoma and Experience with FOLFIRINOX - a Cross Sectional Analysis From a Developing Country.

Pancreatic cancer is the fourth leading cause of cancer related death with median survival ranging from 3 to 6 months for metastatic disease. Palliative chemotherapy has been the backbone of treatment in advanced stage and has evolved over time. Data pertaining to the disease are scarce from our part of the world where treatment poses a significant challenge due to lack of resources. A retrospective chart review was performed for all patients presenting with stage IV pancreatic carcinoma at a tertiary care hospital in Karachi, Pakistan between January 2008 and December 2012. Data were collected using a pre-designed, coded questionnaire looking at patient characteristics, treatment given and outcome. 101 patients were found to be eligible. Mean age was 56.7 ± 12.8 years, the male to female ratio was 2:1 and most patients had a good performance status. More than half of the tumors were located in the head (57%, n=58) and almost all were adenocarcinomas (95%, n=96). Some 58% (n=59) received first line chemotherapy of which 49% (n=29) received gemcitabine-based regimens and 39% (n=23) received FOLFIRINOX. The median progression free survival for gemcitabine based treatment was 2.9 months (IQR=1.6-5.6) as opposed to 7.3 months (IQR=4.5-9.2) for FOLFIRINOX (P=0.02). Median overall survival was 4.9 months (IQR=2.3-9.5) for first line gemcitabine based treatment and 10.5 months (IQR=7.0-13.2) for first line FOLFIRINOX therapy (P=0.002). Patients on FOLFIRINOX had better survival across all subgroups. Inpatient admissions and dose reductions were more frequent with FOLFIRINOX but the difference between the two regimens was not statistically significant. FOLFIRINOX could be successfully administered as outpatient therapy to a number of patients. FOLFIRINOX remains a suitable first line option in patients with metastatic pancreatic cancer with good performance status even in a resource-poor country where diagnostic and supportive care facilities may be less than optimal and cost is a limitation.

Clinical value of stereotactic body radiotherapy for the treatment of metastatic pancreatic cancer

Objective To discuss the clinical value of stereotactic radiotherapy for the treatment of metastatic pancreatic cancer. Methods Data of 17 patients with metastatic pancreatic cancer were retrospectively studied. All patients were admitted to Air Force General Hospital from January 2006 to December 2014. Lung carcinoma was the most common primary tumor (n=7), followed by cystic carcinoma (n=3), esophageal cancer (n=1), gastric carcinoma (n=1), renal carcinoma (n=1), colon carcinoma (n=1), acute myeloid leukemia (n=1), left chest fibrous histiocytoma (n=1), and upper extremity synovial sarcoma (n=1). There were 8 patients choosing the therapy of body gamma knife, 5 choosing the therapy of IMRT, 3 choosing the therapy of 3DCRT and 1 choosing the therapy of TOMO. Metastases median maximum diameter was 3.6 cm (range, 1.6-1.7 cm), median target volume was 37.1 mm3 (range, 11.1-72.1 mm3) and median GTV dose was 50 Gy (range, 40-70 Gy). Patients treatment time was 14 to 22 days, 5 fractions/week and median single dose was 3 Gy. Results Of all the patients of this group, 4 patients qualified as complete remission (CR), 8 patients reached the standard of partial remission (PR), and 2 patients maintained the situation of stable disease (SD). The total percentage of therapeutic efficiency was 70.1 % (12/17). As for the analgesic therapy, 3 patients qualified as CR, 5 patients reached the standard of PR, and 1 patient maintained the situation of MR (minimal response). The total percentage of analgesic therapeutic efficiency was 100 %. The local control rates for six-month and 1 year were both 100 %, and the overall survival rates for 1 year and 2 years were 35.3 % and 5.9 %. No Grade 3 or more acute and late radiation reaction was observed. Conclusion The majority of patients with pancreatic metastatic carcinoma have lost the opportunity to have surgery, but the stereotactic radiation therapy can improve the quality of life and local control rate with small toxicity and acceptable complications. Key words: Pancreatic neoplasms; Metastatic/Stereotactic; Radiotherapy; Prognosis

Le nab-paclitaxel

Paclitaxel is conventionally used in a wide range of oncology indications. Nab-paclitaxel is synthesized by a process of high pressure homogenization of paclitaxel in the presence of human albumin and it was originally developed to reduce the toxicity usually associated with cremophor in soluble paclitaxel and to increase its penetration in tumor tissues. After the trials that led to its approval in first-line treatment of metastatic pancreatic carcinomas and in second line therapy for metastatic breast cancer, nab-paclitaxel is being tested for many other situations in oncology due to its profile of security and its good tolerance. Different lines of research are being developed about the possible biomarkers that could predict the effect of nab-paclitaxel. This review summarizes the results of trials that led to the approval of the nab-paclitaxel in advanced breast cancer and pancreatic cancer, and also resumes the lines of research to the future development of the drug.

Evolution of pain in patients with metastatic pancreatic carcinoma treated with FOLFIRINOX or gemcitabine in a randomized phase III study (ACCORD11/PRODIGE4).

e15251 Background: Efficacy of FOLFIRINOX regimen versus Gemcitabine (gem) as first-line therapy among patients (pts) with metastatic pancreatic adenocarcinoma (mPAC) has already been reported (NEJM, 2011; 364:1817-25). An analysis of EORTC Quality of Life (QoL) Questionnaire QLQ-C30 based on a time to definitive deterioration approach (TUDD) confirmed that FOLFIRINOX significantly reduces QoL impairment compared with gem in patients with mPAC. The present exploratory analysis aims to provide some additional insight about the impact of FOLFIRINOX on pain evolution. Methods: Baseline pain scores measured withQLQ-C30 were available for a total of 333/342 pts from the ACCORD11/PRODIGE4 trial (167 and 166 pts in FOLFIRINOX groupand Gem group respectively). The considered endpoint was pain intensity as perceived by the pt according to QLQ-C30 scale and the analgesic consumption at baseline and during treatment. A Linear Mixed Model was used to assess pain score evolution. Results: Baseline QLQ-C30 pain scores ...

Unsustainable Claims

Troger and co-authors assume to have presented evidence proving that mistletoe treatment in patients with locally advanced or metastatic pancreatic carcinoma significantly improves quality of life compared with best supportive care (BSC). In the original publication (1) the authors claim that survival was significantly extended by this therapy. To publish the primary endpoint, survival, and the secondary endpoint, quality of life, separately (2), follows in the tradition of unnecessary multiple publications. Both statements are unsustainable because of the study’s serious methodological shortcomings. Without blinding, it is not possible to make a valid statement with regard to quality of life and the chosen method of randomization using sealed envelopes does not meet the requirements of good study practice. The study was terminated early after enrolment of approximately half of the intended number of patients. The authors do not mention that early termination may lead to significant overestimation of treatment effects, especially in small studies (3). The therapy standard at the time of the study was not adequately reported. Best supportive care is here a commonly used “euphemism” for doing without sensible disease-modifying therapies. The authors declare financial support from the Swiss Cancer Research Association (Verein fur Krebsforschung e. V. (VfK), Schweiz) which generates revenues from license fees received from Weleda AG for the preparation of the active substance and, at the same time, state that no conflict of interest exists.

Retrospective analysis of CA19-9 decrease in patients with metastatic pancreatic carcinoma (MPC) treated with FOLFIRINOX or gemcitabine (gem) in a randomized phase III study (ACCORD11/PRODIGE4).

4115 Background: RECIST criteria remain the reference for tumor response evaluation. Carbohydrate antigen 19-9 (CA19-9) is known to be a sensitive and specific serum marker in pancreatic cancer. It...

P0218 Metastatic pancreatic carcinoma and experience with FOLFIRINOX: A cross-sectional analysis from a developing country

Background Pancreatic cancer is the fourth leading cause of cancer-related deaths, with median survival ranging from 3 to 6 months for metastatic disease. Palliative chemotherapy has been the backbone of treatment in advanced stage disease and has evolved over time. Data pertaining to the disease is scarce from our part of the world, where treatment poses a significant challenge due to lack of resources. Methods Retrospective chart review was performed for all patients presenting with stage IV pancreatic carcinoma at a tertiary care hospital in Karachi, Pakistan between January 2008 and December 2012. Data was collected using a pre-designed, coded questionnaire that covered patient characteristics, treatment, and outcome. Findings One hundred and one patients were eligible. Mean age was 56.7 ± 12.8 years, male to female ratio was 2:1, and most patients had a good performance status. More than half of the tumours were located in the head (57%, n = 58) and almost all were adenocarcinomas (95%, n = 96). 58% (n = 59) received first-line chemotherapy, of which 49% (n = 29) received gemcitabine-based therapy and 39% (n = 23) received fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Median progression-free survival for gemcitabine-based treatment was 2.9 months (interquartile range [IQR] 1.6–5.6), compared with 7.3 months (IQR 4.5–9.2) for FOLFIRINOX (p = 0.02). Median overall survival was 4.9 months (IQR 2.3–9.5) for first-line gemcitabine-based treatment and 10.5 months (IQR 7.0–13.2) for first-line FOLFIRINOX therapy (p = 0.002). Patients who received FOLFIRINOX had better survival across all subgroups. Inpatient admissions and dose reductions were more frequent with FOLFIRINOX, but the difference between the two regimens was not statistically significant. FOLFIRINOX was successfully administered as outpatient therapy for some patients. Interpretation FOLFIRINOX remains a suitable first-line option in patients with metastatic pancreatic cancer and good performance status, even in a resource-poor country where diagnostic and supportive-care facilities may be suboptimum and cost is a limitation.

CD44v/CD44s expression patterns are associated with the survival of pancreatic carcinoma patients

Background and purposeCD44 variants have been associated with tumor invasion and metastasis, but CD44 expression patterns have not been systematically investigated in pancreatic carcinoma. This study systematically investigated whether CD44 expression patterns are involved in pancreatic carcinoma metastasis and prognosis.MethodsWe applied primers specific for all CD44 variants and CD44s to analyze the expression patterns of CD44 (CD44v2-CD44v10 and CD44s) using quantitative real-time PCR (qRT-PCR). We then further evaluated their roles in pancreatic carcinoma metastasis and prognosis using clinical survival analysis.ResultsIncreased CD44v expression and decreased CD44s expression were found in metastatic pancreatic carcinoma in three different cell lines and in human tumor tissue. Clinical analysis showed that CD44v6+ and CD44v9+ were correlated with lymph node metastasis, liver metastasis and TNM stage. However, CD44s− was associated with liver metastasis, tumor differentiation and TNM stage. Survival analysis showed that patients with CD44v6+/CD44s− or CD44v6+/CD44s− had lower overall survival (OS) rates, although the individual expression of CD44v6, CD44v9 and CD44s was also related to decreased OS rates. Univariate analysis showed that lymph node metastasis; vessel invasion; hepatic metastases; TNM stage; and individual or co-expression of CD44v6, CD44v9 and CD44s were risk factors affecting survival. Multivariate analysis showed that CD44v6+/CD44s− was an independent predictor of survival.ConclusionsWe found that CD44v6+, CD44v9+ and CD44s− were associated with pancreatic carcinoma metastasis and progression and that CD44v6+/CD44s− was an independent risk factor affecting survival in pancreatic carcinoma. Therefore, the different expression patterns of CD44v/CD44s may determine pancreatic carcinoma prognosis.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1579257224116287.

The American Pancreatic Association/Hirshberg Foundation Symposium Celebrating the 10th Anniversary of the Seed Grant Program

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the ‘‘unknown enemy’’ (http:// www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/ Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease. 1 The Annual Report to the Nation on the Status of Cancer, 1975Y2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer. 2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: & To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. & To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. & To be recognized as a patient support reference source for

Anti-Ge2: further evidence for lack of clinical significance

Abstract Anti-Ge2 may be immune or naturally occurring, and it reacts with an antigen on glycophorin D. Ge2 is encoded by a gene, GYPC, which is located on the long arm of chromosome 2. Anti-Ge2 is usually an immunoglobulin G (IgG) antibody. In the available literature, we have not been able to find any reported cases of proven acute hemolytic transfusion reactions caused by anti-Ge2. We present the case of a 67-year-old man with metastatic pancreatic carcinoma who had symptomatic anemia and a hemoglobin concentration of 6.3 g/dL. During pretransfusion testing, anti-Ge2 was identified in his serum. Only a single unit of compatible, Ge:–2 frozen red blood cells (RBCs) could be provided by the blood supplier. A second unit of crossmatched, least-incompatible, leukocyte-reduced RBCs, presumably Ge:2, was also transfused. The transfusion was completed without incident, and the patient’s hemoglobin concentration rose appropriately. Posttransfusion values for haptoglobin, lactate dehydrogenase, and urine hemoglobin were within normal limits. A monocyte monolayer assay performed on this anti-Ge2 supports the data that antibodies of this specificity do not cause hemolysis. The clinical and laboratory data obtained in our patient clearly indicated that no hemolysis of transfused RBCs occurred during and for 24 hours after transfusion. We believe that this report adds to a limited experience with anti-Ge2 and provides further evidence for concluding that, in all likelihood, this is not a clinically important RBC antibody. The risk of transfusing apparently “incompatible” (Ge:2) RBCs seems remote and should allow for timely administration of RBCs when treating patients with serious anemia. Immunohematology 2014;30:156–157.

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

Efforts to model human pancreatic neuroendocrine tumors (PanNETs) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene, although classically associated with expression in the kidney, is also expressed in many other extrarenal tissues including the pancreas. To induce tumorigenesis within rennin-specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon; furthermore, an increased level of glucagon is found in the serum, identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to the lymph nodes and the liver, mimicking human disease, and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides an unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying cooperating mutations that are necessary for progression of disease.

FOLFIRI in patients with locally advanced or metastatic pancreatic or biliary tract carcinoma

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.

Expression and Epigenetic Regulation of E-cadherin in Metastatic Gastrointestinal and Pancreatic Neuroendocrine Tumors and Carcinomas

Gastrointestinal (GI) and pancreatic neuroendocrine tumors/carcinomas (NET/C) are a heterogeneous group of tumors, behaving differently depending upon their site of origin. Loss of the cell adhesion factor, E-cadherin (E-cadh), characterizes the transition from benign to invasive cancer cells. We undertook this study to investigate the role of epigenetic regulation of E-cadherin in tumor metastasis. NEC resection specimens from different sites in the GI tract and pancreas with available tissue and clinicopathologic information were selected …

P-0164 - Folfirinox as First–Line Therapy in Metastatic Pancreatic Carcinoma (Mpc)

P-0164 - Folfirinox as First–Line Therapy in Metastatic Pancreatic Carcinoma (Mpc)

Abstract 665: Promoter DNA methylation is associated with metastatic properties of pancreatic cancer.

Abstract The inability of early detection of pancreatic tumors is largely due to a lack of biomarkers and a poor understanding of molecular mechanisms conferring carcinogenic dissemination. Recent evidence has indicated that various neoplastic phenotypes are governed by epigenomic alterations (DNA methylation or histone modifications) which confer reversible effects without changing nucleotide sequences themselves. During the past years, we have compared DNA methylation profiles between the parental pancreatic cells FG and its isogenic variant L3.6pl that gained remarkable migratory and invasive properties in culture (33- and 20-fold increase) and in mice (Neoplasia; 1(1); page 50, 1999). DNA methylation profiling was conducted by a method known as MBD-isolated Genome Sequencing which captures methylated DNA via a methyl-CpG binding protein followed by genome-wide DNA sequencing using Illumina sequencer (GAII). Reads were then aligned to a reference human genome browser (HG18) whereby the abundance of read coverage was calculated and indicative of methylation levels occurring at given loci. These methylation profiles were used to generate a list of candidate genes that displayed higher levels of DNA methylation within the L3.6 compared to FG cell lines. We hypothesize that these hypermethylated loci may be correlated to the enhanced invasive properties associated with not only L3.6pl, but also other metastatic pancreatic carcinomas in general. Among these candidates, COL7A1 was of interest. It encodes for a basement membrane protein that is known to be a type VII collagen and is the main component of anchoring fibrils that are involved in cellular processes such as cell adhesion and motility. Silenced expression of COL7A1 by DNA methylation has been shown by two lines of evidence generated from our laboratory. (1) CpG islands situated within COL7A1 promoter displayed prominent promote activity. (2) The induction of methylation by an in vitro method impaired its transcriptional activity. To determine if other epigenetic alterations such as histone modifications led to a similar reduction of COL7A1 expression, a histone deacetylase inhibitor, Trichostatin A, was introduced. It was found that this agent was unable to restore similar expression levels of COL7A1 compared to treatment of de-methylation agent (5-azacytidine). These data suggest that DNA methylation is an important mechanism governing COL7A1 expression We further suggest that this aberration may serve as a general phenomenon, as COL7A1 was concordantly methylated in other metastatic pancreatic cell lines including ASPC-1, Capan-2, and Miacapa-2. Taken together, we hypothesize that promoter methylation leads to a reduced COL7A1 expression followed by an induction of metastasis in pancreatic adenocarcinoma. Thus, COL7A1 promoter could potentially serve as a diagnostic marker and a therapeutic target for impeding metastasis. Citation Format: Huey-Jen L. Lin, Zhengang Peng, Amanda Fisher, Jennifer C. Weber, Ying-Wei Li. Promoter DNA methylation is associated with metastatic properties of pancreatic cancer. [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 665. doi:10.1158/1538-7445.AM2013-665

Abstract No. 298 - Efficiency and safety of percutanous CT-guided cryoablation of celiac plexus in treating intractable pain caused by pancreatic cancer

Purpose The current WHO policy for treating patients with pain from pancreas cancer is sequential pharmacologic (NSAID-opioids) treatment. If this fails, neurolytic (alcohol) celiac plexus block (NCPB) is appropriate to achieve pain relief. However, if NCPB also fails, not many other non-invasive treatments are available. The aim of our study was to evaluate the efficiency and safety of percutaneous CT guided cryoablation of the celiac plexus in treating patients with intractable abdominal pain caused by advanced adenocarcinoma of the pancreas. Materials and Methods In a prospective study, from January 2010 to March 2012, 6 consecutive patients with advanced adenocarcinoma and intractable pain were enrolled. IRB approval was obtained. A 17-gauge 17 cm cryoablation probe (Galil Medical Inc. Arden Hills, MN) was placed into the expected location of the celiac plexus via a left paraspinal approach under CT guidance and two cycles of freeze-thaw were performed. All patients were admitted for overnight observation. They were followed in 24 hours, one week and one month intervals for complications and pain. Pain was evaluated with subjective pain scoring using a visual analog scale; VAS; 0-10. Results Mean patients’ pain was 8.5 out of 10 (subjective pain scoring using a visual analog scale; VAS; 0-10; pain range of 8 to 10) which significantly decreased to 3.5 (range 3-4; p Conclusion Percutaneous cryoablation is an effective and safe alternative to neurolytic (alcohol) celiac plexus block for palliative treatment of intractable abdominal pain in patients with metastatic pancreatic carcinoma.