bluuebunny/crossref_metadata_2025 huggingface dataset:
The accuracy of endoscopic ultrasonography for identifying stomach neoplasm before endoscopic submucosal dissection.
Authors: Song Pil Hun , Sung Hyun , Lee Jeonghun , Yoon Won Jae , Kim You Sun , Moon Jeong Seop , Ryu Soo Hyung , Lee Sang Woo , Jung Hyun chae
Published: February 2017

22

Background: The treatment of stomach neoplasm was determined by the identification on of invasion extent and perigastric lymph node through endoscopic ultrasonography (EUS). In this study, we investigated diagnostic accuracy of EUS examination before endoscopic submucosal dissection (ESD). Methods: A retrospective study was conducted to both EUS and ESD for stomach neoplasms that were performed at Seoul Paik Hospital between January 2006 and July 2015. We compared the accuracy of EUS according to the location of lesion, tumor size and ulcer presence or absence on lesion. Results: 49 patients were enrolled in this study; their mean age was 64.14 ± 11.33 years. There were 40 male (81.6%) and 9 female (18.4%) patients. The cases of confined to the mucosa on pathology finding were 41 (83.6%) and involved to submucosal layer(sm) 1 were 3 (6.1%) and sm2 were 2 (4%) and sm3 were 1 (2%) and proper muscle layer were 2 (4%). The cases of lymphatic invasion were 2 (4%). The sensitivity and accuracy of antrum were 91.6 % (95% CI: 0.81-1.03) and 83.3 % (95% CI: 0.70-0.97), body of stomach were 92.3 % (CI: 0.78-1.07) and 83.3% (CI: 0.66-1.00), respectively. Whether lesions were no significant differences in any location. The tumor size was divided by smaller than 20 mm group, 20-30 mm group and more than 30 mm group. The smaller than 20 mm group, 20-30 mm group and more than 30 mm group were 36, 9, 2 patients. The remaining 2 patients were not described. The sensitivity and accuracy of smaller than 20 mm group were 96.6 % (95% CI: 0.90-1.03) and 83.3 % (CI: 0.71-0.95) and 2-30 mm group were 66.7 % (CI: 0.29-1.04) and 77.8 % (CI: 0.51-1.04), respectively. All patients were divided by ulcer presence or not. 27 patients were ulcer presence and 22 patients were not. The sensitivity and accuracy of ulcer presence group were 77.3 % (CI : 0.60-0.95) and 74 % (CI : 0.57-0.90), ulcer absence group were 95 % (CI : 0.85-1.04) and 91 % (CI : 0.79-1.02). Conclusions: The EUS for stomach neoplasm was reliable of lesion without ulcerous finding, smaller than 20 mm in diameter and irrespective of stomach neoplasm location.
Recurrence rates of resected appendix carcinoid tumors: A 20-year experience at Memorial Sloan Kettering Cancer Center.
Authors: Murphy Jennifer , Rosowicz Andrew , Saltz Leonard , Paty Philip , La Quaglia Michael P. , Reidy Diane Lauren
Published: February 2017

221

Background: NETs of the appendix are rare neoplasms most often discovered during incidental appendectomy. Risk of nodal metastases based on single institution series has suggested that appendix carcinoid tumors > 2 cm should undergo a right colectomy. Unlike other tumors, lymph node involvement does not change management given the lack of adjuvant therapies. We sought to evaluate our experience of patients with resected appendix carcinoid, the risk of recurrence, and the benefit of surveillance following resection. Methods: A single institution database of all patients with diagnosis of neuroendocrine tumors was queried for all resected appendix carcinoid tumors. Excluded were patients with large and small cell neuroendocrine tumors, goblet carcinoid, and patients with inaccessible patient records. Results: 88 patients were included from August, 1994 through December, 2013. The mean age at diagnosis was 37.1(9.9-75.8). There were 19 (22%) children (less than 18 years of age) and 69 (78%) adults. Females represented 72% of all patients. All patients had well differentiated tumors. Median follow-up was 2.5 years (1-16.5 years, 45% of which had longer than 3-year follow-up). 43/88 (49%) patients underwent right hemicolectomy (average size 2 cm) and 45/88 (51%) simple appendectomy (average size 0.9 cm). Most patients were followed with CT scans and laboratory evaluations and frequency of surveillance was inconsistent. There were no recurrences (0/88). Ten-year survival was 100%. Conclusions: This is one of the largest series of resected appendix carcinoid reported and no patients recurred. Prognosis was excellent and in the absence of metastatic disease, excessive imaging and/or laboratory testing should be avoided. We question the use of routine right hemocolectomy in these patients.
Diagnostic potential of mucins in pancreatic juice for pancreatic cancer.
Authors: Patel Asish , Kaur Sukhwinder , Smith Lynette , Are Chandrakanth , Batra Surinder
Published: February 2017

222

Background: Pancreatic juice remains an underutilized resource for diagnosing pancreatic cancer. Mucins are high molecular weight glycoproteins differentially upregulated in pancreatic cancer, and we hypothesize that their profile in pancreatic juice may have diagnostic potential. Methods: Pancreatic juice was obtained during endoscopy from non-healthy non-pancreatic control (NHPC, n = 57), chronic pancreatitis (CP, n = 23), and pancreatic cancer (PC, n = 23) patients. Sandwich ELISA was used to detect MUC1, MUC4, MUC5AC, CA125, and CA19-9. Kruskal-Wallis test and Wilcoxon rank sum test for group and pairwise comparison was done with p < 0.05 as significant. Logistic regression with ROC curve modeling of log transformed data was done for each biomarker individually and in combination to determine odds ratio (OR), sensitivity (SN), and specificity (SP) for PC. Results: PC vs NHPC: MUC5AC had the best individual performance for diagnosing PC with an OR = 2.78 (95% CI = 1.51-5.13), AUC = 0.81, and optimal SN/SP of 0.83 and 0.67, respectively. CA125 was increased in PC with an OR = 2.31 (95% CI = 1.4-4.0), AUC = 0.73, and optimal SN/SP of 0.88 and 0.67. CA19-9 was increased in PC with an OR = 1.5 (95% CI = 1.2-1.8), AUC = 0.76, and optimal SN/SP of 0.73 and 0.70. A combination of MUC1, MUC5AC, CA125, and CA19-9 outperformed all individual markers and had the largest AUC (0.89) with optimal SN/SP of 0.84 and 0.79. PC vs CP: MUC1 concentration in PC was significantly less than CP with an OR = 0.21 (95%CI = 0.088-0.49), AUC = 0.82, and optimal SN/SP of 0.87 and 0.78. PC vs NHPC+CP: MUC1 was decreased significantly in PC with an OR = 0.65 (95% CI = 0.44-0.96), AUC = 0.69, and optimal SN/SP of 0.87 and 0.63. CA125 was increased in PC with an OR = 1.64 (95%CI = 1.1-2.4), AUC = 0.66, and optimal SN/SP of 0.67 and 0.64. CA19-9 was increased in PC with an OR = 1.32 (95%CI = 1.1-1.6), AUC = 0.68, and optimal SN/SP of 0.63 and 0.67. A combination of MUC1, MUC5AC, CA125, and CA19-9 had an AUC = 0.86 with optimal SN/SP of 0.87 and 0.77 for PC. Conclusions: MUC1, MUC5AC, CA125, and CA19-9 combination provides a significantly improved diagnostic panel compared to any individual marker in pancreatic juice for detecting malignancy.
Lymph node metastases in the prognosis of gastroenteropancreatic neuroendocrine tumors.
Authors: Martin Jacob Andrew , Wisnivesky Juan P. , Kim Michelle Kang
Published: February 2017

224

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a diverse group of malignancies affecting over 65,000 patients in the United States. GEP-NETs are currently classified as lymph node positive (N1) or negative (N0). The prognostic utility of the extent of lymph node involvement remains unknown. In this study, we used a population-based registry to investigate the relationship between lymph node ratio (LNR) and survival in patients with GEP-NETs. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) data registry to identify patients with histologically confirmed, surgically resected NETs with lymph node involvement diagnosed between 1988 and 2011. Patients were divided into three groups based on the ratio of positive lymph nodes to total lymph nodes examined (LNR): ²0.20, >0.2-0.5, and >0.5. Kaplan-Meier, log-rank analysis, and Cox models were used to compare NET cancer-specific survival according to LNR category. Results: We identified 8,113 patients with GEP-NETs. Primary sites included small intestine (N=3,651), colon (N= 2,042), pancreas (N=1,070), appendix (N= 683), stomach (N=389), and rectum (N=278). Patients were 49% female, 76% white, and 12% black. Ten-year NET-specific survival rates were significantly different among patients in the three LNR groups and LN negative controls (p<.0001). Survival was worse in patients with LNRs of >0.2-0.5 (Hazard Ratio (HR) 1.338, p=.0002), and >0.5 (HR 1.692, p<.0001) compared to LN-negative controls. Higher LNR was correlated with worse survival. Conclusions: The degree of lymph node involvement is a prognostic factor across the most common primary sites of GEP-NETs. This information may be used clinically and in stratifying patients for clinical trials. Results across multiple sites may also be generalizable to GEP-NETs from rare primary locations that are difficult to study. [Table: see text]
Prevalence of radiologic evidence of metastatic pancreatic ductal adenocarcinoma (PDAC) at first post-operative restaging studies in patients (pts) undergoing pancreatic cancer surgery with curative intent.
Authors: Palacio Sofia , Hosein Peter Joel , Levi Joe U , Merchan Jaime R. , Monge Jorge , Portelance Lorraine , Reis Isildinha M. , Rocha Lima Caio Max S.
Published: February 2017

225

Background: Surgical resection is the only potentially curative modality for PDAC. However, even after a successful surgical resection outcomes are poor due to both local and distant disease recurrence. Patients with early recurrence likely derive no benefit from surgery and could be considered for a non-surgical approach as initial therapy. Since the incidence of recurrent/metastatic disease at first post-operative staging scan is not well documented, our aim was to determine this incidence. Methods: This IRB-approved analysis identified all pts diagnosed with resectable PDAC that underwent surgery with intent to cure at the University of Miami/Sylvester Comprehensive Cancer Center between 2010 and 2012. Patients with imaging before and within 6 months after surgery were included. All post-operative CT scans performed within 3 months after surgery were reviewed for the presence of recurrent and/or metastatic disease. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: Data from105 pts were analyzed. Mean age was 61, 63% were male, 91% had adenocarcinoma, 84% had disease in the head of the pancreas. 11 out of 85 (13%) pts had recurrent/metastatic disease detected on first post-operative CT scan; 64% stage IIB and 73% had positive lymph nodes. 54 out of 105 (51%) had disease progression. 60% had local recurrence, 40% had distant metastasis. The mean time from preoperative CT scan to surgery was 35 days. Patients with early and late recurrence had similar OS from diagnosis (median 27.7 and 27.1 months, respectively) but worse than those with no disease recurrence (median not reached, OS rate 78% at 36 months). Conclusions: The relatively high incidence (13%) of early recurrence in this retrospective cohort suggests that further studies aimed at improving patient selection for surgery are warranted and provides a strong rationale for the use of neoadjuvant therapy to select patients with early disease progression who would not have benefitted from surgery.
The usefulness of condom method EUS for esophageal mass evaluation.
Authors: Moon Jeong Seop , Seol Sang Yong , Song Pil Hun , Sung Hyun , Lee Jeonghun , Kim Jae J , Yoon Won Jae , Ryu Soo Hyung , Kim You Sun
Published: February 2017

23

Background: The endoscopic ultrasonography (EUS) is positioned as the method of choice to evaluate the origin and depth of invasion for the esophageal mass. To overcome the disadvantages as aspiration resulting from water filling EUS and balloon rupture resulting from balloon EUS, we used condom method EUS for esophageal mass evaluation. Methods: We investigated retrospectively twenty six patients examined condom method EUS using high frequency ultrasound probes after diagnosed esophageal mass lesion including submucosal tumor by standard endoscopy between January 2007 and April 2015 at Seoul Paik Hospital, Seoul, Korea. We checked the originating layer, invasion depth and echogenicity of the mass and events complicated by procedure. Results: The condom method EUS provided high quality images without aeration and well-defined five layers of esophagus through 360 degrees. In all segments of esophagus; upper (n = 5), middle (n = 10), lower esophagus(n = 11), showed high resolution images without difference. Diagnosis were squamous cell cancer (n = 4), leiomyoma (n = 5), squamous intraepithelial neoplasia (n = 2), acanthosis (n = 2), inflammatory fibrinoid polyp (n = 1) and extrinsic compression (n = 1). Tumors were originated from mucosa (n = 5), muscularis mucosa (n = 10), submucosa (n = 3), mucosa invading into submucosa (n = 4), muscle propria (n = 3). One was diagnosed as outer compression. In esophageal cancer patients, by confirming the location and invasion of the tumor, we could make a decision the next step such as follow up, endoscopic removal or surgery. No complications had occurred in all cases, aspiration or balloon rupture. Conclusions: The condom method EUS is already known as a safe image diagnostic tool of high resolution. Simply to apply inexpensive latex condom filled with water can provide good EUS visual field and images of the esophageal mass lesions along the whole esophagus without aspiration risk.
A molecular biomarker targeted approach to adjuvant therapy for resected pancreatic adenocarcinoma: Results of a phase II prospective trial.
Authors: Postlewait Lauren McLendon , Ethun Cecilia G. , Kooby David A. , Sarmiento Juan , Staley Charles A. , Brutcher Edith , Adsay Volkan , El-Rayes Bassel F. , Maithel Shishir Kumar
Published: February 2017

230

Background: Standard adjuvant treatment for resected pancreatic adenocarcinoma is gemcitabine (Gem) (CONKO-001 trial: Gem vs placebo DFS 13.4 vs 6.7 mo; p<0.001; OS 22.8 vs 20.2 mo; p=0.01). Adding cisplatin (Cis) to Gem has shown increased response rates in the metastatic setting. This benefit may be inhibited by high expression of excision repair cross-complementing gene–1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis chemotherapy, stratifying results by tumor ERCC1 expression. Methods: Patients with resected pancreatic adenocarcinoma at a single institution were enrolled from 2010-2013. Initially, patients received Gem (1000 mg/m2) / Cis (50 mg/m2) Day 1/8/15, Q28d for 6 cycles. After enrolling 5 pts, this was modified to Day 1/15 due to toxicity. Two dose reductions were permitted. Intent to treat analyses were conducted. Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low and high expression groups. Primary outcomes were RFS and OS stratified by ERCC1 expression. Results: Of 22 pts, 16 (73%) had Stage IIB disease, 5 (23%) Stage IIA, and 1 (4%) Stage IA. Thirteen (59%) completed all 6 cycles of therapy, of whom 9 required dose reduction. Of the remaining 9 pts, 4 completed >68% of intended therapy. Grade 3 and 4 toxicity occurred in 13 pts (59%); neutropenia was most common (n=9;41%). Median follow-up was 37.5 mo. Median RFS was 16.7 mo, and OS was 35.5 mo. ERCC1 tumor expression data were available for 20 pts: 15 low (75%) and 5 high (25%). Low compared to high ERCC1 was not associated with improved RFS (12.4 vs 16.7 mo; p=0.68) or OS (Median not reached vs 21.6 mo; p=0.22). Conclusions: Adjuvant gemcitabine/cisplatin is tolerated by patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in the majority of patients. Further prospective trials evaluating Gem/Cis as an adjuvant regimen and ERCC-1 as a biomarker in resected pancreatic adenocarcinoma are warranted. Clinical trial information: NCT01188109.
Stereotactic body radiation therapy for pancreatic cancer: Assessing motion with and without abdominal compression.
Authors: Stumpf Priscilla K. , Jones Bernard , Jain Supriya K. , Amini Arya , Thornton Dale A. , Dzingle Wayne , Schefter Tracey E.
Published: February 2017

234

Background: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for locally advanced pancreatic cancer. This ablative therapy requires highly accurate delivery due to nearby organs at risk. To minimize tumor motion, our institution applies abdominal compression during computed tomography (CT) simulation. The purpose of this study is to evaluate the effect of compression in the context of pancreatic SBRT. Methods: In the last 6 months, 32 patients who completed SBRT to the pancreas at our institution were selected for analysis. In each patient, two 4DCT images were acquired, one with and one without abdominal compression. Abdominal compression was achieved with an indexed compression belt with a customized degree of inflation. Each patient had fiducial markers implanted in or near the pancreatic tumor prior to simulation. These fiducials were contoured on both planning CT scans for each gated phase. Motion was assessed by fiducial position changes throughout each gated phase. Results: In the anterior to posterior, transverse, and superior to inferior dimension, compression decreased motion in 19 of 32 cases (59%), 21 of 32 cases (66%), and 28 of 32 cases (88%) respectively. In the anterior to posterior (AP) dimension compression decreased motion by a mean of 0.43mm ± 1.7mm with a range of -2.1-6.5mm (p = 0.16). The mean decrease in motion with compression in the transverse dimension was 0.93mm ± 1.9mm with a range of -1.6-8.6mm (p = 0.01). In the superior to inferior dimension, compression decreased motion by a mean of 2.72mm ± 2.8mm with a range of -1.2-11.5mm (p < 0.001). Displacement of tissue due to compression led to increased patient AP separation at the level of T12 by a mean of 9.1±5.8mm (p < 0.001). Conclusions: Abdominal compression significantly reduced tumor motion in the superior to inferior and transverse directions for patients undergoing SBRT to the pancreas. This decrease in motion allows for significant reductions in the size of the volume necessary to treat the tumor. Given our findings, we would recommend using abdominal compression over free-breathing for pancreatic SBRT.
Genomically adjusted radiation dose to predict for survival with adjuvant radiation in resectable pancreatic cancer.
Authors: Strom Tobin Joel Crill , Hoffe Sarah E. , Frakes Jessica M. , Fulp William J. , Coppola Domenico , Springett Gregory M. , Malafa Mokenge Peter , Harris Cynthia L. , Eschrich Steven A. , Shridhar Ravi , Torres-Roca Javier
Published: February 2017

240

Background: The median survival of patients with resectable pancreatic cancer remains low at approximately 2 years. A major limitation of treating patients with postoperative radiation therapy (RT) is the close proximity of the small bowel, which confines the RT dose. We hypothesized that a subset of patients might exist who would benefit from an escalated RT dose based on their underlying tumor radiosensitivity. Methods: Genomically-profiled patients with pancreatic cancer were identified from an IRB-approved prospective observational protocol. Patients treated with upfront surgery and postoperative RT were included. Briefly, the radiosensitivity index (RSI) is derived from the expression of 10 specific genes and a linear regression algorithm modeled on SF2 of 48 cancer cells. The RSI was combined with the delivered RT dose to derive a genomically adjusted RT dose (GAD). The GAD patient subsets were split at the middle GAD value and rounded up to the nearest integer (27). Our primary endpoint was to assess whether the GAD would predict for survival. Results: Forty patients underwent surgery and postoperative RT with GAD and clinical outcome data available. The median RT dose was 50.4 Gy (range 45-54) and the median follow-up among surviving patients was 68 months (range 42-141). Eighteen patients with a GAD > 27 had a median survival of 32.1 months, while 22 patients with a GAD < 27 had a median survival of 17.9 months (p = 0.48). On Cox multivariate analysis, both high-risk pancreatic cancer patients (positive margins, positive lymph nodes or a postoperative CA 19-9 > 90) and patients with a GAD < 27 had significantly decreased survival (Hazard ratio [HR] 5.0 [95%CI 1.8,13.6], p = 0.002 and HR 2.6 [1.1-6.0], p = 0.03, respectively). Among patients with a GAD < 27, 3 of 22 (14%) would have exceeded a GAD of 27 with an escalated RT dose of 54 Gy, and 8 of 22 (36%) patients would have exceeded a GAD of 27 with an escalated dose of 56 Gy to the pancreatic bed. Conclusions: GAD is predictive of survival among patients with resectable pancreatic cancer when combined with known prognostic factors. The GAD provides a tool to determine who might benefit from dose-escalated RT based on the underlying tumor radiosensitivity.
A new immunohistochemistry prognostic score (IPS) for recurrence and survival in pancreatic neuroendocrine tumors (PanNET).
Authors: Viudez Antonio , Carvalho Filipe LF , Maleki Zahra , Zahurak Marianna , Laheru Daniel A. , Stark Alejandro , Azad Nilofer Saba , Wolfgang Christopher Lee , Baylin Stephen , Herman James Gordon , De Jesus-Acosta Ana
Published: February 2017

241

Background: We aimed to evaluate the expression and prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in resected pancreatic neuroendocrine tumors (PanNET). Methods: Ninety-two patients with resected primary PanNET and follow-up > 24 months were included in this study. Nuclear staining for MGMT and PHLDA-3 were scored as 0, 1-5%, 6-50% and ≥ 51%; cytoplasmic NDRG-1 staining was scored based on intensity and pattern from 0 to 2. We then grouped IHC scores for MGMT (absent versus any expression); for NDRG-1 (0 versus 1 versus 2) and for PHLDA-3 ( < 50% versus ≥ 51%). Finally, we developed an immunohistochemistry prognostic score (IPS) based on MGMT, NDRG-1 and PHLDA-3 IHC expression to predict disease free survival (DFS) and overall survival (OS). The discriminatory ability of multivariate models combining the IPS and important clinical variables was assessed with Harrel’s c-index (HCI) and a modification of Harrell’s c-index (mHCI). Results: DFS was significantly worse in patients without any expression of MGMT compared with those with any grade of expression (HR: 2.21; 95%CI: 0.97-5.02; p = 0.013), in patients with moderate or high score for NDRG-1 (p = 0.005), and in those with high-expression for PHLDA-3 (HR: 1.94; 95%CI: 1.05,3.6; p = 0.036). A significant difference in OS was observed based on NDRG-1 score (p = 0.013). In multivariate analyses, ki-67 (HR: 2.45; 95% CI: 1.20-5.01; p = 0.01) and IPS (HR: 2.68; 95% CI: 1.60,4.49; p = 0.00018) were independent prognostic factors for DFS, while age (HR: 7.67; 95% CI: 2.14,27.45; p = 0.0017) and IPS (HR: 2.67; 95% CI: 1.11, 6.41; p = 0.03) were independent prognostic factors for OS. HCI for the multivariate DFS and OS models were 0.796 and 0.788, respectively. Conclusions: Our IPS is a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET. Prospective studies are warranted to validate our findings and determine its role for patients’ selection to neo/adjuvant treatments
Impact and mechanistic role of MicroRNA-1291 on pancreatic tumorigenesis.
Authors: Tu Mei-Juan , Pan Yu-Zhuo , Qiu Jing-Xin , Kim Edward Jae-hoon , Yu Aiming
Published: February 2017

243

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Better understanding of pancreatic cancer biology and identification of new targets are highly warranted. MicroRNAs (miRs or miRNAs) play a critical role in the control of tumor progression via crosstalk with cancer signaling pathways. Our recent studies showed that miR-1291 improved chemosensitivity through targeting of efflux transporter ABCC1. This current study investigated the mechanistic role of miR-1291 in the suppression of pancreatic tumorigenesis. Methods: PANC-1 and AsPC-1 cell lines were stably transfected with miR-1291. Cell cycle status and apoptosis of stable miR-1291-expressing cells were tested against control cells using flow cytometry. Cells were injected subcutaneously into nude mice and tumorigenesis was measured in vivo. Proteomic studies were performed by two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. Computationally predicted miR-1291 targets were assessed by luciferase reporter assay and Western blot. Primary PDAC and control samples were tested for miR-1291 and target gene expression levels. Results: Our data showed that stable miR-1291-expressing PANC-1 and AsPC-1 cells both showed a significantly lower rate of proliferation than the control cells, which was associated with a cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 suppressed the tumorigenesis of PANC-1 cells in mouse models in vivo. Proteomic studies revealed the protein level of several cancer-related genes were downregulated by miR-1291, including a pancreatic tumor promoting protein AGR2 which was reduced ~10-fold. Through computational and experimental studies we further identified that FOXA2, a transcription factor governing AGR2 expression, was a direct target of miR-1291. In addition, we found a significant down-regulation of miR-1291 in a set of PDAC patient tumor samples overexpressing AGR2. Conclusions: These results indicate that miR-1291 suppresses pancreatic tumorigenesis via targeting of FOXA2-AGR regulatory pathway providing new insight supporting development of miR-1291-based therapy for PDAC.
Overall survival and clinical characteristics of BRCA germline/somatic cholangiocarcinoma (CCA).
Authors: Golan Talia , Raitses-Gurevich Maria , Kelley Robin Kate , Bocobo Andrea Grace , Borgida Ayelet , Shroff Rachna T. , Holter Spring , Gallinger Steven , Lowery Maeve Aine , Abou-Alfa Ghassan K. , Ahn Daniel H. , Jain Apurva , Bekaii-Saab Tanios S. , Friedman Eitan , Javle Milind M.
Published: February 2017

244

Background: Biliary tract cancers (BTC) exhibit a diverse and high frequency of actionable mutations detectable using next generation sequencing (NGS). The Breast Cancer Linkage Consortium reported that BRCA2 mutation carriers are at increased risk for BTC with estimated relative risk of 4.97, (95% CI = 1. 50-16.52). The purpose of this study was to evaluate the clinical characteristics of germline/somatic BRCA1/2mutations in CCA patients. Methods: Multi-center retrospective analysis of patients with germline/somatic BRCA1/2- associated CCA diagnosed between January 2000 and December 2013. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures and systemic chemotherapy or radiation were extracted from patient records. Results: Overall, we identified 18 cases including 5 carriers of germline BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic mutations (7 BRCA1; 6 BRCA2) using a NGS panel testing tumor for 'actionable' mutations. One patient presented with two different somatic mutations in the BRCA2gene. Mean age at diagnosis was 60 years (range 36-75), male: females (61.2% vs 38.8%, respectively). Stage at diagnosis: I (n = 4), II (n = 3), III (n = 3) and IV (n = 8). Six patients had extrahepatic CAA; twelve patients had intrahepatic CCA. Prior therapy in 13 patients included platinum-based therapy with one patient receiving prior olaparib. Median overall survival for patients with stage I/II is 34.7 months (95% CI, 7.06-62.9) and for stages III/IV is 25 months (95% CI, 12.02-35.84). Conclusions: BRCA associated CCA may have an enhanced therapeutic sensitivity to DNA damaging agents. This needs confirmation in a larger cohort of patients.
Genomic landscape of pancreatic adenocarcinoma: Does age matter?
Authors: Ben-Aharon Irit , Elkabets Moshe , Pelossof Raphael , Yu Kenneth H. , Allen Peter J. , Iacobuzio-Donahue Christine A , Leach Steven D. , Lowery Maeve Aine , Goodman Karyn A. , O'Reilly Eileen Mary
Published: February 2017

250

Background: State-of the art genomic analyses of pancreatic adenocarcinoma (PDAC) has yielded insights into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine if early-onset PDAC ( ≤ 55 yrs) displays a distinctive molecular landscape from average-age onset PDAC ( ≥ 70 yrs). Methods: Three distinct datasets of PDAC in age groups ≤ 55 and ≥ 70 years old were analyzed. In the first, patients undergoing treatment at MSKCC were consented for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) next generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression and protein expression. The third dataset was the Australian cohort of PDAC (Waddell et al, Nature, 2015). Clinical data were correlated with genomic analyses. Results: One hundred and eighty-three samples were analyzed, yielding N = 56 patients (pts) aged ≤ 55 years and N = 127 pts aged ≥ 70 years. Several genes known to be associated with carcinogenesis differed in mutation frequency across age groups: SMAD4, MYC and PIK3CA displayed higher mutation rates in younger patients (p < 0.05, table below). Comprehensive analysis by cellular pathways indicated that the PI3Kpathway is further altered in the younger population. Protein expression had different patterns in younger versus older patients. Smoking was more prevalent in the early-onset group in all three cohorts (59% vs. 47%). Survival outcomes revealed no differences between the age groups. Conclusions: This exploratory analysis suggests that there may be somatic gene alterations within the population of early onset PDAC patients that involve unique cellular pathways compared with average onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future analysis to support this observation. [Table: see text]
A pooled analysis of long pentraxin for patients with advanced pancreatic cancer.
Authors: Sasaki Mitsuhito , Kondo Shunsuke , Hosoi Hiroko , Koga Futa , Sakamoto Yasunari , Morizane Chigusa , Ueno Hideki , Okusaka Takuji
Published: February 2017

251

Background: Pancreatic carcinoma is one of the most lethal cancers and is the fourth leading cause of cancer-related death in Japan. Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis, affecting immune surveillance and response to therapy. We previously reported that pentraxin family members, especially long pentraxin (PTX3), are promising biomarkers for the prognosis of pancreatic carcinoma patients. The objective of the present study was to determine whether PTX3 levels could be a prognostic factor for patients with unresectable or recurrent pancreatic carcinoma. Methods: We analyzed data from two clinical trials (UMIN000002323 and UMIN000009474) using the Kaplan-Meier method and Cox proportional hazards model. We included data from patients who were chemo-naïve pancreatic invasive ductal carcinoma patients, had a 0–2 performance status score, and had adequate organ function. PTX3 levels and other laboratory and clinical data were assessed before initial treatment. Results: Overall, 181 patients with unresectable or recurrent pancreatic carcinoma were evaluated for the baseline plasma PTX3 level (median, mean, and range PTX3: 3.54 ng/mL, 4.34 ng/mL, and 0.9–17.7 ng/mL, respectively). In this study population, the median overall survival was 327 days (95% confidence interval, 281–372 days). The median overall survival was significantly shorter at high PTX3 levels( > 4.34ng/mL) than at low PTX3 levels ( < 4.34ng/mL)(223days vs 409 days; log rank test, P < 0.0001). In a multivariate analysis, the PTX3, C-reaction protein (CRP), and cancer antigen (CA) 19-9 levels, and performance status were independent predictors of survival. High PTX3 levels were associated with high CA19-9 and high CRP levels. Conclusions: We confirmed that a high PTX3 level may be a useful prognostic marker for advanced pancreatic carcinoma. However, the mechanism of tumor inflammation and the exact nature of the role of PTX3 expression remain unclear, calling for investigation of the mechanisms underlying PTX3 activity in carcinoma cells and in the tumor environment. Clinical trial information: UMIN000002323 and UMIN000009474.
Sensitivity and specificity of signs and symptoms to determine the risk of death associated with gastric cancer patients.
Authors: Rojas Uribe Gustavo A. , Martinez Jose , Londono Paula
Published: February 2017

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Background: Risaralda (Colombia) has an irregular pattern in the risk of death for gastric cancer; for these reasons, the survival analysis was made with the information of gastric cancer patients treated in Oncólogos del Occidente clinic during 2014. Methods: A cross-sectional study was done with oncologic patients in order to evaluate the replicability of a binary list of signs and symptoms of gastric cancer, also its corresponding principal component factors for the proper identification of their dimensions. A sum of the set of signs and symptoms was done. This total sum of signs and symptoms was used to identify the sensitivity and specificity of each of cut-off related to the patient’s death condition. This evaluation was established by the ROC (Receiver Operating Characteristic) methodology, which is a graphic representation of the sensitivity in front of the specificity for a classifying binary system that may vary the threshold of rejection. The analysis was done in Stata. Results: There were 173 patients, of whom 69.9% were males; the group with the highest incidence was the 60-69 years old group (32%); These patients referred 5 signs and symptoms that conformed the list from which every single item behaved as a binary variable. Cronbach’s alpha was 0.62 and the analysis of principal components factors defined only one dimension. The ROC curve established a sensitivity of 65% and a specificity of 72% for the determination of the risk of death with a score equal or higher to 4 in the sum of the list of signs and symptoms. Adding the gender, the sensitivity increased to 66%. In the ≥ 80 years old group the sensitivity was 70.9%, meanwhile the group of ≥ 40 years old the sensitivity was 93%. Conclusions: The list of signs and symptoms could be a diagnostic technology relevant for unspecific clinical but has an important high frequency in Colombia for gastric cancer patients. The sensitivity was very variable according to the age range, being more sensible and specific for the patients of the ≥ 40 years old group.
Assessment of genomic alterations in adenosquamous carcinoma of the pancreas (ASCOP).
Authors: Jordan Emmet , Basturk Olca , Leach Steven D , Klimstra David S. , Allen Peter J. , Berger Michael F. , Askan Gokce , Yu Kenneth H. , O'Reilly Eileen Mary , Lowery Maeve Aine
Published: February 2017

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Background: ASCOP represents a rare subtype (1-4%) of exocrine pancreatic cancer for which the clinical and molecular features are not well defined. We reviewed clinical characteristics and performed comprehensive molecular profiling in a cohort of patients with ASCOP treated at MSKCC. Methods: Patients (pts) with ASCOP diagnosed from January 2000-July 2015 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to progression (TTP), recurrence-free interval (RFI) and overall survival (OS) were recorded. Samples were reviewed by a pancreas pathologist to optimally select the squamous component for molecular profiling using MSK-IMPACT platform. This is a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of 410 key cancer genes. Tumor and matched normal libraries (where available; n=9) were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline to detect single nucleotide variants, short indels, copy number aberrations and structural rearrangements. Results: We identified 84 pts with ASCOP of whom 15 had sufficient tissue/consent for analysis. Median OS for resected pts was 17 months (mo) and 6 mo respectively. Median PFS on 1st line therapy (FLT) for stage IV disease was 3 mo. 53 pts underwent surgical resection, of whom 11 remain disease free at median follow up of 24 mo. 15/15 (100%) had KRAS mutations (mut). 11/15 (73%) had TP53 mut. 6/15 (40%) had SMAD4 mut [4 point mutations (PM), 2 frameshift deletions]. 6/15 (40%) had CDKN2A mut (4 deletions, 2 PM). Mut were also found in FAT 1 (3/15), JAK3 3 (3/15), TBX 3 (2/15) and FGFR amplification was found in 1 pt sample. Conclusions: ASCOP like conventional ductal adenocarcinoma has a poor prognosis with a comparable molecular signature in the most common alterations. Potential targets e.g., FGFR1 may allow novel agents in select pts. [Table: see text]
The mitochondrial metabolism inhibitor CPI-613 in combination with mFOLFIRINOX for pancreatic adenocarcinoma.
Authors: Alistar Angela Tatiana , Desnoyer Rodwige , D'Agostino Ralph
Published: February 2017

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Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.
Preliminary observations of blood-based (BB) molecular testing in a subset of patients with pancreatic cancer (PDA) participating in the Know Your Tumor (KYT) initiative.
Authors: Pishvaian Michael J. , Matrisian Lynn , Hendifar Andrew Eugene , Engebretson Anitra , Rahib Lola , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Madhavan Subha , Petricoin Emanuel , Brody Jonathan Robert
Published: February 2017

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Background: Obtaining an adequate tissue sample for molecular profiling to guide therapy selection for patients with advanced cancers can be clinically difficult, and/or patients may not want to undergo a biopsy. There has been a growing interest in the use of BB tests, including cell free DNA (cfDNA) and exosome/circulating tumor cell based-analyses as surrogates for tumor tissue (TT) testing. Validation of BB tests in PDA is possible because > 90% of PDAs harbor KRAS mutations – thus providing a reliable “internal control.” Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated an IRB-approved registry trial for patients with pancreatic cancer wherein we facilitated commercially available, CLIA certified multi-Omic profiling including next generation DNA sequencing (NGS), immunohistochemistry, and phosphoproteomics on patient tumor samples. In a subset of these patients, we incorporated BB testing. Results: A KRAS mutation has been identified in 87% of KYT patients based on TT NGS in general. As of this report, 17 BB test results (cfDNA NGS) were available. In 8 patients we were able to compare the cfDNA NGS directly with TT NGS. BB testing identified a KRAS mutation in 1/8 compared to 8/8 from the tumor tissue. Of the 9/17 patients who did not have corresponding TT NGS, a KRAS mutation was found on BB testing in 3/9 samples. 4/17 BB cases overall revealed KRAS mutations, but when cases were filtered for patients with extensive metastatic disease and progressive disease at the time of blood sampling, the KRAS mutation rate increased to 2/5 overall. Actionable findings (i.e. linked to a specific therapeutic option) were identified in 6/17 cases, of which 3/17 had both an actionable mutation and a KRAS mutation. Conclusions: Although we are aware of the limitations of this study, we recommend that for patients who have biopsiable disease, a TT test should still be the gold standard for molecular profiling. For those without biopsiable disease, the KYT program presents an opportunity to determine the parameters that influence the probability of obtaining reliable molecular profiling information from a BB sample.
PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy in patients with advanced pancreatic adenocarcinoma.
Authors: Rivera Fernando , Gallego Javier , Guillen Carmen , Benavides Manuel , Lopez-Martin Jose A. , Betticher Daniel C. , Kueng Marc
Published: February 2017

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Background: TTFields are alternating electric fields delivered to the region of the tumor by means of non-invasive transducer arrays. TTFields interfere with mitotic spindle formation, thus having an anti-mitotic activity. In pancreatic cancer, TTFields decreased proliferation and clonogenic potential in vitro, and reduced tumor volume in vivo. The PANOVA trial was designed to test TTFields, combined with chemotherapy, in pancreatic cancer. Methods: Twenty patients with advanced pancreatic adenocarcinoma were enrolled in a prospective, single arm study of TTFields at 150 kHz, concomitant with standard weekly gemcitabine. All patients had histologically-confirmed unresectable tumors, with an ECOG performance score of 0-1 and no prior chemotherapy or radiation therapy. The primary endpoint was incidence and severity of treatment emergent adverse events (AEs). Secondary endpoints included progression free survival (PFS), PFS rate at 6 months, overall survival (OS) and response rate. Results: The median age was 73 (range – 49-81) and 60% of the patients were females. Most patients (80%) had an ECOG score of 1. Twelve patients (60%) had distant metastases, while the others had locally advanced disease. Median compliance with TTFields was 78% (14 hours/day), with median duration of 5 months. Fourteen patients (70%) had serious (grade 3-5) AEs during the study period. Six patients (30%) had hematological, 45% gastrointestinal and 15% pulmonary AEs. Ten patients (50%) had treatment-related skin toxicity, of which only 2 were grade 3, both resolved with appropriate treatment. No TTFields-related serious AEs were reported. The median PFS was 8.3 months (95% CI 4.3, 10.3). PFS rate at 6 months was 56%. Of the evaluable tumors, 30% had partial response and another 30% stable disease. The median OS was 14.9 months and 1-year survival rate was 55%. Conclusions: TTFields concomitant to gemcitabine are tolerable and safe for advanced pancreatic cancer patients. The efficacy results are promising and support further research in this indication. An extension of the PANOVA protocol, including 20 additional patients who receive gemcitabine, nab-paclitaxel and TTFields is ongoing. Clinical trial information: NCT01971281.
Antitumor activity and immune reponse in CD40 immunotherapy with gemcitabine and nab-paclitaxel in an orthotopic pancreatic cancer mouse model.
Authors: Siolas Despina , Cullis Jane , Avanzi Antonina , Byrne Kate , Leichman Lawrence P. , Vonderheide Robert H. , Bar-Sagi Dafna
Published: February 2017

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Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a KrasG12D;Trp53R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy.