docs = [{"summary":"\nBackground:  Surgery is the only curative option currently available for carcinoid cancer.  Recent work has identified the Raf-1 pathway as a potential therapeutic target. In order to identify possible Raf-1 activating drugs, we examined Leflunomide (LFN), currently FDA approved for rheumatoid arthritis and its metabolite, Teriflunomide (TFN).  We hypothesized these compounds would inhibit carcinoid growth through activation of the Raf-1 pathway.\n\nMethods:  Gastrointestinal carcinoid cells treated with LFN or TFN were analyzed using the MTT colorimetric growth assay, propidium iodide exclusion flow cytometry, serotonin ELISA, quantitative PCR, and western blotting for cyclin B1, Achaete-Scute Complex-Like 1 (ASCL1), Chromogranin A (CgA) and markers of Raf-1 pathway activation.  In vivo studies were performed using a subcutaneous xenograft in nude mice.\n\nResults:  Treatment of carcinoid cells with LFN and TFN resulted in dose dependent inhibition of growth and induction of cell cycle arrest.  These changes were associated with Raf-1 pathway activation.  In our in vivo model, oral administration of LFN resulted in significant inhibition of tumor growth.  Cellular levels of serotonin and CgA protein were reduced.  Importantly the protein and mRNA levels of the transcription factor, ASCL1, were dose dependently suppressed. The effects on cyclin B1 as well as ASCL1 were reversed by pretreatment with U0126, a Raf-1 pathway inhibitor, illustrating that the anti-cancer effects of these drugs are mediated via the Raf-1 pathway.\n\nConclusions:  LFN and TFN induce in vitro cell cycle arrest while suppressing in vivo carcinoid growth. Importantly, levels of key carcinoid markers are suppressed.  These effects are mediated through the Raf-1 pathway.  LFN thus represents one of the first clinically applicable Raf-1 pathway activators in carcinoid cancer, and given its clinical safety record in humans, is worthy of further investigation. ","title":"Identification of a Novel Raf-1 Activating Drug That Inhibits Gastrointestinal Carcinoid Growth","authors":"Mackenzie R. Cook, Scott N. Pinchot, Renata Jaskula-Sztul, Jie Luo, Muthusamy Kunnimalaiyaan, Herbert Chen","filename":"Bcookabstract","id":"B1"},{"summary":"\nBackground:  Increased expression of DNA repair proteins has been implicated in chemoresistance to alkylating agents in lung, ovarian and other malignancies. We have investigated whether C&PET express high levels of these proteins potentially explaining their known in vivo chemoresistance.\n\nMethods:  We stained tumor samples from 17 patients (pts) with C&PETs of various Wick grades (four gr 1, seven gr 2 and six gr 3) for: 1. Ki-67, a marker of cell proliferation and DNA replication but not DNA repair, using MIB-1 antibody, 2.  PCNA, an established DNA replication and repair biomarker (Cell 1992; 69:367-74), 3. Somatostatin receptor type 2 (SST2). The % Ki-67 and PCNA positive cells were compared between patients and correlated with the Wick grades and SST2 staining intensity.\n\nResults:  Median %Ki-67-positive cells was only 1.5% (range; 0.5-3%). In contrast, median %positive cells for PCNA was 90% (range; 5-100%) with 4 pts showing \u2264 50% and the remainder \u2265 60% PCNA expression. PCNA showed a characteristic staining pattern with 4+ staining of the small fraction of proliferating Ki-67-positive cells vs. 2+ to 3+ staining of quiescent cells. SST2 staining intensity was 1+ in 3, 2+ in 10 and 3+ in 4 pts with no apparent correlation between the SST2 expression and Wick grade or Ki-67 and PCNA expression. There was also no correlation between the Wick grade and Ki-67 or PCNA expression.\n\nConclusions:  This is the first demonstration of a very high expression of PCNA in C&PET that is clearly discordant with cellular proliferation/Ki-67 expression. This finding likely indicates enhanced DNA repair in most C&PET and may explain their general in vivo chemoresistance. Further studies with other DNA replication and repair biomarkers such as thymidine kinase 1 (TK1), replication protein A (RPA), and excision repair cross-complementation group 1 (ERCC1) are ongoing.  ","title":"Discordant Expression of Proliferating Cell Nuclear Antigen (PCNA) and Ki-67 Antigen in Carcinoid and Pancreatic Neuroendocrine Tumors (C&PET) Likely Indicates Enhanced DNA Repair","authors":"Malik E. Juweid, Sergei Syrbu, Barry DeYoung, Sue O\u2019Dorisio, Thomas O\u2019Dorisio","filename":"Bjuweidabstract","id":"B2"},{"summary":"\nAims: In addition to the well-known markers in patients with neuroendocrine tumors (NETs), chromogranin A (CgA) and neuron specific enolase (NSE), two new markers, pro-Gastrin Releasing Peptide (proGRP) and MonoTotal (MT), a cytokeratin marker, were measured in order to evaluate if the established diagnostic and prognostic values improved.\n\nMethods:  CgA (CIS Bio-international), NSE (Roche Diagnostics), proGRP (Abbott Laboratories) and MT (IDL) were measured in 300 healthy persons, 314 NET not otherwise specified (NETNOS) and 254 small cell cancer (SCC) patients.\n\nResults: \nNETNOS\nMedian\n25%-75% \nSCC\nMedian\n25%-75%  \nP-value\nUpper reference value\nChromogranin A (\u00b5g/l)\n   \n176\n66-534\n66\n42-115\n<0.001\n98\nNSE (\u00b5g/l)\n   \n8.4\n6.0-13.8\n17.6\n8.3-59.3\n<0.001\n12.6\nproGRP (ng/l)\n   \n39\n29-56\n233\n46-1235\n<0.001\n55\nMonoTotal (U/l)\n   \n80\n49-146\n108\n60-264\n<0.001\n127 (M)\n84 (F)\nCgA was the best marker discriminating NETNOS from healthy (Area under ROC curve (AUC)\u00b1SE: 0.857\u00b10.018). ProGRP was the best discriminating marker for SCC (0.846\u00b10.021), but combined with MT, the accuracy was even better (0.937\u00b10.012, p =0.0002). Survival analyses demonstrated that in well differentiated NET (carcinoid), MT and CgA remained associated with survival (p<0.001 and p =0.025, respectively) after correction for age, sex, grade, stage, site and pretreatment. In the moderately differentiated NETNOS (atypical carcinoid), NSE remained the only marker marginally associated with survival (p =0.087). In SCC, NSE and MT remained associated with survival (p<0.001 and p =0.005, respectively).\n \nConclusion:  The combination of CgA, NSE, proGRP and MT is a promising marker panel for diagnostics in NET. 1: CgA remains the most useful marker in NETNOS, while the combination of proGRP and MT gives a high accuracy for predicting SCC. 2: CgA and MT are independent prognostic variables for survival in well differentiated NETNOS, while NSE and MT are the prognostic variables in SCC.","title":"New Biomarkers in Neuroendocrine Tumors: A Retrospective Study of Their Diagnostic and Prognostic Value","authors":"Department of Clinical Chemistry, Department of Medical Oncology, The Netherlands Cancer Institute \u2013 Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands","filename":"Bkorseabstract1","id":"B3"},{"summary":"\nAims:  The aim of this study is to investigate angiogenesis activity after embolization by measuring of midregional pro-Adrenomedullin (proADM), C-terminal pro-Endothelin-1 (proET), vascular endothelial growth factor (VEGF) and endothelin-1 (ET). To examine necrosis activity MonoTotal (MT), a cytokeratin marker, was measured.\n\nMethods:  Between 2003 and 2008 12 patients (M/F: 6/6, age (mean \u00b1 SD): 59 \u00b1 9 years) were treated with transcatheter embolization of whom blood was obtained before embolization and the days following this treatment during hospitalization. ProADM was detected on the Kryptor and proET levels were measured with an immunoassay (BRAHMS AG; Hennigsdorf, Germany). VEGF and ET were measured with ELISA kits (R&D Systems, Minneapolis, USA) and MT was measured with an IRMA-assay (IDL Biotech AB, Bromma, Sweden).\n\nResults:  From 12 patients 90 blood samples were obtained before and during 8 days after embolization. Mean (\u00b1 SD) pretreatment proADM levels were 0.77 (\u00b10.29) nmol/l. The follow-up samples showed no significant difference with pretreatment samples. Mean (\u00b1 SD) pretreatment proET levels were 9.2 (\u00b1 7.0) pmol/l. An increase of proET levels was observed with the highest levels 6 days after treatment: mean \u00b1 SD: 40.8 \u00b1 17.0 pmol/l (p=0.002, Bonferroni test). VEGF, ET and MT levels will be presented at the congress.\n\nConclusions:  The increase of the endothelial growth factors shows that angiogenesis plays an important role after embolization. This indicates a need for the development of adjacent therapy.","title":"Angiogenesis Markers After Chemoembolization of Liver Metastases in Patients with Neuroendocrine Tumour","authors":"Catharina M. Korse, Babs G. Taal, Johannes M.G. Bonfrer","filename":"Bkorseabstract2","id":"B4"},{"summary":"\nBackground: Somatostatin receptors (SSTR) are effective therapeutic targets for neuroendocrine tumors.  SSTR are comprised of five major subtypes, namely subtypes 1, 2 (A and B), 3, 4 and 5.  Previously, we reported that SST signaling is a determinant for the TGF-beta dependent neuroendocrine-mesenchymal transition (NMT) process in BON cells.  NMT is similar to the epithelial-mesenchymal transition (EMT) in epithelial cancers, but has the opposite cellular differentiation outcome in response to the TGF-beta treatment.  In EMT, the miR-200c has been shown to negatively regulate ZEB1 (an E-cadherin\u2019s transcriptional repressor) and keeping EMT invasiveness in check.  Here we examined the participation of miR-200c in NMT, and the anti-SSTR antibodies\u2019 impact on both NMT and neuroendocrine tumor cell death.\n\nMethods:  BON cells were transiently transfected with 40nM XmiR-200c (miR-200c repressor, Oligoengine Inc.) for 30 minutes before adding 10\uf06dg/ml rabbit IgG (negative control), 100nM Octreotide and 10\uf06dg/ml anti-SSTR2,3 or 5 antibody. Next, 48 hours after treatments, cells were collected for Western blot analysis to detect NMT related protein changes.  Alternatively, 40 minutes after treatments, we used live cell microscopy to record BON cells\u2019 migratory behavior in real time for the next 14 hours.  BON and CNDT2.5 cells were treated with octreotide and anti-SSTR antibodies in suspension, cell mortality was determined using Guava viacount, Nexin assay, or MTS proliferation assays.\n\nResults: The XmiR-200c transfected BON cells have elevated ZEB1 protein level, with decreased E-cadherin, and increased Vimentin and Twist mesenchymal markers.  The transfected BON cells also displayed an increase in mobility as exhibited under the live cell microcopy.  Anti-SSTR antibody treatments reversed BON cells back to the differentiated state even in the presence of XmiR-200c.  BON and CNDT2.5 cells both have shown increased cell death upon anti-SSTR antibody treatments.\n\nConclusions:  Similar to EMT, miR-200c and ZEB1 are involved in the cellular dedifferentiation in NMT.  Anti-SSTR antibodies are successful in overcoming the effect of XmiR-200c by reversing metastasis marker expressions with decreasing cellular mobility and increasing neuroendocrine tumor cell death.\n","title":"Somatostatin Receptor Activation by Agonist-like Antibodies can Reverse miR-200c/ZEB1 Dependent Cell Dedifferentiation and Increase Cell Death in Neuroendocrine Tumor Cells","authors":"Frank Leu, Minesh Nandi, Chung Wong","filename":"Bleuabstract","id":"B5"},{"summary":"\t\nBackground:  G protein coupled receptors (GPCR) have emerged as candidates for molecular targeting in neuroendocrine tumors (NETs).  GPCR characteristics that account for their success as drug targets include cell surface expression, exquisite specificity of ligand-receptor interactions, and key roles in NET signal transduction pathways.  We hypothesize that pancreatic and ileal NETs have distinct GPCR signatures that can be exploited to develop tumor specific Positron Emission Tomography (PET) imaging agents.  \n\nMethods:  Specimens of ileal and pancreatic NET plus adjacent normal tissue were obtained at surgery according to an IRB approved protocol.  RNA was isolated from matched tissues, reverse transcribed, and applied to TaqMan Human GPCR arrays for quantitative PCR.   Results were confirmed using genome wide EXON chip analysis.  Data were analyzed using Relative Quantification Manager and StatMiner software.  Octreotide and \u03b1-MSH were synthesized using solid phase chemistry, conjugated with DOTA, purified by HPLC, and radiolabeled with Gallium-68 for in vitro membrane binding and in vivo PET imaging.\n\nResults:  Tumor specific GPCR signatures were identified in pancreatic and ileal NETs.  Pancreatic NETs over-express somatostatin (sst2) and serotonin (HTR1D) receptors. In contrast, ileal NETs over-express melanocortin (MC1R), opiate (OPRK1), ghrelin (GHSR), and calcitonin (CALCR) receptors.  [68Ga]-DOTATOC and [68Ga]-DOTA-\u03b1-MSH targeting sst2 and MC1R, respectively, were synthesized and radiolabeled with high specific activity and radiochemical purity. High affinity binding of [68Ga]-DOTATOC was demonstrated in vitro in NET cell lines.  Localization of NET xenografts was demonstrated in vivo using [68Ga]-DOTATOC PET.\n\nConclusions:  GPCR TaqMan arrays have identified tumor specific molecular signatures for pancreatic and ileal NETs that are distinct from adjacent normal tissue. Development of receptor specific ligands as PET imaging agents will enable more sensitive, non-invasive identification of primary tumors as well as quantitative assessment of response to therapy.  Molecularly targeted PET imaging may also pave the way for development of tumor specific radiotherapy.  ","title":"Discovery of G Protein Coupled Receptor Tumor Signatures and Identification of Positron Emission Tomography Imaging Targets in Ileal and Pancreatic Neuroendocrine Tumors","authors":"Molly E. Martin, Daniel Calva-Cerqueira, Blanca Schafer, Whitney Leverich, Michael K. Schultz, Damon C. Shutt, Thomas M. O\u2019Dorisio, M. Sue O\u2019Dorisio, and James Howe","filename":"Bmartinabstract","id":"B6"},{"summary":"\nBackground:  Neuroendocrine tumors (NETs) of the pancreas and small intestine frequently metastasize; however, no standard therapy exists for patients with unresectable, progressive disease.  Components of the mTOR signaling pathway have been identified as potential therapeutic targets in NETs, and inhibitors of the pathway are being investigated in clinical trials.  We evaluated the expression and activity of mTOR pathway components in NETs of the pancreas (PNET), small bowel (SINET), and normal tissues.\n\nMethods:  Archived formalin-fixed, paraffin-embedded tissues were obtained from 28 patients: 16 PNETs and 12 SINETs.  Expression and phosphorylation of mTOR and its downstream effectors S6K and 4E-BP1 were assessed by immunohistochemistry.\n\nResults:  Distinct activation (phosphorylation) of mTOR, 4E-BP1 and S6K was observed in PNETs, SINETs, and normal tissues.  We observed p-mTOR in 12/16 (75.0%), p-4E-BP1 in 0/16 (0.0%), and p-S6K in 2/16 (12.5 %) PNETs.  In normal islets, we detected p-mTOR in 0/11 (0%), p-4E-BP1 in 5/12 (41.7%), and p-S6K in 3/12 (25%).  We observed p-mTOR in 12/12 (100%), p-4E-BP1 in 1/12 (8.3%), and p-S6K in 3/12 (25%) SINETs.  Phospho-mTOR was detected in 6/6 (100%), p-4E-BP in 5/6 (83.3%), and p-S6K in 3/6 (50%) normal SI.\n\nConclusions:  We show that activated components of the mTOR signaling pathway are present in PNETs and SINETs.  Our analysis reveals distinct profiles of active mTOR pathway components in PNETs and SINETs compared with each other and with their respective normal tissues.  Our results suggest a lack of concordance among p-mTOR and p-4E-BP1 and p-S6K; this may result from the actions of other signaling pathways that affect S6K and/or 4E-BP1, non-coordinate dephosphorylation of S6K and 4E-BP1 in tissue sections, or variances in the efficacies of the antibodies employed.  The work herein provides important information for the evaluation of potential predictive biomarkers that could be validated in future clinical trials.","title":"Distinct mTOR Pathway Activity in Neuroendocrine Tumors of the Pancreas and Small Intestine Revealed by Immunohistochemical Analysis","authors":"Eric Nakakura, Melissa Wong, Yucheng Wang, Gioia Iezza, Marlene Zuraek, Xiaochen Yuan, David Donner, Douglas Hanahan, Robert Warren, Emily Bergsland","filename":"Bnakakuraabstract","id":"B7"},{"summary":"\nBackground:  Molecular mechanisms of progression in pancreatic endocrine tumors/carcinomas (PETs/PECAs) are not fully understood. We have identified a novel set of potential molecular markers of progression in these clinically unpredictable neoplasms.\n\nMaterials and Methods:  Five clinically-localized primary (CLP)-PETS from 5 patients (mean age 66; 3M/2F) and 6 well-differentiated (WD) metastatic primary (MP)-PECAs from 6 other patients (mean age 59, 3M/3F) were macro dissected to achieve 80-98% viable tumor for RNA extraction and run on Affymetrix U133 2.0 gene chip. The data were RMA normalized and differentially expressed genes in MP-PECAs vs. CLP-PETs were identified by t-test. This gene set was further refined by excluding those with a significant frequency of Type I errors and enforcing a median 2-fold change between these two groups. Genes satisfying these criteria were grouped into functional categories based on GO annotation and for a correlative analysis to select \u2018putative progression genes\u2019 for further validation on the original frozen PETs/PECAs and also on independent test sets of archival MP-PECAs and CLP-PETs by real-time PCR using micro fluidics cards (ABI).\n\nResults:  217 transcripts were differentially expressed between MP-PECAs and CLP-PETs, using p-value <0.05 and fold-change values >1.5/>2/>4/>8 (217/94/19/1 gene respectively). Among those with a fold-change >2, several exhibited a high level of reliability, based on similar patterns of differential expression for multiple probe sets targeting the same mRNA. Among our 85 \u2018putative progression genes\u2019 from the original frozen tumors, we validated under-expression of RUNX1T1, DRD1IP, ISL1, ETV1 and GCG and over-expression of TMPRSS6, SERPINA1, SSTR5, SMURF1 and CD24 on independent test sets of archival MP-PECAs relative to CLP-PETs.  \n\nConclusion: We have discovered a novel set of \u2018putative progression genes\u2019 in sporadic primary WD-pancreatic endocrine carcinomas. Further validation of these candidate genes will support their role as potential prognostic markers in primary pancreatic endocrine tumor tissues.  \n\n","title":"Discovery and Validation of a Novel Set of Putative Progression Markers in Well-Differentiated Primary Pancreatic Endocrine Carcinomas","authors":"Aejaz Nasir, SM McCarthy, Nelly A Nasir, Dung-Tsa Chen, Deepak Agrawal, Jihad Skaf, Mike Gruidl, Gregory C Bloom, Steven Eschrich, Nancy M Gardner, Jonathan Strosberg, Pamela Hodul, Emily Zeringer, Steven Enkemann, Domenico Coppola, Mokenge P Malafa ., Timothy J Yeatman, Larry K Kvols","filename":"BNasirabstract1","id":"B8"},{"summary":"\nBackground:  The clinical course of pancreatic endocrine tumors/carcinomas (PETs/PECAs) is currently unpredictable with substantial variability in rate of disease progression and patient outcomes. Using Affymetrix platform, we discovered and validated a set of molecular markers of metastases including RUNX1T1 and palladin. Here we present a comparative analysis of RUNX1T1 and palladin versus conventional pathologic criteria of malignancy as predictors of liver metastasis in primary pancreatic endocrine neoplasms.\n\nPatients and Methods:  Thirty-five primary well-differentiated (WD) PETs/PECAs (13 metastatic, 22 clinically localized) were immunostained for RUNX1T1 (Sigma) and palladin (ProteinTech) proteins on a custom-designed tissue microarray (TMA).  Expression of these markers was quantified by the Allred-score, based on intensity (1-3) and % stained cells (0-5). Allred-score thresholds for optimal sensitivity and specificity of each marker were determined by receiver operating characteristic (ROC) analysis. Using those thresholds, the predictive accuracy of each marker was compared with conventional pathologic criteria of malignancy: Tumor size, mitotic count, Ki-67 index, and tumor necrosis (Fisher\u2019s exact test).\n\nResults: Metastatic primaries (MP-PECAs) (N=13): Presence of liver metastases was more accurately predicted by the molecular markers [RUNX1T1-11/13 (85%), palladin-13/13 (100%)] than the pathologic criteria. Non-metastatic PETs (N=22): Absence of liver metastases was more frequently predicted by the molecular markers and mitotic-count [RUNX1T1-21/22 (95%), palladin-15/22 (68%), mitotic-count 17/22 (77%)] than other pathologic criteria. Overall, RUNX1T1 had higher predictive accuracy to identify patients with and without liver metastases than mitotic-count (p=0.02), Ki-67 index (p=0.01), tumor size (p=0.004) and necrosis (p=0.03). However, predictive accuracy of palladin was higher than mitotic-count (p=0.01), tumor size (p=0.02) and necrosis (p=0.001).\n\nConclusion: In pancreatic endocrine neoplasms, molecular markers (RUNX1T1 and palladin) emerge as more accurate predictors of liver metastases than conventional pathologic criteria. These proteins may serve as surrogate markers to identify patients with resected, clinically localized primaries who may benefit from close surveillance and adjuvant therapy trials.  ","title":"RUNX1T1 and Palladin Outperform Pathologic Criteria of Malignancy in Predicting ","authors":"Aejaz Nasir, Evita B Henderson-Jackson, James Helm, Jonathan Strosberg, Nelly A Nasir, Pamela Hodul, Masoumeh Ghayouri, Barbara A. Centeno, Ardeshir Hakam, Mokenge P Malafa, Timothy J Yeatman  Domenico Coppola, Larry K Kvols","filename":"BNasirabstract2","id":"B9"},{"summary":"\nBackground:  Palladin is a proto-oncogene, intimately involved in cell structure and motility.  Recently, palladin has been associated with tumor invasion and metastasis. In our microarray analysis palladin was one of the most differentially expressed genes in metastatic relative to clinically-localized primary pancreatic endocrine neoplasms. The purpose of this study was to validate the over-expression of palladin at the protein level in well-differentiated pancreatic endocrine carcinomas and to determine its association with liver metastases.\n\nMethods:  A tissue microarray (TMA) comprising well-differentiated pancreatic endocrine tumors/carcinomas (N=38) and matched non-neoplastic pancreatic islets was immunostained with rabbit anti-human Palladin antibody. The immunohistochemical expression of palladin was quantified using the Allred scoring scheme (Intensity score 0-3; stained cells (%) score 0-5; Total Allred score 0-8). Palladin expression and conventional pathologic criteria of malignancy were correlated with the presence of liver metastases.  \n\nResults: Patients: 19 males and 19 females.  Age range: 27-79 (mean age 54). Tumor size: 0.9-11.5 cm (mean 3.8).  Palladin was expressed by all 14 pancreatic endocrine carcinomas with hepatic metastases whereas 14 of 24 (58%) clinically-localized primary pancreatic endocrine tumors expressed palladin (p<0.01) with median Allred scores of 5 (range 3-7) and 2 (range 0-6) respectively (p < 0.0001). High tumor expression of palladin showed strong association with liver metastasis (p<0.0001) compared to other pathologic criteria of malignancy (tumor size, mitotic count, Ki-67, T-stage and N-stage). Mean Allred score for normal-neoplastic pancreatic-islets in metastatic (N=6) was higher (4.2) as compared to 2.5 for clinically-localized primaries (N=11) (p= 0.23).  \n\nConclusion: Palladin appears to be a reliable marker of liver metastases in primary pancreatic endocrine tumors. Large-scale clinical validation studies are needed to further test palladin as a prognostic marker. The over-expression of palladin in metastatic primary PECAs and matched normal islets points toward its role both in the initiation and progression of these neoplasms. \n\n","title":"Palladin is a Reliable Marker of Liver Metastasis in Primary Pancreatic Endocrine Neoplasms","authors":"Aejaz Nasir, Evita B Henderson-Jackson, James Helm, Jonathan Strosberg, Nelly A Nasir, Domenico Coppola, Larry K Kvols","filename":"BNasirabstract3","id":"B10"},{"summary":"\nBackground: Patient outcome in well-differentiated pancreatic endocrine tumors can be difficult to predict based exclusively on pathologic criteria. We recently identified a novel set of 3 metastasis-associated genes by microarray analysis of fresh-frozen pancreatic endocrine neoplasms: Palladin, p21, RUNX1T1. The aim of this analysis was to evaluate the potential for these markers, individually or in combination, to predict liver metastases as an indicator of adverse outcome. \nMethods: Palladin, p21, and RUNX1T1 immunostains were carried out on a tissue microarray of 39 resected primary pancreatic endocrine neoplasms, 14 of which had hepatic metastases. The Allred score was independently determined by 2 pathologists as the sum of stain intensity (scored 0-3) and % cells stained (scored 0-5). Receiver operating characteristic (ROC) analysis was used to choose the cutpoint in Allred score (high vs low protein expression) to optimize sensitivity and specificity for predicting liver metastases. \nResults: Nearly all tumors with liver metastases showed high Palladin and p21 expression (Allred score > 3 and > 4, respectively), while expression was lower in the majority of non-metastatic tumors. In contrast, RUNX1T1 expression was low (Allred score < 4) in most tumors with liver metastases, but was higher in all except one of the non-metastatic tumors. Individual test sensitivities for predicting liver metastases were 100% for high Palladin, 93% for high p21 and 85% for low RUNX1T1, while corresponding specificities were 63%, 75%, and 96%. Tumors were correctly classified as being metastatic or not (predictive accuracy) by Palladin, p21, or RUNX1T1 expression in 76%, 76%, and 92% of cases, respectively. If abnormal expression of even one of 3 proteins is considered a positive test (parallel testing), then sensitivity of all 3 together for predicting liver metastases was 100%, specificity 48%, and predictive accuracy 68%. \nConclusions: 1) High Palladin, high p21, or low RUNX1T1 expression have good sensitivity and specificity for predicting liver metastases in pancreatic endocrine tumors. 2) Parallel testing with all 3 markers achieved 100% sensitivity but at a cost of reduced specificity. 3) Differential expression of these biomarkers may predict aggressive tumor behavior that warrants more aggressive management.","title":"Metastasis-associated Gene Products and Liver Metastases in","authors":"Aejaz Nasir, James Helm, Jonathan R. Strosberg, Leslie M. Turner, Evita B Henderson-Jackson, Naiel Hafez, Nelly A. Nasir, Ardeshir Hakam, Domenico Coppola, Larry K. Kvols","filename":"BNasirabstract6","id":"B11"},{"summary":"Fax: 319-353-7850.  E mail Thomas-odorisio@uiowa.edu\n\nObjective:  Pancreastatin is a fragment of the chromogranin A (CgA) molecule. Existing pancreastatin assays, which depend on antibodies which cross-react in varying percents with the larger prohormone, may lack sensitivity and specificity to detect small changes in neuroendocrine tumor volume.  \n\nMethods:  We developed a highly specific, sensitive pancreastatin assay. The antibody used recognizes the carboxyl terminal of the peptide hormone and was raised against a 17-amino acid porcine pancreastatin fragment with high homology with the carboxy-terminal amino-acids 286-301 of human CGA.\n\nResults:  Our assay measures > 95% of circulating pancreastatin levels; has little or no cross-reactivity with CGA, even at plasma concentrations of 1,000 ng/ml; and can detect pancreastatin levels of 17 pg/ml.  Inter-assay reproducibility for the pancreastatin RIA was determined from results of three quality control pools in 15 consecutive assays.  Coefficients of variation for low, medium, and high pancreastatin levels were < 20%.  The sensitivity of serial pancreastatin assays to detect early tumor recurrence was demonstrated in two patients with slowly progressive neuroendocrine tumors and in patients undergoing surgical cytoreduction.\n\nConclusion: This highly specific, sensitive pancreastatin assay can detect small changes in liver tumor progression and is up to 100-fold more sensitive and specific than CgA assays in the U.S.","title":"Development of a Highly Sensitive and Specific Carboxy-terminal Human Pancreastatin Assay to Monitor Neuroendocrine Tumor Behavior","authors":"Thomas M. O\u2019Dorisio, Siegfried R. Krutzik, Eugene A. Woltering, Erika Lindholm, Saju Joseph, Yi- Zarn Wang, J. P. Boudreaux, Aaron I. Vinik, V.L.W. Go, James R. Howe, Thor Halfdanarson, M. Sue O\u2019Dorisio, Gregg Mamikunian","filename":"Bodorisiotomabstract","id":"B12"},{"summary":"\nBackground:  Gallium-68 (68Ga) labeled analogs of somatostatin (sst) have been demonstrated to be effective for imaging NETs by positron emission tomography (PET) in European clinical studies. These radiopharmaceuticals are more reliable (and prepared more conveniently) than fluorine-18 (18F) labeled glucose (18F-FDG) and dihydroxyphenylalanine (18F-DOPA); with superior image quality/sensitivity compared to indium-111 single-photon-emission computed tomography (SPECT). 68Ga-sst analogs target upregulation of sst receptor subtype-2 (sst2) in NETs. However, upregulated sst2 in NET is not ubiquitous and alternative-receptor targets (e.g., G-protein coupled receptors) are needed. We examined [68Ga]-labeled analogs of sst and neuropeptide-Y (NPY) for imaging xenograft NETs in rats.\nMethods:  Cells (BON, SKNBE, SHSY5Y) were cultured by standard techniques. Sst analog tyr3-octreotide (TOC) and NPY derivative YPSKxRHYINLITRQRY (NxPY; targeting NPY receptor subtype 2; x = hexanoic acid) were conjugated to chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) by standard methods. Radiolabeling was performed at pH 3.5 (100\uf0b0C, 10-20 minutes). Competitive binding assays established receptor specificity. Tumors were induced by subcutaneous flank injection of cells in nude rats (~4 weeks). Radiochemical purity (RP) and specific activity (SA) were monitored by radioHPLC. Imaging was performed using a Phillips Mosaic microPET.\n\nResults:  Binding assays demonstrate receptor specific binding with low IC50\u2019s (nM range) for [68Ga]-DOTATOC and [68Ga]-DOTANxPY. Western blots confirmed receptor expression. Dynamic PET imaging of [68Ga]-DOTATOC (15.6 MBq) revealed SKNBE2 tumor:background accumulated to a constant value of 7 (120 min. PI), while BON tumor activity increased for approximately 60 minutes and then decreased to a final value of 3.6 (120 min. PI). Static imaging of [68Ga]-DOTANxPY (11.6 MBq) revealed a tumor(SHSY5Y):background of 2 at 60 min. PI. Radiolabeling results:\n\nConclusions:  These results prepare us to move forward with [68Ga]-DOTATOC for early phase PET imaging trials of NETs. [68Ga]-DOTANPY is a promising radiopharmaceutical.\n\n","title":"Development of Gallium-68 Labeled Neuropeptide Analogs for Imaging NET by Positron Emission Tomography","authors":"Michael K. Schultz, Damon C. Shutt, Nicholas A. Weiland, Neja White, Blanca Schafer, Molly E. Martin, Laura L. Boles Ponto, Susan Walsh, Thomas M. O\u2019Dorisio, and Sue O\u2019Dorisio","filename":"Bschultzabstract","id":"B13"},{"summary":"\nBackground:  Neuroendocrine tumors (NET) are rare hormone-secreting cancers arising primarily in the gastrointestinal and respiratory tracts. We performed a case-control analysis with a large scale assessment of common single nucleotide polymorphisms (SNPs) in known cancer genes to evaluate their potential association with neuroendocrine tumor risk.\nMethods:  We evaluated 261 neuroendocrine tumor cases and 319 controls (N= 580, Caucasian), all obtained from Dana-Farber/Harvard Cancer Center Institutions. 1334 tagging and functional SNPs in 354 known cancer genes were evaluated after genotyping with the Illumina BeadArray platform. The associations were evaluated using multiple logistic regression, after adjusting for age, gender, and smoking status, with the dominant model and test for trend and the Benjamini-Hochberg false discovery rate (FDR) multiple testing correction.\n\nResults: The neuroendocrine tumor cases comprised 55 patients with pancreatic neuroendocrine tumor and 207 patients with carcinoid tumors, of whom 91 had primary small bowel carcinoid.  Thirty-seven SNPs in 19 genes were associated (after covariate adjustment) with overall NET risk at p<0.01, under either model. The top 3 genes were TSC2, IL1RN and CYP1B1. After multiple testing adjustment, only the TSC2 synonymous SNP rs13337626, Phe860Phe, remained significant for all cases at PFDR-dominant =0.0005 and PFDR-trend=0.004.  The TSC2 association was significant in the subgroup of small bowel carcinoids, where the PFDR-dominant =0.001 and PFDR-trend=0.01, but not in the subgroup of pancreatic neuroendocrine tumor.\nConclusion: Genetic variation in TSC2, and potentially in other genes, may be associated with neuroendocrine tumor risk.","title":"A Large-scale SNP Evaluation Reveals an Association of a TSC2 SNP with Sporadic Neuroendocrine Tumor Risk","authors":"Monica Ter-Minassian, Zhaoxi Wang, Kofi Asomaning, Michael Wu, Chen-Yu Liu, Jessica Paulus, Geoffrey Liu, Penny Bradbury, Li Su, Christine Frauenhoffer, Susanne M. Hooshmand, Jamie Silver, Immaculata De Vivo, Xihong Lin, David C. Christiani, Matthew H. Kulke","filename":"BTer-Minassianabstract","id":"B14"},{"summary":"\nBackground:  Vatalanib inhibits endothelial growth factor receptor (VEGFR) by binding to the intracellular kinase domain of all 3 VEGFRs. Neuroendocrine tumors (NETs) express VEGF receptors. Inhibiting VEGF with bevacizumab, sorafenib, and sunitinib reduced time to progression or tumor size in some NET patients (pts). To determine vatalanib\u2019s tolerability and efficacy in NET pts, a trial was performed.\n\nMethods:  Eligibility criteria included NET pts with biopsy-proven metastatic disease and rising biomarkers on somatostatin analog therapy. Eligible pts had measurable lesions, a KPS > 60%, and normal hematologic, renal, and hepatic functions. A stable octreotide LAR dose, not exceeding 30 mg monthly, was required. Initial total daily dosing of vatalanib was 1,250mg. Biochemical responses within a 90 day interval were the primary response criteria. Secondary endpoints included radiographic/scintigraphic scan changes and safety.\n\nResults:  Twenty-four pts (12 males) were enrolled between 5/20/05 to 5/28/09. The median age (range) was 60.4 (25-74). Eighteen pts were evaluable for efficacy and safety. Four pts continue on therapy. One pt withdrew consent; 2 pts died of disease prior to first cycle initiation; 1 pt was allergic to vatalanib. Six pts required a 10-28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase, G2 proteinuria, G2 headache, and G3 nausea/vomiting. Resumption of vatalanib at 1,000mg daily was well tolerated in 2 pts and 750mg in another. One pt developed carcinoid crisis with fever, flushing, and rising 5HIAA. Grade 1 nausea occurred in 15 pts with antiemetics required for 4 pts. A partial (> 50% decrease) biochemical response occurred in 4 pts. The observed radiographic and scintigraphic responses in 16 pts have shown progressive disease in 6 and stable/minimal response in 10 pts. Accrual continues.\n\nConclusions:  Vatalanib is well tolerated in most pts and results in a 24% biochemical partial response rate in NET pts with rising biochemical markers on somatostatin analog therapy.","title":"An Open-label, Phase II Study Evaluating the Safety and Efficacy of PTK787/ZK222584 in Patients with Metastatic Neuroendocrine Tumors that Have Evidence of Progressive Disease or an Increase in Disease Related Syndrome Symptoms","authors":"Lowell B. Anthony, Maria M. Chester, Bernard J. Brown, Stacy L. Michael, Jacky R. Seward, M. Sue O\u2019Dorisio, Thomas M. O\u2019Dorisio","filename":"Canthonyabstract","id":"C1"},{"summary":"\nBackground:  Health-related quality of life (HRQL) can be disrupted in patients with chronic illnesses such as cancer. The study evaluated the HRQL burden of patients with neuroendocrine tumor (NET), testing the hypothesis that NET patients have reduced HRQL compared to the general United States population.\n\nMethods:  NET patients were invited via email to participate in an online, anonymous survey. This survey consisted of a brief set of demographic and disease-related items, the RAND-36 and the PROMIS-29, the latter two of which are standardized measures of HRQL with general population normative values available for comparison. Norm-based scores were calculated for all subscales, such that a score of 50 represents the mean of the general population (standard deviation=10). For the anxiety and fatigue subscale, higher scores (> 50) represent worse outcome. Results are presented as means and 95% confidence intervals.\n\nResults: Data collection is currently ongoing but at the time of this writing 565 eligible participants have completed the survey. Demographics: 66% were female, 91% white, 3% Hispanic, 40% 60 years or older. 25% require some amount of bed rest during the day, 35% have diarrhea and 51% experienced at least one flushing episode in the past two weeks. NET patients demonstrated worse HRQL scores compared to the general population mean of 50 on all subscales of the RAND-36 and PROMIS-29. For example, mean scores (95% confidence interval) in NET patients were: physical function = 45.2 (44.4\u201346.0); anxiety = 54.2 (53.4\u201355.0); fatigue = 54.7 (53.8\u201355.6); and general health = 40.0 (39.0\u201341.0).\n\nConclusion:  In this preliminary evaluation of the survey results, NET patients reported worse HRQL outcomes compared to the general population on all subscales of the RAND-36 and PROMIS-29. Symptom management and/or psychosocial interventions may be warranted to ease the HRQL burden experienced by patients with NETs.","title":"Health-related Quality of Life of Patients with Neuroendocrine Tumor Compared to the United States General Population","authors":"Jennifer L. Beaumont, Zhimei Liu, Seung Choi, James C. Yao, David Cella","filename":"Cbeaumontabstract","id":"C2"},{"summary":"\nBackground:  Gluteal intramuscular injection remains an important method for delivery of a variety of medications including octreotide LAR. In one study, only 32% of gluteal injections were delivered into the intramuscular space (Chan et al, Eur J Radiol. 2006). We examined nursing factors that are associated with successful gluteal intramuscular injections.\n\nMethods:  Patients receiving intramuscular injection of octreotide LAR at the Gastrointestinal Center, University of Texas M. D. Anderson Cancer Center were identified. Pelvic CTs were reviewed for evaluation of injection success, measurement of injection depth, and skin to muscle depth.\nResults:  22 Nurses were interviewed. 251 intended intramuscular injections between 12/21/2005 and 6/25/2008 were evaluable by CT. 105 (42%) Were associated with subcutaneous nodules indicating subcutaneous placement; 146 (58%) were deemed successful intramuscular injection. Factors associated with successful intramuscular injection included self-reported indicators of experience, landmark based localization of injection site, depth of needle insertion, and use of non-syringe hand.  \nConclusion:  A significant number of octreotide LAR injections are not successfully delivered into the intramuscular space. Nursing experience and injection technique were highly associated with successful injection. Nursing education may improve successful intramuscular injection rate.\nSelf-reported parameter\nGroup\nIM success rate\nP\nIndicators of experience\n\n\tExperience with IM injection\nModerate\nVery\n44%\n63%\n0.008\n\tFrequency of IM injection\nFew per year\nMonthly\nDaily/weekly\n29%\n63%\n60%\n0.007\n\tComfort with LAR injection\n  \t  (Scale 1 \u2013 10)\n1-9\n10\n40%\n74%\n<0.001\nTechnique\n\n\tInjection site selection\nLandmark*\nLandmark* + other\nUpper outer quadrant\nOther\n71%\n38%\n30%\n50%\n<0.001\n\tDepth of needle placement\nFull needle length\nTo resistance\n57%\n20%\n0.031\n\tNeedle insertion speed\nQuick\nSlow/steady\n63%\n31%\n<0.001\n\tUse of non-syringe hand\nCompress tissue\nStabilize tissue\nPinch tissue\n92%\n44%\n39%\n<0.001\n   *Bony landmarks, greater trochanter to posterior superior iliac spine.\n","title":"Gluteal Intramuscular Injections: Techniques Associated with Successful Octreotide LAR Injection","authors":"April E. Boyd, Colleen C. Leary, James P. Brook, Valentine G. Boving, Cecile G. Dagohoy, Linda L. DeFord, Jeana L. Garris, Jeannette E. Mares, Alexandria T. Phan, James C. Yao","filename":"Cboydabstract","id":"C3"},{"summary":"\nBackground:  Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT).  TPH1, the isoform located in enterochromaffin cells, is responsible for the majority of systemic 5-HT production. Patients with carcinoid syndrome (CS) commonly have gastrointestinal symptoms, due to increased 5-HT produced by metastatic GI tumor cells. LX1032 is an oral TPH inhibitor which represents a new mechanism for potentially managing GI symptoms associated with CS by reducing 5HT production. \n\nMethods:  Single (n=47 subjects) and multiple (n=40 subjects) ascending dose studies with LX1032 have been completed in normal volunteers. Twenty four hour urinary 5-HIAA and blood 5-HT were measured as biomarkers of pharmacodynamic activity.\n\nResults:  LX1032 produced a significant dose-dependent reduction in urinary 5-HIAA  and blood 5-HT levels, with maximal reductions observed at doses \u2265500 mg, once daily, in the 14 day multiple ascending dose (MAD) study. Single doses up to 500 mg were well tolerated with no evidence of dose-limiting toxicity or tolerability; GI related adverse events (nausea, emesis, and diarrhea) started to emerge at the 1000 mg dose level and became dose-limiting at the 1500 mg single dose level. Multiple doses were well tolerated at all dose levels up to 1500 mg (500 mg TID). Adverse events (AEs) were mild to moderate and no serious AEs occurred; a dose-dependent, mild increase in hepatic transaminase levels was observed in the MAD study.\n\nConclusion:  Inhibiting TPH, and thereby reducing peripheral 5-HT production, represents a potential new approach for managing GI symptoms in CS patients. LX1032 is a novel, orally bioavailable TPH inhibitor that significantly reduces 5-HT production and is well tolerated. The favorable safety profile and observed decrease in urinary 5-HIAA and blood 5-HT levels indicate that LX1032 could be used to lower 5-HT as a potential new approach for managing hyperserotonemia-related complications of CS.","title":"LX1032: A Novel Agent to Reduce Serotonin In Carcinoid Syndrome","authors":"Philip Brown, Kenny Frazier, Shanna Jackson, Anne Turnage, Qingyun Liu","filename":"Cbrownabstract","id":"C4"},{"summary":"\nBackground:  Neuroendocrine tumors (NET) frequently metastasize to the liver.  Aggressive management of metastatic disease has been advocated due to the indolent course of NET.  We sought to evaluate factors affecting survival in surgically treated hepatic metastases from NET.  \n\nMethods:  Clinicopathologic data was retrospectively gathered from the records of 34 patients at our center who underwent liver surgery for NET.  Chi-square and Analysis of Variances was performed to test differences between groups.  Survival was assessed using Kaplan-Meier analysis.  \n\nResults:  Median survival of the entire sample was 70.7 months.  Resection alone was performed in 68%, and 32% had resection coupled with RFA.  Liver disease was synchronous with the primary in 68%, and bilobar in 85% of patients. There was no difference in survival based on primary site (p=0.53), tumor histology (p=0.66), or synchronicity (p=0.48).  R0/R1 resection was achieved in 65%.  There was no significant difference in survival comparing R0/R1 (87 months; 95% CI 10-164 months) and R2 resections (71 months; 95% CI 32-108 months; p=0.65).  Recurrence occurred in 41% of patients undergoing R0 or R1 resection in a mean of 23.8 months, with no difference in time to recurrence between R0 and R1 resection (p=0.73).  Patients 51-69 years old had the best survival (115 months; 95% CI 26-204 months) followed by those <51 (31 months; 95% CI 15-137 months) and those >69 (39 months; 95% CI 15-64 months; p=0.04).  \n\nConclusions:  Surgical resection of NET hepatic metastases may result in long term survival.  Long term survival was only influenced by age at resection.  In those achieving R0 and R1 status, positive microscopic margins did not adversely affect survival, suggesting that surgical debulking may have a positive effect on survival.  Our cohort and survival data underscores the need for a multicenter investigation of NET surgical management.","title":"Surgical Management of Neuroendocrine Tumors Metastatic to the Liver","authors":"Scott Celinski MD, Jennifer Steel PhD, Kevin Tri Nguyen MD PhD, J. Wallis Marsh MD, David A. Geller MD, Richard Raizman MD, Allan Tsung MD, T. Clark Gamblin MD, MS","filename":"Ccelinskiabstract","id":"C5"},{"summary":"\nBackground:  I-131-iobenguane, a substrate for the norepinephrine transporter, has been shown to be effective in the treatment of neuroendocrine cancers such as Pheo. Non-radioactive iobenguane has been shown to inhibit uptake of radioiodinated iobenguane by tumors and has potential to cause cardiovascular AEs.  Ultratrace iobenguane I 131 (Ultratrace) is devoid of cold iobenguane thereby enhancing tumor accumulation of radiolabeled iobenguane and limiting iobenguane dose dependent AEs.\n\nMethods:  Adult patients with metastatic/recurrent Pheo with a least 1 Ultratrace-avid CT-measurable lesion were enrolled. A 3+3 dose escalation design was used, initiated at 6.0 mCi/kg and escalated in 1.0 mCi/kg increments. Safety and efficacy data were obtained, including tumor markers and assessment of CT and bone scans by two blinded reviewers per RECIST. \n\nResults:  Twenty-one patients were treated: 3 at 6 mCi/kg (0/3 DLTs), 6 at 7 mCi/kg (1/6 DLTs), \n6 at 8 mCi/kg (1/6 DLTs), and 6 at 9 mCi/kg (2/6 DLTs).  The DLTs were neutropenia (2), febrile neutropenia (1), and thrombocytopenia (1).  Two patients died within the 12 month efficacy follow-up (disease progression, thalamic infarction).  The best overall response was 3 (14%) PRs, 14 (67%) SDs, 2 (10%) PDs, and 2 (10%) NEs.  All 3 PRs were documented at the 3 month visit, and have continued; 2 at 12 months, and 1 at 18 months.  Mean serum chromogranin A and vanillylmandelic acid levels decreased through 9 months.  Furthermore, 5 of 15 (33%) patients on anti-hypertensives at the time of treatment reduced or discontinued following treatment.\n\nConclusions:  The MTD in this dose escalation study was 8 mCi/kg.  A single dose of Ultratrace iobenguane I 131 demonstrated clinical benefit and stabilized or reduced tumor dimensions and tumor marker levels.  Objective tumor response was durable.\n\n","title":"One year Follow-up for the Phase I MTD study of Ultratrace Iobenguane I 131 in Patients with Malignant Pheochromocytoma/Paraganglioma (Pheo)","authors":"R. Edward Coleman, Stanley J. Goldsmith, Richard B. Noto, Kimberly R. Pearson, Katherine A. Kacena, John A. Barrett, Norman D. LaFrance, John W. Babich\n Corresponding author","filename":"Ccolemanabstract","id":"C6"},{"summary":"\nBackground:  Metastatic carcinoid to the liver is often incurable but long-term survival is still possible. Transarterial chemoembolization (TACE) has traditionally been the locoregional therapy of choice for the management of patients with incurable carcinoid liver metastases. In this study, we reviewed the outcomes of patients who, in retrospect, may have been potential candidates for cytoreductive hepatectomy compared to those in whom surgery would never be offered. We hypothesize that patients with disease amenable to surgical debulking would have better tumor response, symptom control, and survival following TACE.\n\nMethods:  We identified 98 patients from our carcinoid database that underwent TACE as primary treatment for incurable liver metastases between October 2000 and July 2008. Two independent liver surgeons reviewed the patients\u2019 pre-TACE imaging studies to classify them as potentially resectable (defined as ability to remove at least 90% of tumor burden) or unresectable. Demographics, clinicopathologic characteristics, response to TACE, complications, and survival were compared.\n\nResults:  The two groups were similar in terms of age, gender, histopathologic characteristics, and complications (p>0.05). Patients considered resectable (N=28) were more likely to present with carcinoid syndrome and had a median survival of 62 months with five-year survival of 53%. Patients considered unresectable (N=70) had a median survival of 21 months with five-year survival of 19% (p<0.001 vs. resectable). No difference was seen between groups in radiographic, symptomatic, or serologic responses or the durability of response following TACE.  \n\nConclusions: Patients with metastatic carcinoid amenable to cytoreductive hepatectomy experienced longer overall survival following TACE compared to those with clearly inoperable disease. However, these seemingly biologically favorable patients did not have better or more durable response to TACE compared to those with more advanced disease.  From this study, we conclude that a clinical trial comparing TACE to cytoreductive hepatectomy in patients with resectable yet incurable carcinoid metastases is warranted.","title":"Transarterial Chemoembolization in Patients with Metastatic Carcinoid Amenable to Cytoreductive Hepatectomy Results in Improved Survival but Similar Regional Disease Control Compared to Those Deemed Inoperable","authors":"Feria-Arias, Enrique; Arrese, David; Hatzaras, Ioannis; Schmidt, Carl; Shah, Manisha; \nBloomston, Mark","filename":"Cferia-ariasabstract","id":"C7"},{"summary":"\nBackground:  Gluteal intramuscular injection of octreotide LAR is effective for control of carcinoid syndrome and delay of tumor growth in midgut carcinoid tumors. However, many intended gluteal intramuscular injections are delivered subcutaneously which may lead to altered pharmacokinetics and suboptimal therapeutic outcomes. We examine gender related issues in gluteal intramuscular injections.\n\nMethods:  Patients receiving intramuscular injection of octreotide LAR at the Gastrointestinal Center, University of Texas M. D. Anderson Cancer Center were identified. Pelvic CTs were reviewed for evaluation of injection success, measurement of injection depth, and skin to muscle depth.\n\nResults:  251 intended intramuscular injections between 12/21/2005 and 6/25/2008 were evaluable by CT. Among these, 119 (47%) were given to males; 132 (53%) were given to females. 105 (42%) were associated with subcutaneous nodules indicating subcutaneous placement; 146 (58%) were deemed successful intramuscular injection. Successful intramuscular injection rate was lower in females (42% vs 77%; P<0.001). Females had lower BMI (mean, 26.6 vs 28.8; P=0.008), but greater skin to muscle depth at optimal injection site (mean, 34 vs 24 mm; P<0.001). BMI correlated linearly with skin to muscle depth (P=0.001). Among those with failed intramuscular injections, depth of needle placement was deeper among females (mean, 30 vs 25 mm; P=0.002). Self reported nursing experience level affected success rate of gluteal intramuscular to a greater degree among females compared to males (see table).\nSelf-reported parameter\nIM success rate\nFemale\nIM success rate\nMale\nP*\nExperience with IM injection \n\tModerate\n\tVery\n33%\n53%\n75%\n73%\n0.001\n0.015\nComfort with LAR injection (scale 1\u201310) \n\t1-9\n\t10\n23%\n68%\n66%\n81%\n<0.001\n0.135\n*Gender difference within experience level\n\nConclusions:  Gluteal intramuscular injections are more difficult in females due to greater skin to muscle distance despite lower BMI. Increased nursing education and introduction of longer needles are needed.\n\n","title":"Gender Related Issues in Gluteal Intramuscular Injections","authors":"Jeana L. Garris, Linda L. DeFord, Cecile G. Dagohoy, Colleen C. Leary, Valentine G. Boving, James P. Brook, Jeannette E. Mares, April E. Boyd, Alexandria T. Phan, James C. Yao","filename":"Cgarrisabstract","id":"C8"},{"summary":"\nBackground:  PNETs are uncommon and often indolent tumors. Little is known about risk factors for PNETs and their association with other cancers. We evaluated smoking, alcohol use, family history of PNET and other cancers, and personal history of diabetes as potential risk factors.\n\nMethods:  Patients with PNETs seen for the first time at the Mayo Clinic Rochester between 2000 and 2005 were evaluated. Primary care patients seen for a general medical evaluation served as controls and were frequency matched (4:1 ratio) to patients with PNETs. Patients and controls completed the same questionnaires at the time of their evaluation. A chi-square test was used for comparing categorical variables; continuous variables were compared using a two-sample t test.\n\nResults:  After excluding insulinoma, high-grade PNETs and cases with MEN 1, 178 patients were evaluated. 111 patients were matched to 420 controls. Mean age was 59.2 years, and 50.4% were males; the majority (96%) of patients were White. 90.4% of tumors were clinically nonfunctional. Personal smoking history was not associated with PNETs; however, environmental tobacco exposure appeared to be more common among cases than controls (98% vs. 57%, p<0.001). Alcohol use was less common among cases (36% vs. 86%, p<0.001). Cases were more likely than controls to report a family member with sarcoma (p=0.001), PNET (p=0.033), and cancer of unknown primary (p=0.05). There was no association with other cancers in family members. 22% of cases reported a history of diabetes compared with 7% of controls (p<0.001).\n\nConclusion:  Patients with PNETs were more likely than controls to report a history of diabetes, to have environmental tobacco exposure and to have a family history of sarcoma, PNET and cancer of unknown primary.","title":"Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors (PNETs): A Single-Center Case Control Study","authors":"Thorvardur R. Halfdanarson, William R. Bamlet, Timothy J. Hobday, Robert R. McWilliams, Gloria M. Petersen.","filename":"Chalfdanarsonabstract","id":"C9"},{"summary":"\nBackground:  Everolimus with or without octreotide LAR has demonstrated promising antitumor activity in advanced low- to intermediate- grade neuroendocrine carcinoma. In a multi-national phase II study (RADIANT-1), early Chromogranin A (CgA) response correlated with improved progression free survival (PFS) (Yao et al, WCGI 2009). In this analysis, we confirm early CgA response as markers of outcome in an independent single institution phase II study.\n\nMethods:  Treatment consisted of everolimus 5 mg/day (30 patients) or 10 mg/day (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled. CgA was assessed at baseline, week-4 and every 3rd cycle. Early CgA response was defined as a 30% decrease at week-4.\n\nResults:  Intent-to-treat response rate was 20%. Per protocol, among 30 carcinoid patients, there were 5 (17%) confirmed PRs, 24 (80%) SDs, and 1 (3%) PD. Among 30 islet cell patients, there were 8 (27%) PRs, 18 (60%) SDs, and 4 (13%) PDs. Median PFS of patients with carcinoid and islet cell tumors were 63 and 50 weeks. Median OS has not been reached. Early CgA responders had a higher response rate (32% vs. 10%; P=.046). Early CgA responders also had longer PFS (72 vs 39 weeks; P=0.04) and OS (45 vs 31 months; P=0.12). Within subgroups, early CgA response correlated with PFS and OS among patient with islet cell (median PFS, 73 vs. 21 weeks, P<.001; median OS, 24 months vs. not reached, P<0.001), but not among patients with carcinoid. Interestingly, trends toward improved response rate, PFS, OS were observed among patients with normal CgA at protocol entry who achieve 30% decrease at week-4.\n\nConclusion:  Daily everolimus with concomitant octreotide LAR, demonstrates antitumor activity. Patients with an early CgA response have clinical outcome. Early CgA response is a promising biomarker of everolimus activity.","title":"Early CgA Response as Predictor of Outcome Following Everolimus Therapy Among Patients with Low- to Intermediate- Grade Neuroendocrine Carcinoma: ","authors":"Carmen B. Jacobs, Alexandria T. Phan, Robert A. Wolff, Funda Meric-Bernstam, James C. Yao","filename":"Cjacobsabstract","id":"C10"},{"summary":"\nBackground:  Octreotide and its long acting form Octreotide LAR are widely used to control the symptoms of patients with functional neuroendocrine tumors. Unfortunately, most patients escape control over time and require higher LAR doses or more frequent rescue therapy to remain asymptomatic. Previous work has shown that body weight and monthly LAR dose will significantly affect circulating plasma octreotide levels in patient undergoing therapy. \n\nMethods:  To determine the parameters that change circulating plasma octreotide levels we prospectively studied 82 (43 F/39M) patients undergoing long term LAR therapy.\n\nResults:  Multivariate analysis demonstrated that the plasma octreotide level decreases by approximately 3.4 percent for each unit that the BMI increases (p-value = 0.030), adjusting for gender and monthly LAR dose. Similarly, plasma octreotide levels for females were about 47.6 percent higher than males (p-value = 0.045), adjusting for BMI and monthly LAR dose. \n\nConclusions:  Initial and subsequent octreotide LAR doses should take into consideration gender and BMI. Males are estimated to require 14.1 mg (SD=7.25) higher monthly LAR dose than females with the same BMI. Also the monthly LAR dose should be increased by 1.3 mg (SD=0.62) for each unit of BMI increase to achieve the same plasma octreotide level. We have shown that octreotide plasma levels are affected not only by LAR dose but also BMI and gender. We have further estimated the adjustments necessary to obtain adequate octreotide levels depending on individual patient characteristics. We hope this will make initial and subsequent Octreotide LAR dosing easier for physicians in the clinical setting.\n\n","title":"A Prospective Trial on the Effect of Body Mass Index and Gender on Plasma Octreotide Levels in Patients Undergoing Long Term Therapy With Octreotide LAR","authors":"Saju Joseph, MD, Gang Li, PhD, Erika Lindholm, MD, Ying Zhou, MS, Vay Liang W. Go, MD, Aaron I. Vinik, MD, PhD, Thomas M. O\u2019Dorisio, MD, Gregg Mamikunian, MS  and Eugene A. \nWoltering, MD, FACS","filename":"Cjoesphabstract","id":"C11"},{"summary":"\nPurpose:  To elucidate the correlation of Ki-67, a growth fraction marker of cell proliferation, with tumor biology and survival in patients with appendiceal carcinoid tumors. \n\nMethod:  A retrospective chart review was conducted on 45 patients with appendiceal carcinoid tumors who underwent operative intervention from 1991 \u2013 2008. MIB-1, a monoclonal antibody of Ki-67 measuring its expression, was used to determine cell proliferation and correlated with clinical and histological parameters. MIB-1 index was based on the WHO (world health organization) classification. \n\nResult:  Of the 45 patients, 28 had tumors <2cm; 8 >2cm; and 9 with unspecified tumor size. No significant difference was demonstrated in MIB-1 index between patients with tumors <2cm vs. >2cm: MIB-1<2% (71% vs. 63%; p=0.146), MIB-1 2-15% (14% vs. 13%; p=0.086) and MIB-1>15% (14% vs. 25%; p=0.356), respectively.\nEleven patients had metastatic disease on presentation: 7 had MIB-1 index <2%, 2 had index 2-15% and 2 with index >15%. No significant correlation between MIB index and metastasis was demonstrated (p=0.774). \nMedian follow-up was 32 months (range 6-122 months) with a 53.3% follow-up rate. Of the 24 patients with follow up, there were 5 mortalities and 2 recurrences. No significant difference in survival was demonstrated by MIB-1 index.\n\nConclusion:  This study demonstrated no correlation between Ki-67 and tumor size or presentation with metastasis. While no significant difference was demonstrated in survival rate with increasing MIB-1 index, sample size and duration of follow-up limits definitive conclusions and further investigation is required. As prognostic factor, Ki-67 may not be valuable in determining tumor aggressiveness or predicting survival. \n\n\n","title":"The Clinical Utility of Ki-67 in Assessing Tumor Biology and Aggressiveness in Patients with Appendiceal Carcinoids","authors":"Eric Liu, MD, Dana A. Telem, MD, John Hwang, BA, Richard R. P. Warner, MD, Steven H. Dikman, MD, and Celia M. Divino, MD, FACS\nDepartment of Surgery, Department of Internal Medicine, Section of Gastroenterology, and Department of Pathology, Mount Sinai School of Medicine, New York, NY","filename":"Cliuabstract","id":"C12"},{"summary":"\nMethods:  We reviewed the medical records of carcinoid patients who underwent cytoreductive surgery from January 2001 to June 2008 by our group.  \n\nResults:  Forty five patients underwent surgical decompression of MVI and their outcomes were compared to 35 surgical patients who underwent cytoreduction but did not demonstrate MVI (control).  The majority of patients (83-100%) in the control and MVI group experienced significant symptom relief following operation.  A greater percentage of control patients vs. MVI patients had previous tumor explorations (60% versus 35.6%; p = 0.0296). No significant differences in the two groups were found with respect to post operative weight change, narcotic usage, surgical complications, or length of hospital stay.   The survival curve of the MVI group did not differ significantly from the control group (median survival times = 392 and 484 days, respectively; p = 0.9437).   Surgeons are often reluctant to explore patients with MVI.  \n\nConclusions:  Resection of metastatic carcinoid in patients with MVI effectively alleviates symptoms with no appreciable increase in morbidity or mortality rates.  Tumor-derived MVI should be resected when encountered in patients with carcinoid, and the presence of MVI alone should not preclude carcinoid patients from undergoing cytoreductive surgery.  ","title":"Extensive Retroperitoneal Carcinoid Involving the Mesenteric Vasculature Does Not Preclude Effective Cytoreduction","authors":"John M. Lyons, III, Erica Lindholm, Yi-Zarn Wang, Jessica L. Thomson, Lowell B. Anthony, Eugene A. Woltering, Daniel J. Frey, Saju Joseph, Thiagaran Ramacharan and  J. Philip Boudreaux","filename":"Clyonsabstract","id":"C13"},{"summary":"\nBackground:   Gluteal intramuscular injection remains an important method for delivery of a variety of medications including octreotide LAR. In one study, only 32% of intended gluteal injections were delivered into the intramuscular space (Chan et al, Eur J Radiol. 2006). \n\nMethods:  Patients receiving intramuscular injection of octreotide LAR at the Gastrointestinal Center, University of Texas M. D. Anderson Cancer center were identified. Pelvic CTs were reviewed for injection success and measurement of injection depth, skin to muscle depth at injection site and at optimal injection site.\n\nResults:  251 intended intramuscular injections between 12/21/2005 and 6/25/2008 were evaluated. 105 (42%) were associated with subcutaneous nodules (mean size 19 mm) indicating subcutaneous placement; 146 (58%) were deemed successful intramuscular injection. CT assessed reasons for missed injections include insufficient needle penetration (36%), injection site being too cranial (36%), lateral (11%), caudal (9%), and insufficient needle length (10%). Among missed injections, mean distances are: skin to injection deposit, 29 (12\u201357) mm; injection deposit to muscle, 15 (1-94) mm; skin to tissue sciatic nerve plane, 72 (43\u2013103) mm. Among all injections, the mean distance from skin to muscle at optimal injection site and from skin to sciatic nerve plane is 29 (9-63) mm, and 58 (38-108) mm respectively. Percentage of all patients with skin to muscle depth at optimal injection site \u226433 mm, and \u226438 mm are 66%, and 86%. Successful, intramuscular injection rate is higher among patient with skin to muscle depth at optimal injection site \u226438 mm (64% vs 21%; P<0.001).\n\nConclusion:  Common reasons for unsuccessful intramuscular injection are poor injection site selection, and not advancing needle to full length. In 14 to 34% of patients, needles greater than 38 mm (length of needle available in US) would be needed for successful intramuscular injection.\n\n","title":"Gluteal Intramuscular Injections: CT Evaluation of Factors Associated with Success and Failure","authors":"Jeannette E. Mares, Cecile G. Dagohoy, Colleen C. Leary, Linda L. DeFord, Valentine G. Boving, James P. Brook, Jeana L. Garris, April E. Boyd, Alexandria T. Phan, James C. Yao","filename":"Cmaresabstract","id":"C14"},{"summary":"\nObjective:  To review our experience with TACE in patients with unresectable hepatic metastatic NET and evaluate if age, number of TACE cycles, site of primary tumor and gender were associated with improved survival.  \n\nBackground:  NETs are rare, slow-growing tumors that often metastasize to the liver.  Most patients present with unresectable disease due to multifocal, bilobar liver metastases.  Systemic chemotherapy is ineffective in this population.  \n\nMethods:  102 patients with unresectable metastatic NET were evaluated at our center and underwent TACE therapy (1990-2009).  We evaluated their pre-operative and treatment characteristics and overall survival.  \n\nResults:  Median age was 61 years (range, 19 - 86) with 52% female.  Primary tumor location included:  pancreas (41%), small bowel (26%), lung (5%), and unknown (28%).  Symptoms were present in 71% of patients and included diarrhea (42%), abdominal cramping (29%), weight loss (29%), flushing (25%), palpitations (3%), rash (2%), and peripheral edema (2%).  Median number of TACE treatments were 5 with patients receiving adriamycin (59%) and/or streptozocin (36%).  TACE was performed every 2 months based on radiographic response.  Of the 102 patients, 62% of patients had died by the time of analysis.  Kaplan-Meier survival analysis revealed the median survival after TACE treatment was 32.6 mos (95%, CI= 18.9 \u2013 46.3 mos).  Patients who were younger (<50 yrs) were found to have significantly longer survival (median survival 86.3 mos) compared to the patients who were older (>50 yrs; median survival 31 mos; p=0.05).  After adjusting for gender, primary site, and number of treatments using Cox regression analysis, age significantly contributed to overall survival (p=0.01).  \n\nConclusion:  Liver-directed TACE therapy provides a viable treatment option for patients with unresectable liver metastatic NET with the best survival results seen in young patients.","title":"Is Patient Age Associated with Improved Survival after Transarterial Chemoembolization (TACE) for Unresectable Neuroendocrine Tumor (NET) Metastasis?","authors":"Ruhina Mehra, Kevin Tri Nguyen MD, PhD, Jennifer Steel PhD, Nikhil Amesur MD, Richard Raizman MD, Scott Celinski MD, Allan Tsung MD, T. Clark Gamblin MD, MS","filename":"Cmehraabstract","id":"C15"},{"summary":"\nBackground:  For patients with neuroendocrine tumor (NET) liver metastases, resection of the primary tumor may prevent local complications (obstruction, ischemia, bleeding) and improve survival.  Despite extensive evaluation, the primary tumor location may remain unknown.  \n\nMethods:  We performed a retrospective cohort analysis of a pathology database at a tertiary academic medical center from January 1, 1993 to August 15, 2008 and identified 123 patients with NET liver metastases.  We sought to determine the utility of pre-operative evaluation for detecting the primary tumor in patients with well-differentiated NET liver metastases and whether laparoscopic or open exploration is effective for identifying an occult primary tumor.\n\nResults:  Computed tomography (34.6%) and OctreoScan\u00ae  (26.2%) were not sensitive in locating primary NETs in the gastrointestinal tract.  Colonoscopy was sensitive in detecting colonic NETs (86.7%).  Seventeen patients (13.8%) had occult primary tumors, and 15 underwent surgical exploration.  The primary tumor was located in 13 cases (86.7%) in the small intestine and resected in 11.  Primary tumors in the small intestine found during surgical exploration were significantly smaller than those identified pre-operatively (1.38 vs 1.91 cm, P = 0.03) and were often multifocal (54.2%).  \n\nConclusions:  For patients with NET liver metastases and unknown primary, surgical exploration effectively identifies and resects occult primary tumors that are often located in the small intestine.  Primary tumors are usually small and multifocal, so careful palpation of the small intestine is essential. Before patients are considered for surgery, a multidisciplinary team assessment and evaluation consisting of computed tomography, OctreoScan, and upper/lower endoscopy should be done.","title":"Identification of Unknown Primary Tumors in Patients with Neuroendocrine Liver Metastases","authors":"Sam C. Wang, Justin R. Parekh, Marlene B. Zuraek, Alan P. Venook, Emily K. Bergsland, Robert S. Warren, Eric K. Nakakura","filename":"Cnakakuraabstract","id":"C16"},{"summary":"\nBackground:  Clinical outcome of patients with well-differentiated pancreatic endocrine tumors (PETs) and carcinomas (PECAs) is often difficult to predict based on conventional pathologic characteristics. We identified a set of candidate progression genes with differential expression in the primary PECAs with liver metastases relative to non-metastatic primary PETs by using gene expression profiling and validated the selected candidates by real-time-PCR. One of the leading progression genes was RUNX1T1. The aim of this analysis was to validate the differential expression of RUNX1T1 at the protein level on independent test sets of PETs and PECAs, and determine if loss of RUNX1T1 expression was predictive of liver metastases in well-differentiated primary PETs.\n\nMethods:  We determined immunohistochemical expression of RUNX1T1 protein in archival PECAs with liver metastases (N=13) and non-metastatic PETs (N=24), using a custom tissue microarray. Allred score (0-8) was used as an independent semi-quantitative measure of RUNX1T1 expression by two pathologists.\n\nResults:  RUNX1T1 protein was expressed by all 37 primary tumors, however, median RUNX1T1 Allred score was 2 (range 2-7) in metastatic PECAs compared to a median of 6 (range 3-8) in non-metastatic PETs (p < 0.0001).  Allred scores of \u22644 were observed in 11 of 13 metastatic PECAs, but in only 1 of 24 non-metastatic PETs (p < 0.0001).  If an Allred score of \u22644 was considered predictive, the sensitivity of this test for predicting hepatic metastases was 85%, with a specificity of 96%.  Low RUNX1T1 expression was highly associated with the presence of hepatic metastases (p < 0.0001), while conventional histologic criteria (Ki67 proliferation index, mitotic rate, presence of necrosis) were only weakly associated with metastases (p = 0.08-0.15). \n\nConclusions:  RUNX1T1 is differentially expressed in metastatic pancreatic endocrine carcinomas relative to non-metastatic pancreatic endocrine tumors and is a promising marker for prediction of liver metastases in well-differentiated, primary pancreatic endocrine neoplasms. ","title":"RUNX1T1: A Novel Predictor of Liver Metastasis in Primary Pancreatic ","authors":"Aejaz Nasir, James Helm, Leslie M. Turner, Evita B Henderson-Jackson, Jonathan R. Strosberg, Nelly A. Nasir, Ardeshir Hakam, Domenico Coppola, Larry K. Kvols","filename":"Cnasirabstract4","id":"C17"},{"summary":"\nBackground:  Primary gastro-entero-pancreatic poorly differentiated neuroendocrine carcinomas (GEP-PDNECAs) are highly aggressive neoplasms with a very poor prognosis. This study was conducted to evaluate the immuno-morphological spectrum of GEP-PDNECA, and survival in patients treated with systemic platinum and etoposide. \n\nMethods:  Clinico-pathologic and survival data were analyzed on 68 adult patients with GEP-PDNECA who had undergone biopsy / resection at MCC or outside institution. Data sources: Pathology archives, consultation files, tumor registry and social security index. All available slides were reviewed independently by two pathologists and tumors were histologically sub-typed.\n\nResults:  Patients: 41 M/27 F. Age: 25-76 yrs (mean 42 yrs). Sites: Colo-rectum 39, pancreas 19, small intestine 4, stomach 3, colon/small-intestine/pancreas 3. Sixty-three of 68 (93%) patients presented with lymph node/distant metastases. 37/68 (54%) tumors were classified as small cell carcinoma (SCCA), 16/68 (24%) large cell carcinoma (LCCA), 5 (7%) mixed small and large cell (MSLCCA) and 10 (15%) poorly differentiated carcinoma with neuroendocrine features (PDCA-NEF). Tumors were positive for chromogranin in 38/65 (55%), synaptophysin in 62/67 (92%), and CD56 in 17/21 (81%) cases. Fifty-eight of 68 (85%) patients were treated with platinum and etoposide. Overall survival at 1, 3 and 5 years was 85%, 40% and 24% respectively. Patient survival was independent of age (r= 0.1022), sex (r= -0.909) and histologic subtype (r=0.1028) (p= 0.128) but was related to distant metastases (r=0.306; p=0.0383).\n\nConclusions:  Diagnosis of GEP-PDNECA can be based on histo-morphologic features and expression of neuroendocrine markers. Because of variable immunoreactivities of basic markers of neuroendocrine differentiation, a multi-marker neuroendocrine diagnostic panel will be prudent to avoid under-diagnosis of GEP-PDNECA, especially in the metastatic setting. Although survival of GEP-PDNECA patients following platinum and etoposide therapy in our series was relatively favorable, it will be critical to identify novel therapeutic targets/biomarkers to improve patient survival in these clinically aggressive neuroendocrine cancers.\n\n","title":"Primary Gastro-entero-pancreatic Poorly Differentiated Neuroendocrine Carcinoma: Clinico-pathologic and Survival Analysis in 68 Cases","authors":"Aejaz Nasir, Mulazim H. Bukhari, Elizabeth Byron, Jonathan R. Strosberg, Evita B. Henderson-Jackson, Domenico Coppola, Larry K. Kvols","filename":"Cnasirabstract5","id":"C18"},{"summary":"\nBackground:  Neuroendocrine tumors (NET) arising from the diffuse endocrine system are thought to be quite rare in children and young adults. However, a surprising number of young people have been referred to our neuroendocrine tumor clinic and the NCI has targeted NET as a high priority for development of new diagnostic and therapeutic options. This analysis of the SEER database was undertaken to determine the incidence, prevalence, and survival of NET in young people. Their incidence, prevalence, and survival were compared with neuroblastoma, a related pediatric malignancy arising in the neural crest.\n\nMethods:  The SEER data were obtained from 9 standard SEER registries for the diagnosis years of 1975 to 2004 using SEER*Stat version 6.4.4. ICD-9 codes related to neuroendocrine tumors and to neuroblastoma were characterized as to patient age, gender, racial and ethnic background, stage, grade, histology, incidence, survival, and prevalence.\n\nResults:  Neuroendocrine tumors occur more often in females among children and young adults with the most common sites being bronchial, ovarian, and breast. The overall incidence of neuroendocrine tumors was lower than for neuroblastoma in the age range 0-30 years. However, the 30 year limited prevalence of neuroendocrine tumors in the 9 SEER registries was 698 compared to 881 for neuroblastoma. This extrapolated to over 7000 children and young adults with neuroendocrine tumors across the United States. Survival rate of young people with neuroendocrine tumors declined from 84% in 1975-1986 to 80% in the 1987-2004 era.\n\nConclusions:  These results indicate that neuroendocrine tumors constitute an unrecognized cancer threat to children and young adults. Survival of children and young adults with neuroendocrine tumors has decreased over the past 30 years in the United States. We recommend the establishment of centers of care for children and young adults diagnosed with neuroendocrine tumors with the expectation that earlier diagnosis coupled with targeted therapies will decrease the incidence of metastatic disease and improve survival.\n\n","title":"Neuroendocrine Tumors in Children and Young Adults: Incidence, Survival, and Prevalence in the United States","authors":"P. Navalkele, M. O'Dorisio, T. M. O'Dorisio, C. F. Lynch","filename":"Cnavalkeleabstract","id":"C19"},{"summary":"\nBackground:  Microsphere radioembolization is a method of delivering radiation therapy directly to tumors thereby minimizing toxicity to adjacent structures. Despite the relatively high precision of this modality numerous adverse effects have been recognized. One particularly untoward complication is the development of severe gastroduodenal ulceration. Since the utilization of this modality in the treatment of primary and metastatic malignancies of the liver continues to rise, we aim to promote awareness of this complication and to advance the understanding of the pathogenesis, incidence, diagnosis, and treatment of this entity.\n\nMethods:  Our institutional experience of gastroduodenal ulceration in patients treated with radioembolization was analyzed and the existing literature on the subject was reviewed.   \n\nResults:  Five cases from our institution and 16 cases reported in the literature were reviewed. The current evidence suggests that radioembolization-associated gastroduodenal ulceration results from the inadvertent delivery of microspheres to the microvasculature of the gastrointestinal tract leading to direct radiation toxicity. The reported incidence of this entity ranges between 3.1% and 4.6%. Most patients with this complication present with abdominal pain often associated with nausea, vomiting, and anorexia. Symptoms can arise from hours to months after the radioembolization treatment and the diagnosis is made by endoscopic biopsy and histopathologic evaluation of the ulcer specimen. Radiation-induced ulcers have proven to be extremely difficult to treat. Current therapy based on acid suppression has had limited success and the evidence for the addition of antioxidants and anti-inflammatory agents is still sparse. For cases refractory to medical therapy surgical resection may be necessary.\n\nConclusions:  The increasing utilization of radioembolization will inevitably lead to adverse events including gastroduodenal ulceration. This entity must be considered in any patient treated with radioactive microspheres presenting with symptoms of dyspepsia. Accurate diagnosis and aggressive treatment are necessary to improved patient\u2019s outcomes.","title":"Gastroduodenal Ulceration Associated with Radioembolization for the Treatment of Liver Malignancies; a Newly Observed Complication","authors":"Steven Naymagon, Richard R.P. Warner, Kalpesh Patel, Josef Machac, Joshua L. Weintraub, Michelle K. Kim","filename":"Cnaymagonabstract","id":"C20"},{"summary":"\nPurpose:  A Phase I trial of 90Y-DOTA-tyr3-Octreotide was conducted in children and young adults with somatostatin receptor positive tumors as indicated by SPECT imaging with 111In-DTPA-Octreotide.  \n\nMethods:  A 3X3 design was utilized to determine highest tolerable dose of 90Y-DOTA-tyr3-Octreotide while limiting renal radiation dose to \u00ad< 21Gy. Activity levels of administered 90Y-DOTA-tyr3-Octreotide were 1.11, 1.48 and 1.85 GBq/m2/cycle in 3 cycles at 6 week intervals, co-administered with Aminosyn II for renal protection.   Eligibility criteria included age 2-25 years, progressive disease, positive 111In-DTPA-Octreotide scan, glomerular filtration rate \u00ad\u00ad>\u00ad\u00ad 80 ml/min/m2, bone marrow cellularity > 40% or stored autologous hematopoietic stem cells, Lansky Play Scale > 60%, and informed consent.\n\nResults:  Seventeen subjects, ages 2 to 24 years, received at least one dose of 90Y-DOTA-tyr3-Octreotide; diagnoses included neuroblastoma, embryonal and astrocytic brain tumors, paraganglioma, MEN IIB, and neuroendocrine tumors.  There were no dose limiting toxicities and no individual dose reductions due to renal or hematologic toxicity.  There were no complete responses; 3/15 subjects experienced partial response, 5/15 had minor responses, 5/15 experienced stable disease, 2/15 patients had progressive disease. Two subjects withdrew.  \n\nConclusions: Molecularly targeted peptide radiotherapy with 90Y-DOTA-tyr3-Octreotide demonstrated a 20% PR plus 33% MR rate in a Phase I trial in children and young adults with somatostatin receptor positive tumors.  No dose limiting toxicities were observed. The recommended Phase II dosing is three cycles of 1.85GBq/m2/dose 90Y-DOTA-tyr3-Octreotide co-administered with amino acids.  In the future, higher doses may be attainable through the use of dosimetry guided therapy.","title":"Phase I Trial of 90Y-DOTA-tyr3-Octreotide in Children and Young Adults","authors":"M. Sue O\u2019Dorisio, Yusuf Menda, Stacy Michael, Simon Kao, Geetika Khanna, Mary Connelly, John Babich, Thomas O\u2019Dorisio, David Bushnell, M.D., Mark Madsen","filename":"Codorisiosueabstract","id":"C21"},{"summary":"\nBackground:  Previous analyses have demonstrated that the grade of tumor correlates well with OctreoScan positivity, with lower grade tumors more likely to be positive. We hypothesized that tumor location, grade, Chromogranin A and SST2 immunohistochemical staining will correlate with Octreotide positivity.\n\nMethods:  We retrospectively analyzed 37 tumor specimens for tumor grade according to the Wick\u2019s grading system of: 1-Well differentiated, 2-moderately differentiated, and 3-poorly differentiated, immunohistochemical staining (IHC) for SST2 receptor, and correlation with OctreoScan imaging.  SST2 and Chromogranin A IHC stains were performed and graded 1 +, 2+ or 3+.\n\nResults:  There were a total of 40 patients, but only 37 tumor specimens were available for complete analysis by their Wick\u2019s grade 1, 2, 3: 13/37, 11/37 and 13/37 respectively. Wick\u2019s grade 1:  39% (5/13) were negative and 61% (8/13) positive by OctreoScan imaging.  Primary tumor status revealed 77% (10/13) samples were of small bowel and colorectal origin with 54% (7/13) being positive by OctreoScan. The remaining tumor primaries were two pulmonary neuroendocrine and one gastric carcinoid, with all being negative by OctreoScan imaging. Specimens with a Wick\u2019s grade 2:  45 % (5/11) were negative and 55% (6/11) positive by OctreoScan imaging. Tumor primaries comprised 36% (4/11) of small bowel and colorectal origin and 18% (2/11) pancreatic neuroendocrine with 50% and 100% respectively being positive by OctreoScan.  Those with a Wick\u2019s grade 3: 18% (2/11) were negative and 82% (9/11) positive by OctreoScan imaging with 8/11 being of pancreatic neuroendocrine origin. Of the pancreatic neuroendocrine tumors 7/8 were positive by OctreoScan.  Of the tumor specimens with 2-3+ staining for STT2, 36% (9/25) had negative OctreoScan and 64% (16/25) were positive. Of those with STT2 IHC 1+ stain, 22% (2/9) and 78% (7/9) were negative and positive respectively by OctreoScan. Of those with a negative SST2 IHC stain 40 % (2/5) and 60% (3/5) were respectively negative and positive by OctreoScan imaging. All tumor specimens had a positive Chromogranin A IHC stain of 1, +, 2+ or 3+.  There were 33 specimens 2-3+ by IHC of which 30% (10/33) and 67% (22/33) were respectively negative and positive by OctreoScan with 1 unavailable for analysis. The 3 samples with a Chromogranin A IHC stain of 1+ were all positive by OctreoScan.  \n\nConclusion: In our retrospective analysis a total of 62% (23/37) of the tumor specimens demonstrated OctreoScan positivity, with 90% of pancreatic neuroendocrine tumors being positive. Chromogranin A and SST2 immunohistochemical staining of 2-3+ appeared to correlate with OctreoScan results, but were neither sensitive nor specific. Although published reports have demonstrated a correlation with OctreoScan positivity with lower grade neuroendocrine tumors, our results demonstrate that pancreatic neuroendocrine tumors were most often of a higher grade and consistently OctreoScan positive.\n\n","title":"Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors (PNETs): ","authors":"Ike Onwere, Thomas O\u2019Dorisio, Sue M. O\u2019Dorisio, Barry DeYoung, Menda Yusuf","filename":"Conwereabstract","id":"C22"},{"summary":"\nBackground:  SCLC represents the most aggressive tumor of the neuroendocrine carcinomas.   We designed this phase II study of temozolomide, a nonclassic oral alkylating agent, in patients with SCLC based on the following rationale: alkylating agents have established efficacy in SCLC; temozolomide penetrates into the CNS with the potential to treat brain metastases commonly seen in SCLC; SCLC has aberrantly methylated MGMT; anecdotal responses to temozolomide in patients with SCLC have been observed.\n\nMethods:  Temozolomide is administered to patients with relapsed sensitive (relapse after 60 days) or refractory (no response to initial therapy, or progression within 60 days) SCLC. Patients who have disease progression after 1 or 2 prior chemotherapy regimens are eligible. Additional eligibility criteria include Karnofsky performance status \u2265 60% and normal organ and marrow function. The primary endpoint is objective response rate. Temozolomide is administered daily for 21 consecutive days of a 28-day cycle. The starting dose for the first cycle is 75mg/m2/day. For those patients without grade 3 or higher toxicities at that dose, in subsequent cycles a single dose escalation to 100mg/m2/day is given. Treatment is to be continued until disease progression, unacceptable toxicity or withdrawal. The target accrual is 64 patients. MGMT promotor methylation status is assessed in available tissue and in peripheral blood.\n\nResults:  Twenty-five patients (12 men, 13 women) have been accrued to date, of which 16 patients have sensitive and 9 have refractory SCLC. Temozolomide was second- and third-line treatment for 13 and 12 patients, respectively. Thirteen patients have brain metastases. Of the 23 patients assessable for response, 3 patients have achieved a partial response and 6 patients have stable disease. All other patients have had progression of disease within one cycle of treatment.  The overall response rate is 13%. Regressions have been observed in five patients with progressive brain metastases, including two patients with recurrent disease after prophylactic cranial irradiation and whole brain radiation therapy. Toxicities include: \u00a0grade 3 lymphopenia (20%); grade 3 thrombocytopenia (4%); grade 1/2 fatigue (32%); grade 1/2 emesis (20%); and grade 3 rash/pruritus (8% each).\n\nConclusions:  \u00a01) In this ongoing trial, three partial responses have been seen in patients with sensitive SCLC. 2) Temozolomide causes regression in SCLC brain metastases. \u00a03) Temozolomide is well tolerated when given on this dose and schedule. 4) At this time, seven samples analyzed for MGMT hypermethylation have not demonstrated methylation. Supported by Schering-Plough.\n\n","title":"Phase II Study of Temozolomide for Relapsed Sensitive or Refractory ","authors":"M. Catherine Pietanza, William D. Travis, Timothy A. Chan, Michelle S. Ginsberg, Andrei Holodny Mark G. Kris, Lee M. Krug","filename":"Cpietanzaabstract","id":"C23"},{"summary":"\nBackground:  Sunitinib, an oral, multitargeted tyrosine kinase inhibitor, is approved for treatment of advanced renal cell carcinoma and imatinib-resistant/intolerant gastrointestinal stromal tumors. Non-clinical data and a phase II study showed activity of sunitinib against pancreatic islet cell tumors. This international placebo controlled phase III study assessed the safety and efficacy of sunitinib for the treatment of progressive pancreatic islet cell tumors. \n\nMethods:  Patients had local, locally advanced, or metastatic, well-differentiated pancreatic islet cell tumors, with disease progression in the previous 12 months and not amenable to curative therapy. They received either placebo or sunitinib 37.5 mg/day continuous daily dosing, with best supportive care. Progression-free survival (PFS) was the primary endpoint; safety and tolerability were monitored. The study was powered to detect a 50% improvement in PFS (target enrollment: 340 patients). \n\nResults:  By February 2009 154 patients had been enrolled; 75 received sunitinib and 79 placebo. Median age was 56 years (range 25\u201378). The preliminary results demonstrated that median PFS was 11.1 months (95% CI: 7.4\u2013NR) for sunitinib versus 5.5 months (95% CI: 3.5\u20137.4) for placebo (73 events evaluated, including 63 incidences of disease progression). Patients receiving sunitinib were significantly less likely to have experienced disease progression/death (hazard ratio for PFS, 0.397 (95% CI: 0.243\u20130.649) in favor of sunitinib (p<0.001). The study was stopped early as recommended by an independent Data Monitoring Committee; patients receiving placebo were permitted to receive sunitinib treatment. Five and 15 deaths occurred in sunitinib and placebo arms, respectively; overall survival analyses are ongoing. The most frequent grade 3\u20134 adverse events in sunitinib-treated patients were neutropenia (12%), hypertension (9%), abdominal pain, diarrhea, hypoglycemia and hand\u2013foot syndrome (7% each). \n\nConclusions:  Sunitinib demonstrated clinical efficacy and acceptable safety in the treatment of progressive, well-differentiated pancreatic islet cell tumors; further data analyses are ongoing.\n\n","title":"Sunitinib versus Placebo for the Treatment of Progressive, Well-Differentiated Pancreatic Islet Cell Tumors: A Phase III, Randomized, Double-Blind Trial","authors":"Eric Raymond, Jean-Luc Raoul, Patricia Niccoli, Yung-Jue Bang, Ivan Borbath, Catherine Lombard-Bohas, Peter Metrakos, Dongrui-Ray Lu, Carolyn Blanckmeister, Aaron Vinik","filename":"Craymondabstract","id":"C24"},{"summary":"\nBackground:  SVV-001 is a naturally-occurring replication competent picornavirus, rarely hosted by humans, with potent and selective tropism for NE tumors, including small cell cancers and carcinoid. SVV-001 causes rapid cytolysis in vitro and durable responses following single IV dosing in multiple xenograft models.  \n\nMethods:  Single dose intravenous SVV-001 was investigated across 5 log-increment dose cohorts from 107 vp/kg to 1011 vp/kg, in patients with carcinoid type cancers.  Study endpoints included toxicity assessment, response assessment, evaluation of viral titers and clearance in blood, sputum, nasal swabs, urine, and stool, and neutralizing antibody development.\n\nResults:  12 carcinoid patients in cohorts 1 to 4 had a 70% SD rate.  Cohort 5, a 12 patient expansion cohort at 1011 vp/kg showed promising antitumor activity including improvement in carcinoid syndrome symptoms, decline in 5HIAA and other serum markers, minor responses by CT scan, and an objective PET response (>50% decrease in SUV).  Median PFS was 6.2 months (95% CI 3.6 to 21.1), median OS was 21.1 months (95% CI 8.9 to not reached).\nThere were no DLTs in any cohort. Side effects were in general mild and self limiting.  Evidence of intratumoral viral replication was demonstrated with detection of delayed viral titers estimated at >1,000\uf0b4 the administered dose.  Viral clearance was documented in all patients and correlated temporally with development of antiviral antibodies.\n\nConclusions:  A single IV dose of 1011 vp/kg of SVV-001 is safe with predictable viral kinetics and shows promising activity against NE tumors. Phase II testing of this novel anticancer agent is warranted.","title":"Phase I study of Seneca Valley Virus (SVV-001), A Replication Competent Oncolytic Virus, in Patients with Carcinoid Cancers","authors":"CM Rudin, N Senzer, J Stephenson, K Burroughs N Senzer, T Williams","filename":"Crudinabstract","id":"C25"},{"summary":"\nIntroduction: Many referring physicians are unfamiliar with the pathologic, biochemical or radiologic evaluation of neuroendocrine tumors (NETS). \n \nHypothesis: Intensive pre- visit counseling using a predetermined list of tests will ensure that patients have the majority of data needed to do proper patient evaluation and treatment planning at their initial visit.\n  \nMethods: Over an 18 month period (January 2008 until July 2009) patients were prospectively studied to determine if intensive pre-visit counseling would result in the requested reports being available at the time of the patient\u2019s initial visit. Scan and biomarker results had to be from studies done within six months of the visit. Results were expressed as the percent of patients who had these requested reports available at the time of their initial evaluation. \nResults: Charts from 288 patients who had been intensively counseled about what data was needed for their initial visit were reviewed. Two hundred and twenty seven (79%) of these patient had previous NETS surgery. Eighty nine percent (89%) of patients who had previous NETS surgery had their operative notes and 93% had their pathology reports available at their initial visit. The percent of patients with other data available at initial visit are listed below.\nPathology Data\nKi-67\nChromogranin \n(CGA) staining\nQuantitative\nCGA\nSynaptophysin\nstaining\nQuantitative\nsynaptophysin\n34%\n68%\n14%\n60%\n11%\nPlasma and Urinary Biomarker Data\nChromogranin A\nPancreastatin\n24 Hour Urine\n5-HIAA\nNeurokinin A\nSerotonin\n82%\n64%\n71%\n61%\n56%\nScan Data\nOctreoScan\u00ae\nCT /MRI scans\n76%\n94%\n\nConclusions: Intensive pre-visit counseling of patients scheduled for appointments with NETS specialists results in those patients having the majority of the requested test results available at the time of their first appointment. Histologic stains that define a tumor\u2019s proliferation rate (Ki-67) and differentiation (quantitative CGA and synaptophysin stains) seem to be the most difficult to obtain.\n\n","title":"Initial Evaluation of Patients with NETS: A Prospective Evaluation of the Influence of Intensive Pre-Visit Counseling","authors":"Pamela Ryan BSN RN, Jarret Brashear BS, Yi-Zarn Wang MD, Lowell B. Anthony MD, J. Philip Boudreaux MD, Saju Joseph MD, Richard Campeau MD and Eugene A. Woltering MD","filename":"Cryanabstract","id":"C26"},{"summary":"\nBackground: Temozolomide is an active agent in metastatic pancreatic endocrine carcinomas. In-vitro data indicates that the combination of capecitabine and temozolomide is synergistic for induction of apoptosis in neuroendocrine tumor cell lines.  We evaluated the efficacy of capecitabine and temozolomide in 33 patients with metastatic pancreatic endocrine carcinomas to assess response rate, progression free survival (PFS) and overall survival (OS).\n\nMethods: Patients with metastatic, differentiated pancreatic endocrine carcinomas who had not received prior systemic chemotherapy were treated with capecitabine 750mg/m2 twice daily days 1-14 and temozolomide 200mg/m2 once daily days 10-14 every 28 days.   Response rates were assessed by RECIST criteria.\n\nResults: Among 33 patients treated, 22 (67%) patients achieved an objective radiographic response.  Median progression-free survival was 18 months.  The rate of survival at two years was 92%.  Only four patients (12%) experienced grade 3 or 4 adverse events.\n\nConclusion: The combination of capecitabine and temozolomide is associated with an exceptionally high and durable response rate in metastatic endocrine carcinomas of the pancreas.  Clinical endpoints, including response rate, survival and toxicity, are superior to those observed with streptozocin-based regimens.","title":"First-Line Treatment of Metastatic Pancreatic Endocrine Carcinomas with Capecitabine and Temozolomide","authors":"Jonathan Strosberg MD, Junsung Choi MD, Aejaz Nasir MD, Larry Kvols MD","filename":"Cstrosbergabstract1","id":"C27"},{"summary":"\nBackground: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) frequently metastasize to the liver. Hepatic artery embolization is an important therapeutic modality in patients with liver-predominant metastases.  NETs are highly vascular and are known to express both VEGF and VEGFR.  We hypothesize that administration of sunitinib malate, a VEGFR inhibitor, following hepatic artery embolizaiton will delay tumor revascularization and extend progression-free survival.\n\nMethods: Patients with differentiated GEP-NETs metastasized to the liver underwent a series of selective arterial embolizations followed by sunitinib (one week after each embolization, and continued until disease progression or up to a maximum of 8 cycles).  Radiographic response rates were assessed by RECIST criteria.\n\nResults: Fourteen patients have been enrolled to date. Primary tumor sites include the small-intestine (11), rectum (2), and pancreas (1).  The initial starting dose of sunitinib was 50mg, however all five patients enrolled at this dose required dose reductions.  Consequently, the starting dose was reduced to 37.5mg resulting in improved tolerance.  Nine patients (64%) had a partial radiographic response (PR), four patients (28%) had stable disease (SD) and one patient (7%) had progressive disease (PD) as best response.  At a median follow-up of 8 months, progression-free survival (PFS) is 79%.  Seven grade 3 toxicity events were reported in six patients.  Serum VEGF levels increased by an average of 107pg/ml (88%) after embolizations. \n\nConclusions: Hepatic artery embolization is a highly active treatment option for patients with metastatic GEP-NETs.   Embolization stimulates release of VEGF into the circulation. Sunitinib can be safely administered following hepatic artery embolization at a dose of 37.5mg.  Longer follow-up is needed to assess whether this strategy results in prolonged time to tumor progression.","title":"Phase II Study of Sunitinib Following Hepatic Artery Embolization for Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)","authors":"H. Lee Moffitt Cancer Center, Tampa, FL","filename":"Cstrosbergabstract2","id":"C28"},{"summary":"\nBackground:   Somatostatin analogs are the mainstay of medical therapy for the symptomatic relief of clinical syndromes associated with GEP-NETs (eg, carcinoid syndrome), which typically arise following liver metastasis. Although most patients with metastatic GEP-NETs will not achieve surgical cure and are resistant to traditional chemotherapy regimens, an analysis of the SEER database identified a lengthening in survival time among patients with metastatic NETs diagnosed 1988\u20132004 vs 1973\u20131987, coinciding with the introduction of octreotide in the US.\n\nMethods:  A review of the literature describing the outcomes of patients with GEP-NETs administered monotherapy with octreotide for symptomatic or antineoplastic treatment. \n\nResults:   Early uncontrolled studies found that 37\u201350% of patients with progressive metastatic GEP-NETs achieved stable disease with octreotide sc 200\u20131000 \uf06dg/tid, with tumor stabilization maintained >42 months in some patients (Saltz 1993; Arnold 1993 and 1996; diBartolomeo 1996). Uncontrolled studies of octreotide LAR 20\u201330 mg/month found tumor stabilization/response in 53% of patients with progressive metastatic gastrinomas for 5.5\u201354 months (Shojamanesh 2002), and 47% of patients with progressive metastatic GEP-NETs following failure with slow-release lanreotide (Ricci 2000). Recently, the first randomized, placebo-controlled, double-blind trial (PROMID) evaluated the antiproliferative effect of octreotide LAR in treatment-na\u00efve patients with well-differentiated, metastatic midgut NETs. In this patient group, octreotide LAR 30mg significantly lengthened time to tumor progression versus placebo, regardless of functional status or hepatic tumor burden (14.3 vs 6.0 months; P<0.000072). At 6 months, partial response or stable disease was achieved in 29/42 patients with octreotide LAR and 17/43 patients with placebo (P=0.0079) (Arnold 2009). \n\nConclusions:   Octreotide has been associated with tumor stabilization in heterogeneous populations of patients with GEP-NETs. The PROMID trial confirmed the antiproliferative effect of octreotide LAR in patients with well-differentiated, metastatic midgut NETs. Patients with functioning or non-functioning GEP-NETs should be considered for octreotide LAR 30mg.","title":"The Antiproliferative Effect of Octreotide in Gastroenteropancreatic (GEP) Neuroendocrine Tumors (NETs)","authors":"Jonathan Strosberg MD and Larry Kvols MD","filename":"Cstrosbergabstract3","id":"C29"},{"summary":"\nBackground: A multidisciplinary approach to gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) is advised for the optimal care of GEP NET patients. A systematic multidisciplinary approach to GEP NETs, including regular bimonthly multidisciplinary team meetings, has been established at our Institution from May 2007 and we have analyzed the initial impact of a systematic multidisciplinary approach on the management of GEP NET patients. \n\nMethods: We have collected and compared the biochemistry, radiology (including endoscopy), and pathology data as well as the therapeutic strategies in the patients with GEP NET diagnosed, treated, or followed-up in our Institution since January 1993 to April 2007 (91 patients in 172 months) with those from patients that came to us after the multidisciplinary approach starting (42 patients from May 2007 to October 2008, 18 months). \n\nResults: Before the establishment of the multidisciplinary approach, a lack of consistency in the laboratory (chromogranin A: 0%), imaging/endoscopy (54.9%), and pathology (Ki-67 and/or mitotic index: 23.1%) findings before the treatment (or the consideration for treatment) as well as in the follow-up (chromogranin A: 0%; imaging/endoscopy: 33.0%) of the patients was identified. These features have been at least partially reversed by the systematic multidisciplinary approach itself (chromogranin A: 16.7% pre-care \u2013 p = 0.00022, 52.4% post-care \u2013 p < 0.00001; imaging/endoscopy: 83.3% pre-care \u2013 p = 0.00174, 73.8% post-care \u2013 p = 0.00001; Ki-67 and/or mitotic index: 52.4% \u2013 p = 0.00128). Also the therapeutic management of the pre-multidisciplinary approach patients was not consistent and has been altered by the multidisciplinary approach (use of somatostatin analogs before and after the establishment of the multidisciplinary approach: 11.0% and 47.4%, respectively \u2013 p = 0.00001). \n\nConclusion: This study suggests that a systematic multidisciplinary approach can significantly impact on GEP NET patient care and should be established in all centers dealing with these tumors.","title":"Initial Impact of a Systematic Multidisciplinary Approach on the Management of Patients with Gastroenteropancreatic Neuroendocrine Tumor","authors":"Department of Endocrinology & Diabetes Mellitus, St Vincent\u2019s University Hospital, Dublin, Ireland\n Department of Pathology & Laboratory Medicine, St Vincent\u2019s University Hospital, Dublin, Ireland\n Department of Radiology, St Vincent\u2019s University Hospital, Dublin, Ireland\n Liver Transplant Unit, St Vincent\u2019s University Hospital, Dublin, Ireland\n Department of Medical Oncology, St Vincent\u2019s University Hospital, Dublin, Ireland\n Department of Gastroenterology, St James\u2019s Hospital, Dublin, Ireland","filename":"Ctamagnoabstract","id":"C30"},{"summary":"\nIntroduction:   Several studies have shown that positron emission tomography with F-18 fluoro-dihydroxyphenylalanine has been useful in the initial diagnosis, staging, and restaging of neuroendocrine disease. We, therefore, sought to determine if F-18 DOPA PET/CT could identify the primary site of disease in a series of 12 patients where other imaging modalities failed to.\n\nMethods:  Twelve consecutive patients with a history of biopsy-proven primary carcinoid tumor that had previously been resected with recurrence of symptoms (n=2), metastatic carcinoid disease (n=3), or a symptom complex with biochemical markers highly suspicious for a neuroendocrine tumor (either carcinoid n=5, or pheochromocytoma n=2) were evaluated.  All patients underwent F-18 DOPA PET/CT scans after undergoing CT and/or MRI, Indium-111 pentetreotide scintigraphy, and I-123 metaiodobenzylguanidine (I-123 MIBG) imaging (specifically in the two patients with suspected pheochromocytoma).  All patients received clinical follow up after all imaging modalities were completed.\n\nResults:  No primary site of disease was found in any of the 12 patients by any of the imaging modalities. Although F-18 DOPA PET/CT did show a suspicious lesion in the pancreatic head in one patient, CT did not show an anatomical correlate.  Endoscopic ultrasound evaluation was performed in this patient, revealing no abnormality to biopsy.  It also appeared that contrast enhanced CT detected more metastatic bone, liver, and retroperitoneal lymphadenopathy lesions with better distinction than F-18 DOPA PET/CT, likely due to the added value of intravenous contrast in better delineating lesions on CT.\n\nConclusion:  Although F-18 DOPA PET/CT has been shown by others to be useful in characterizing the disease extent in patients with known neuroendocrine tumors, this observational investigation raises the possibility that, in a small subset of patients with an unidentified primary site of disease, it may be not useful in identifying the primary site of disease.  \n\n","title":"The Utility of F-18 DOPA PET/CT in Identifying Unknown Site of Primary ","authors":"Damita Thomas MD, Yusuf Menda MD, David Bushnell MD, Thomas O\u2019Dorisio MD","filename":"Cthomasabstract","id":"C31"},{"summary":"\nObjective:  Our objective was to examine quality-of-life (QOL) in patients with neuroendocrine tumors (NETs), using two disease-specific questionnaires, the validated Norfolk QOL-NET and European EORTC QLQ-C30/GI.NET-21 and to correlate QOL measures to symptoms, tumor burden, serotonin and Chromogranin A (CgA).\n\nMethods:  De-identified data from the Norfolk QOL-NET and EORTC QLQ-C30/GI.NET-21 questionnaires, simultaneous data on tumor burden, biochemical status and symptoms were extracted. Nonparametric correlations were used to explore the relationship between total QOL scores from both questionnaires, each individual domain of the Norfolk QOL-NET, tumor burden, biochemical markers and symptom scores. P values <0.05 were accepted as statistically significant.\n\nResults:  A strong positive correlation was found between the total scores of both questionnaires; both questionnaires correlate with tumor burden and the carcinoid symptom score; in each, high circulating serotonin levels correlated with depression, GI symptoms and impaired physical functioning. There were none with CgA. Norfolk QOL-NET total score correlated positively with all its domains - physical functioning (r=0.96, p<0.0001), depression(r=0.73, p<0.001), gastrointestinal (r=0.78, p<0.001), flushing(r=0.62, p<0.0003), respiratory(r=0.65, p<0.0002), positive attitude(r=0.52, p<0.004), cardiovascular (r=0.46, p<0.012).\n\nConclusions:  Both tools do well in measuring QOL in NETs and may be useful guides for therapy and responses in clinical trials. Norfolk QOL-NET captures more aspects of flushing, respiratory and cardiovascular impact.  Paradoxically, correlation between circulating serotonin values and depression may reflect a CNS deficiency of serotonin, which cannot cross the blood brain barrier and is deviated into tumor biosynthesis offering an opportunity to treat NETS with precursor 5-HTP which crosses the blood brain barrier.\n","title":"Relationship Between Quality Of Life And Health-Related Measures Including ","authors":"Etta Vinik, Maria Silva, Aaron Vinik","filename":"Cvinikabstract","id":"C32"},{"summary":"\nIntroduction: The extensive mesenteric lymphadenopathy associated with midgut carcinoids often causes lymphatic obstruction and leads to the development of alternative lymphatic drainage pathways. We hypothesized that altered lymphatic drainage makes traditional determination of resection margins inadequate.\n\nMethods: 170 patients underwent cytoreductive surgery for neuroendocrine tumors from November 2006 to August 2008. Forty nine (49) patients underwent intraoperative lymphatic mapping with lymphazurin dye as a single agent. Twenty seven (27) patients had midgut primaries. We reviewed operative findings and pathology to evaluate the safety and efficacy of lymphatic mapping for midgut carcinoids. Lymphatic mapping defined resection margins were compared to traditional surgical margins.\n\nResults: There were no adverse events associated with the 49 lymphatic mapping procedures. Twenty five (25/27, 92%) patients had ileal and two had jejunal primaries. Lymphatic mapping changed traditional resection margins in 88% of patients. We preserved the ileo-cecal valve in 6/15 (40%) of patients with terminal ileal primaries.\n\u00a0\nConclusion:  Lymphatic mapping appears to be safe, time-efficient and effective way to determine adequate resection margins for midgut carcinoids. We advocate using lymphatic mapping for patients with midgut carcinoids to identify adequate resection margins and assist in preservation of the ileo-cecal valve in patients with terminal ileal primary carcinoids.\u00a0\u00a0\u00a0","title":"Lymphatic Mapping Helps Define Resection Margins for Midgut Carcinoids","authors":"Wang, Yi-Zarn DDS, MD, Joseph, Saju MD, Lindholm, Erika BSE, Lyons, John MD, Boudreaux, J. Philip MD, Woltering, Eugene A. MD","filename":"Cwangabstract","id":"C33"},{"summary":"\nBackground:  Pasireotide is a novel multi-receptor ligand somatostatin analogue with high affinity for somatostatin receptor subtypes sst1,2,3 and sst5. Twice daily subcutaneous pasireotide has shown activity in controlling symptoms of metastatic carcinoid tumors in patients refractory or resistant to octreotide long-acting-release (LAR).  An LAR formulation of pasireotide administered monthly has been developed, and PK and safety results from a randomized, open-label, multicenter, Phase I study of pasireotide LAR in patients with metastatic carcinoid tumors are presented.\n\nMethods:  Patients with histopathologically confirmed carcinoid, elevated 5- hydroxyindole acetic acid (HIAA) and/or chromogranin A (CgA), measurable tumor, and carcinoid syndrome inadequately controlled by other somatostatin analogues were enrolled. Patients received intramuscular depot injections of pasireotide LAR 20, 40 or 60 mg every 28 days for 3 doses. PK, safety, and tolerability were assessed regularly.\n\nResults: A total of  42 patients received \u22651 dose of pasireotide LAR. Steady state was reached within three injections. Trough plasma concentrations of pasireotide on day 84 were 5.6 \u00b1 2.0, 16.6 \u00b1 10.2 and 25.0 \u00b1 20.5 ng/mL for the 20, 40 and 60 mg dose levels respectively. Plasma concentrations with pasireotide LAR 40 and 60 mg were comparable to those achieved with pasireotide 600 and 900 \u00b5g sc bid, respectively; with comparable peak concentrations and ~2-fold higher trough concentrations. 60% of patients reported \u22651 treatment-related adverse event (AE), most of which were mild. AEs with a suspected pasireotide relationship occurring in \u22653 patients were related to glucose metabolism (diabetes mellitus [n=5]; hyperglycemia [n=5]; worsening of type 2 diabetes mellitus [n=3]).\n\nConclusion:  Pasireotide LAR had dose-related PK and was generally well tolerated. Adverse events were similar to pasireotide sc. The availability of a long-acting release formulation of pasireotide will provide a convenient treatment option.","title":"Pasireotide LAR in Metastatic Carcinoid Tumors: A Randomized Phase I Study","authors":"Edward. M. Wolin, Larry K. Kvols, Shereen Ezzat, Walter I. Kocha, Brigitte Weisshaar, Ke Hu, Pharis Mohideen, Eric Van Cutsem","filename":"Cwolinabstract","id":"C34"},{"summary":"\nBackground: No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mTOR, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. \n\nMethods:  This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs progressing on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/day [n = 115]; stratum 2: everolimus 10 mg/day plus octreotide long-acting release [LAR; n= 45]). Tumor assessments (RECIST) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed.\n\nResults: By central radiology review, in stratum 1, there were 11 (9.6%) partial responses (PR), 78 (67.8%) stable disease (SD), and 16 (13.9%) progressive disease (PD); median progression-free survival (PFS) was 9.7 months. In stratum 2, there were 2 (4.4%) PR, 36 (80%) SD and 0 PD; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Co-administration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus.  \n\nConclusion:  Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by ORR and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.\n\nSponsor: This study was sponsored by Novartis Pharma AG, Basel, Switzerland.\n\n","title":"Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors after Failure of Cytotoxic Chemotherapy: A Phase II Trial","authors":"James C. Yao, Catherine Lombard-Bohas, Eric Baudin, Larry K. Kvols, Philippe Rougier, Philippe Ruszniewski, Sakina Hoosen, Jessica St. Peter, Tomas Haas, David Lebwohl, Eric Van Cutsem, Matthew Kulke, Timothy J. Hobday, Thomas M. O'Dorisio, Manisha H. Shah, Guillaume Cadiot, Gabriele Luppi, James A. Posey, Bertram Wiedenmann for the RADIANT- Study Group","filename":"Cyaoabstract","id":"C35"}];