bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 366: Enhanced tumor detection of fluoroscence laparoscopy improves laparoscopic resection of primary pancreatic cancer in mouse models
Authors: Metildi Cristina A. , Kaushal Sharmeela , Snyder Cynthia S. , Luiken George A. , Hoffman Robert M. , Bouvet Michael 
Published: August 2012

Abstract
The aim of this study was to evaluate the utility of fluorescence laparoscopy for resection of primary pancreatic cancer. Orthotopic mouse models of human pancreatic cancer were established with the brightly-fluorescent BxPC-3 RFP human pancreatic cancer cell line. Two weeks after implantation, mice were randomized to undergo either bright light laparoscopic resection (BLR) or fluorescence-guided laparoscopic resection (FLR). Fluorescence laparoscopy (FL) was performed with a Stryker L9000 LED light source 24 hours after tail vein injection of CEA antibodies conjugated to Alexa 488. Bright light laparoscopy (BL) was performed with a Stryker X8000 xenon light source. Pre- and postoperative images were taken with the Olympus OV-100 Small Animal Imaging System to assess completeness of resection. Postoperatively, whole body images were obtained to assess for recurrence and follow tumor progression. All resected tumors were collected for histologic review. Fluorescence laparoscopy with a 495-nm emission filter and an LED light source enabled real-time identification and localization of the brightly-fluorescent BxPC-3 RFP tumor additionally labeled with anti-CEA-Alexa 488. The combination of red and green fluorophores optimized the fluorescence signal of the tumor thereby enabling accurate distinction of tumor margins from normal surrounding tissue without compromising background illumination. Furthermore, adequate visualization of surrounding structures enabled surgical navigation for resection of primary pancreatic tumor. Tumor was more readily detected and resected under fluorescence guidance than under standard bright light. In addition, sub-millimeter lesions within the pancreas that were undetected by bright light laparoscopy were easily identified and resected by fluorescence laparoscopy. This study demonstrates the capabilities of laparoscopic fluorescence-guided surgery of primary pancreatic cancer. The optimal combination of fluorophores with the use of an LED light source enhanced the fluorescence tumor-to-background ratio while permitting enough light leakage for background illumination for surgical navigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 366. doi:1538-7445.AM2012-366
Abstract 3662: FGFR2 gene amplification and overexpression frequently occur in squamous cell carcinomas of the lung
Authors: Kikuchi Ryutaro , Huang Cheng-long , Sonobe Makoto , Kobayashi Masashi , Imamura Naoto , Horiuchi Marika , Kitamura Jiro , Ishikawa Masashi , Date Hiroshi 
Published: August 2012

Abstract
Introduction: To date, only a few genetic abnormalities have been reported to be involved in tumorigenesis of squamous cell carcinomas (SqCCs) of the lung. Recently, fibroblast growth factor receptor (FGFR) 1 gene amplification was identified as a potential target for treatment in approximately 20% of SqCCs. In order to identify the clinical significance of FGFR family (FGFR1, FGFR2, FGFR3, and FGFR4) in SqCC, we performed a clinical study on the FGFR family in patients with non-small cell lung cancers (NSCLCs). Methods: Consecutive 138 NSCLC patients were studied. Gene expressions of FGFR family were evaluated by quantitative real-time RT-PCR. Intratumoral protein expressions of FGFR1, FGFR2, and Ki-67 were evaluated by immunohistochemistry. Gene amplifications of FGFR1 and FGFR2 were investigated by FISH. In addition, mutations of EGFR (exon 19-22) and KRAS (exon 1) were also investigated using either PCR-SSCP or PCR-RFLP, confirmed by direct sequencing. Results: Among 138 NSCLCs, 91 tumors were adenocarcinoma, 37 tumors were SqCCs, and 10 tumors were other types. Regarding FGFR gene expressions in NSCLCs, The FGFR2 gene expression was significantly higher in NSCLCs with both wild-type EGFR and wild-type KRAS than in NSCLCs with either mutant EGFR or mutant KRAS (P = 0.0012). FGFR2 gene expression was significantly higher in SqCCs than in adenocarcinomas (P &lt; 0.0001). Furthermore, the FGFR2 gene expression was the highest among the gene expressions of FGFR family in SqCC. In contrast, no significant difference was observed in FGFR1 gene expression in relation to tumor histology. Regarding FGFR protein expressions in NSCLCs, the intratumoral FGFR2 protein expression significantly correlated with the FGFR2 gene expression (P &lt; 0.0001, r = 0.5492), and the intratumoral FGFR2 protein expression was also significantly higher in SqCCs than in adenocarcinomas (P = 0.0008). Furthermore, the FGFR2 protein expression significantly correlated with Ki-67 proliferation index (P &lt; 0.0001, r = 0.4677). In FISH analysis, FGFR1 gene amplification was detected in 34.3% (12/35) of SqCCs, and FGFR2 gene amplification was detected in 22.9% (8/35) of SqCCs. Furthermore, the Ki-67 proliferation index was significantly higher in SqCCs with FGFR2 gene amplification than in SqCCs without FGFR2 gene amplification (P = 0.0069). Conclusions: FGFR2 gene amplification and overexpression frequently occur and correlate with the tumor proliferation in SqCCs of the lung. FGFR2 could be a potential molecular target for the treatment of SqCCs of the lung as well as FGFR1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3662. doi:1538-7445.AM2012-3662
Abstract 3667: Inactivating BRAF mutations confer dasatinib sensitivity in lung cancer
Authors: Sen Banibrata , Peng Shaohua , Tang Ximing , Erickson Heidi , Galindo Hector , Mazumdar Tuhina , Stewart David J. , Wistuba Ignacio , Johnson Faye M. 
Published: August 2012

Abstract
NSCLC is a lethal disease for which personalized therapies that target specific genetic aberrations have been markedly effective in subsets of patients. An important approach for discovering effective cancer therapeutic targets is to characterize responsive tumors. We conducted a phase II trial of the tyrosine kinase inhibitor dasatinib in stage IV NSCLC. The dramatic response of one patient, who remains cancer free four years later, led us to examine the molecular characteristics of his tumor. We performed a comprehensive analysis of this NSCLC patient's tumor including mutational analysis of 40 genes, array comparative genomic hybridization, and immunohistochemistry. We discovered a novel, inactivating BRAF mutation (Y472CBRAF) in the patient's tumor; no inactivating BRAF mutations were found in the non-responding patients. Cells transfected with Y472CBRAF exhibited CRAF, MEK, and ERK activation, which were identical to signaling changes that occur with previously known inactivating BRAF mutants. Dasatinib induced senescence in NSCLC cells with endogenous inactivating BRAF mutations. Transfection of cells with inactivating BRAF mutations led to increased dasatinib sensitivity; conversely, cells transfected with an activating BRAF mutation were more resistant. Likewise, BRAF inhibition in NSCLC cells expressing wild-type BRAF enhanced dasatinib sensitivity. Dasatinib sensitivity may depend upon CRAF since dasatinib led to decreased CRAF activity and only NSCLC cells with inactivating BRAF mutations were sensitive to CRAF inhibition. We hypothesize that patient's BRAF mutation was likely responsible for his marked response to dasatinib and suggests that tumors bearing inactive BRAF mutations will be exquisitely sensitive to dasatinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3667. doi:1538-7445.AM2012-3667
Abstract 3669: Autocrine interleukin/STAT3 signaling in breast implant-associated T cell anaplastic large cell lymphoma cell lines suggests a mechanism for tumor progression and effective therapy
Authors: Church Connor H. , Lechner Melissa G. , Megiel Carolina , Bass Rikki S. , Russell Sarah M. , Epstein Alan L. 
Published: August 2012

Abstract
Recently, over 80 cases of anaplastic large-cell kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphomas (T-ALCL) have been identified worldwide in patients with textured saline and silicone breast implants. These breast implant-associated T-ALCL cases are striking for their homogeneous clinical presentation and pathology that is distinct from established classes of ALCL. In order to understand the nature of this newly emerged clinical entity, we have established three new cell lines, designated T cell Breast Lymphoma (TLBR) -1, -2, and -3, from patient primary tumor biopsy specimens. Characterization of these pre-clinical models confirmed fidelity to the original tumor biopsy specimens and highlighted unique features that may aid the development of effective treatments for these cancers. Gene expression analysis demonstrated significant up-regulation of survivin and down-regulation of pro-apoptotic genes (BID, BAK, BBC3) by all TLBR cell lines relative to healthy donor T cells. This preliminary finding prompted examination of upstream regulators of cell survival in T cells, namely the interleukin signaling associated with the JAK/STAT pathway. TLBR cell lines were found to secrete high levels of IL-6 and IL-10, and were strongly positive for the cognate receptors. The TLBR cell lines also showed elevated levels of STAT3 and pSTAT3 by immunoblotting techniques, along with a simultaneous reduction in expression of the pSTAT3 phosphatase, SHP-1. These results implicate an unregulated autocrine STAT3 pathway present in the TLBR cell lines that strongly contributes to their tumorigenesis. Assays of various inhibitors of this pathway support this hypothesis since targeting of STAT3 with the tyrosine kinase inhibitor, Sunitinib, led to dramatic in vitro cell death in all TLBR cell lines. More specific inhibition of STAT3 with S3I-201 had comparable results with Sunitinib. Furthermore, IL-6 neutralization by a monoclonal antibody or SHP-1 restoration by 5-azacytidine treatment also demonstrated moderate efficacy in inhibiting TLBR cell line growth in vitro. These discoveries strongly suggest the use of these reagents in the clinical treatment of Breast Implant Associated T-ALCL. The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived, and as such provide valuable preclinical models to study the unique biology and provide clinicians with improved knowledge for treatment and diagnosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3669. doi:1538-7445.AM2012-3669
Abstract 3671: A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression
Authors: Wiesner Thomas , Murali Rajmohan , Fried Isabella , Cerroni Lorenzo , Kutzner Heinz , Bastian Boris C. 
Published: August 2012

Abstract
We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinctive clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called “atypical Spitz tumors” (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biologic behavior cannot be reliably predicted. Based on the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations, and for BAP1 expression. To determine the utility of immunohistochemistry to assess BAP1 status, we analyzed samples from 42 patients with the above syndrome as well as 46 melanocytic nevi and found that loss of BAP1 expression was restricted to patients with the syndrome. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which of 8 (89%) had concomitant BRAF mutations. Only one of the BAP1-positive ASTs (4%) had a BRAF mutation (p&lt;0.0001). BRAF mutated, BAP1-negative tumors were primarily located in the dermis, and were composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei were commonly vesicular, and exhibited substantial pleomorphism and conspicuous nucleoli. The combination of BRAF mutation and loss of nuclear BAP1 expression thus characterizes a subset of ASTs with distinctive histologic features. The typical morphology of these tumors and BAP1 immunohistochemistry provide pathologic clues that will enable accurate identification of this subset. Future studies are necessary to determine whether this subset has a predictable clinical behavior.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3671. doi:1538-7445.AM2012-3671
Abstract 3674: Next generation cancer gene sequencing for clinically actionable mutations
Authors: Wen Yu-Ye , Douglas Ganka , Hu Xiafeng , Millham Michele , Cifuentes Francisco , Peters Garrick , Carmack Condie Edwin , Li Marilyn 
Published: August 2012

Abstract
Cancer gene mutations are important diagnostic, prognostic, and predictive biologic markers. Mutation detection in cancer tissues has been a real challenge for researchers as a cancer is often associated with multiple mutations and new mutations may occur as the disease progresses and during treatments. Essentially, all cancer tissues are a mosaic mixture of normal and abnormal cell clones. Therefore, a new technology that can target many mutations simultaneously with high sensitivity is exceedingly desirable. Targeted next generation sequencing permits deep sequencing of hundreds of mutations concurrently. We have used a novel next generation sequencing technology that merges multiplex PCR with ion semiconductor sequencing (AmpliSeq, Life Technology) to sequence a panel of clinically actionable cancer gene mutations on 12 tumor samples including 6 archived FFPE samples, 2 bone marrow samples, and 4 cell lines with known mutations, and a normal blood sample as a control. Each sample was run three times to assay for inter-run variability. The panel contains 739 mutations including clinically actionable mutations such as EGFR mutations in exons 18-21, BRAF V600E, KRAS mutations at codons 12, 13, and 61, and many more. Using this technology we successfully identified all known mutations previously detected using Pyposequencing or Sanger sequencing technologies. The most common somatic mutations were also confirmed by Competitive Allele-Specific TaqMan® PCR (castPCR, Life Technology). To determine the sensitivity of the test, we studied mutation positive FFPE samples with serial dilutions. Our results showed that the test can detect mutations at frequencies as low as 5% with 99% confidence. Analysis of mutation calls in different runs showed little inter-run variation. Other benefits of this novel technology are its fast turn around time, which can be as short as two days, and its low cost. Our experience demonstrates that this technology holds great potential clinical utility including diagnostic and therapeutic applications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3674. doi:1538-7445.AM2012-3674
Abstract 3678: Combination analysis of oncogenic mutations and signaling pathway proteins identifies effective therapeutic targets in colorectal cancers
Authors: Lee Jeeyun , Kim Phillip S. , Lee Tani , Kuller Anne , Princen Fred , Singh Sharat , Kim Hee C. 
Published: August 2012

Abstract
Despite overall improvements in colorectal cancer (CRC) therapies, an understanding of reasons for therapeutic response/non-response as well as disease recurrence remains poor. Currently, the gold standard for CRC prognosis remains the clinicopathological staging of tumors. Addition of molecular markers for predicting prognosis and therapeutic outcomes can significantly enhance the clinical managements of CRCs. A comprehensive molecular characterization of 116 stages I to IV Asian CRC patients that also included 2 paired normal samples and 19 hepatic metastases of which 10 were from paired primary tumor samples (total 136 specimens) was performed. Somatic mutational analysis scored for 12 different mutations resident within the KRAS, BRAF and PIK3CA oncogenes alongside a parallel determination of kinase activation profiles for HER1, HER2, HER3, c-MET, IGF1R, PI3K, Shc, AKT and ERK using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER™) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Various mutations of KRAS and BRAF were found in 41% (48/116) and 4% (5/116) of patients, respectively. Incidence of PIK3CA mutations were 11% (13/116) in this cohort. Overall, KRAS G12D and G13D mutations were the most frequent in this cohort. Several primary as well metastatic CRCs with KRAS mutations demonstrated a second mutation in the PIK3CA gene. While both ErbB-driven and non-ErbB-driven pathway signatures were observed in this cohort, there was no apparent correlation found between the KRAS mutational status of the tumors and the activation status of the downstream/upstream pathway signals. Molecular characterization of CRC samples for oncogenic mutations should be complemented with functional pathway profiling to pinpoint potential therapeutic target(s). The tumor's dependence on specific pathway cannot be predicted based on mutations alone hence it is critical to also evaluate pathway activation for selecting more effective clinical strategy. Our study also demonstrated modulation in signaling pathways concomitant with disease recurrence. Such clinical validations and comprehensive molecular profiles of CRC tumors can allow for the implementation of these companion biomarkers in CRC therapeutic clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3678. doi:1538-7445.AM2012-3678
Abstract 3683: Crenolanib, a novel Type I, mutant-specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases
Authors: Muralidhara Chaitanya , Ramachandran Abhijit , Jain Vinay K. 
Published: August 2012

Abstract
Introduction: Crenolanib (CP-868,596) is a benzimidazole tyrosine kinase inhibitor (TKI), known to potently inhibit the platelet derived growth factor receptors (PDGFR) alpha and beta, and the Fms-like tyrosine kinase 3 (FLT3). Crenolanib has been evaluated as a single agent (Lewis N, et al, J Clin Oncol 2009), and in combination with docetaxel ± axitinib (Michael M, et al, Br J Cancer 2010), and was found to be well tolerated, with transient elevation of liver enzymes at higher doses. We describe here the characterization of crenolanib as a unique chemotype, mutant-specific Type I TKI. Methods: The relative affinities of tyrosine kinase inhibitors for phosphorylated and non-phosphorylated ABL1 have been previously used to accurately distinguish type I from type II inhibitors (Wodicka LM, et al, Chem Biol 2010). The effect of ABL1 A-loop phosphorylation on crenolanib affinity was investigated in a competition binding assay (Karaman MW, et al, Nat Biotech 2008). The binding constants (Kds) of crenolanib for FLT3 (wild-type and five mutant isoforms) were also determined using the KINOMEscan KdELECT Assay (DiscoveRx, San Diego, CA), and compared with the Kds of 442 TKIs reported (Davis MI, et al, Nat Biotech 2011). The Kds of crenolanib for PDGFRα, PDGFRα, and c-KIT (wild-type and two mutant isoforms) are being determined. Results: The Kd of crenolanib for phosphorylated ABL1 and ABL(T315I) were 7- and 15-fold lower than the Kds for non-phosphorylated ABL1 and ABL(T315I) respectively. Based on this higher affinity for p-ABL1 relative to np-ABL1, crenolanib appears to be a Type I inhibitor. Furthermore, crenolanib has a 10-fold affinity shift between the non-autoinhibited and autoinhibited states of FLT3, which is in the range of affinity shifts reported for other Type I TKIs, in contrast to the 100- to 1000-fold affinity shift reported for Type II TKIs. Crenolanib also has the highest affinity for three constitutively activate isoforms of FLT3 (FLT3-ITD, FLT3-D835Y, FLT3-D835V) compared to 442 kinases reported (Davis MI, et al, Nat Biotech 2011). Crenolanib is a next-generation, mutant-specific TKI, currently in Phase II development in adult and pediatric gliomas, and in PDGFRAD842V-mutant GIST. The unique and specific kinase inhibition profile is hypothesized to translate to greater therapeutic effect, accompanied by fewer adverse events in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3683. doi:1538-7445.AM2012-3683