bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2224: EGFR mutation screening in non-small cell lung cancer: Results from 4 German molecular pathology laboratories
Authors: Hartmann Arndt , Stöhr Robert , Gschwendtner Andreas , Geissinger Eva , Gattenlöhner Stefan , Glück Thomas , Rümmele Petra , Dietmaier Wolfgang 
Published: June 2012

Abstract
Aims: Somatic mutations in the epidermal growth factor receptor gene (EGFR) have evolved as predictors for sensitivity to EGFR tyrosine kinase inhibitors (TKI) in patients with non-small-cell lung cancer (NSCLC). To date, molecular data underlining the role of EGFR mutations in the tumor as a strong predictor for a better treatment outcome were mostly collected from Asian patients (mutation frequency up to 59.7%). Only one European study (Rosell et al., 2009) verified the predicting power of EGFR mutations in Caucasians living in Europe so far, and reported a notably lower mutation frequency (16.6%) compared to Asian collectives. For Germany, only sparse data are available about the mutation frequency in NSCLC. Here we report the intermediate results from 4 pathology institutes performing quality approved approved EGFR testing certified by the Quality Initiative of the German Society of pathology (QuiP) in non-small cell lung cancer.
Material and Methods: Overall, 787 (males: 474, females: 312, n.a.: 1) cases were analysed. The cohort consisted of 782 NSCLC (99.4%) and 5 SCLC (0.6%) selected by attending physicians for EGFR mutation analysis considering TKI treatment. After microdissection, DNA was isolated from serial sections of formalin-fixed, paraffin-embedded tumor tissue after microdissection to obtain at least 70% tumor cells. Exons 18, 19 and 21 of the EGFR gene were analysed using Sanger sequencing.
Results: In 72/787 cases (9.2%) an EGFR mutation was detected. Deletions in exon 19 were the most frequent alterations detected (46/72 mutations; 63.9%), followed by point mutations in exon 21 (23/72 mutations; 31.9%). Mutation in exon 18 was a rare event (2/72 mutations; 2.8%). EGFR mutations were significantly associated with adenocarcinomas (p&lt;0.001) (mutation frequency: 11.4%) and female gender (p&lt;0.001). Overall, there was a trend (p=0.052) towards higher age in patients with adenocarcinoma and EGFR mutation compared to cases with EGFR wildtype. This increased age was significantly (p=0.009) associated with an EGFR mutation in female patients.
Conclusion: EGFR mutation frequency in this German cohort is lower than reported in Asian or Spanish studies. Mutations in exon 19 were detected more frequently than described in the literature so far. The association with adenocarcinoma histology and female gender could be verified. EGFR mutations seem to be more frequent in patients with higher age. Screening of patients with advanced NSCLC for EGFR mutations is feasible and should be used for improvement of therapy options.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2224. doi:10.1158/1538-7445.AM2011-2224
Abstract 2239: Buthionine sulfoximine enhanced melphalan cytotoxic activity against multiple myeloma cell lines
Authors: Tagde Ashujit , Reynolds C Patrick 
Published: June 2012

Abstract
Multiple myeloma (MM) is a neoplasm of terminally differentiated antibody secreting B cells commonly treated with myeloablative doses of the alkylating agent melphalan (L-PAM) and supported by stem cell transplantation (SCT). Relapse after SCT is common and a second SCT with L-PAM for patients achieving less than a complete response or at time of relapse is usually only modestly effective. Glutathione (GSH) is ubiquitous intracellular tripeptide that acts as antioxidant and protects cells against reactive oxygen species (ROS) and xenobiotics. Conjugation of GSH to alkylating agents is known to be one mechanism of melphalan resistance. Buthionine sulfoximine (BSO) inhibits synthesis of GSH and enhances the activity of melphalan in preclinical and clinical studies of neuroblastoma. The potent hematopoietic toxicity of BSO + L-PAM led us to conduct an ongoing phase I trial in recurrent neuroblastoma of escalating L-PAM + BSO given with SCT. To explore the potential for a similar trial in MM, we have undertaken preclinical studies of BSO + L-PAM in MM.
We determined if buthionine sulfoximine (BSO) enhanced the activity of melphalan (L-PAM) against MM cell lines. In-vitro cytotoxicity mediated by BSO (0-400 micro molar) alone and in combination with L-PAM (0-50 micro molar) was assessed in a panel of six MM cell lines in both “standard cell culture conditions” (20% O2) and “bone marrow level hypoxia” (5% O2) using the DIMSCAN digital image fluorescence assay. Single-strand DNA (ssDNA) damage by F7-26 antibody, apoptosis by TdT labeling (TUNEL) and mitochondrial depolarization by JC-1 were measured by flow cytometry.
At clinically achievable concentrations, BSO consistently caused two to four logs synergistic enhancement of L-PAM cytotoxicity (combination index &lt; 1) in all six multiple myeloma cell lines at both 5% and 20% O2. BSO + L-PAM caused a significant increase in single strand DNA damage (p&lt;0.001), mitochondrial depolarization (p&lt;0.001), and apoptosis (p&lt;0.001) compared with L-PAM alone. Thus BSO can enhance L-PAM activity and overcome L-PAM resistance in multiple myeloma cell lines and BSO/L-PAM synergy is also achieved in bone marrow level hypoxia. Obtaining additional data on this novel combination approach to therapy of multiple myeloma is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2239. doi:10.1158/1538-7445.AM2011-2239
Abstract 2257: The survival impact of XPA and XPC genetic polymorphisms on patients with esophageal cancer
Authors: Lee Jang-Ming , Yang Pei-Wen , Hsieh Ching-Yueh , Tsai Pey-Yu , Chen Chun-Hui , Chen Jin-Shing , Huang Pei-Ming , Hsu Hsao-Hsun , Kuo Sunn-Wen , Lee Yung-Chie 
Published: June 2012

Abstract
Purpose: To investigate the association of the genetic variants in xeroderma pigmentosum groups A (XPA) and C (XPC) with the overall survival duration of the patients with esophageal cancer.
Patients and Methods: A total of 531 patients with a diagnosis of esophageal cancer were enrolled in the study. The genetic variants of XPA in 5’UTR (rs1800975) as well as XPC at exon 15 Lys939Gln (rs2228001) were analyzed with the TaqMan assay from the genomic DNA of peripheral leukocytes. The association of the genotypes and the survival of the patients were analyzed with Cox's multivariate analysis.
Results: There was no significant difference of XPA and XPC genotype distribution among patients with various clinical profiles. The overall survival of the patients was significantly influenced by the tumor stage, cell type (squamous cell carcinoma vs. adenocarcinoma) and curative surgical resection (p&lt;0.05 respectively). There was an insignificant unfavorable trend for survival outcome of the patients with XPA 5’UTR (rs1800975) C/T or XPC Lys939Gln (rs2228001) G/G genotypes, compared with those who with other genotypes. Cox's multivariate analysis revealed that accumulation with any one this two unfavorable genotype would associate with a significantly increased risk of death (adjusted HR [95% CI]: 1.27[1.07-1.50]; p=0.005). Compared to those patients without any of these unfavorable genotype, simultaneously having both of these genotype would impose a significantly higher risk of death on the patients after treatment (adjusted HR [95% CI]: 1.86[1.24-2.81]; p=0.003).
Conclusion: Our study demonstrates that the hereditary genetic variants in XPA and XPC may play a role for the clinical outcome of the patients with esophageal cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2257. doi:10.1158/1538-7445.AM2011-2257
Abstract 2279: The response of breast cancer cell lines to HET0016 alone or in combination with other chemotherapeutics
Authors: Slaughter Tiffani , Gunter Barak W. , Fan Fan , Huang Chenghui , Pannuti Antonio , Baker Rodney C. , Falck John R. , Miele Lucio , Roman Richard J. , Duhe Roy J. 
Published: June 2012

Abstract
One of the vexing problems in controlling breast cancer is the emergence of acquired endocrine-resistance in estrogen receptor positive breast cancers that initially respond to endocrine therapy. Published reports suggest there is a close overlap between the signal transduction pathways affected by 20-hydroxyeicosatetraenoic acid (20-HETE) and those which may confer endocrine-resistance. Preliminary data indicate that 20-HETE-targeted drugs have direct cytotoxic and indirect anti-angiogenic effects on multiple carcinomas, and they therefore might be extended to unsolved problems in breast cancer control. Yet almost nothing is known about the specific role(s) of 20-HETE in either healthy breast tissue or in breast cancer. We observed that treatment of certain tamoxifen-resistant human breast cancer cell lines with HET0016, a compound which inhibits the biosynthesis of 20-HETE, restores sensitivity to tamoxifen in cell culture. We are elucidating the signal transduction pathways involved in this phenomenon. We also observed that certain human breast cancer cell lines with intrinsic tamoxifen resistance (such as the “triple-negative” MDA-MB-468 cell line) express cytochrome P450 isoforms essential for the synthesis of 20-HETE, and we are evaluating whether we can exploit a synergistic effect of HET0016 with anti-cancer drugs currently used to treat aggressive “triple-negative” breast cancers which have an intrinsic resistance to endocrine therapy. We hypothesize that a 20-HETE-targeted agent such as HET0016 will provide an additional anti-cancer benefit due to its anti-angiogenic activities, and we are further exploring the characteristics of breast cancers that may be susceptible to combination therapy involving HET0016 and related compounds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2279. doi:10.1158/1538-7445.AM2011-2279
Abstract 2292: Absent E2 liganded AhR inhibits tumor inhibition by ERα in Min mice
Authors: Carothers Adelaide M. , Rizvi Hira , Lubet Ronald , Bertagnolli Monica 
Published: June 2012

Abstract
Previously, we showed that E2 and ERα prevent intestinal tumor formation in the Min mouse. Others showed that Aryl hydrocarbon Receptor (AhR) associates with ubiquitin ligase to down-regulate β-catenin and Wnt signaling. AhR activity also may affect ERα. AhR has endogenous, dietary, and xenobiotic ligands. We hypothesized that the tumor inhibiting function of ERα promotes Wnt signaling in vivo and is antagonized by liganded-AhR in the absence of E2. In groups of 10, ovariectomized Min (OvxMin) mice were treated w/wo AhR ligand 5, 6-benzoflavone (BF; 2,000 ppm) by diet for 17 weeks. Treated mice developed more tumors in the small intestine (54.7±11.1) than controls (38.3±4.5 P&lt;0.0001). Protein expression was evaluated in non-tumor ileum of study mice by immunohistochemistry, immunoprecipitation (IP), and immunoblotting (IB). ERα and β-catenin nuclear expression in crypt base cells, total β-catenin and ERα protein amounts, and Wnt signaling-dependent Paneth cell markers (Sox9 and Lysozyme) were significantly reduced in BF-treated OvxMin compared to control mice. Reciprocal IP/IBs using total cell lysates from study mice and antibodies for β-catenin and ubiquitin (Ub) showed increased expression of ubiquitylated β-catenin in BF-treated OvxMin mice relative to controls. Wnt signaling-dependent cell proliferation (Ki67+ nuclei/crypt) was reduced in BF-treated OvxMin (11.4±2.5) relative to controls (16.2±3.0) and untreated intact Min (20.7±3.2) mice (P&lt;0.01). AhR was expressed throughout the crypt-villus unit of OvxMin ileum; its activity was assessed by induction of Cyp1A1. A minimal amount of Cyp1A1, but elevated levels were found in untreated mucosa of intact Min vs. OvxMin mice w/wo BF, respectively. Lower expression of the AhR negative regulator, AhR Repressor, was present in ileum of OvxMin mice regardless of treatment relative to untreated intact Min mice. In study mice mucosa, other xenobiotic responsive regulators (Pxr, Nrf2, Car1/2) were minimally expressed, not affected by BF, hence not implicated in Cyp1A1 induction. In conclusion, these results indicate that E2 loss reduces AhR feedback inhibition and Wnt signaling in Min intestine. Since liganded-AhR promoted β-catenin turnover and reduced ERα expression absent E2, our data suggest that deficient Wnt signaling in the non-tumor mucosa of Min mice provides a selective pressure for Apc functional loss in intestinal stem cells and tumor initiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2292. doi:10.1158/1538-7445.AM2011-2292
Abstract 2300: Insulin receptor kinase inhibition is better tolerated than hypoinsulinemia and more effective than metformin in treating breast cancer
Authors: Dool Carly , Mashhedi Haider , Zakikhani Mahvash , David Stephanie , Zhao Yunhua , Birman Elena , Carboni Joan M. , Gottardis Marco , Blouin Marie-Jose , Pollak Michael N. 
Published: June 2012

Abstract
Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin-responsive, but it is unclear if safe and effective therapies that target the insulin receptor can be developed. We demonstrate that both insulin receptor family tyrosine kinase inhibition and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer in mice metabolically normal at baseline. In contrast to insulin deficiency, insulin receptor inhibition does not lead to hyperglycemia and is well-tolerated. We show that pharmacokinetic factors explain the safety of receptor inhibition relative to ligand deficiency, as BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers the elevated insulin levels present in settings of insulin resistance, had minimal activity in this model. The findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors, and suggest that therapeutic targeting of the insulin receptor family for cancer treatment is practical.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2300. doi:10.1158/1538-7445.AM2011-2300
Abstract 2317: Mild hyperthermia and thermosensitive liposomes to improve chemotherapy delivery to solid tumors
Authors: Li Li , ten Hagen Timo L.M. , Schipper Debby , Seynhaeve Ann L.B. , van Rhoon Gerard , Eggermont Alexander M.M. , Lindner Lars H. , Haemmerich Dieter , Koning Gerben A. 
Published: June 2012

Abstract
Long circulating liposomes are potent nanocarriers for the delivery of chemotherapeutic drugs to tumors. These liposomes can extravasate through leaky tumor microvasculature, and accumulate in the intratumoral space. However, inefficient drug release impairs efficacy, and hinders a successful application. Local hyperthermia (HT) can augment drug bioavailability and treatment efficacy by enhancing tumor vessel leakage for intratumoral liposomal drug accumulation, and triggering drug release from thermosensitive liposomes (TSL). Our study explored the thermal dose to maximize the permeability of tumor microvasculature for liposome extravasation and sequentially trigger drug release from the TSL in a two-step approach.
We have optimized long-circulating TSL to improve content release efficiency under mild HT (Li et al. J Control Release 143(2):274-9, 2010). Doxorubicin (Dox) at a quenching concentration was encapsulated in TSL. In vitro temperature/time-dependent content release and TSL stability in serum were quantified by fluorometry. In vivo liposome extravasation was studied in dorsal skin flap window chamber models implanted with murine B16 melanoma, LLC carcinoma, BFS-1 sarcoma, and human BLM melanoma tumors in mice with constitutive vascular endothelial cell expression of an eNOS-Tag-GFP fusion protein using confocal microscopy. In vivo Dox release was observed in the same window chamber models.
Mild HT induced a significant amount of liposome extravasation through tumor microvasculature, and intratumoral accumulation in the interstitial space in all tumor models. Minimum thermal dose of 41 °C for 30 min is required to open up tumor vessels. The permeability of tumor vessels increased over time with increasing thermal dose to 41 °C for 1 hr, and vasculature remained leaky for up to 8 hr post-HT. Increased permeability was not observed in heated normal vasculature or in non-heated tumor vasculature. Optimized Dox-TSL were stable at 37 °C and demonstrated efficient in vitro and in vivo drug release at 42 °C. Rapid intratumoral distribution of released Dox and delivery into tumor cells was observed, demonstrating strongly improved drug bioavailability. The superior application of TSL and mild HT will achieve both maximal intratumoral liposomal drug accumulation and rapid triggered drug release to aid liposomal chemotherapy in clinical practice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2317. doi:10.1158/1538-7445.AM2011-2317
Abstract 234: Fibroblast growth factor receptor (FGFR)-3 as a suitable target in bladder cancer
Authors: Gust Kilian M. , McConkey David J. , Hegarty Paul K. , Bondaruk Jolanta E. , Czerniak Bogdan A. , Dinney Colin P. , Black Peter C. 
Published: June 2012

Abstract
Introduction and Objective: Mutations in the FGFR3 gene, which can confer constitutive activity, are found in up to 80% of low grade papillary bladder cancers (BC). Overexpression of FGFR3 has been detected in approximately half of high grade and invasive tumors. In this study we evaluate FGFR3 in a cohort of American patients and investigate the effect of targeting FGFR3 in pre-clinical models of bladder cancer.
Materials and Methods: DNA was extracted from 170 fresh frozen BC specimens using a commercial kit and PCR of exons 7 and 10 was performed. Mutation analysis was performed by ABI Big Dye Terminator Cycle Sequencing. FGFR3 expression was analyzed by immunohistochemistry in an overlapping cohort of 143 patients with BC. FGFR3 expression, phosphorylation and downstream signaling were measured in a panel of BC cell lines, and the efficacy of two small molecule inhibitors (TKI258 and BGJ398) was tested on signaling and 3H-thymidine incorporation. A specific inhibitory monoclonal antibody targeting FGFR3 was evaluated in an orthotopic xenograft model of BC. Tumor burden was measured with bioluminescent imaging.
Results: FGFR3 mutations were identified in 44 (26%) BC samples, including 28/50 (56%) of low grade papillary lesions. Overexpression of FGFR3 was noted in 53% of all BC specimens regardless of stage and grade, but not in normal urothelium. FGFR3 inhibition effectively abrogated constitutive phosphorylation of FGFR3 and p42/44MAPK in a subset of bladder cancer cell lines. A growth inhibitory effect was observed in the same cell lines. The growth of UC14 xenografts in the bladder of nude mice was inhibited by 40%.
Conclusion: These studies underline the potential clinical relevance of FGFR3 mutation and expression in bladder cancer. Furthermore, the preclinical investigations offer proof of principle for moving forward with clinical trials studying the administration of specific FGFR3 inhibitors in patients with bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 234. doi:10.1158/1538-7445.AM2011-234
Abstract 2346: Switching from an ROR1-positive phenotype to an ROR2-positive phenotype promotes melanoma progression
Authors: O'Connell Michael P. , Nelson Janelle L. , Fiori Jennifer L. , Subaran Sarah S. , Indig Fred E. , Weeraratna Ashani T. 
Published: June 2012

Abstract
The orphan tyrosine kinase receptors, ROR1 and ROR2, make up a superfamily of receptors that, until recently, had no known signal pathway association or ligand identification. ROR2 has since been shown to play a role in Wnt signal transduction and studies from our laboratory have demonstrated an important role for ROR2 in increasing the metastatic potential of melanoma cells. Here, we demonstrate, that, despite significant homology, ROR1 expression is inversely correlated to that of ROR2 in melanoma and decreasing ROR1 expression increases overall metastatic potential. ROR1 is expressed on the cell surface in the hydrophobic region of the cell membrane and in the cytoplasm of less metastatic melanoma cells. Treatment of less metastatic melanoma cells with recombinant Wnt5A decreased the levels of ROR1 in these cells. We have previously demonstrated that increases in Wnt5A result in an increase in metastatic capacity of melanoma cells, and a decrease in the melanoma differentiation antigens MART1 and gp100. These data have been supported by several other laboratories, giving rise to the phenotype switching model of melanoma progression that suggests that melanomas express a “proliferative” gene expression signature governed by the transcription factor MITF, and its targets MART1, gp100, DCT, etc., during the initial stages of melanoma development, and an “invasive” gene expression signature governed by Wnt5A in the later stages of melanoma progression. In keeping with these data, reduction of ROR1 by siRNA demonstrates a decrease in the melanoma differentiation markers MART1 and GP100, and motility, and an increase in the invasive capability of melanoma cells. In addition, siRNA knockdown of ROR1 expression increased WNT5A expression, implying that downregulation of ROR1 may be a step in the progression towards melanoma metastasis. Further, WNT5A knockdown in cells that have high levels of WNT5A, but low levels of ROR1, increases ROR1 expression and knockdown of ROR2 increases ROR1 expression. These data suggest that melanoma receptors in the ROR superfamily can influence the expression of one another and the switch from ROR1 positivity to ROR2 positivity can contribute to metastatic potential. The search for the micro-environmental factors that can initiate this switch is currently under investigation in our laboratory.
(This work was supported in part by the Intramural Research Program of the National Institute on Aging, Baltimore, MD).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2346. doi:10.1158/1538-7445.AM2011-2346