bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-431: Augmented induction of tumor antigen-specific CTL by cetuximab in head and neck cancer patients does not correlate with Fcγ receptor IIIa genotype, but relies on NK:DC cross talk mediated by interferon-γ and NKG2D
Authors: Lord Christopher A. , Srivastava Raghvendra M. , Lee Steve C. , Filho Pedro A. Andrade , Gibson Sandra P. , Gooding William E. , Ferrone Soldano , Ferris Robert L. 
Published: August 2012

Abstract
Despite over-expression of epidermal growth factor receptor (EGFR) in 80-90% of head and neck cancers (HNC), only ∼20% of HNC patients are clinically responsive to treatment with the EGFR-specific monoclonal antibody (mAb) cetuximab. To date, no reliable biomarker of clinical efficacy has been identified to predict clinical response to cetuximab therapy in HNC. Modest, yet statistically significant correlations of Fcγ receptor (FcγR) IIIa polymorphisms with clinical outcome have been noted in B cell lymphoma, breast, and colorectal cancer patients treated with rituximab, trastuzumab, and cetuximab, respectively. Therefore, we have investigated whether a known FcγRIIIa polymorphism in natural killer (NK) cells at amino acid position 158 (valine [V] vs. phenylalanine [F]) correlates with the anti-tumor activity of cetuximab in immunodeficient mice engrafted with human HNC tumors as well as with the induction of EGFR-specific cytotoxic T lymphocytes (CTL) and clinical course in HNC patients treated with cetuximab. When injected into immunodeficient mice, human NK cells expressing the V allele at this position demonstrated significantly greater ability to control the growth of xenografted HNC tumors. However, we did not find a significant correlation between FcγRIIIa genotype and disease free survival (p=0.683) in a cohort of 107 consecutive HNC patients treated with regimens incorporating cetuximab. Furthermore, we demonstrate for the first time that in the presence of cetuximab-opsonized HNC cells, NK cells trigger maturation of dendritic cells (DC), leading to augmented TA-specific cross-priming of EGFR and MAGE-specific CTL in vitro, and in vivo in cetuximab-treated HNC patients. The significantly higher frequencies of EGFR-specific CTL we found in HLA-A2+ PBMC from cetuximab-treated HNC patients relative to cetuximab-naive HNC patients (p&lt;0.001) also did not correlate with FcγRIIIa genotype, but their induction was dependent on NK:DC cross talk mediated by interferon-γ and NKG2D. Taken together, our data indicate that cetuximab treatment augments the priming of both EGFR and non-EGFR TA-specific cellular immunity in vivo, thereby providing a novel immune mechanism for enhanced anti-tumor activity of TA-specific mAb relevant to clinical response, as well as a potential biomarker for monitoring this response in mAb-treated cancer patients.
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 LB-431. doi:1538-7445.AM2012-LB-431
Abstract LB-434: Baseline serum adrenal androgens are prognostic and predictive of overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC): Results of the COU-AA-301 phase 3 randomized trial
Authors: Ryan Charles , Li Jinhui , Kheoh Thian , Scher Howard I. , Molina Arturo 
Published: August 2012

Abstract
Objective In COU-AA-301 the androgen biosynthesis inhibitor abiraterone acetate (AA) significantly increased OS vs placebo (PL) in mCRPC post-docetaxel (HR=0.74; Scher, ASCO 2011). The objective of the current study was to determine the effect of baseline levels of adrenal androgens (testosterone [T], androstenedione [A4], and dehydroepiandrostenedione [DHEA]) on OS in COU-AA-301. Methods COU-AA-301 is a randomized double blind study of AA (1000 mg QD + prednisone [P] 5 mg po BID) vs PL + P. In this post hoc exploratory analysis, the effect of baseline serum androgen levels (T, A4, DHEA) on OS was determined by univariate and multivariate analyses using the Cox proportional hazards regression model. Cut offs for high hormone (HH; above median) and low hormone (LL; below median) levels were used. Pts were stratified by ECOG PS (0-1 vs 2), pain (pain 4-10 [present] vs pain 0-3 [absent]), 1 vs 2 prior chemotherapy regimens, and type of progression (PSA only vs radiographic). Results Higher baseline serum androgens (T, A4, and DHEA) were associated with significantly improved OS, in either univariate or multivariate analysis, adjusting for treatment, other androgens, and other lab parameters (ie, LDH, HGB, ALKP, PSA; all p&lt;0.0001). OS was significantly longer in HH group vs LH group in both AA + P and PL + P arms for T, A4, and DHEA (Table); the longer OS observed with AA + P vs PL + P was observed in both HH and LH groups for T, A4, and DHEA. Conclusions In study COU-AA-301, baseline adrenal androgens were both prognostic and predictive of OS in patients with mCRPC. Pts treated with P alone had longer OS in the HH group vs LH group, suggesting P modulation of the adrenal axis. AA was beneficial in both HH and LH groups, but the effect appeared more pronounced in the HH group. Additional work is underway to further understand the relationship between serum and intratumoral androgens and outcomes.
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 LB-434. doi:1538-7445.AM2012-LB-434
Abstract LB-435: Double-blind randomized clinical trial of vitamin D3 showing effects on tissue calcitriol levels, gene expression and proliferation immunohistochemistry in prostate cancer
Authors: Wagner Dennis , Nonn Larisa , Antonio Angeline , Vaishnav Avani , Klotz Laurence , Fleshner Neil , Finelli Antonio , Trudel Dominique , van der Kwast Theodorus , Vieth Reinhold 
Published: August 2012

Abstract
Background: Preclinical data suggest that vitamin D plays a favourable role in prostate cancer prevention and prognosis, but its putative anticancer effects have not been validated in clinical prostate tissue samples. Here, we report the results from a randomized clinical trial (RCT). Objectives: We conducted an RCT to determine whether simple cholecalciferol (vitamin D3) consumed orally elicits effects on prostate cancer pathology in prostate tissue obtained at surgery. Methods: Prostate cancer patients (n=66) with Gleason scores 6 or 7 and scheduled for radical prostatectomy were randomized to daily vitamin D doses of 400, 10,000, or 40,000 IU for 3-8 wk before surgery. Results: Laser-capture microdissected paraffin-embedded prostate tissue showed differential expression, between benign and cancerous regions, for the cancer-related mRNAs and miRNAs, as well as for the Ki-67 proliferation marker (p0.07 among groups). The group consuming 40,000 IU/d vitamin D exhibited the highest levels of both calcitriol and its precursor as measured in frozen prostate tissue and in serum (p&lt;0.02 each). Prostate tissue calcitriol correlated strongly with the expression of androgen receptor mRNA (r = -0.58, p=0.001), NKX3.1 mRNA (r = -0.39, p=0.02), miR-100 (r = 0.44, p=0.01), miR-125b (r = 0.37, p=0.03), Let-7a (r = 0.47, p=0.03), miR-141 (r = 0.51, p=0.002), miR-106b (r = 0.45, p=0.01), and miR-331-3p (r = 0.47, p=0.005). Automated digital analysis of immunohistochemically stained prostate cancer regions showed that prostate tissue calcitriol related negatively with Ki67 intensity (r = -0.38, p =0.02) and percent of nuclei stained strongly positive (3+) for Ki67 (r = -0.41, p=0.008). A threshold effect was evident such that patients at the highest quartile of prostate tissue calcitriol (≥ 37 pmol/kg) had significantly lower AR mRNA (p&lt;0.001), NKX3.1 mRNA (p=0.01), and Ki67 measures (p&lt;0.05), as well as higher levels of the correlated miRNAs (p&lt;0.05), compared to those with lower levels. Conclusions: We provide level-1 clinical evidence that higher oral vitamin D doses produce higher levels of calcitriol within prostate tissue, and that higher prostate calcitriol relates to lower androgen receptor mRNA, higher miRNA signalling, and diminished expression of the proliferation marker Ki67 in prostate cancer. These RCT results justify a need to explore strategies that may maximize calcitriol within prostate for cancer chemoprevention.
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 LB-435. doi:1538-7445.AM2012-LB-435
Abstract LB-437: Co-amplification of ALK and c-MET in a subset of pulmonary sarcomatoid carcinoma (PSC)
Authors: Gasparini Patrizia , Sozzi Gabriella , Cavazza Alberto , Rossi Giulio , Papotti Mauro , Pastorino Ugo , Scanagatta Paolo , Nakatani Yukio , Pelosi Giuseppe 
Published: August 2012

Abstract
The prevalence of ALK gene alterations for targeted therapy with specific inhibitors is a largely unexplored issue in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset whose treatment still is disappointing. ALK gene status by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) were carried out on formalin-fixed, paraffin-embedded material from 34 PSC. Fifty-one consecutive metastatic lung adenocarcinomas (MELAD) were also assessed in parallel for ALK with both FISH and IHC. While no rearrangements of ALK gene were detected in PSC, relevant amplification was identified in 6/34 (18%) tumors, while other genes known to behave as driver mutations according to an oncogene addiction criterion, such as EGFR, KRAS, HER2, BRAF, PIK3CA and CTNNB1, were consistently lacking. The percentage of amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG) ± standard deviation (SD) of 7.5 ± 1.5. We have also investigated 51 MELAD observing that, while 10 of them showed the expected ALK rearrangement (p=0.012), only 1/51 showed the gene amplification (p=0.015). No cases of ALK-amplified tumors, either PSC or adenocarcinoma, expressed the relevant protein, whereas it was otherwise detectable in all ALK-rearranged adenocarcinomas. Interestingly all ALK-amplified tumors, either PSC or adenocarcinoma, showed also c-MET amplification consisting of variably sized clusters of specific signals, whereas negative tumors, regardless of histology, and ALK-rearranged adenocarcinomas did not show c-MET alteration. ALK and c-MET gene amplification clustered into a significant subset of elderly, smoking, predominantly male PSC patients, revealing significant differences with lung adenocarcinoma These encouraging data, however, need to be reinforced on a wider series of tumors in order to elucidate this issue, which could potentially lead to a truly effective treatment of these so life-threatening tumors.
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 LB-437. doi:1538-7445.AM2012-LB-437
Abstract LB-441: Mutation in SLX4 gen in a multiple case breast cancer family
Authors: de Garibay Ponce Gorka Ruiz , Díaz María Avellaneda , Gaviña Belén , Perez-Segura Pedro , Díaz-Rubio Eduardo , Caldés Trinidad , de la Hoya Miguel 
Published: August 2012

Abstract
Fanconi Anemia (FA) is a genetically heterogeneous, rare autosomal recessive disorder characterized by development abnormalities, bone marrow failure, and childhood cancers. Over the past few years, a common genetic basis for FA and breast and/or ovarian cancer susceptibility has been uncovered. In particular, BRCA2 (FANCD1), BRIP1 (also known as BACH1 and FANCJ), PALB2 (FANCN), and RAD51C germ-line mutations have been found to lead both to FA (when biallelic) and to increased breast and/or ovarian cancer risk (when monoallelic). Recently, two studies demonstrated that biallelic germ-line mutations in SLX4, which encodes an endonuclease, cause a previously unknown FA subtype (FA-P). Therefore, SLX4 should be considered a bona fide candidate gene for breast cancer susceptibility, as suggested in both studies. We have screened 347 non-BRCA1/BRCA2 index cases from multiple case breast and/or ovarian cancer families for point mutations in the SLX4 gene. The whole coding sequence and flanking intronic regions were analyzed using High Resolution Melting (HRM) analysis followed by direct sequencing of abnormal melting curve samples. An SLX4 missense change in c.1114C&gt;T (p.Arg372Trp) was detected in a family with four cases of breast cancer in two generations. This mutation segregates with disease within the family and is not present in the dbSNP (build 34). Polyphen-2 and SIFT in silico analysis tools predict a deleterious effect on protein structure and multiple alignment within orthologous proteins suggests a high degree of conservation. Previous studies in FA patients have identified two different splicing mutations (c.1163+2T&gt;A and c.1163+3dupT) that cause in frame exon 5 skipping. The resulting protein (p.Arg317_Phe387del) lacks two repeated UBZ4 domains known to interact with other endonucleases, mismatch repair proteins, and ubiquitin. It has been suggested that UBZ4 may be involved in targeting SLX4 to sites of DNA damage by binding to ubiquitinated proteins. The missense change we have found introduces a highly hydrophobic amino acid within the same region, which could affect the folding of the UBZ4 domain or disrupt a specific protein-protein interaction. Our study supports a role for SLX4 in breast cancer susceptibility. Further studies performed in larger cohorts will be necessary to determine the prevalence of SLX4 mutations among breast cancer risk factors.
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 LB-441. doi:1538-7445.AM2012-LB-441
Abstract LB-443: The Simple Western rapidly generates quantitative profiles of MAPK and PI3K proteins in clinical specimens
Authors: Fan Alice C. , Banerjee Prajna , Felsher Dean W. 
Published: August 2012

Abstract
In this era of targeted therapeutics, there is a need for highly sensitive and quantitative methods to measure proteins in clinical specimens to define and predict of specific therapies for patients. However, the current gold standard in proteomic analysis, Western Immuno Blotting, has many manual steps, is insensitive and provides only semi-quantitative data. Here, we present the first report of a novel automated platform, the Simple Western(TM), a novel automated nanovolume size-based protein separation platform used to quantify proteomic profiles of clinical specimens. Since the Simple Western automates all steps of proteomic analysis including sample loading, size-based protein separation, immunoprobing, washing, detection and data analysis, we are able to make up to 96 measurements in a single experiment, in a highly quantitative manner, minimizing errors due to manual variability. We were able to perform direct proteomic comparison of oral cavity tumors paired with adjacent normal tissues, acquired from the Stanford University Tissue Bank that had been preserved at -80C in Optimum Cutting Temperature Compound (OCT). Tissues were homogenized and lysed in a commercially available Bicine/CHAPS lysis buffer, denatured and loaded in duplicate in a 384-well plate at a final concentration of 1-2 mg/ml in each well. 40 nanoliters of lysate was used for each protein measurement. We measured 10 proteins (including AKT and ERK) from the mitogen activated protein kinase (MAPK) signaling pathways, normalized to loading controls (β-actin) from 4 distinct clinical specimens and 2 additional cell line controls. It took 1 hour to prepare a run and 14 hours of unattended automated machine time to generate the analyzed data. Therefore this technology enables us to report highly quantified protein profiles to the clinical team in less than 24 hours of receiving a clinical sample. Moreover, the highly quantitative nature of the measurements allowed us to determine that AKT2 levels were 80% lower in the tumor tissue as compared to their adjacent normal samples. Furthermore, we have been able to show that levels of both ERK1 and ERK2 were independently lower by 71% and 70%, respectively, in the tumor samples as compared to their corresponding adjacent normal tissues. The ability to make rapid and quantitative measurements will be useful to measure and predict responses to targeted therapeutics. The Simple Western is an extremely efficient, quantitative and high-throughput platform that can be used to rapidly generate proteomic profiles for clinical specimens for the development of novel diagnostic and predictive biomarkers.
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 LB-443. doi:1538-7445.AM2012-LB-443
Abstract LB-444: SATB2 is a novel prognostic factor in colorectal cancer
Authors: Naicker Kirsha , Brennan Donal , Klinger Rut , Ponten Fredrik , Jirstrom Karin , O'Sullivan Jacintha , Gallagher William M. , O'Connor Darran P. 
Published: August 2012

Abstract
SATB2 is a nuclear matrix-associated transcription factor that orchestrates gene expression in a tissue-specific manner by regulating higher order chromatin structure. Using antibody-based screening of 48 normal human tissues and 20 cancer types, we identified SATB2 as a protein almost exclusively expressed in gastrointestinal tissue. Differential expression of SATB2 was observed in colorectal cancer, with loss of expression occurring along the adenoma-carcinoma sequence. We further confirmed this observation at the mRNA level in 10,533 colorectal cancer samples. Additionally, SATB2 expression was markedly decreased in a metastatic variant of SW480 colon cancer cells and siRNA knockdown of SATB2 expression in parental SW480 cells increased their growth and migratory capacity. Ectopic expression of SATB2 in the metastatic variant reversed the observed phenotype. Using tissue microarray and automated image analysis of SATB2 expression in colorectal cancers (n=309), SATB2 was demonstrated by multivariate Cox regression analysis to be an independent predictor of disease-specific survival (HR=0.52, 95% CI 0.32-0.83, p=0.006) and loss of SATB2 expression significantly correlated with poor differentiation (p=0.001). SATB2 mRNA levels were examined in a second cohort (n=290) and again, SATB2 was demonstrated to be an independent predictor of disease-specific survival (HR=0.40, 95% CI 0.18-0.92, p=0.031). Interestingly, in colorectal cancer patients, SATB2 levels significantly correlate with CD3+ T-cell infiltrates in the tumours (p=0.006) and inversely correlate with COX2 expression (p=0.019). Gene set enrichment analysis in two independent colorectal cancer cohorts (n&gt;500) revealed that SATB2 low tumours demonstrate altered immune signalling with significant increases in IFN-gamma(p=0.001), IL6 (p=0.021) TFGβ (p&lt;0.001). Furthermore, in patients with inflammatory bowel disease (n&gt;1000), we observed a significant correlation between loss of SATB2 expression and occurrence of future cancers (p=0.013). We therefore postulate that SATB2 acts as a master regulator of the inflammatory response in the gut and loss of expression is significantly associated with the progression of colorectal cancer.
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 LB-444. doi:1538-7445.AM2012-LB-444
Abstract LB-446: Target-based therapeutic matching in patients with PIK3CA mutations and PTEN aberrations
Authors: Janku Filip , Wheler Jennifer J. , Piha-Paul Sarina A. , Stepanek Vanda M. , Fu Siqing , Hong David S. , Naing Aung , Falchook Gerald S. , Moulder Stacy L. , Luthra Rajyalakshmi , Tsimberidou Apostolia M. , Kurzrock Razelle 
Published: August 2012

Abstract
Background: Activating mutations of PIK3CA or loss of PTEN function result in increased PI3K/AKT/mTOR signaling and may predict sensitivity to drugs targeting the PI3K/AKT/mTOR pathway, while simultaneous KRAS mutations may mediate resistance. Methods: From 10/2008, available tumor samples from advanced cancer patients referred to the Phase I Clinical Trials Program were screened for PIK3CA mutations and PTEN aberrations (loss of expression on immunohistochemistry or mutation) in a CLIA-certified laboratory. Patients with tumors carrying PIK3CA mutations and/or PTEN aberrations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway. Results: Overall, 1,540 patients were tested, and 285 (19%) had PIK3CA mutations (n=141), PTEN aberrations (n=130), or a simultaneous PIK3CA mutation and PTEN aberration (n=14). Of these 285 patients, 131 (46%) were treated in clinical trials containing a PI3K/AKT/mTOR inhibitor (median age, 56; median number of prior therapies, 3). Of these 131 patients, 26 (20%, 95% CI 0.14-0.27) achieved a partial response (PR) (4/21 breast cancers; 4/19 endometrial cancers; 3/13 ovarian cancers; 4/9 head and neck cancers; 4/10 cervical cancers; 2/9 renal cancers; 2/4 salivary gland cancers; 1/4 sarcomas; 1/3 non-small cell lung cancers; 1/2 melanomas). Patients without known PIK3CA mutations and/or PTEN aberrations treated on the same protocols had a PR rate of 6% (26/458; 95% CI 0.04-0.08, p=0.0001). Treated patients with wild-type KRAS had a higher PR rate of 20% compared to 8% in patients with simultaneous KRAS mutations (p=0.05). Conclusion: Heavily pretreated patients with PIK3CA mutations and/or PTEN aberrations had higher PR rates on protocols with PI3K/AKT/mTOR inhibitors than patients without these aberrations (20% vs 6%; p = 0.0001). Simultaneous KRAS mutations were associated with a lower PR rate. Screening for PIK3CA mutations and PTEN aberrations merits further evaluation in making treatment decisions.
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 LB-446. doi:1538-7445.AM2012-LB-446