bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2709: Peritoneal carcinomatosis from ovarian cancer: tissue markers as predictors of response to chemotherapy
Authors: Chiara Arienti , Zoli Wainer , Verdecchia Giorgio Maria , Virzi Salvatore , Grassi Antonio , Scarpi Emanuela , Turci Livia , Bravaccini Sara , Sacanna Emanuele , Silvestrini Rosella , Amadori Dino , Tesei Anna
Published: February 2011

Background: Epithelial ovarian cancers represent 80 to 90% of all ovarian malignancies and are the most common cause of death from gynecological tumors in the Western world. The absence of specific symptoms in the early stages of disease means that around two-thirds of patients are initially diagnosed with advanced disease and/or peritoneal dissemination. Although standard primary treatment now exists for advanced ovarian cancer, there is still no single accepted therapeutic strategy for those who develop recurrent intra-abdominal disease more than 6 months after a complete response. The present study aimed to identify a panel of genes whose expression is correlated with sensitivity or resistance to platinum compounds.

Material and methods: Fresh surgical biopsy specimens were obtained from 22 patients with advanced epithelial ovarian cancer during intra-abdominal cytoreductive surgery. Expression levels of ERCC1, GSTP1, MGMT, XPD, BRCA1 were determined by Real Time RT-PCR. Relative gene expression was quantified according to the comparative threshold cycle method (2-ΔΔCτ) using β2-microglobulin and HPRT as endogenous controls and commercial RNA controls derived from normal ovarian tissue mRNA as calibrators. The correlation between pre- and post-surgery expression levels of these markers and response to platinum treatment was examined.

Results: Time to progression (TTP) was calculated from the first day of treatment to the date on which objective disease progression was first documented, or death in the absence of progressive disease. At univariate analysis, estimated hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated using the Cox proportional hazard model. In particular, the risk of progression increased significantly as ERCC1 (HR=12.00, 95% CI 1.08-133.35, p=0.04), GSTP1 (HR=6.01, 95% CI 1.09-33.01, p=0.004), XPD (HR=10.37, 95% CI 1.26-85.52, p=0.003), MGMT (HR=10.26, 95% CI 1.18-88.94, p=0.035) and BRCA1 (HR= 7.52, 95% CI 1.32-42.74, p=0.023) levels increased.

Conclusions: Our results indicate that these biomarkers could be useful predictors of clinical response to platinum compounds in patients with advanced ovarian cancer who develop recurrent intra-abdominal disease. It is now planned to compare tailored and empiric therapy in a well-designed randomized trial.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2709.
Abstract 2710: SRC/STAT related parameters might predict for prognosis and response to targeted treatments in squamous cell carcinomas of the head and neck (SCCHN)
Authors: Kotoula V. , Lampaki S. , Televantou D. , Psyrri A. , Pectasides D. , Mavropoulou X. , Misailidou D. , Syrigos K. N. , Fountzilas G.
Published: February 2011

The anti-EGFR antibody cetuximab (Erbitux®, CTX) has been introduced into clinical practice for the treatment of SCCHN, as yet with modest effectiveness. Src family targeting agents have shown anti-growth activity in SCCHN preclinical models and are currently considered for further exploration in the same tumor system. In this study we investigated the expression and activation of SRC/STAT pathway components in SCCHN in order to assess how they are related to already in use and upcoming, targeted treatment modalities. Relative expression of SRC, STATs 1,3,5 and related genes was assessed with real time PCR in tumor tissue extracts from SCCHN patients treated with combined radiotherapy and cetuximab-based regimens (RT-CTX). Stat and Akt/PKB protein activation were assessed with immunohistochemistry. SCCHNs always expressed SRC, STAT1, STAT3 and ANXA1 mRNA, variably high levels of IGFBP2 and STAT5A and mostly low STAT5B, PIAS3 and MSN. Stat1, Stat3 and Stat5 proteins were usually found activated in neoplastic nuclei (70.4%, 85.7% and 70.8%, respectively), although not correlating to the respective STAT mRNA expression levels. Activated Stat3 and Stat5 were associated with each other (p=0.017) and with relatively high CAV1 (pStat3=0.0079; pStat5=0.0107) and MSN (pStat3=0.0463; pStat5=0.0077), as well as with relatively low IGFBP2 expression (pStat3=0.0181; pStat5=0.0328). Akt was phosphorylated at Thr308 in the majority of SCCHN (86.7%) and less so at Ser473 (41.9%) in association with low STAT1 mRNA expression (p=0.0316). All patients with very high expression (upper quartile) of STAT5A and/or EPHA2 experienced a complete response upon RT-CTX treatment (p<0.0001), while all patients without activated Stat1 were also responders (p=0.009). Few tumors (3 of 31, 9.7%) expressed relatively high ANXA1/CAV1/EPHA2 and low IGFBP2, a profile previously proposed to predict response to dasatinib. Very high expression of ANXA1 (an anti-inflammatory molecule possibly associated with chemoradiation resistance) was associated with poor overall (p=0.0009) and progression-free survival (p=0.0004) in this cohort of SCCHN patients. In conclusion, the proposed signature for predicting response to dasatinib in solid tumors is seldom observed in SCCHN. Stat3 and Stat5 activation is common and seems to occur in the anti-oncogenic setting in SCCHN, where overexpression of STAT5A and EPHA2 may predict for response to RT-CTX treatment. If validated in larger cohorts, these data may be applied for assessing SCCHN patient treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2710.
Abstract 2713: Helicobacter pylori increases the risk of colorectal polyps in African Americans
Authors: Zahaf Marwah , Adeyinka Laiyemo , Nouraie Mehdi , Brim Hassan , Smoot Duane , Lee Edward , Ashktorab Hassan
Published: February 2011

Background: H. Pylori infection have linked to colorectal polyps, mainly through hypergastrinemia and its trophic effect on colon mucosa. African Americans were under represented despite both common diseases are more prevalent in them.

Aim: The aim of this study was to investigate whether H. Pylori infection has a role in development of colorectal polyps in Africans Americans.

Methods: Retrospectively, Africans Americans (n=1262) greater than 40 years old who underwent bidirectional gastrointestinal endoscopy on the same day were enrolled. The pre-procedure indication and post-procedure diagnosis were recorded (n=1262). H. Pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of biopsies from complete colonoscopy. Multivariable logistic regression was used to assess the independent risk factors of polyp occurrence.

Results: Colorectal polyps (regardless polyp pathology) were more prevalent in H. Pylori-infected subjects (43%; 160/368) compared to (34%; 302/894) uninfected subjects (OR=1.5; 95 %CI=1.2-1.9). Furthermore, there was a trend toward larger polyp size ≥ 1cm in H. Pylori positive patients (P=0.07). There was no difference in histopathology or location of polyps in regard to H. Pylori status. Among the participants, 21 (2%) were defined with baseline above average risk for colorectal polyps justifying colonoscopy and of those; the polyps were detected in 62% (OR; 95%CI=2.9; 1.2-7.1). Age and male gender were independent risk factors for colorectal polyps.

Conclusion: H. Pylori increases the risk of developing colorectal polyps and may increase the chances for having a larger size polyp in Africans Americans. These findings suggest that H. Pylori might have a role in the initiation and/or promotion of polyps. Further studies are needed to explore its mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2713.
Abstract 2716: Tailored-dose capecitabine chemotherapy as adjuvant treatment in elderly colon cancer patients
Authors: Chang Hye Jung , Lee Keun-Wook , Choi In Sil , Kim Yu Jung , Kim Jee Hyun , Bang Soo-Mee , Lee Jong-Seok
Published: February 2011

Backgrounds

Elderly patients with curatively resected colon cancer (CC) receive adjuvant chemotherapy less frequently and show poorer compliance than young patients. The dosage of capecitabine in elderly patients is still controversial. Although the capecitabine dosage of 2000 mg/m2/day (days 1∼14, every 3 weeks) is commonly used in elderly patients with various solid tumors, fixed-dose reduction in all patients may compromise the effect of adjuvant treatment. Therefore, in this study, we analyzed the feasibility of tailored-dose capecitabine therapy, and clinical parameters associated with dose reduction of capecitabine and toxicities in elderly CC patients.

Methods

Elderly CC patients (≥70 years) with high risk stage II or stage III who had received adjuvant capecitabine monotherapy were prospectively enrolled. Eight cycles of capecitabine was planned. The starting dosage of capecitabine was 2000 mg/m2/day (days 1∼14, every 3 weeks). On the second cycle, the dosage was escalated to 2500 mg/m2/day if the patient was tolerable to the first cycle.

Results

Eighty-two patients were enrolled and 582 cycles of capecitabine were administered. Median age was 74.5 years (range: 70-90 years). Fifty-six patients (68%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade 0/1 and 26 patients (32%) had ECOG PS grade 2, respectively. Sixty-seven patients (82%) completed 8 cycles of chemotherapy. Fifty-six patients (68%) could receive the escalated dose of capecitabine at the second cycle and 24 patients (29%) could complete the 8 cycles at escalated dose (2500 mg/m2/day). The mean relative dose intensity (RDI) of capecitabine was 81.3% compared with escalated dose (2500 mg/m2/day). Creatinine clearance (Ccr) < 50 mL/min and Charlson Age Comorbidity Index (CACI) ≥ 8 were independent predictive factors for reduced administration of capecitabine dosage in multivariate analysis (P = 0.02 and 0.03, respectively). Severe hematologic toxicities (per cycle) included grade 3/4 neutropenia (0.9%) and thrombocytopenia (0.3%). Severe non-hematologic toxicities (per patient) included grade 3/4 hand-foot syndrome (26%), anorexia (6%) and diarrhea (6%).

Conclusion

The tailored-dose for elderly CC patients receiving adjuvant capecitabine therapy is feasible and may be an appropriate approach to avoid unnecessarily uniform dose reduction and increased toxicities. When determining adequate dosage for elderly patients, Ccr and CACI should be considered as predictive factors for capecitabine dose reduction.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2716.
Abstract 2718: Fasting and cancer treatment: A case series
Authors: Safdie Fernando M. , Dorff Tanya , Quinn David , Fontana Luigi , Wei Min , Lee Changhan , Cohen Pinhas , Longo Valter D.
Published: February 2011

Short-term fasting (48 hours) was shown to be effective in protecting normal cells and mice but not cancer cells against high dose chemotherapy, termed Differential Stress Resistance (DSR), but the feasibility and effect of fasting in cancer patients undergoing chemotherapy is unknown. Here we describe 10 cases in which patients diagnosed with a variety of malignancies had voluntarily fasted prior to (48-140 hours) and/or following (5-56 hours) chemotherapy. None of these patients, who received an average of 4 cycles of various chemotherapy drugs in combination with fasting, reported significant side effects caused by the fasting itself other than hunger and lightheadedness. Chemotherapy associated toxicity was graded according to the Common Toxicity Criteria (CTC) of the National Cancer Institute (NCI). The six patients who underwent chemotherapy with or without fasting reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. In those patients whose cancer progression could be assessed, fasting did not prevent the chemotherapy-induced reduction of tumor volume or tumor markers. Although the 10 cases presented here suggest that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies they are not meant to establish practice guidelines for patients undergoing chemotherapy. Only controlled-randomized clinical trials will determine the effect of fasting on clinical outcomes including quality of life and therapeutic index.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2718.
Abstract 272: Direct binding of neuregulin-1 to integrins is involved in neuregulin-1/ErbB signaling
Authors: Ieguchi Katsuaki , Ma Zi , Takada Yoko K. , Takada Yoshikazu
Published: February 2011

Crosstalk between growth factor receptors and integrins play a role in growth factor signaling. In current models of NRG/ErbB signaling, integrins and ErbB receptors transduce signals independently upon binding to their ligands (e.g., extracellular matrix and NRGs, respectively) and their signals are merged inside the cells. We discovered that the EGF-like domain of NRG1 binds directly to integrins αvβ3 and α6β4. Docking simulation predicted that three Lys residues at the amino terminus of NRG1 are involved in integrin binding. We mutated these residues to Glu (designated the 3KE mutant). Indeed the 3KE mutation markedly reduced the NRG1 binding to integrins, while the 3KE mutation did not affect the NRG1 binding to ErbB3. This is consistent with the prediction that the Lys residues critical for integrin binding are not involved in ErbB binding. We studied the effect of the 3KE mutation on NRG1/ErbB signaling in MCF-7 and T47D human breast cancer cells. The 3KE mutation markedly reduced the levels of ErbB3 phosphorylation, AKT and Erk1/2 activation, suggesting that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Furthermore, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with integrin α6β4. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. WT NRG1 induced co-precipitation of ErbB3 with integrin αvβ3 to a less extent than with integrin α6β4. This probably reflects low levels of integrin αvβ3 expression compared to integrin α6β4 in these cells. In contrast, the 3KE mutation markedly reduced the levels of ternary complex formation, suggesting that this process depends on the ability of NRG1 to bind to integrins. Notably, the 3KE mutant acted as an antagonist to ErbB/NRG1 signaling in vitro and effectively suppressed proliferation of breast cancer cells in vivo. These results suggest that 1) NRG1-integrin interaction mediates crosstalk of integrins with ErbB receptors, 2) integrin α6β4 plays a major role in ErbB/NRG signaling in the cancer cells tested, and 3) the 3KE mutant has potential as a therapeutic in cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 272.
Abstract 2722: Development of automated methods of in-situ hybridization for the detection of ETS gene re-arrangements in FFPE biopsy and archived prostatectomy specimens
Authors: Nagy Dea , Santa- Cruz Ashley , Riley Janice P. , Sathyanarayana Ubaradka G. , Pommier C J. , Yun Steven , Ashworth-Sharpe Julia , Kosmeder Jerry , Nagle Raymond B. , Miller Phillip , Pestano Gary A.
Published: February 2011

Abstract

Prostate cancer (PCa) is the most common visceral neoplasm in men. In most cases, the disease is slowly progressive. Five year survival with organ-confined disease is 100%, while even distal spread is 32%. ETS gene re-arrangements in PCa have been shown to be associated with disease progression and have therapeutic and diagnostic implications.

The goal of this study was to develop methods of automated in-situ hybridization to detect the ETS gene re-arrangements in formalin fixed, paraffin-embedded (FFPE) prostate tissue. Methods were developed on the Ventana Benchmark®XT and Discovery®XT instruments for prostate cancer cell line xenografts, including VCap, LnCaP and H660, as well as for primary biopsy and archived prostatectomy specimens.

Key modules in the protocol have been evaluated and modified both in manual (offline) and automated (online) process of method development. Specific protocols were developed for deparaffinization, antigen retrieval, DNA denaturation, probe hybridization, sample washing, and detection with Quantum Dots (Qdots). Six different FISH probes specific for 3′ ERG, 5′ ERG, 5′ SLC45A3, and 3′ETV1 were used in assay development. Probe hybridization time was held to 8 hours, with overnight completion of the fully automated protocol.

Assay conditions on both instruments were similar for xenografts and in archived prostectomy specimens; however increased stringency of target retrieval was required for processing of the biopsy specimens. This adjustment was necessary to compensate for the tendency of biopsy specimens to become overly fixed during procurement and routine shipping and handling. In addition we observed that the presence of commonly used detergents in washing buffers post-hybridization may increase background staining with QDots.

In conclusion, we have developed fully automated protocols for the processing of clinically relevant tissue specimens. The xenograft cell line controls developed as a part of this study may also enable evaluation of assay performance in routine specimen processing for the detection of the ETS genes in biopsies and in prostatectomies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2722.
Abstract 2729: Galectin-4 in colorectal cancer
Authors: Satelli Arun , Rao Prema S. , Rao U Subrahmanyeswara
Published: February 2011

Introduction: Colorectal cancer (CRC) is one of the leading diseases in the western world and is curable if diagnosed at an early stage. The normal-adenoma-carcinoma sequence concept suggests that the normal epithelia in the colorectal region transform into adenomas, which progress to invasive carcinomas. The role of galectin-4 (gal-4) a protein abundantly expressed in normal colonic epithelia, hereto considered a differentiation marker, on the onset or progression of colorectal cancer (CRC) is unknown. The main aim of this study is to evaluate gal-4 as a potential biomarker in detecting the onset of CRC and to determine the function of gal-4 in CRC development.

Methods: We analyzed the paraffin-embedded normal, adenomatous polyps and invasive carcinomas of the human colon biopsies and tissue microarrays for gal-4 expression by immunohistochemistry. Gal-4 expression in CRC cell lines was characterized by RT-PCR, western blotting, immunofluorescence microscopy and FACS analysis. The functional role of gal-4 was examined by cell proliferation, migration, motility, transfection and RNAi experiments.

Results: Biopsies immunostained for gal-4 were quantified using ImageJ software. The normal tissue as well as normal tissue adjacent to cancer contained highest amount of gal-4. Gal-4 intensity decreased in all the disease-states, which was found to be statistically significant (P <0.05). The results suggested that as the normal colon develops adenomatous polyps, which transform subsequently into invasive carcinomas, the epithelial cells lining the crypts shut off gal-4 expression. Gal-4 negative cells showed increased cell proliferation, motility and migration, in comparison to gal-4 positive CRC cells. Transfection of the CRC cells (gal-4 -ve) with gal-4 led to decreased motility and cell cycle arrest. Externally added gal-4 on gal-4 -ve cells induced retarded cell migration. Gal-4 down-regulates cyclin D1 level and upregulates p15 and p21 levels.

Conclusions: We conclude that galectin-4 plays a key role the maintenance of epithelial cells in a differentiated state, and its loss allows the cells to de-differentiate, leading to increased cell proliferation, migration and motility, which are hallmark features of cancer. Galectin-4 brings about these changes through cell cycle regulation by modulating the cyclin D1, p15 and p21 levels. Finally, our findings that extracellular galectin-4 retards the migratory potential raise a possibility for it to serve as a therapeutic agent in controlling CRC progression. Thus beyond shedding light on the role of tumor-suppressor gal-4 in CRC, this study underscores the potential clinical value of gal-4 in prognosis and diagnosis of CRC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2729.
Abstract 2733: Molecular markers for predicting progression of pure ductal carcinoma in situ of the breast
Authors: Abuázar Carolina Sens , Napolitano e Ferreira Elisa , de Toledo Cynthia Aparecida Bueno , Soares Fernando Augusto , Rocha Rafael Malagoli , Carraro Dirce Maria
Published: February 2011

INTRODUCTION: Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of tumors which has an uncertain and poorly understood evolution. For this reason, the identification of molecular factors necessary for progression to invasive disease is one of the main concerns of the scientific community. We previously identified, by a microarray assay, a group of genes potentially involved in progression of DCIS, which are differentially expressed between pure DCIS and in situ component of lesions with co-existing invasive ductal carcinoma (DCIS-IDC). For this experiment, only the in situ components of pure DCIS and DCIS-IDC lesions were isolated using laser microdissection technique. AIM: Seek novel molecular markers to predict invasiveness potential in a DCIS group of breast carcinomas by qRT-PCR and Immunohistochemistry (IHC). METHODS: For qRT-PCR, 18 genes were selected, for which there were available antibodies. The qRT-PCR reactions were performed in ABIPrism 7700 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) and the criterion of gene expression difference was equal or greater than 2-fold change. IHC was performed in a tissue microarray (TMA), using a biotin-free polymeric system for visualization (Flex+, DAKOTM). The distribution of IHC markers was analyzed using the Chi-square test for trend or Fisher's exact test. RESULTS: The expression of 4 genes (ADFP, ARHGAP19, ANAPC13 and CLTCL1) was confirmed by qRT-PCR, in the initial sample set used in the microarray experiment, presenting higher expression in the pure DCIS group. IHC was conducted to evaluate the corresponding proteins, using an independent group of 47 pure DCIS and 35 DCIS-IDC samples arrayed in TMA. Two genes, ANAPC13 (p=0.0379) and CLCTL1 (p=0.0471), confirmed the expression at protein level, showing significant higher cytoplasm staining in the pure DCIS group. CONCLUSION: ANAPC13 and CLTCL1 may be involved in progression of DCIS, being good candidates for predicting invasion of pure DCIS.

Financial support: CEPID and FAPESP.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2733.
Abstract 2738: Early detection of colorectal cancer applying a combination of serum markers
Authors: Wild Norbert , Andres Herbert , Rollinger Wolfgang , Krause Friedemann , Dilba Peter , Tacke Michael , Karl Johann
Published: February 2011

Background: Fecal occult blood testing (FOBT) is the recommended first line screening for the detection of colorectal cancer (CRC). To improve the detection of CRC we evaluated serum markers and combinations of serum markers as an alternative approach.

Methods: Applying Lasso Regression, a specialized form of penalized logistic regression, we selected six markers for an evaluation in a collective of 857 patients including 301 CRC patients, 143 patients with adenoma, 266 healthy controls and 147 disease controls. For each marker and marker combination the performance was assessed.

Results: We tested a total of 22 biomarkers for the detection of CRC from serum. Of these six markers were selected for a marker combination by Lasso Regression. Included were the well-known tumor markers CEA and CYFRA21-1 as well as novel markers or markers that are less routinely used for the detection of CRC: ferritin, osteopontin, anti-p53 and seprase. CEA showed the best sensitivity of all markers with 43.9 % at 95% specificity, followed by seprase (42.4%), CYFRA21-1 (35.5%), osteopontin (30.2%), ferritin (23.9%) and anti-p53 (20.0%). When these markers were combined a sensitivity of 72.3% was reached at a corresponding specificity of 95% and of 62.1% at 98% specificity. Focusing on more screening relevant stages, UICC stages 0-III, reduced the sensitivity slightly to 68.0% and 53.3%, respectively. In a sub-collective where matched stool samples were available (75 CRC cases and 234 controls) the sensitivity of the marker combination was comparable to fecal immunochemical testing (FIT) with 82.4% and 68.9% vs. 81.8% and 72.7% at 95% and 98% specificity, respectively.

Conclusion: When six markers were combined to detect CRC from serum, the combination reached a performance that was comparable to FIT. This provides a novel tool for CRC screening to trigger a follow-up colonoscopy for a final diagnosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2738.
Abstract 2740: Increased accuracy of TRAP-FISH combination in bladder cancer diagnosis in symptomatic patients
Authors: Bravaccini Sara , Casadio Valentina , Gunelli Roberta , Nanni Oriana , Arienti Chiara , Sacanna Emanuele , Zoli Wainer , Amadori Dino , Silvestrini Rosella , Calistri Daniele
Published: February 2011

Introduction: Previous case-control studies have shown the importance of urine telomerase activity determined by the telomerase repeat amplification protocol (TRAP) assay to detect early bladder cancer. However, its validation is needed in large and consecutive series of symptomatic patients before it can be considered for routine clinical use. The aim of the present study was to verify whether a multiple approach based on first-level TRAP assay analysis and successive evaluation with UroVysion test, limited to patients with TRAP-positive urine samples, could unmask false-positive results and improve diagnostic specificity.

Patients and methods: Three hundred individuals with urinary tract symptomatology (50 females, 250 males), but without prior history of bladder malignancy were consecutively enrolled between January 2007 and June 2008. All urine samples were processed for cytological examination and also for telomerase activity determination using a quantitative TRAP assay. FISH analysis was carried out only in TRAP-positive samples.

Results: At a cut-off of 50 arbitrary enzymatic units (AEUs), shown in previous case control-studies as the most accurate diagnostic discriminant, the positive predictive value (PPV) and negative predictive value (NPV) using TRAP assay were 48% and 86%, respectively, with an overall accuracy of 71%. With the two-step TRAP-FISH approach, PPV increased to 75% and overall accuracy to 83%.

Conclusion: Our results indicate that TRAP assay by itself could make a valid contribution to early bladder cancer diagnosis in high-risk patients with urinary tract symptomatology, and that its combination with FISH could improve specificity by unmasking false-positive TRAP results.

*Contributed equally to this work

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2740.
Abstract 2742: Identification of tumor antigens in neu transgenic mice may provide biomarkers useful for the early detection and diagnosis of human breast cancer
Authors: Wu Mei , Marzbani Edmond , Mao Jianning , Shehata Mariam , Kim Rachel Y. J. , Lu Hailing , Disis Mary L.
Published: February 2011

Early detection of breast cancer is crucial for better prognosis and successful treatment of the patients. Development of novel methods for screening for breast cancer is needed for early detection and diagnosis. The human immune system responds to tumor-specific antigens in the pre-malignant stage of breast cancer and produces specific antibodies, which can be detected as potential breast cancer biomarkers. Due to the limited availability of well-annotated pre-cancer and post-cancer sera from human subjects, we performed serial serum collection in a neu transgenic mouse model from the age of 10 weeks to the terminal stage of disease. Using a technique called serological screening of cDNA expression library (SEREX), a high-throughput method to rapidly screen recombinant proteins expressed in a bacteriophage-based cDNA library, we have previously identified tumor antigens in the late stage of neu breast cancers. The mouse tumors have similar immunogenicity as their human counterparts due to the fact that some of these antigens are also immunogenic in human. Indeed, we have found that one mouse antigen called gelsolin, shares 93% homology with human gelsolin and has the highest response to human serum antibody among other antigens. In an ELISA analysis using the serum samples from 50 breast cancer cases and 50 normal donors, the area-under-curve (AUC) value of the receiver-operating-characteristic (ROC) curve of gelsolin ELISA detects more than 70% of cancer patients. Using the SEREX technique, we sought to further identify the early-stage serum antibody biomarkers by comparing the pre-cancer, early stage, and late stage sera from the same mouse. We have identified three early-stage biomarkers, A20/TNFaip3, Rpl5, and Pdhx, in neu mice. In summary, we conclude that identification of tumor antigens in the neu transgenic animal model is useful for the discovery of serum antibody biomarkers for early detection and diagnosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2742.
Abstract 2758: Population pharmacokinetics of cyclophosphamide in infants and young children
Authors: Tagen Michael , Panetta John C. , Gajjar Amar , Stewart Clinton F.
Published: February 2011

Cyclophosphamide (CTX) is an anticancer pro-drug used for induction therapy of brain tumors and other malignancies. An adequate pharmacokinetic study of CTX and its active metabolite, 4-hydroxy-cyclophosphamide (4OH-CTX), has never been performed in infants and young children. We are therefore examining the disposition of CTX, 4OH-CTX, and its inactivated metabolite, carboxyethylphosphoramide mustard (CEPM), in children < 3 years of age with brain tumors. CTX was administered during the first course of treatment (1.5 g/m2 infused over 1 h), and serial samples were collected prior to infusion, at the end of infusion, and 3, 6, and 24 h after the end of infusion. CTX and CEPM were quantitated in plasma with a validated LC-MS/MS method and 4OH-CTX was stabilized by addition of phenylhydrazine to whole blood and quantitated with a validated LC-MS/MS method. A nonlinear mixed-effects model was fit to the data using NONMEM software and covariates were added to the model based on reduction in objective function value and improvement in diagnostic plots. Pharmacokinetic studies were performed with 28 patients. The median (range) age was 17.3 months (0.87 − 35.9 months) and median (range) BSA was 0.49 m2 (0.24 − 0.71 m2). A model with one compartment for CTX and each of its metabolites adequately described the data. BSA normalization of the dose reduced the inter-individual variability (IIV) in the volume of distribution of CTX (VCTX) from 32% to 13% and reduced the IIV in the elimination of 4OH-CTX through non-CEPM pathways (k4OH-CTX) from 60% to 38%. The covariate analysis showed that the BSA-normalized clearance of CTX to 4OH-CTX (CLCTX) increased slightly with age, whereas k4OH-CTX increased rapidly with age. The net effect was that exposure to 4OH-CTX decreased with age in a nonlinear fashion. These results demonstrate the importance of studying the pharmacokinetics of anticancer drugs in infants and young children, and will provide the basis for the rational design of CTX dosing strategies for infants and young children with brain tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2758.
Abstract 276: Docosahexaenoic acid alters the spatio-temporal segregation and activation of EGF receptor
Authors: Turk Harmony F. , Lupton Joanne R. , Chapkin Robert S.
Published: February 2011

We have previously demonstrated that dietary docosahexaenoic acid (DHA, 22:6n-3), a component of fish oil, profoundly alters the biochemical make up of colonocyte lipid rafts/caveolae microdomains. Since epidermal growth factor receptor (EGFR, ErbB1) is considered a major target for treatment of colorectal cancer and its activation can be regulated by manipulating the lipid composition of the membrane, we further elucidated the effects of DHA with respect to the EGFR signaling axis. Immortalized mouse colonocytes (YAMC cells) were treated with fatty acids (50 μM) for 72 h and stimulated in the presence or absence of EGF (0-50 ng/mL) for 0-10 min and receptor stimulation was assessed by determining levels of phosphotyrosine-EGFR. Downstream signaling was evaluated by measuring Akt, ERK 1/2, and Stat3 phosphorylation. EGFR phosphorylation was increased >2-fold (p<0.05) in DHA treated cells compared to control. Erk 1/2 activation was significantly increased >4-fold, while Stat 3 activation was decreased by 2-fold (p<0.05). No change in activation of Akt was observed. In addition, chronically inflamed (DSS treated) and carcinogen (AOM) injected C57BL/6 mice were maintained on diets ± DHA (fish oil) for 18 wks. Protein from scraped colonic mucosa was analyzed for EGFR phosphorylation and downstream signaling. DHA-fed animals displayed >2-fold (p<0.05) increase in EGFR phosphorylation compared to corn oil fed animals. Total Erk 1/2 and activated Erk 1/2 were significantly increased in DHA-fed animals. Stat3 phosphorylation was decreased by ∼3-fold (p<0.05). Akt activation showed no change. These data indicate that although DHA treatment results in an unexpected increase in EGFR phosphorylation, aspects of downstream signaling are suppressed. This could, in part, explain why fish oil feeding promotes colonocyte apoptosis and inhibits tumor growth. This work was supported in part by NIH grants CA59034, P30ES09106.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 276.
Abstract 2766: Multicenter pharmacokinetic evaluation of ON 01910. Na, a novel broad-spectrum anticancer agent, in Phase I single agent clinical trials in patients with solid tumors
Authors: Maniar Manoj , Mani Sridhar , Ghalib Mohammed H. , Roboz John , Ohnuma Takao , Advani Suresh , Rao Raghunadh , Doval D , Acharya Manmohan , O'Rourke Edward , Wilhelm Francois , Holland James F. , Taft David
Published: February 2011

Introduction: ON 01910. Na is an anti-cancer agent with demonstrated activity against both solid tumors and hematological cancers. The purpose of this research was to evaluate the effect of dose and administration schedule on ON 01910. Na pharmacokinetics (PK) in advanced, heavily pre-treated solid tumor patients. Methods: Data was collected in three Phase I protcols conducted in the US and in India covering a wide range of doses and intraveous infusion schedules: Protocol 1 (50-1375 mg/m2/day over 72 h); Protocol 2 (250 – 4450 mg/m2/day over 24 h) and Protocol 3 (2400-3200 mg over 2, 4 or 8 h). In several patients, pharmacokinetics were evaluated for more than 1 dosing cycle. Plasma samples were collected pre-dose and up to 72 hours post-infusion. ON 01910. Na plasma levels were determined by a validated LC/MS/MS method. Results: Ninety-five data sets from 81 patients were evaluated in this study. ON 01910. Na showed biphasic elimination from the plasma, regardless of dose and administration schedule. The functional half-life of ON 01910. Na, estimated from the initial decline of plasma levels following infusion termination, was less than 2 hours. This was confirmed in data from patients receiving prolonged infusions as ON. 01910. Na approached steady state levels within several hours after dose initiation. As noted in the table below, ON. 01910. Na clearance was lower at higher drug dosing rates. There were no differences in drug pharmacokinetics among the infusion schedules. Conclusion: The pharmacokinetics of ON 01910. Na is dose dependent. A continuous IV infusion would be recommended to treat patients because of its short plasma half-life and rapid clearance. Systemic drug exposure is not affected by type of dosing (flat dosing vs. BSA adjusted). No significant differences were noted between the PK profiles of patients in the US centers and the patients in the India centers.Effect of Dosing Rate on Clearance of ON 01910. NaDosing Rate (mg/m2/hr)NClearance (L/hr/m2)0-25189.3 ± 4.725-501610.0 ± 5.050-75209.2 ± 3.175-10065.5 ± 2.6100-200126.2 ± 3.8200-40083.3 ± 1.6400-800112.5 ± 1.8800-125041.9 +/− 0.47

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2766.
Abstract 2768: Development of a tubulin fractionation assay for the evaluation of “on target” activity of tubulin targeting agents in clinical PBMC samples
Authors: Matthews Clayton A. , Bibby David , Leske Annabell F. , Harvey Andrew J. , Kremmidiotis Gabriel
Published: February 2011

The novel agent, BNC105, is a tubulin polymerization inhibitor which acts as a vascular disruption agent (VDA). BNC105 exhibits 100-fold selectivity for activated endothelial cells compared to quiescent endothelial cells, providing a large differential between effects on cancer vasculature and normal vasculature. We developed a tubulin fractionation assay that enables evaluation of tubulin polymerisation changes in peripheral blood mononuclear cell samples (PBMCs) obtained from patients treated with BNC105. The assay capitalizes on the mass differences between polymerized and depolymerised tubulin to separate each fraction in a density gradient by ultracentrifugation. Experimental conditions during the extraction process were optimised to maintain the polymerisation state of tubulin. This optimisation was carried out in cell lines and PBMCs from healthy volunteers. Critical parameters include temperature, GTP concentration, DMSO concentration, pH, and buffer density. Tubulin monomer and polymer extracts were resolved using SDS-PAGE and transferred onto nitrocellulose membranes followed by detection using βI tubulin specific antibodies. The tubulin bands were analysed by densitometry and normalized to an actin loading control. Following exposure of cell lines or PBMCs to tubulin polymerisation inhibitors for a period of 60 minutes, the depolymerised tubulin fraction increased, while the polymerised tubulin fraction decreased. Conversely, exposure to tubulin polymerizing agents caused a greater proportion of tubulin to appear in the polymerized fraction. We used this method to evaluate the tubulin polymerisation status in PBMC samples obtained from cancer patients treated with BNC105. Samples were obtained prior to dosing and at 1, 2, 3-5, 7, and 24 hours post-dosing. Based on the data obtained, BNC105 treatment caused an 80% reduction in the polymerised tubulin fraction at the 1, 2 and 3-5 hour sampling time points. The amount of tubulin in the polymerised fraction returned to pre-dose levels by the 7 hour post-dose time point. The pharmacokinetic profile of BNC105 shows a steep curve reaching Cmax at around 20 minutes post-administration, followed by plasma clearance with no BNC105 detectable after the 7 hour time point. The pharmacokinetics of BNC105 supports our tubulin depolymerisation data with respect to response time and the subsequent recovery period. These results were reproducible, and have shown a similar pattern in all patients tested to date.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2768.
Abstract 2771: Clinical outcomes and prognostic factors in 83 patients with pancreatic cancer treated in phase I clinical trials at M.D. Anderson Cancer Center
Authors: Tsimberidou Apostolia M. , Vaklavas Christos , Wen Sijin , Hong David , Wheler Jennifer , Ng Chaan S. , Naing Aung , Uehara Cynthia , Wolff Robert , Kurzrock Razelle
Published: February 2011

Introduction. The outcomes of patients with pancreatic cancer treated on early-phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase I clinical trials at a single institution.

Patients and Methods. We reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics.

Results. Eighty-three patients were identified. The median age was 62 years (range, 39-81). There were 40 men and 43 women. The most common metastatic sites were liver (54% of patients), lung (51%), lymph nodes (37%), and peritoneum and omentum (24%). The median number of prior therapies was 2 (range, 0-7). Thirty-two (39%) patients had a history of pancreatectomy. Sixty-seven (81%) patients had ≥1 comorbidity. Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow-up for survivors of 3.7 months, the median survival from presentation in the Phase I Clinic was 5.0 months (95% CI, 3.3-6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9-26.5). The median time to treatment failure (TTF) was 1.5 months (95% CI, 1.3-1.8). In multivariate analysis, independent factors associated with lower rates of PR or SD were liver metastases (p = 0.001) and PS greater than 0 (p = 0.01) (Table 3). Independent factors associated with shorter survival were liver metastases (p = 0.007), calcium ≤ 8.4 mg/nL (p = 0.015), and elevated serum levels of CEA (>6 ng/mL; p = 0.005). Independent factors associated with shorter TTF were history of smoking (p = 0.009), liver metastases (p = 0.001), serum bilirubin levels >1 mg/dL (p = 0.007), and >1 prior therapy (p = 0.002).

Conclusions. The median survival in the current study (5 months) compares favorably to the median survival reported with best supportive care (3 months). Our results suggest that phase I clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2771.
Abstract 2780: Mammographic density and breast cancer tumor characteristics in the Multiethnic Cohort Study
Authors: Conroy Shannon M. , Pagano Ian , Kolonel Laurence N. , Maskarinec Gertraud
Published: February 2011

Mammographic density (MD), a strong risk factor for breast cancer, may reflect proliferation of breast epithelial and stromal cells in response to cumulative exposure to endogenous and exogenous hormones. Whether MD predicts subtypes of breast cancer defined by expression of the estrogen (ER+) and/or progesterone (PR+) receptor is unclear. Because factors associated with higher MD are associated with ER+PR+ breast cancers, we hypothesized that women with higher percent MD (dense breast tissue area to total breast area) would have a higher risk for ER+PR+ and a lower risk for ER-PR- breast cancers as compared to women with lower percent MD. In a nested case-control study, we compared the MD of 667 controls and 607 breast cancer cases among women of Caucasian, Japanese and Native Hawaiian ancestry in the Hawaii component of the Multiethnic Cohort Study. A reader blinded to disease status performed computer assisted density assessment on prediagnostic mammograms. Receptor status for breast cancers was obtained from the statewide Hawaii Tumor Registry. Tumors were classified into ER+PR+ (n=341), ER-PR- (n=50), ER+PR-/ER-PR+ (n=64) and unstaged/unknown (n=152). Mean density values were computed for women with more than one mammogram and modeled using polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for confounders. Mean percent MD was significantly greater for ER+PR+, but not for ER-PR- breast cancers compared to controls after adjusting for age: 37.3%, 28.9%, versus 29.4%, respectively. The overall ORs for a 10% increase in percent MD were similar for all breast cancer cases and for ER+PR+ and ER+PR-/ER-PR+ cancer subtypes: 1.22 (95% CI, 1.14-1.30), 1.25 (95% CI, 1.16-1.35) and 1.23 (95% CI, 1.07-1.42), respectively. Percent MD was not found to be a predictor for ER-PR- subtypes (OR for a 10% increase = 1.00, 95% CI, 0.84, 1.18). Our findings indicate that within a multiethnic population, women with higher MD have an increased risk for ER+PR+, but not ER-PR- breast cancer. Breast cancer subtypes are suspected to have diverse etiologies that respond to different treatments. Our findings support specific models of hormone-related triggers for the increased breast cancer risk associated with MD. Research supported by NCI grants: R37CA54281, R01CA85265 and R25CA90956.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2780.