bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2704: Efficacy and candidate biomarker evaluation for the anti-MN immunoconjugate BAY 79-4620, MN-IC in MN (CAIX) positive preclinical xenograft models
Authors: Schatz Christoph A. , Peña Carol E. , Petrul Heike , Röse Lars , Kopitz Charlotte 
Published: February 2011

Abstract
BAY 79-4620 is a novel immunoconjugate consisting of a fully human monoclonal antibody directed against MN (carbonic anhydrase IX, CAIX) conjugated with the auristatin derivative MMAE currently in Phase I clinical testing. MN is overexpressed in a range of tumor types, such as gastric cancer, non-small cell lung cancer, pancreatic cancer or colorectal cancer. CAIX expression is regulated by HIF-1α and therefore associated with tumor hypoxia.
Here we report on the correlation of tumor CAIX antigen expression levels, as determined by a newly developed CAIX IHC staining protocol, and the efficacy of BAY 79-4620 in six preclinical tumor models. Further, CAIX levels in xenograft tumors were compared to those in clinical samples of human tumors. Efficacy of BAY 79-4620 in tumor models increased with their CAIX expression levels. HeLa-MaTu, HT29 and PC3mm2 models characterized by the highest expression of CAIX showed 56-92 % tumor growth inhibition, when treated with 1 mg/kg BAY 79-4620. Hs746T, the tumor model with the lowest CAIX level, did not show tumor growth inhibition at 1 mg/kg MN-IC, but responded to higher doses. Analysis of CAIX expression by IHC using human tumor samples (gastric, CRC, NSCLC and breast) demonstrated that tumor cell CAIX expression varied both within and between tumor types. IHC scoring revealed that 95% of colon cancer tumors, 55% of NSCLC tumors, and 35% of breast cancer tumors assayed had ≥10% of cells scoring 2+ or 3+ by IHC. In preclinical models analysis of serum CAIX extracellular domain (ECD) by ELISA revealed an initial rise in plasma CAIX ECD as early as 2 days after 30 mg/kg BAY 79-4620 followed by a decrease to below-baseline levels. In two out of three models tested, changes or increased levels of the apoptosis marker CK18 were observed following BAY 79-4620 administration. Changes in serum CAIX ECD levels as well as CK18 will be explored as an early pharmacodynamic (PD) response markers in clinical trials for BAY 79-4620.
In summary, these results demonstrate that targeted delivery of MMAE resulted in higher efficacy of BAY 79-4620 in tumor models with high CAIX expression. Responsive xenograft models were representative of clinical samples with respect to CAIX expression scored by IHC. Quantification of MN (CAIX) by IHC is a candidate stratification biomarker for the immunoconjugate BAY 79-4620 currently in Phase I testing.
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 2704.
Abstract 2705: Quantitative targeted proteomics in pancreatic cancer: Combinations of enzyme and transporter protein expression are novel indicators for gemcitabine sensitivity
Authors: Kawaguchi Kei , Motoi Fuyuhiko , Ohmine Ken , Ohtsuka Hideo , Ohtuki Sumio , Rikiyama Toshiki , Katayose Yu , Egawa Shinichi , Terasaki Tetsuya , Unno Michiaki 
Published: February 2011

Abstract
Background and Aims: Gemcitabine (GEM) is widely used as a first line agent for the treatment of pancreatic cancer. In some patients, it provides a long-term survival, while there are many non-responders. Recent advances in proteomics technology made it possible to quantitate trace proteins such as transporters and metabolic enzymes at high sensitivity enough to reflect the function of proteins in living organisms. In this study, we exhaustively quantitated the protein profiles of GEM related transporters and metabolic enzymes in pancreatic cancer cell lines and resected specimen using LC-MS/MS technique. We created the GEM sensitivity equation based on the profiles and the IC50 values of cell lines. This equation was validated using surgical specimens of pancreatic cancer.
Materials and Methods: We used 6 pancreatic cancer cell lines for profiling. Surgical specimens from 9 patients from March 2004 to January 2006 were classified GEM respond group (RS), GEM non-respond group (NR) and surgery effect group (SE) according to post-operative CA 19-9 value. The expression levels of 90 membrane proteins and 15 enzymes were quantified in 6 pancreatic cancer cell lines and 9 surgical specimens, by means of multiplexed MRM analysis with LC-MS/MS.
Results: Significant differences in the expression levels of dCK and Purine-5-NT were observed between responsive and non-responsive groups of patients, although no correlation of the expression levels of these proteins with IC50 of gemicitabine was found in the cell lines. The expression levels of ten membrane proteins in the cell lines were correlated to IC50 of gemcitabine, but the expression levels of these proteins failed to predict the gemcitabine sensitivity of cancer tissues. Next, expression ratios of multiple proteins (transporters and enzymes) that were present in cancer tissues were calculated for the cell lines. dCK/(MRP1+MRP4), dCK/(MRP1+MRP4+Purine-5NT), dCK/(MRP1+MRP4+CTPS1) and dCK/(MRP1+MRP4+Purine-5NT+CTPS1) showed high correlation with IC50 values. For all four combinations, the protein expression ratio in the RS group was significantly higher than those in NR and SE groups.
Conclusion: Applying these equations, we can predict GEM sensitivity and tailor-made chemotherapy can be implemented.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 2705.
Abstract 2706: Discovery of predictive biomarkers based on differential chemosensitivity of colorectal cell lines
Authors: Unger Florian T. , Meyer Markus , Harasym Agnieszka , Spangenberg Jörg , Sullivan Kevin , Juhl Hartmut , David Kerstin A. 
Published: February 2011

Abstract
Chemoresistance is the main reason for therapeutic ineffectiveness and recurrence in colorectal cancer. Furthermore, the choice of optimal chemotherapy is complicated by an interpatient variability in drug response caused by the individual geno- and phenotype. To promote a more individualized therapy, predictive biomarkers which indicate individual drug response of patients are urgently needed.
In this study, using a combination of HPLC and mass spectroscopy, we discovered differentially expressed proteins which might be linked to specific phenotypes of intrinsic chemoresistance in colorectal cancer cell lines. Several commercially available cell lines as well as primary mixed cultures and clonal cell lines established from colorectal cancer patients were treated with different drugs, such as 5-Fluorouracil, Oxaliplatin and drug combinations e.g. FOLFOX. Two different assays, the ATPliteTM-(Perkin Elmer) and FMC-assay (according to Larsson et al.) were used in parallel to measure cytotoxic and cytostatic drug effects. Both assays showed time and dose dependent drug responses which differed significantly among the 18 colorectal cell cultures. The analysis of obtained in vitro chemosensitivity data allowed us to cluster sensitive versus resistant cell lines by determining IC50-values.
From all 18 cell cultures, differential protein expression was analyzed using a combination of reversed phase high performance liquid chromatography and matrix assisted laser desorption/ionization mass spectrometry (RP-HPLC MALDI MS) workflow. Up to 3500 m/z ion signals in the molecular mass range between 2500-35000 m/z were detected reflecting a complex pattern of small proteins and peptides. For protein identification, RP-HPLC fractionated samples were digested by trypsin and fragments of interest were subjected to MS/MS analysis in the TOF/TOF mode. The corresponding MS/MS spectra were used to search the NCBInr database using MASCOT software. Based on these data, we hope to gain more understanding of the biological processes of chemoresistance concerning important cellular drug responses (e.g. signal transduction pathways) and thereby obtain insight into new drug targets for future therapeutic intervention.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 2706.
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

Abstract
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

Abstract
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&lt;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

Abstract
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

Abstract
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) &lt; 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

Abstract
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.