Chemotherapy is frequently used in the treatment of advanced breast cancer. The identification of patient-specific tumor characteristics that can improve the ability to predict response to chemotherapy would help optimize advanced breast cancer treatment approaches. Quantitative immunofluorescence (QIF) may be applied to the standardization of protein analysis, resulting in increased sensitivity and reproducibility. In the current pilot study, QIF was used to correlate the expression of beta tubulin III and thymidylate synthase with clinical outcome associated with taxane and capecitabine treatment, respectively. QIF analysis is based on fluorescent dye-labeled monoclonal antibody staining followed by computer-assisted microscopy to measure the expression of molecular markers in tumor samples derived from a retrospective database. The interpretation of the tumor marker expression levels results in classification of breast tumors as sensitive or resistant to a mechanistically related drug. Overall diagnostic accuracy of QIF for taxane based therapy was 88% (CI 75.0 - 95.3) with a positive predictive value of 86% and a negative predictive value of 100%, while diagnostic accuracy QIF for capecitabine therapy was 86% (CI 88.0-96.0) with a positive predictive value of 80% and a negative predictive value of 100%. In this study, QIF showed retrospectively a potential for predictive value when analyzing chemotherapeutic treatments for individual advanced stage breast cancer patients. The predictive power of the QIF for chemotherapy confirms that further studies utilizing larger clinical cohorts are warranted.

B35 For treatment of breast cancer patients, limited options are available for selecting optimal treatment regimen for a particular patient at a given stage of disease. DRIT is a diagnostic service that predicts treatment outcomes prior to selection of anticancer drug therapy for individual patients. A retrospective study utilizing DRIT was conducted to predict treatment outcomes in advanced breast cancer patients (ABC). DRIT quantitatively measures Drug Response Indicator (DRI) expression levels in formalin fixed, paraffin embedded tumor tissue. DRI chosen for each drug is indicative of tumor response as related to mechanism of drug action. This relationship is verified in vitro with 8-10 cancer cell lines of differing drug sensitivity by correlating drug toxicity (IC50) and DRI expression. For each drug/DRI pairing, a cut off level for dichotomized prediction of sensitive versus resistant tumor is generated based on DRI expression level in tumor. DRI quantitation in over 500 tumor cells is based on fluorescent dye-labeled monoclonal antibody staining, followed by analysis of digital images using computer-assisted microscopy, calibrated to external standard. DRI expression measurement results in tumor classification as sensitive or resistant to a particular drug. A tumor classified as sensitive by DRIT predicts that patient (Pt) will respond to treatment, while a tumor that is classified as resistant predicts that Pt will be non-responsive. Clinically, treatment outcome is based on RECIST guidelines and classified into responsive group (non-progressive disease, CR, PR, SD) and non-responsive group (progressive disease, PD). The drugs and DRI tested are: capcitabine/thymidylate synthase; taxanes /β-tubulin isoform III; trastuzumab/HER-2; endocrine therapy/estrogen receptor; gemcitabine/ribonucleotide reductase. Fifty-one ABC received mono or doublet therapy as first 3 lines of therapy (80 treatments). Retrospective trial results are shown with values representing - Accuracy %, Sensitivity, Specificity, Positive Predictive Value and Negative Predictive Value, respectively: Endocrine Therapy - 93 %( 39/42), 1.00, 0.40, 0.93, 1.00; Chemotherapy - 81 %( 22/27), 1.00, 0.58, 0.75, 1.00; Doublet Therapy - 91 %( 10/11), 0.89, 1.00, 1.00, 0.67; Cumulative Results - 89 %( 71/80), 0.98, 0.58, 0.88, 0.92. Favorable response rate for standard of care outcome is 75% (60/80), while the potential favorable response rate using DRIT is 88% (60/68). Accuracy for prediction of ineffective treatments is 92% (11/12). In addition, DRIT prediction accuracy for estrogen receptor expression (ER) was compared with that of a FDA approved commercial assay for prediction of ER status. The objective prediction accuracy of DRIT is 93% (39/42), while the objective prediction accuracy of commercial assays is 74 % (31/42). A prospective study using DRIT to predict treatment outcomes in ABC is underway. The above study has been extended to consider Pts with GI cancer. Preliminary results indicate that DRIT may be used to predict patient response to drug therapy in GI cancer as well. These retrospective studies demonstrate that DRIT is a platform technology that can accurately predict treatment outcomes and can potentially improve response rates in treatment of ABC and possibly other cancers. Supported in part by Maryland Industrial Partnership Program.

Objectives: To evaluate whether two molecular biomarkers, thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), could be clinically useful in predicting and improving the chemotherapeutic outcome of the oral fluoropyrimidine capecitabine (5'-DFUR or Xeloda (R)), in the treatment of human head and neck squamous cell carcinoma (HNSCC).Experimental Design: Quantitative reverse-transcriptase polymerase chain reaction was used to determine the TP and DPD expression levels in different HNSCC cell lines. The TP to DPD ratio was calculated and compared to the relative chemosensitivity between cell lines after treatment with 5'-DFUR. The effect of TP transgene expression to alter the TP to DPD ratio and hence optimize the therapeutic outcome of capecitabine treatment was further evaluated in a murine model of human HNSCC using immunohistochemistry to detect TP and DPD expression in vivo.Results: No correlation was detected between sensitivity to 5'-DFUR and the relative expression levels of TP or DPD in the multiple HNSCC cell lines tested. However, significant correlation was observed between the TP to DPD ratio versus drug resistance of the HNSCC cells (r = -0.914, p = 0.0281). In addition, we demonstrate that transgene expression of TP significantly enhanced the tumoricidal effect of capecitabine in HNSCC tumors with otherwise low endogenous TP to DPD ratios. This antitumor effect was observed up to 30 days after treatment.Conclusions: The results of this study suggest that HNSCC patients who would most benefit from capecitabine-based chemotherapy could be identified by examining the TP to DPD ratio of their tumors. Furthermore, we demonstrate the potential role of TP gene therapy in TP to DPD ratio manipulation to optimize the tumoricidal effect of capecitabine.

Patients with recurrent SCCHN need effective therapies that do not compound tumor morbidity. We investigated the long term safety and prognostic factors influencing efficacy of adenoviral p53 gene therapy in a large series of SCCHN patients.

Otolaryngology–Head and Neck SurgeryVolume 129, Issue 2 p. P111-P112 Tuesday, September 23, 2003, Room OCCC 203 Session Category: Session B: Head and Neck Surgery and Oncology 11:20 am Targeted Adenovirus-Mediated RB94 and Cisplatin Approach for Head and Neck Cancer Douglas Chepeha MD, Douglas Chepeha MDSearch for more papers by this authorTerry TerryDay MD, Terry TerryDay MDSearch for more papers by this authorTed Teknos (moderators) MD, Ted Teknos (moderators) MDSearch for more papers by this authorBrian F Worden (presenter), Brian F Worden (presenter) San Francisco, CA Baltimore, MDSearch for more papers by this authorDaqing Li (presenter) MD, Daqing Li (presenter) MD San Francisco, CA Baltimore, MDSearch for more papers by this authorGuoyan Li MD, Guoyan Li MD San Francisco, CA Baltimore, MDSearch for more papers by this authorDavid Van Echo MD, David Van Echo MD San Francisco, CA Baltimore, MDSearch for more papers by this authorUwe Wirtz PhD, Uwe Wirtz PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorSunil X Sreedharan PhD, Sunil X Sreedharan PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorBert W O'Malley Jr MD, Bert W O'Malley Jr MD San Francisco, CA Baltimore, MDSearch for more papers by this author Douglas Chepeha MD, Douglas Chepeha MDSearch for more papers by this authorTerry TerryDay MD, Terry TerryDay MDSearch for more papers by this authorTed Teknos (moderators) MD, Ted Teknos (moderators) MDSearch for more papers by this authorBrian F Worden (presenter), Brian F Worden (presenter) San Francisco, CA Baltimore, MDSearch for more papers by this authorDaqing Li (presenter) MD, Daqing Li (presenter) MD San Francisco, CA Baltimore, MDSearch for more papers by this authorGuoyan Li MD, Guoyan Li MD San Francisco, CA Baltimore, MDSearch for more papers by this authorDavid Van Echo MD, David Van Echo MD San Francisco, CA Baltimore, MDSearch for more papers by this authorUwe Wirtz PhD, Uwe Wirtz PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorSunil X Sreedharan PhD, Sunil X Sreedharan PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorBert W O'Malley Jr MD, Bert W O'Malley Jr MD San Francisco, CA Baltimore, MDSearch for more papers by this author First published: 17 May 2016 https://doi.org/10.1016/S0194-59980300973-2Read the full textAboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume129, Issue2August 2003Pages P111-P112 RelatedInformation

Otolaryngology–Head and Neck SurgeryVolume 129, Issue 2 p. P111-P112 Tuesday, September 23, 2003, Room OCCC 203 Session Category: Session B: Head and Neck Surgery and Oncology 11:20 am Targeted Adenovirus-Mediated RB94 and Cisplatin Approach for Head and Neck Cancer Douglas Chepeha MD, Douglas Chepeha MDSearch for more papers by this authorTerry TerryDay MD, Terry TerryDay MDSearch for more papers by this authorTed Teknos (moderators) MD, Ted Teknos (moderators) MDSearch for more papers by this authorBrian F Worden (presenter), Brian F Worden (presenter) San Francisco, CA Baltimore, MDSearch for more papers by this authorDaqing Li (presenter) MD, Daqing Li (presenter) MD San Francisco, CA Baltimore, MDSearch for more papers by this authorGuoyan Li MD, Guoyan Li MD San Francisco, CA Baltimore, MDSearch for more papers by this authorDavid Van Echo MD, David Van Echo MD San Francisco, CA Baltimore, MDSearch for more papers by this authorUwe Wirtz PhD, Uwe Wirtz PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorSunil X Sreedharan PhD, Sunil X Sreedharan PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorBert W O'Malley Jr MD, Bert W O'Malley Jr MD San Francisco, CA Baltimore, MDSearch for more papers by this author Douglas Chepeha MD, Douglas Chepeha MDSearch for more papers by this authorTerry TerryDay MD, Terry TerryDay MDSearch for more papers by this authorTed Teknos (moderators) MD, Ted Teknos (moderators) MDSearch for more papers by this authorBrian F Worden (presenter), Brian F Worden (presenter) San Francisco, CA Baltimore, MDSearch for more papers by this authorDaqing Li (presenter) MD, Daqing Li (presenter) MD San Francisco, CA Baltimore, MDSearch for more papers by this authorGuoyan Li MD, Guoyan Li MD San Francisco, CA Baltimore, MDSearch for more papers by this authorDavid Van Echo MD, David Van Echo MD San Francisco, CA Baltimore, MDSearch for more papers by this authorUwe Wirtz PhD, Uwe Wirtz PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorSunil X Sreedharan PhD, Sunil X Sreedharan PhD San Francisco, CA Baltimore, MDSearch for more papers by this authorBert W O'Malley Jr MD, Bert W O'Malley Jr MD San Francisco, CA Baltimore, MDSearch for more papers by this author First published: 17 May 2016 https://doi.org/10.1016/S0194-59980300973-2Read the full textAboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume129, Issue2August 2003Pages P111-P112 RelatedInformation

Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50–100 μM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 μM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.

The plasma pharmacokinetics of the antineoplastic anthracycline antibiotic aclacinomycin A (Acm) and its metabolites were studied in 12 patients treated with 60–120 mg/m2 during a phase I clinical trial. Total plasma drug fluorescence initially declined very rapidly, but from 2 to 24 h after injection, fluorescence rose progressively to intensities greater than those measured 1 min after Acm injection. Plasma total drug fluorescence slowly declined from 24 to 72 hours after Acm administration. These events reflected the rapid disappearance of Acm and the subsequent appearance of two highly fluorescent metabolites. One metabolite co-chromatographed with and had a fluorescence spectrum identical to known metabolite F1 (bisanhydroaklavinone). The other metabolite did not co-chromatograph with any previously described Acm metabolite. This metabolite had a fluorescence spectrum unlike any previously described Acm metabolite and was not altered by treatment for 60 min with 0.2N HCl at 100°C or by treatment for 24h at 37°C with bacterial β-glucuronidase or limpet aryl sulfatase.