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This music score was submitted for the Kaleidoscope 2020 Call for Scores, an open access collaboration with the UCLA Music Library.

PurposeTo determine the safety and efficacy of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with radiation for newly diagnosed glioblastoma (GBM) patients.Methods and materialsBetween March 21, 2002, and May 3, 2004, Radiation Therapy Oncology Group (RTOG) 0211 enrolled 31 and 147 GBM patients in the phase 1 and 2 arms, respectively. Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy (RT) and continued post RT for 18 months or until progression. Tissue microarrays from 68 cases were analyzed for EGFR expression.ResultsThe maximum tolerated dose (MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs (non-EIAEDs). All patients in the phase 2 component were treated at a gefitinib dose of 500 mg; patients receiving EIADSs could be escalated to 750 mg. The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal. Median survival was 11.5 months for patients treated per protocol. There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone, matched by RTOG recursive partitioning analysis (RPA) class distribution. Younger age was significantly associated with better outcome. Per protocol stratification, EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.ConclusionsThe addition of gefitinib to RT is well tolerated. Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.

Context.--Hormone receptors HER2/neu and Ki-67 are markers of residual risk in early breast cancer. An algorithm (IHC4) combining these markers may provide additional information on residual risk of recurrence in patients treated with hormone therapy. Objective.--To independently validate the IHC4 algorithm in the multinational Tamoxifen Versus Exemestane Adjuvant Multicenter Trial (TEAM) cohort, originally developed on the trans-ATAC (Arimidex, Tamoxifen, Alone or in Combination Trial) cohort, by comparing 2 methodologies. Design.--The IHC4 biomarker expression was quantified on TEAM cohort samples (n = 2919) by using 2 independent methodologies (conventional 3,30-diaminobezidine [DAB] immunohistochemistry with image analysis and standardized quantitative immunofluorescence [QIF] by AQUA technology). The IHC4 scores were calculated by using the same previously established coefficients and then compared with recurrence-free and distant recurrence-free survival, using multivariate Cox proportional hazards modeling. Results.--The QIF model was highly significant for prediction of residual risk (P < .001), with continuous model scores showing a hazard ratio (HR) of 1.012 (95% confidence interval [95% CI]: 1.010-1.014), which was significantly higher than that for the DAB model (HR: 1.008, 95% CI: 1.006-1.009); P < .001). Each model added significant prognostic value in addition to recognized clinical prognostic factors, including nodal status, in multivariate analyses. Quantitative immunofluorescence, however, showed more accuracy with respect to overall residual risk assessment than the DAB model. Conclusions.--The use of the IHC4 algorithm was validated on the TEAM trial for predicting residual risk in patients with breast cancer. These data support the use of the IHC4 algorithm clinically, but quantitative and standardized approaches need to be used. (Arch Pathol Lab Med. 2016; 140:66-74; doi: 10.5858/arpa.2014-0599-OA), With progressively improving outcomes, particularly for patients with estrogen receptor (ER)-positive early breast cancers, personalized risk stratification to direct appropriate therapy is increasingly important. Multiple approaches to the assessment of [...]

* Context.--There is critical need for standardization of HER2 immunohistochemistry testing in the clinical laboratory setting. Recently, the American Society of Clinical Oncology and the College of American Pathologists have submitted guidelines recommending that laboratories achieve 95% concordance between assays and observers for HER2 testing. Objective.--As a potential aid to pathologists for achieving these new guidelines, we have conducted an examination using automated quantitative analysis (AQUA analysis) to provide a standardized HER2 immunohistochemistry expression score across instruments (sites), operators, and staining runs. Design.--We analyzed HER2 expression by immunohistochemistry in a cohort (n = 669) of invasive breast cancers in tissue microarray format across different instruments (n = 3), operators (n = 3), and staining runs (n = 3). Using light source, instrument calibration techniques, and a new generation of image analysis software, we produced normalized AQUA scores for each parameter and examined their reproducibility. Results.--The average percent coefficients of variation across instruments, operators, and staining runs were 1.8%, 2.0%, and 5.1%, respectively. For positive/negative classification between parameters, concordance rates ranged from 94.5% to 99.3% for all cases. Differentially classified cases only occurred around the determined cut point, not over the entire distribution. Conclusions.--These data demonstrate that AQUA analysis can provide a standardized HER2 immunohistochemistry test that can meet current guidelines by the American Society of Clinical Oncology/College of American Pathologists. The use of AQUA analysis could allow for standardized and objective HER2 testing in clinical laboratories. (Arch Pathol Lab Med. 2009;133:1413-1419), HER2 testing in the clinical pathology laboratory has become commonplace as a companion diagnostic for determination of breast cancer patients to receive trastuzumab (Herceptin, Genentech Inc, San Francisco, California), a [...]

* Context.--Increased thymidylate synthase expression is a marker for decreased survival in colorectal cancer. Objective.--Thymidylate synthase localizes to both the nucleus and cytoplasm, but how the relationship of these expression levels affects colon cancer outcome has yet to be determined. Design.--Using AQUA, we assessed prognosis of thymidylate synthase expression as a function of subcellular localization in 2 retrospective cohorts of colorectal carcinoma. We used the first cohort (n = 599) as a training set, subsequently validating optimal expression cut points in the second cohort (n = 447). Results.--A significant association between decreased 5-year disease-specific survival and increased nuclear expression (16% decreased survival [72% to 56%] for the top 60% of nuclear-expressing tumors [P < .001]) and cytoplasmic expression (12% decreased survival [70% to 58%] for the top 54% of cytoplasmic-expressing tumors [P = .02]) was observed for the training set. A higher nuclear to cytoplasmic ratio also correlated significantly with decreased survival (15% decreased survival [66% to 51%] for the top 25% of tumors [P < .001]). Applying these findings to the validation set, as a function of time to recurrence, only the ratio (P = .03 [expression ratio]; P = .18 [nuclear]; P = .71 [cytoplasmic]) showed a significant association with decreased time to recurrence. Additionally, the expression ratio significantly added to the prognostic value given by the primary tumor pathologic classification and nodal status. Conclusions.--These data suggest the relationship of nuclear to cytoplasmic thymidylate synthase expression, given as a ratio of continuous AQUA scores, to be a strong predictor of colon cancer survival., Thymidylate synthase (TS) catalyzes the reductive methylation of deoxyuridylate in the pathway for the production of deoxythymidine triphosphate, which is critical for DNA synthesis. (1) Thymidylate synthase expression, as a [...]