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Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer.
Lee, JS, Yost, SE, Blanchard, S, Schmolze, D, Yin, HH, Pillai, R, Robinson, K, Tang, A, Martinez, N, Portnow, J, et al
Breast cancer research : BCR. 2019;(1):119
Abstract
BACKGROUND Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). RESULTS Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). CONCLUSION Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.
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The impact of self-identified race on epidemiologic studies of gene expression.
Sharma, S, Murphy, A, Howrylak, J, Himes, B, Cho, MH, Chu, JH, Hunninghake, GM, Fuhlbrigge, A, Klanderman, B, Ziniti, J, et al
Genetic epidemiology. 2011;(2):93-101
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Abstract
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4(+) lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10(-16)). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV(1)). Though unadjusted linear models of FEV(1) identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV(1) and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
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Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma.
Dempsey, MF, Wyper, D, Owens, J, Pimlott, S, Papanastassiou, V, Patterson, J, Hadley, DM, Nicol, A, Rampling, R, Brown, SM
Nuclear medicine communications. 2006;(8):611-7
Abstract
BACKGROUND Herpes simplex virus 1716 (HSV1716), a selectively replication competent mutant of HSV1, is under investigation as an oncolytic viral therapy in human malignant glioma. As with similar therapies, a technique for measurement of viral replication and distribution over time following virus administration is required. Imaging expression of the HSV-thymidine kinase (HSV-tk) gene offers an opportunity for non-invasive assessment of viral distribution in living subjects. This is the first study to explore the use of HSV-tk as a reporter gene and radiolabelled thymidine analogue 5-[(123)I]iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil ((123)I-FIAU) as a marker substrate to non-invasively monitor HSV1716 replication in humans during treatment of high-grade glioma. METHODS I-FIAU brain SPECT imaging was undertaken in eight patients receiving intra-tumoural injection of HSV1716, before and after administration of the virus. Baseline images were acquired 3 days prior to virus administration and between 1 and 5 days following virus administration. Region of interest analysis was used to investigate whether there was an increase in (123)I-FIAU concentration following virus administration due to HSV-tk expression. RESULT Increased (123)I-FIAU accumulation due to HSV-tk expression was not detected in this study. The possible explanations for this finding are explored and design options for future studies are discussed.
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D-GPCR: a novel putative G protein-coupled receptor overexpressed in prostate cancer and prostate.
Weigle, B, Fuessel, S, Ebner, R, Temme, A, Schmitz, M, Schwind, S, Kiessling, A, Rieger, MA, Meye, A, Bachmann, M, et al
Biochemical and biophysical research communications. 2004;(1):239-49
Abstract
The use of molecular targets in novel strategies of tumor treatment largely depends on the identification of proteins with a tumor- or tissue-restricted expression. We identified the novel protein D-GPCR that is selectively overexpressed in human prostate cancer and prostate and belongs to the subfamily of odorant-like orphan G protein-coupled receptors. Quantification of D-GPCR transcripts in different human tissues by real-time PCR demonstrated 27-fold overexpression in prostate compared to skeletal muscle, the organ with second highest transcript numbers in males. Investigation of tumor/normal cDNA pairs obtained from 241 cancer patients including four prostate tumors confirmed the preferential expression in prostate. When comparing the mean transcript level of 15 prostate cancer tissues to their non-tumorous counterparts, D-GPCR was almost 6-fold upregulated. Coupled in vitro transcription and translation of D-GPCR cDNA produced a protein band of approximately 28 kDa. Recombinant, His-tagged protein was expressed in transfected HEK293 cells and gave rise to a 30 kDa band specifically detected by anti-His antibody. These data provide the basis for future studies evaluating the diagnostic potential of D-GPCR and its utility as a novel target in immunotherapy of prostate cancer.
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How really rare are rare diseases?: the intriguing case of independent compound mutations in the long QT syndrome.
Schwartz, PJ, Priori, SG, Napolitano, C
Journal of cardiovascular electrophysiology. 2003;(10):1120-1