Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139937/1/onco0795-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139937/2/onco0795-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139937/3/onco0795.pd

Randomized trial of standard adjuvant chemotherapy regimens versus capecitabine in older women with early breast cancer: 10-year update of the CALGB 49907 trial

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician's choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer-specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor-negative patients (HR, 0.66; P = .02), but not among hormone receptor-positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor-negative disease. Competing risks in this older population dilute overall survival benefits

Adjuvant Chemotherapy in Older Women with Early-Stage Breast Cancer

Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older

Enrichment of Hepatocyte-like Cells with Upregulated Metabolic and Differentiated Function Derived from Embryonic Stem Cells Using S-NitrosoAcetylPenicillamine

The generation of a large number of fully functional hepatocytes from a renewable cell source can provide an unlimited resource for bioartificial liver devices and cell replacement therapies. We have established a directed differentiation system using sodium butyrate treatment to generate an enriched population of hepatocyte-like cells from embryonic stem cells. A metabolic analysis of the hepatocyte populations revealed glycolytic and mitochondrial phenotypes similar to mouse hepatoma cells, implying that these cells represent an immature hepatocyte phenotype. To mediate further differentiation, S-NitrosoAcetylPenicillamine (SNAP), a nitric oxide donor, was utilized to induce mitochondrial development in the precursor populations. A comparative analysis of the different treated populations showed that 500 μM SNAP treatment resulted in the generation of an enriched population of metabolically mature hepatocyte-like cells with increased differentiated function. Specifically, 500 μM SNAP treatment increased glucose consumption, lactate production rates, mitochondrial mass, and potential as compared to untreated populations. In addition, functional analysis revealed that intracellular albumin content, urea secretion rates, and cytochrome P450 7a1 promoter activity were increased in the treated population. The methodology described here to generate an enriched population of metabolically and functionally mature hepatocyte-like cells may have potential implications in drug discovery and regenerative medicine

Aminoguanidine reduces glomerular inducible nitric oxide synthase (iNOS) and transforming growth factor-beta 1 (TGF-β1) mRNA expression and diminishes glomerulosclerosis in NZB/W F1 mice

Over-expression of iNOS is implicated in the pathogenesis of glomerulonephritis in animal models of systemic lupus erythematosus. The aim of this study was to evaluate the effect of aminoguanidine, a selective inhibitor of iNOS, for the protection from glomerulosclerosis in NZB/W F1 mice. Female NZB/W F1 mice (n = 8) were treated with aminoguanidine (1 g/l) in drinking water for 4 months starting at age 2 months before the onset of glomerulonephritis. Controls were age- and sex-matched mice (n = 10) without aminoguanidine treatment. By glomerular microdissection and reverse-transcription competitive polymerase chain reaction, we found that glomerular iNOS/β-actin and TGF-β1/β-actin mRNA ratios were reduced 15.1% (P < 0.05) and 61.3% (P < 0.01), respectively, in aminoguanidine-treated mice. Aminoguanidine significantly reduced the glomerular iNOS staining, urinary nitrite production and degree of glomerulosclerosis. In addition, the glomerular volume and mean glomerular cell number were reduced 33.2% (P < 0.01) and 32.8% (P < 0.01), respectively. Likewise, the urinary proteinuria was also significantly reduced by aminoguanidine. These results indicate that administration of aminoguanidine may reduce the progression of glomerulosclerosis in NZB/W F1 mice, possibly through inhibition of glomerular nitric oxide production