ABSTRACT
Previous studies have shown that eye drop application of the selective α7 nicotinic acetylcholine receptor agonist, PNU-282987, induces neurogenesis of RGCs in adult wild-type rodents. This study was designed to test the hypothesis that PNU-282987 reverses the loss of RGCs associated with glaucoma. A DBA/2J mouse model that auto-induces a glaucoma-like condition in adulthood was used for these studies. Short-term effects using PNU-282987 and BrdU eye drop treatments were examined, as well as the effects of early treatment and the effects in a chronic early treatment group in DBA/2J mice aged 3, 6 and 10 months. With and without treatment, retinas were removed, fixed, immunostained and RGC counts were assessed. IOP measurements were obtained weekly using a Tonolab tonometer. Results showed an average typical loss of BrdU positive RGCs by 29% by 10 months of age in this DBA/2J colony corresponding with a significant increase in IOP. However, the two-week short term application of PNU-282987 and BrdU induced a significant 21% increase in RGCs for DBA/2J mice at all ages. Chronic early PNU-282987 treatment produced a similarly significant increase in RGCs, while acute early treatment had no effect on RGC numbers. IOP measurements were not affected with PNU-282987 treatment. These studies demonstrated that 2-week treatment with PNU-282987, as well as chronic long-term treatment, induced a significant increase in the number of RGCs in the DBA/2J retina, counteracting the effects of the DBA/2J genetic glaucoma-like condition. These results suggest a potential future treatment of degenerative retinal diseases with PNU-282987.
ABSTRACT
PURPOSE: To assess the effect of local-regional radiotherapy (RT) on the outcome of breast cancer patients with > or = 10 positive axillary lymph nodes who have received modern conventional or high-dose systemic therapy. METHODS AND MATERIALS: A total of 55 women with local-regionally confined breast cancer involving 10 or more axillary nodes were treated between October 1983 and January 1996. Local-regional therapy consisted of modified radical mastectomy in 39 and breast-conserving surgery in 16. Postoperative radiotherapy was given to 44 of the 55 patients. Radiotherapy consisted of tangential fields to the chest wall or intact breast to a median dose of 50.40 Gy. A total of 86% (38 of 44) received regional nodal irradiation as follows: 35 patients received RT to the supraclavicular (SC) region and axillary midplane to a median dose of 50.40 Gy and 46.20 Gy, respectively; 3 patients received RT to the SC region without inclusion of the axilla to a median dose of 50. 40 Gy. All patients received adjuvant standard-dose systemic chemotherapy, 9 of whom received additional intensification chemotherapy followed by autologous bone-marrow transplant (ABMT) or peripheral blood stem-cell transplant (PBSC). Twenty-five patients received adjuvant tamoxifen. RESULTS: With a median follow-up of 30 months, the crude overall survival (OS) and disease-free survival (DFS) for the entire group were 67% and 53%, respectively. On univariate analysis of various clinical, pathological, and therapy-related features, radiotherapy emerged as the most important factor influencing the relapse rate. The addition of RT was significantly associated with an improved DFS (p = 0.003), specifically by prolonging the time to disease progression. The median time to failure was 61 months and 12.5 months with and without RT, respectively. Patients receiving RT also appeared to survive longer; however, the groups were not statistically different (p = 0.10). Analysis of the patterns of failure showed local-regional recurrence (LRR) as the first site of failure in 12 (22%) of 55 and distant failure in 20 (36%) of 55. Univariate results revealed both radiotherapy and tamoxifen to be significantly associated with decreased LRR rates (p = 0.0001 and p = 0.03, respectively); only RT remained independently significant on multivariate analysis. CONCLUSION: Local-regional radiotherapy is an essential component of the management of breast cancer patients with extensive nodal involvement, despite the use of contemporary adjuvant chemotherapy including high-dose regimens with autologous rescue. In addition to the expected improvement in LRR, radiotherapy is also associated with significantly prolonged DFS and a trend for improvement in OS.
