Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer.

PURPOSE: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. RESULTS: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. CONCLUSIONS: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.

Long-term outcomes in fellow eyes after acute primary angle closure in the contralateral eye.

PURPOSE: To determine the long-term outcome of the contralateral eye in Asian persons with a unilateral attack of acute primary angle closure (APAC). DESIGN: Cross-sectional observational case series. PARTICIPANTS: Seventy-nine individuals who were examined from 4 to 10 years after a unilateral episode of APAC at 2 Singapore hospitals. METHODS: All subjects underwent a complete eye examination. The optic discs were graded clinically and photographically for the presence of glaucomatous optic neuropathy, and automated visual field tests were assessed for damage. All visual fields and optic nerve photographs (when available) underwent a second evaluation by a masked glaucoma specialist, who assessed whether the changes were compatible with glaucoma. MAIN OUTCOME MEASURES: Glaucomatous optic neuropathy, intraocular pressure (IOP), and visual impairment (defined as best-corrected visual acuity of worse than 6/12). RESULTS: Ninety of 138 eligible patients (65.2%) with APAC were examined, 79 with unilateral attacks. Subjects were predominantly Chinese (n = 68; 86%). There were 54 females (68%), and mean age was 68.5+/-8.9 years (standard deviation) at the time of APAC, with a mean duration of 6.3+/-1.5 years from the time of the APAC episode to the study examination. The contralateral eyes of 7 patients (8.9%) had definite or probable glaucoma, 2 of whom were felt to have glaucoma in that eye at the time of the attack. Three eyes had markedly cupped optic discs (cup-to-disc ratio > or = 0.9). Thirteen eyes (16.9%) had best-corrected vision worse than 6/12, due to cataract in almost half the cases. Only 1 eye had vision < 6/60, the cause of which was corneal decompensation. One other patient had only a central island remaining with vision of 6/12. Mean IOP of the study participants was 15.7+/-4.7 mmHg, with 6 subjects (7.6%) having undergone trabeculectomy. CONCLUSIONS: Definite or probable glaucoma was present at the time of diagnosis in 2 (2.5%) fellow eyes and developed in an additional 5 (6.5%) with a mean follow-up of 6 years. More than 80% of this cohort retained good vision in the contralateral eye, in contrast to the eye that underwent APAC. Unoperated cataract accounted for most of the visual impairment in this group.

Long-term outcomes in asians after acute primary angle closure.

PURPOSE: To determine the long-term outcome of Asian eyes with an acute attack of primary angle closure (APAC) and to identify risk factors at presentation associated with the development of glaucomatous optic nerve damage. DESIGN: Cross-sectional observational case series. PARTICIPANTS: Ninety individuals who were initially seen with APAC 4 to 10 years previously at 2 Singapore hospitals. METHODS: All subjects underwent a complete eye examination, including visual acuity, visual field testing, dilated eye examination, and optic nerve head photography. The optic discs were judged clinically and photographically as to whether there was glaucomatous optic neuropathy present, and visual fields were assessed for corresponding visual field loss. All visual fields and optic nerve photographs underwent a second evaluation by an experienced, but masked, glaucoma specialist, who assessed whether the changes were compatible with glaucoma. MAIN OUTCOME MEASURES: The main outcome measures were blindness (defined as best-corrected visual acuity worse than 6/60 and/or central visual field of less than 20 degrees in the attack eye) and glaucomatous optic neuropathy (GON). RESULTS: A total of 90 of 170 eligible subjects (65.2%) were examined. All subjects were Asian and were predominantly Chinese (78 subjects [86.7%]). There were 61 females (67.8%), and the age of the subjects was 62.0+/-9.0 years (mean +/- standard deviation) at the time of APAC, with a mean duration of 6.3+/-1.5 years from the time of the APAC episode to the study examination. Sixteen (17.8%) subjects were blind in the attack eye; half of the cases of blindness were caused by glaucoma. Forty-three subjects (47.8%) had GON, with 13 eyes (15.5%) having markedly cupped optic discs (cup-to-disc ratio >0.9). Thirty-eight eyes (58%) had best-corrected vision worse than 6/9, with cataract responsible for close to half the cases of poor vision. There were no identifiable risk factors related to the APAC episode that were significantly associated with the presence of GON. CONCLUSIONS: Several years after being seen with APAC, 17.8% of subjects examined were blind in the attack eye, and almost half had glaucomatous optic nerve damage. Vision was also reduced in a large number of individuals, largely from unoperated cataract. Subjects with APAC would benefit from regular follow-up to monitor for visual field decline and glaucoma development.