Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.

Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36-39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

Delay in the diagnosis of testicular tumours - changes over the past 18 years.

BACKGROUND: Delay in the diagnosis of testicular cancer is associated with greater morbidity and poorer prognosis. While the national agenda relates to reducing time to referral and diagnostic delay, delay in presentation has previously been recognised as a major cause of delay in the diagnosis of this patient group. AIMS: To evaluate changes in referral times and patient awareness among men with testicular cancer in Yorkshire over the past 18 years. DESIGN OF STUDY: Prospective cohort study. Comparison was made with a similar study in Yorkshire in 1985. SETTING: Leeds Cancer Centre Testicular Germ Cell Outpatient Clinic. METHOD: Three hundred and thirty-one men, newly diagnosed with testicular cancer between August 1998 and October 2002, were asked to complete a questionnaire. The time taken from when the patient first noticed symptoms to their first visit to their general practitioner (GP), from their first GP visit to their first hospital visit, and from their first hospital visit to orchidectomy were recorded. We also asked patients about the treatment they were offered at their first GP visit. RESULTS: Questionnaires were completed by 180 (54%) men. The median time that men took between when they first noticed symptoms and first visited their GP has decreased compared with 1985 (5 versus 2 weeks, respectively). No improvement was observed in referral times (mean = 3.55 versus 4.8 weeks). Ninety-one per cent of responders had heard of testicular cancer prior to diagnosis. CONCLUSION: Patient performance has improved over the past 18 years. The data lends support to the effectiveness of national health education initiatives aimed at increasing public awareness and self-examination. GPs performed well in this study, assessing and referring men appropriately and urgently into secondary care.

Lack of pharmacokinetic interaction between 5-fluorouracil and oxaliplatin.

OBJECTIVE: Our objective was to investigate the influence of oxaliplatin on the pharmacokinetics of 5-fluorouracil (5FU) administered in a bolus plus infusional regimen. PATIENTS AND METHODS: All patients had advanced/metastatic colorectal cancer. In study 1, 19 patients were studied after bolus (400 mg/m(2)) plus a 22-hour infusion (600 mg/m(2)) of 5FU/leucovorin in the standard de Gramont regimen or the same regimen with oxaliplatin (85 mg/m(2)) given before 5FU. In study 2, 12 patients were studied for 2 treatment cycles, with 5FU given in a modified de Gramont regimen comprising bolus (400 mg/m(2)) plus a 46-hour infusion (2400 mg/m(2)) of 5FU. During 1 of these cycles, oxaliplatin (85 mg/m(2)) was given before 5FU. RESULTS: The coadministration of oxaliplatin did not significantly alter 5FU area under the plasma concentration-time curve from 0 to 1 hour, area under the plasma concentration-time curve from time 0 to the last time point, or steady-state concentration in either the de Gramont (11.6 +/- 3.8 mg/L x h(-1), 14.9 +/- 4.2 mg x h/L, and 0.17 +/- 0.06 mg/L, respectively, for 5FU alone versus 9.4 +/- 2.6 mg/L x h(-1), 13.3 +/- 2.3 mg x h/L, and 0.16 +/- 0.04, respectively, for 5FU plus oxaliplatin) or modified de Gramont regimens (13.4 +/- 2.2 mg x h/L, 35.4 +/- 4.2 mg x h/L, and 0.46 +/- 0.08 mg/L, respectively, for 5FU alone versus 13.9 +/- 3.3 mg x h/L, 38.1 +/- 7.4 mg x h/L, and 0.53 +/- 0.12, respectively, for 5FU plus oxaliplatin). The inclusion of oxaliplatin coadministration as a covariate in a NONMEM analysis did not result in any change in the objective function or mean values for the following derived parameters: maximum velocity (1590 mg x h(-1)), day 1 Michaelis-Menten constant (7.8 mg x h(-1)), and day 2 Michaelis-Menten constant (11.9 mg x h(-1)). CONCLUSIONS: The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.