Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III.

Hereditary spherocytosis (HS) is an inherited haemolytic anaemia, characterized by spheroidal, osmotically fragile red blood cells. This disorder exhibits heterogeneity in terms of both clinical severity and underlying molecular defect. We have studied a South African Cape Coloured individual with severe HS owing to a band 3 deficiency caused by two mutations, occurring in trans, in the band 3 gene: a novel variant that we have designated band 3 Cape Town and a previously described mutation, band 3 Prague III. Analysis of erythrocyte membrane proteins indicated a deficiency of both band 3 and protein 4.2, as well as a decreased functional capacity of band 3 to transport anions. Band 3 Cape Town is defined by a GAG-->AAG point mutation at codon 90, substituting a glutamic acid with a lysine in the cytoplasmic domain of the molecule, while band 3 Prague III is a codon 870 CGG-->TGG point mutation, replacing an arginine with a tryptophan in the transmembrane region of band 3. mRNA is transcribed from both mutant alleles, implying that mutant proteins are synthesized, but are either degraded prior to membrane incorporation or insertion is impaired. We conclude that the combination of these two mutations exacerbated the clinical presentation of the proband.

Wagering on a large scale: Relationships between public gambling and game manipulations in two state lotteries.

Public wagering was examined in relation to game adjustments during the first 523 draws of Oregon's "Megabucks" lottery and the first 540 draws of Arizona's "The Pick" lottery. Oregon's lottery was modified five times during this period, and Arizona's lottery underwent four modifications. Public wagering was not related to decreases in the odds of winning in either state. Wagering increased in both states following the introduction of a minimum $1 million jackpot. Wagering also increased following a change in game frequency from weekly to semiweekly draws. Sales trends in both states suggest that over the period examined, larger jackpots were required to maintain previous levels of lottery play. These data suggest that public participation in gambling can be manipulated by state lottery commissions through adjustments in lottery contingencies.

Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors.

This study was designed to identify clinical predictors for early and late ovarian hyperstimulation syndrome (OHSS). A retrospective analysis of all 592 in-vitro fertilization (IVF) cycles from the programme's inception in 1988 up to March 1993 was performed. Six patients (1.0% of cycles) had moderate or severe OHSS presenting 3-7 days post-human chorionic gonadotrophin (HCG), and four patients (0.7% of cycles) had severe OHSS presenting 12-17 days post-HCG. No patient with early OHSS went on to develop late OHSS, and no patient with late OHSS had demonstrated early OHSS. Stepwise logistic regression showed that early OHSS was predicted by the number of oocytes retrieved (range 18-46) (P = 0.0001) and the oestradiol concentration on the day HCG was given (range 12,122-24,454 pmol/l) (P = 0.0003). Late OHSS was predicted by the number of gestational sacs (range 2-3) on ultrasound 4 weeks after embryo transfer (P = 0.0001) but not by the number of oocytes or oestradiol. Early OHSS was an acute effect of the HCG administered prior to egg retrieval in women with high oestradiol and larger numbers of follicles (range 22-51). Late OHSS was induced by the rising serum concentration of HCG produced by the early pregnancy, and in this series of cases it was associated only with multiple gestation.

Peer-managed self-control program for prevention of alcohol abuse in American Indian high school students: a pilot evaluation study.

A peer-managed self-control program to teach responsible drinking was tested with 30 American Indian teenagers at high risk for problem drinking. Students were randomly assigned to three groups incorporating combinations of self-monitoring, peer-assisted self-control training, and alcohol education. Significant decreases were observed in quantity and frequency of drinking and in peak blood alcohol levels. These improvements were maintained at follow-ups of 4, 9, and 12 months posttreatment. Self-report data were corroborated by breath tests and official records. No group differences were found, indicating that minimal and full program interventions had comparable effects.

Time reallocation in a multiresponse environment: Effects of restricting response classes.

Four adult male rats were each placed for three hours daily into an apparatus that provided individual compartments for six separate location-defined responses. The available responses consisted of: (1) the opportunity to turn off room lighting, producing darkness; (2) the opportunity to view a female rat; (3) the opportunity to turn off white noise; (4) the opportunity to drink; (5) the opportunity to eat; and (6) "other," representing time in the hallway between compartments. Each subject underwent a series of conditions characterized as an A-B-A-C-A design. Manipulations consisted of the removal of a low-probability response (darkness) and of a high-probability response (escape from noise) in a counter-balanced manner across subjects. The dependent measure for all subjects was the percentage of total session time spent in each compartment. Four predictive rules concerning the redistribution of behavior after response restriction were tested, including the constant-ratio rule, equal time redistribution, the most probable alternative, and the sequential-dependency rule. The results indicate no support for any of the four predictive rules and suggest that empirical assessment of restriction effects is necessary in reinforcement studies involving temporally extended responses.