Cell of origin of transformed follicular lymphoma.

Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.

Estimating the contributions of speeding and impaired driving to insurance claim cost.

INTRODUCTION: Logistic regression modelling of crash counts likely associated with speeding and impaired driving was earlier found [Zheng, Y., Cooper, P. J., & Dean, C. B. (2007). Modeling the contribution of speeding and impaired driving to insurance claim counts and costs when contributing factors are unknown. Journal of Safety Research, 38(1)] to successfully predict known outcomes in a series of simulations, but the same types of models did not accurately predict average crash costs. The aim of the study reported here was to develop a means to adjust classification model results that would improve their cost-predicting efficiency. METHOD: A classification modelling process was adjusted at the back-end using non-linear optimization to rationalize the classified proportions with the true proportions when the model was applied to representative subsets of the training data. Corrections were developed to account for cost (severity) differences arising from the classification process that were not due to true variations. The process was then applied to insurance claim test data where crash contributors were unknown. RESULTS: The optimization and severity correction procedure resulted in substantial improvement in average crash cost prediction for both impaired and unsafe speed collision involvements. The error measured against true values in 20 simulations was about half for the adjusted classification model of what it was for either unadjusted classification or logistic regression models. CONCLUSIONS: Non-linear optimization of classification matrices appears to be a workable tool for improving the predictive efficiency of models where desired outcomes represent average characteristics of records as compared to simple counts or proportions. IMPACT ON INDUSTRY: Using the methodology on a full-year of insurance claim data indicated that reliance on police-reported records alone would have underestimated the total cost of unsafe speed and impaired crashes by about 40%. Since most jurisdictions use police data to base policy decisions and set program spending around such safety issues, this finding has important implications.

Modeling the contribution of speeding and impaired driving to insurance claim counts and costs when contributing factors are unknown.

PROBLEM: There are no specific indicators for distinguishing insurance claims related to speeding and impaired driving in the information warehouse at the Insurance Corporation of British Columbia. Contributing factors are only recorded for that part of the claim data that is also reported by the police. Most published statistics on crashes that are related to alcohol or speeding are based on police-reported data, but this represents only a fraction of all incidents. METHOD: This paper proposes surrogate models to estimate the counts and the average costs associated with speeding and impaired driving to insurance claims when contributing factors are unknown. Using police-reported data, classification rules and logistic regression models are developed to form such estimates. One approach applies classification rules to categorize insurance claims into those related to speeding, impaired driving, and other factors. The counts and the costs of insurance claims for each of these strata and overall are then estimated. A second method models the probability that an insurance claim is related to speeding or impaired driving using logistic regression and uses this to estimate the overall counts and the average costs of the claims. The two methods are compared and evaluated using simulation studies. RESULTS: The logistic regression model was found to be superior to the classification model for predicting insurance claim counts by category, but less efficient at predicting average claim costs. IMPACT: Having estimates of counts and costs of insurance claims related to impaired driving or speeding for all reported crash events provides a more accurate basis for policy-makers to plan changes and benefits of road safety programs.

Secondary Breast Cancer Risk by Radiation Volume in Women With Hodgkin Lymphoma.

PURPOSE: To determine whether the risk of secondary breast cancer (SBC) is reduced in women with Hodgkin lymphoma (HL) treated with smaller field radiation therapy (SFRT) versus mantle field radiation therapy (MRT). METHODS AND MATERIALS: We used the BC Cancer Agency (BCCA) Lymphoid Cancer Database to identify female patients treated for HL between January 1961 and December 2009. Radiation therapy volumes were categorized as MRT or SFRT, which included involved field, involved site, or involved nodal radiation therapy. SBC risk estimates were compared using competing risk analysis and Fine and Gray multivariable model: MRT ± chemotherapy, SFRT ± chemotherapy, or chemotherapy-only. RESULTS: Of 734 eligible patients, 75% of the living patients have been followed up for more than 10 years, SBC has developed in 54, and 15 have died of breast cancer. The 20-year estimated risks (competing risk cumulative incidence) for SBC differed significantly: MRT 7.5% (95% confidence interval [CI] 4.4%-11.5%), SFRT 3.1% (95% CI 1.0%-7.7%), and chemotherapy-only 2.2% (95% CI 1.0%-4.8%) (P=.01). Using a Fine and Gray model to control for death and patients lost to follow-up, MRT was associated with a higher risk of SBC (hazard ratio [HR] = 2.9; 95% CI 1.4%-6.0%; P=.004) compared with chemotherapy-only and with SFRT (HR = 3.3; 95% CI 1.3%-8.4%; P=.01). SFRT was not associated with a greater risk of SBC compared with chemotherapy-only (HR = 0.87; 95% CI 0.28%-2.66%; P=.80). CONCLUSION: This study confirms that large-volume MRT is associated with a markedly increased risk of SBC; however, more modern small-volume RT is not associated with a greater risk of SBC than chemotherapy alone.

Evaluation of the Risk of Relapse in Classical Hodgkin Lymphoma at Event-Free Survival Time Points and Survival Comparison With the General Population in British Columbia.

PURPOSE: Studies in classical Hodgkin lymphoma (cHL) typically measure the time to events from diagnosis. We evaluated the risk of relapse at event-free survival time points in cHL and compared the risk of death to expected mortality rates in British Columbia (BC). METHODS: The BC Cancer Agency Lymphoid Cancer Database was screened to identify all patients age 16 to 69 years diagnosed with cHL between 1989 and 2012 treated with the chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (or equivalent). We compared the observed mortality to the general population using age-, sex-, and calendar period-generated expected mortality rates from BC life-tables. Relative survival was calculated using a conditional approach and expressed as a standardized mortality ratio of observed-to-expected deaths. RESULTS: One thousand four hundred two patients were identified; 749 patients were male (53%), the median age was 32 years, and 68% had advanced-stage disease. The median follow-up time was 8.4 years. Seventy-two percent of relapses occurred within the first 2 years of diagnosis. For all patients, the 5-year risk of relapse from diagnosis was 18.1% but diminished to 5.6% for patients remaining event free at 2 years. For advanced-stage patients who were event free at 2 years, the 5-year risk of relapse was only 7.6%, and for those who were event free at 3 years, it was comparable to that of limited-stage patients (4.1% v 2.5%, respectively; P = .07). Furthermore, international prognostic score ≥ 4 and bulky disease were no longer prognostic in patients who were event free at 1 year. Although the relative survival improved as patients remained in remission, it did not normalize compared with the general population. CONCLUSION: Patients with cHL who are event free at 2 years have an excellent outcome regardless of baseline prognostic factors. All patients with cHL had an enduring increased risk of death compared with the general population.

Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008.

PURPOSE: To determine whether the patterns of relapse according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status changed in the contemporary era. PATIENTS AND METHODS: Female patients referred to the British Columbia Cancer Agency with biopsy-proven stage I to III breast cancer (BC), diagnosed between 1986 and 1992 (cohort 1 [C1]) and between mid-2004 and 2008 (cohort 2 [C2]), and with known ER and HER2 status were eligible. Data were prospectively collected. C2 patients were matched to C1 patients for stage, grade, and ER and HER2 status. The primary end point was hazard rate of relapse (HRR) for BC by study cohort according to biomarker status. Secondary outcomes included HRR according to stage, grade, and age and hazard rate of death (HRD). RESULTS: After matching, 7,178 patients were included (3,589 patients in each cohort). BC subtype distribution was as following ER positive/HER2 negative, 70.8%; ER positive/HER2 positive, 6.9%; ER negative/HER2 positive, 6.6%; and ER negative/HER2 negative, 15.8%. For the overall population, the HRR approximately halved in all yearly intervals to year 9 in C2 compared with C1. Differences in HRR between cohorts were greater in the initial five intervals for HER2-positive and ER-negative/HER2-negative BC. The HRR decreased in C2 compared with C1 for all disease stages and grades. The HRD in C2 also decreased compared with C1, although to a lesser extent. CONCLUSION: Although the pattern of relapse remains similar, there has been a significant improvement in BC relapse-free survival. Outcomes have improved for all BC subtypes, especially HER2-positive and ER-negative/HER2-negative BC, with the early spike in disease recurrence markedly decreased. These contemporary hazard rates are important for treatment decisions, patient discussions, and planning clinical trials of early BC.

The impact of hands-free message reception/response on driving task performance.

A series of closed-course driving experiments were conducted in which 41 drivers ranging in age from 19 to 70 were put through a series of increasingly challenging driving performance tasks both in the presence and absence of audible messages. The messages required specific responses and these, along with driving performance measures based on driver/vehicle response characteristics, were recorded. The results clearly showed a negative impact of the message task on driver decision-making performance when this involved the more complex tasks of weaving and especially left-turning. Such decision-making decrements in the presence of the messages were exacerbated by adverse pavement surface conditions.

Turning gap acceptance decision-making: the impact of driver distraction.

PROBLEM: A number of studies have found that use of in-car phones by drivers can interfere with the cognitive processing necessary for making appropriate and timely vehicle control decisions. However, the specific linkage between communication-based distraction and unsafe decision-making has not been sufficiently explored. METHOD: In a closed-course driving experiment, 39 subjects were exposed to approximately 100 gaps each in a circulating traffic stream of eight vehicles on an instrumented test track that was wet about half the time. The subjects were at the controls of an instrumented car, which was oriented in a typical left-turn configuration (traffic-crossing situation in North America) and with parking brake on and the transmission in neutral. The subjects were instructed to press on the accelerator pedal when they felt that a gap was safe to accept. Their performances were monitored and incentives were provided for balancing safe decision-making with expeditious completion of the task. For half of the gap exposures (randomly assigned), each subject was required to listen and respond to a complex verbal message. RESULTS: When not distracted, the subjects' gap acceptance judgment was found to be significantly influenced by their age, the gap size, the speed of the trailing vehicle, the level of "indecision," and the condition of the track surface. However, when distracted, the subjects did not factor pavement surface condition into the decision process. On wet pavement, the subjects were judged to have initiated twice the level of potential collisions when distracted by the messages that they did when not distracted. DISCUSSION: Listening/responding to verbal messages may reduce the capacity of drivers to process adequately all the important information necessary for safe decision-making. The effects of the messages in our study seemed to cause the subjects to misjudge gap size and speed information when operating under the additional disadvantage of adverse pavement condition. SUMMARY: Attention to complex messages while making decisions about turning through gaps in an on-coming vehicle stream was associated with significantly increased unsafe decision making by subjects in our experiment when the additional complexity of wet surface condition was introduced. IMPACT ON INDUSTRY: While the results reflected a somewhat artificial situation where the measure was signaled intention to act rather than the act itself, nevertheless, they do strongly suggest a scenario in which mental distraction could contribute to crash risk. With the rapid proliferation of telematics in the vehicle market, even with the laudable objectives represented by the Intelligent Transportation Systems initiative, there is a danger of the primary task of the driver being subordinated to a perceived need to enhance information flow to/from the external "world." Industry and governments need to work together to ensure that apparently desirable in-vehicle communication improvements do not compromise safety.

Computational approaches to predicting the impact of novel bases on RNA structure and stability.

The use of computational modeling techniques to gain insight into nucleobase interactions has been a challenging endeavor to date. Accurate treatment requires the tackling of many challenges but also holds the promise of great rewards. The development of effective computational approaches to predict the binding affinities of nucleobases and analogues can, for example, streamline the process of developing novel nucleobase modifications, which should facilitate the development of new RNAi-based therapeutics. This brief review focuses on available computational approaches to predicting base pairing affinity in RNA-based contexts such as nucleobase-nucleobase interactions in duplexes and nucleobase-protein interactions. The challenges associated with such modeling along with potential future directions for the field are highlighted.

The impact of replacing heavy passenger vehicles (LTVs and SUVs) in the British Columbia fleet with lighter versions.

OBJECTIVE: The study reported in this article addressed the potential safety impact of consumer movement toward smaller vehicle choices by examining the makeup of the full British Columbia (BC) vehicle fleet--from smaller cars to heavy commercial vehicles. The basic assumption made was that some operators of heavy light trucks/vans (LTVs) or sport utility vehicles (SUVs) would, in the short term, be induced to downsize to lighter vehicles of the same type. METHOD: The 2000-2007 BC crash-claim data at the Insurance Corporation of British Columbia (ICBC) was used to create matrices of average information by culpable and nonculpable entities in two-vehicle collisions in 15 weight categories. Models for the effects of various driver/crash characteristics on injury potential were created and used to adjust the effect calculated solely on the basis of weight change. Levels of heavy LTV/SUV replacement from 0.05 to 0.95 of the current population were tested and the redistribution of vehicles was done in such a way that the relationship between small-large vehicle injury ratio and large-small vehicle mass ratio over the whole fleet remained constant as did the relative proportions of culpable and nonculpable involvements. RESULTS: The net effect of downsizing in the manner assumed for this study was mildly positive in terms of overall injury risk--that is, downsizing resulted in slightly fewer total injuries--but not in the case of fatalities, which tended to be increased by a more substantial margin. However, the results showed that even replacing substantial proportions of the heavy LTV/SUV population would not result in a large impact on safety. CONCLUSIONS: Replacing almost all the heavy LTV/SUVs with lighter versions should reduce injuries by less than 1 percent and increase fatalities by 3.5 percent percent. Nevertheless, in terms of persons impacted and the associated costs, the effects would be noticeable. The issue for policy-makers is to judge how the environmental benefits associated with encouraging such change compare with the net costs in terms of safety outcomes.