Jennifer I. Payne

The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: Studies of drug use and dependence in caucasians†‡

A genetic variation in fatty acid amide hydrolase (FAAH), C385A (P129T), has been previously associated with risk for problem street drug use. FAAH is a mammalian enzyme that inactivates neuromodulatory‐signaling lipids including the endogenous cannabinoid 1 receptor agonist anandamide. We investigated in adult Caucasians (N = 749) whether this FAAH variant altered the risk for trying, regular use of or dependence on cannabis, alcohol or nicotine, traditional “gateway” drugs. Consistent with our knowledge that the A/A genotype results in reduced FAAH expression and activity in humans, subjects with the A/A genotype were less likely to be THC dependent than subjects with either a C/C or C/A genotype (11% vs. 26%, P < 0.05). No association was observed between the A/A genotype and risk for alcohol or tobacco regular use, or DSM IV dependence. Controlling for regular use of nicotine and sedatives, both identified as confounders, those with the A/A genotype were at significantly reduced risk for being THC dependent (OR 0.25, 95% CI: 0.07–0.88) as compared with those with the C/A or C/C genotype, supporting a link between alterations in the endocannabinoid system and THC dependence. Unexpectedly, we found an increased risk for regular use of sedatives among the A/A genotype group. The relationship between the FAAH A/A genotype and risk for drug dependence in this study was drug class specific, suggesting it is not part of a more general drug abuse effect. These results, particularly the observation of altered risk for sedative drug use, should be investigated further in multiple ethnic populations.

A Review of Interval Breast Cancers Diagnosed among Participants of the Nova Scotia Breast Screening Program

PURPOSE To conduct a radiologic review of interval breast cancer cases to determine rates of true interval and missed cancers in Nova Scotia, Canada. MATERIALS AND METHODS This quality assurance project was exempt from institutional review board approval. Interval cancer cases were identified among women aged 40-69 years who were participants in the Nova Scotia Breast Screening Program from 1991 to 2004. For each case, the index negative screening mammogram was reviewed blindly by three radiologists from a pool of experienced radiologists. Cases were identified as those with normal or abnormal findings, the latter being a case that required further investigation. True interval cases were identified as cases in which a minimum of two radiologists reviewed the findings as normal. True interval and missed cancer rates were calculated separately for women according to age group and screening interval (for ages 40-49 years, a 1-year interval; for ages 50-69 years, a 1-year and a 2-year interval). RESULTS The rate of missed cancers per 1000 women screened was one-half of the true interval rate among women screened annually (for ages 40-49 years, 0.45 vs 0.93; for ages 50-69 years, 1.08 vs 2.22). Among women aged 50-69 years who were screened biennially, the rate of missed cancers per 1000 women screened was one-third of the true interval rate (0.90 vs 3.15). Similarly, the rate of missed cancers per 10,000 screening examinations was one-half of the true interval rate among those 40-49 years old (1.95 vs 3.99) and one-third of the true interval rate among those 50-69 years old (3.34 vs 10.44). CONCLUSION In screening programs, true interval cancer rates should be differentiated from missed cancer rates as part of ongoing quality assurance.

The Burden of False-Positive Results in Analog and Digital Screening Mammography: Experience of the Nova Scotia Breast Screening Program

Purpose The Canadian Task Force on Preventive Health Care released recommendations for breast cancer screening, in part, based on harms associated with screening. The purpose of this study was to describe the rate of false-positive (FP) screening mammograms and to describe the extent of the investigations after an FP. Methods A cohort was identified that consisted of all screening mammograms performed through the Screening Program (2000-2011) with patients ages 40-69 years at screening. Rates of FP screening mammograms were calculated as well as rates of further investigations required, including additional imaging, needle core biopsy, and surgery. Analyses were stratified by 10-year age group, screening status (first vs rescreen), and technology. Results A total of 608,088 screening mammograms were included. The FP rate varied by age group, and decreased with increasing age (digital, 40-49 years old, FP = 8.0%; 50-59 years old, FP = 6.3%; 60-69 years old, FP = 4.6%). The FP rate also varied by screening status (digital, first screen, FP = 12.0%; rescreen, FP = 5.6%), and this difference was consistent across age groups. The need for further investigation varied by age group, with invasive procedures being more heavily used as women age (digital, rescreen group, surgery: 40-49 years old, 1.1%; 50-59 years old 1.6%, 60-69 years old, 1.8%). Conclusions Both the FP screening mammogram rate and the degree to which further investigation was required varied by age group and screening status. Reporting on these rates should form part of the evaluation of screening performance.

Utility of relative and absolute measures of mammographic density vs clinical risk factors in evaluating breast cancer risk at time of screening mammography

OBJECTIVE Various clinical risk factors, including high breast density, have been shown to be associated with breast cancer. The utility of using relative and absolute area-based breast density-related measures was evaluated as an alternative to clinical risk factors in cancer risk assessment at the time of screening mammography. METHODS Contralateral mediolateral oblique digital mammography images from 392 females with unilateral breast cancer and 817 age-matched controls were analysed. Information on clinical risk factors was obtained from the provincial breast-imaging information system. Breast density-related measures were assessed using a fully automated breast density measurement software. Multivariable logistic regression was conducted, and area under the receiver-operating characteristic (AUROC) curve was used to evaluate the performance of three cancer risk models: the first using only clinical risk factors, the second using only density-related measures and the third using both clinical risk factors and density-related measures. RESULTS The risk factor-based model generated an AUROC of 0.535, while the model including only breast density-related measures generated a significantly higher AUROC of 0.622 (p < 0.001). The third combined model generated an AUROC of 0.632 and performed significantly better than the risk factor model (p < 0.001) but not the density-related measures model (p = 0.097). CONCLUSION Density-related measures from screening mammograms at the time of screen may be superior predictors of cancer compared with clinical risk factors. ADVANCES IN KNOWLEDGE Breast cancer risk models based on density-related measures alone can outperform risk models based on clinical factors. Such models may support the development of personalized breast-screening protocols.

Impact of Detection Method and Age on Survival Outcomes in Triple-Negative Breast Cancer: A Population-Based Cohort Analysis

Background Most investigations have compared triple‐negative breast cancer (TNBC) to non‐TNBC to elucidate clinical or epidemiologic differences between subtypes. We examined a contemporary cohort of patients with primary TNBC by detection and age at diagnosis within a population‐based breast screening program to examine survival outcomes. Patients and Methods All women with a diagnosis of primary TNBC between January 1, 2005, and December 31, 2012, in Nova Scotia, Canada, were included. Clinicopathologic and detection variables were abstracted from the Nova Scotia Breast Screening Program. Patient charts were abstracted for adjuvant therapies and survival outcomes, supplemented by provincial vital statistical data. Results A total of 412 patients comprised the study population, with almost half aged over 60 years (46.3%) and 30.2% having screen‐detected disease. There were no significant differences in prognostic variables between age groups. Younger patients were more likely to receive adjuvant chemotherapy (96.3% ≤ 49 years vs. 31.2% ≥ 70 years), but there were no differences in disease‐free or breast cancer–specific survival between the age groups. For those with disease recurrence, median time to recurrence and death was shorter for younger patients (17 vs. 26 months, 16 vs. 33 months respectively; age 40‐49 vs. 70+). Those with screen‐detected disease had better disease‐free, breast cancer–specific, and overall survival outcomes. Conclusion Detection method may play a role in TNBC survival outcomes, thus supporting novel screening strategies for TNBC. Shorter time to survival events in the younger patient groups suggests that TNBC is a clinically heterogeneous disease despite similarities in prognostic factors across age. Micro‐Abstract Population‐based information on triple‐negative breast cancer (TNBC) is limited. We describe 412 patients with TNBC diagnosed between 2005 and 2012 within a population‐based comprehensive breast screening program. Younger patients experienced shorter times to disease recurrence and death compared to older patients. Screen‐detected cases had better survival than others, suggesting that new screening strategies for TNBC may improve outcomes.

Change is Afoot: Lower Extremity Amputation in Nova Scotia, 1996/97 to 2012/13

Results: Nearly 3,500 individuals had ≥1 LEA admissions over the period. On average, there were 281 LEA admissions annually (DM=194, no DM=87). Over time, the annual number of LEA admissions among those with DM was relatively stable despite increasing DM prevalence (3% in 1996/97 to 11% in 2012/13). The LEA admission rate among those with DM decreased > 55% from 47/10,000 to 21/10,000. Those with DM (vs those without) were far more likely to have an LEA admission: 51x, 16x, 10x, and 5x for individuals 20-59yr, 60-69yr, 70-79yr, and ≥80yr respectively. LEAs among those with DM were more likely to be at a lower level (41% at level of toe/foot/ankle vs 26% among those without DM). Length of LEA-related hospitalisation was similar for those with and without DM.