External validation of a mammographic texture marker for breast cancer risk in a case–control study

Purpose: The pattern of dense tissue on a mammogram appears to provide additional information than overall density for risk assessment, but there has been little consistency in measures of texture identified. The purpose of this study is thus to validate a mammographic texture feature developed from a previous study in a new setting. Approach: A case–control study (316 invasive cases and 1339 controls) of women in Virginia, USA was used to validate a mammographic texture feature (MMTEXT) derived in a independent previous study. Analysis of predictive ability was adjusted for age, demographic factors, questionnaire risk factors (combined through the Tyrer-Cuzick model), and optionally BI-RADS breast density. Odds ratios per interquartile range (IQ-OR) in controls were estimated. Subgroup analysis assessed heterogeneity by mode of cancer detection (94 not detected by mammography). Results: MMTEXT was not a significant risk factor at 0.05 level after adjusting for classical risk factors (IQ-OR  =  1.16, 95%CI 0.92 to 1.46), nor after further adjustment for BI-RADS density (IQ-OR  =  0.92, 95%CI 0.76 to 1.10). There was weak evidence that MMTEXT was more predictive for cancers that were not detected by mammography (unadjusted for density: IQ-OR  =  1.46, 95%CI 0.99 to 2.15 versus 1.03, 95%CI 0.79 to 1.35, Phet 0.10; adjusted for density: IQ-OR  =  1.11, 95%CI 0.70 to 1.77 versus 0.76, 95%CI 0.55 to 1.05, Phet 0.21). Conclusions: MMTEXT is unlikely to be a useful imaging marker for invasive breast cancer risk assessment in women attending mammography screening. Future studies may benefit from a larger sample size to confirm this as well as developing and validating other measures of risk. This negative finding demonstrates the importance of external validation

The effect of phosphor persistence on image quality in digital x-ray scanning systems

grantor: University of TorontoA digital x-ray scanning system offers several advantages over conventional film-screen systems. However, there are sources of image degradation resulting from the scanning motion. One type of scanning motion blur is due to the temporal response of the phosphor. This mechanism produces an asymmetrical blur, requiring the use of the complex optical transfer function (OTF) for correct characterization of image resolution. The luminescence response of eight phosphors was measured under pulsed x-ray excitation. A weighted exponential model was used to represent the primary luminescence. The dominant luminescence lifetimes ranged from 2.7 $\mu$s for \rm Gd\sb2O\sb2S:Pr to 558 $\mu$s for \rm Gd\sb2O\sb2S:Tb. The long term response was also measured, monitoring significant increases in a slow form of luminescence known as afterglow. Afterglow was modeled by an inverse power law equation. Afterglow was found to be strong in at least two of the phosphors studied (ZnCdS:Ag and YTaO\sb4:Tm). In selecting a phosphor for a scanning system, it must satisfy several criteria, including a fast temporal response. Thus, a phosphor like \rm Gd\sb2O\sb2S:Tb, which has a slow luminescence, but otherwise excellent imaging properties, may not be as useful as a more rapid phosphor like CsI:Tl.M.Sc

Overdetection of Breast Cancer

Overdetection (often referred to as overdiagnosis) of cancer is the detection of disease, such as through a screening program, that would otherwise remain occult through an individual’s life. In the context of screening, this could occur for cancers that were slow growing or indolent, or simply because an unscreened individual would have died from some other cause before the cancer had surfaced clinically. The main harm associated with overdetection is the subsequent overdiagnosis and overtreatment of disease. In this article, the phenomenon is reviewed, the methods of estimation of overdetection are discussed and reasons for variability in such estimates are given, with emphasis on an analysis using Canadian data. Microsimulation modeling is used to illustrate the expected time course of cancer detection that gives rise to overdetection. While overdetection exists, the actual amount is likely to be much lower than the estimate used by the Canadian Task Force on Preventive Health Care. Furthermore, the issue is of greater significance in older rather than younger women due to competing causes of death. The particular challenge associated with in situ breast cancer is considered and possible approaches to avoiding overtreatment are suggested

Effect of Breast Screening Regimen on Breast Cancer Outcomes: A Modeling Study

Guidelines vary for the age at which to begin breast cancer screening and the interval between examinations. A validated computer model was used to compare estimated outcomes between various screening regimens. The OncoSim-Breast microsimulation model (Canadian Partnership Against Cancer) was used to simulate a cohort of 1.53 million Canadian women born in 1975. The effect of screening regimen on absolute breast cancer mortality rates, stage at diagnosis, number needed to be screened to avert a breast cancer death or save a life year, abnormal recall rates and negative biopsy rates was examined for unscreened women or those entering screening at age 40 or 50 and screened annually or biennially to age 74. Compared to no screening, absolute mortality reduction was 4.6 (biennial 50–74), 5.9 (biennial 40–74) and 7.9 (annual 40–74) fewer deaths per 1000 women. The absolute rate of diagnosis of advanced cancers (Stage 2, 3 and 4) falls in favor of earlier stages as the number of lifetime screens increases. Annual screening beginning at age 40 until age 74 would provide an additional reduction of 2 and 3.3 breast cancer deaths per 1000 women compared to biennial screening beginning at ages 40 and 50, respectively. There is a corresponding drop in the absolute number of Stage 2, 3 and 4 cancers diagnosed

Investigating the feasibility of stratified breast cancer screening using a masking risk predictor

Abstract Background Women with dense breasts face a double risk for breast cancer; they are at a higher risk for development of breast cancer than those with less dense breasts, and there is a greater chance that mammography will miss detection of a cancer in dense breasts due to the masking effect of surrounding fibroglandular tissue. These women may be candidates for supplemental screening. In this study, a masking risk model that was previously developed is tested on a cohort of cancer-free women to assess potential efficiency of stratification. Methods Three masking risk models based on (1) BI-RADS density, (2) volumetric breast density (VBD), and (3) a combination of VBD and detectability were applied to stratify the mammograms of 1897 cancer-free women. The fraction of cancer-free women whose mammograms were deemed by the algorithm to be masked and who would be considered for supplemental imaging was computed as was the corresponding fraction in a screened population of interval (masked) cancers that would be potentially detected by supplemental imaging. Results Of the models tested, the combined VBD/detectability model offered the highest efficiency for stratification to supplemental imaging. It predicted that 725 supplemental screens would be performed per interval cancer potentially detected, at an operating point that allowed detection of 64% of the interval cancers. In comparison, stratification based on the upper two BI-RADS density categories required 1117 supplemental screenings per interval cancer detected to capture 64% of interval cancers. Conclusion The combined VBD/detectability models perform better than BI-RADS and offer a continuum of operating points, suggesting that this model may be effective in guiding a stratified screening environment

Familial Posterior Fossa Brain Tumors of Infancy Secondary to Germline Mutation of the hSNF5 Gene

We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind beta-catenin, export it from the nucleus, and thereby repress beta-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of beta-catenin, and cannot inhibit beta-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB