Cancer Yield and Patterns of Follow-up for BI-RADS Category 3 after Screening Mammography Recall in the National Mammography Database.

Background The literature supports the use of short-interval follow-up as an alternative to biopsy for lesions assessed as probably benign, Breast Imaging Reporting and Data System (BI-RADS) category 3, with an expected malignancy rate of less than 2%. Purpose To assess outcomes from 6-, 12-, and 24-month follow-up of probably benign findings first identified at recall from screening mammography in the National Mammography Database (NMD). Materials and Methods This retrospective study included women recalled from screening mammography with BI-RADS category 3 assessment at additional evaluation from January 2009 through March 2018 from 471 NMD facilities. Only the first BI-RADS category 3 occurrence for women aged 25 years or older with no personal history of breast cancer was analyzed, with biopsy or 2-year imaging follow-up. Cancer yield and positive predictive value of biopsies performed (PPV3) were determined at each follow-up. Results Among 45 202 women (median age, 55 years; range, 25-90 years) with a BI-RADS category 3 lesion, 1574 (3.5%) underwent biopsy at the time of lesion detection, yielding 72 cancers (cancer yield, 4.6%; 72 of 1574 women). For the remaining 43 628 women who accepted surveillance, 922 were seen within 90 days (with 78 lesions biopsied and 12 [15%] classified as malignant). The women still in surveillance (31 465 of 43 381 women [72.5%]) underwent follow-up mammography at 6 months. Of 3001 (9.5%) lesions biopsied, 456 (15.2%) were malignant (cancer yield, 1.5%; 456 of 31 465 women; 95% confidence interval [CI]: 1.3%, 1.6%). Among 18 748 of 25 997 women (72.1%) in surveillance who underwent follow-up at 12 months, 1219 (6.5%) underwent biopsy with 230 (18.9%) malignant lesions found (cancer yield, 1.2%; 230 of 18 748 women; 95% CI: 1.1%, 1.4%). Through 2-year follow-up, the biopsy rate was 11.2% (4894 of 43 628 women) with a cancer yield of 1.86% (810 malignancies found among 43 628 women; 95% CI: 1.73%, 1.98%) and a PPV3 of 16.6% (810 malignancies found among 4894 women). Conclusion In the National Mammography Database, Breast Imaging Reporting and Data System (BI-RADS) category 3 use is appropriate, with 1.86% cumulative cancer yield through 2-year follow-up. Of 810 malignancies, 468 (57.8%) were diagnosed at or before 6 months, validating necessity of short-interval follow-up of mammographic BI-RADS category 3 findings. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Moy in this issue.

Criteria for identifying radiologists with acceptable screening mammography interpretive performance on basis of multiple performance measures.

OBJECTIVE: Using a combination of performance measures, we updated previously proposed criteria for identifying physicians whose performance interpreting screening mammography may indicate suboptimal interpretation skills. MATERIALS AND METHODS: In this study, six expert breast imagers used a method based on the Angoff approach to update criteria for acceptable mammography performance on the basis of two sets of combined performance measures: set 1, sensitivity and specificity for facilities with complete capture of false-negative cancers; and set 2, cancer detection rate (CDR), recall rate, and positive predictive value of a recall (PPV1) for facilities that cannot capture false-negative cancers but have reliable cancer follow-up information for positive mammography results. Decisions were informed by normative data from the Breast Cancer Surveillance Consortium (BCSC). RESULTS: Updated combined ranges for acceptable sensitivity and specificity of screening mammography are sensitivity≥80% and specificity≥85% or sensitivity 75-79% and specificity 88-97%. Updated ranges for CDR, recall rate, and PPV1 are: CDR≥6 per 1000, recall rate 3-20%, and any PPV1; CDR 4-6 per 1000, recall rate 3-15%, and PPV1≥3%; or CDR 2.5-4.0 per 1000, recall rate 5-12%, and PPV1 3-8%. Using the original criteria, 51% of BCSC radiologists had acceptable sensitivity and specificity; 40% had acceptable CDR, recall rate, and PPV1. Using the combined criteria, 69% had acceptable sensitivity and specificity and 62% had acceptable CDR, recall rate, and PPV1. CONCLUSION: The combined criteria improve previous criteria by considering the interrelationships of multiple performance measures and broaden the acceptable performance ranges compared with previous criteria based on individual measures.

Rate and Timeliness of Diagnostic Evaluation and Biopsy After Recall From Screening Mammography in the National Mammography Database.

OBJECTIVE: To describe the rate and timeliness of diagnostic resolution after an abnormal screening mammogram in the ACR's National Mammography Database. METHODS: Abnormal screening mammograms (BI-RADS 0 assessment) in the National Mammography Database from January 1, 2008, to December 31, 2021, were retrospectively identified. The rates and timeliness of follow-up with diagnostic evaluation and biopsy were assessed and compared across patient and facility demographics. RESULTS: Among the 2,874,310 screening mammograms reported as abnormal, follow-up was documented in 66.4% (n = 1,909,326). Lower follow-up rates were observed in younger women (59.4% in women < 30 years, 63.2% in women 30-39 years), Black (57.4%) and American Indian (59.5%) women, and women with no breast cancer family history (63.0%). The overall median time to diagnostic evaluation was 9 days. Longer median diagnostic evaluation time was noted in Black (14 days), other or mixed race (14 days), and Hispanic women (13 days). Of the 318,977 recalled screening mammograms recommended for biopsy, 238,556 (74.8%) biopsies were documented. Lower biopsy rates were noted in older women (71.5% in women aged ≥80) and Black (71.5%) and American Indian (52.2%) women. The overall median time from diagnostic evaluation to biopsy was 21 days. Longer median biopsy time was noted in older (23 days aged ≥80), Black (25 days), mixed or other race (26 days), and Hispanic women (23 days), and rural (24 days) or community hospital affiliated facilities (22 days). DISCUSSION: There is variability in the rates and timeliness of diagnostic evaluation and biopsy in women with abnormal screening mammogram. Subsets of women and facilities could benefit from targeted interventions to promote timely diagnostic resolution and biopsy after an abnormal screening mammogram.

Mammographic interpretive volume and diagnostic mammogram interpretation performance in community practice.

PURPOSE: To investigate the association between radiologist interpretive volume and diagnostic mammography performance in community-based settings. MATERIALS AND METHODS: This study received institutional review board approval and was HIPAA compliant. A total of 117,136 diagnostic mammograms that were interpreted by 107 radiologists between 2002 and 2006 in the Breast Cancer Surveillance Consortium were included. Logistic regression analysis was used to estimate the adjusted effect on sensitivity and the rates of false-positive findings and cancer detection of four volume measures: annual diagnostic volume, screening volume, total volume, and diagnostic focus (percentage of total volume that is diagnostic). Analyses were stratified by the indication for imaging: additional imaging after screening mammography or evaluation of a breast concern or problem. RESULTS: Diagnostic volume was associated with sensitivity; the odds of a true-positive finding rose until a diagnostic volume of 1000 mammograms was reached; thereafter, they either leveled off (P < .001 for additional imaging) or decreased (P = .049 for breast concerns or problems) with further volume increases. Diagnostic focus was associated with false-positive rate; the odds of a false-positive finding increased until a diagnostic focus of 20% was reached and decreased thereafter (P < .024 for additional imaging and P < .001 for breast concerns or problems with no self-reported lump). Neither total volume nor screening volume was consistently associated with diagnostic performance. CONCLUSION: Interpretive volume and diagnostic performance have complex multifaceted relationships. Our results suggest that diagnostic interpretive volume is a key determinant in the development of thresholds for considering a diagnostic mammogram to be abnormal. Current volume regulations do not distinguish between screening and diagnostic mammography, and doing so would likely be challenging.

Mammographic interpretation: radiologists' ability to accurately estimate their performance and compare it with that of their peers.

OBJECTIVE: The purposes of this study were to determine whether U.S. radiologists accurately estimate their own interpretive performance of screening mammography and to assess how they compare their performance with that of their peers. SUBJECTS AND METHODS: Between 2005 and 2006, 174 radiologists from six Breast Cancer Surveillance Consortium registries completed a mailed survey. The radiologists' estimated and actual recall, false-positive, and cancer detection rates and positive predictive value of biopsy recommendation (PPV(2)) for screening mammography were compared. Radiologists' ratings of their performance as lower than, similar to, or higher than that of their peers were compared with their actual performance. Associations with radiologist characteristics were estimated with weighted generalized linear models. RESULTS: Although most radiologists accurately estimated their cancer detection and recall rates (74% and 78% of radiologists), fewer accurately estimated their false-positive rate (19%) and PPV(2) (26%). Radiologists reported having recall rates similar to (43%) or lower than (31%) and false-positive rates similar to (52%) or lower than (33%) those of their peers and similar (72%) or higher (23%) cancer detection rates and similar (72%) or higher (38%) PPV(2). Estimation accuracy did not differ by radiologist characteristics except that radiologists who interpreted 1000 or fewer mammograms annually were less accurate at estimating their recall rates. CONCLUSION: Radiologists perceive their performance to be better than it actually is and at least as good as that of their peers. Radiologists have particular difficulty estimating their false-positive rates and PPV(2).

Impact of the COVID-19 Pandemic on Breast Imaging: An Analysis of the National Mammography Database.

PURPOSE: The aim of this study was to quantify the initial decline and subsequent rebound in breast cancer screening metrics throughout the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Screening and diagnostic mammographic examinations, biopsies performed, and cancer diagnoses were extracted from the ACR National Mammography Database from March 1, 2019, through May 31, 2021. Patient (race and age) and facility (regional location, community type, and facility type) demographics were collected. Three time periods were used for analysis: pre-COVID-19 (March 1, 2019, to May 31, 2019), peak COVID-19 (March 1, 2020, to May 31, 2020), and COVID-19 recovery (March 1, 2021, to May 31, 2021). Analysis was performed at the facility level and overall between time periods. RESULTS: In total, 5,633,783 screening mammographic studies, 1,282,374 diagnostic mammographic studies, 231,390 biopsies, and 69,657 cancer diagnoses were analyzed. All peak COVID-19 metrics were less than pre-COVID-19 volumes: 36.3% of pre-COVID-19 for screening mammography, 57.9% for diagnostic mammography, 47.3% for biopsies, and 48.7% for cancer diagnoses. There was some rebound during COVID-19 recovery as a percentage of pre-COVID-19 volumes: 85.3% of pre-COVID-19 for screening mammography, 97.8% for diagnostic mammography, 91.5% for biopsies, and 92.0% for cancer diagnoses. Across various metrics, there was a disproportionate negative impact on older women, Asian women, facilities in the Northeast, and facilities affiliated with academic medical centers. CONCLUSIONS: COVID-19 had the greatest impact on screening mammography volumes, which have not returned to pre-COVID-19 levels. Cancer diagnoses declined significantly in the acute phase and have not fully rebounded, emphasizing the need to increase outreach efforts directed at specific patient population and facility types.

Timeliness of follow-up after abnormal screening mammogram: variability of facilities.

PURPOSE: To describe the timeliness of follow-up care in community-based settings among women who receive a recommendation for immediate follow-up during the screening mammography process and how follow-up timeliness varies according to facility and facility-level characteristics. MATERIALS AND METHODS: This was an institutional review board-approved and HIPAA-compliant study. Screening mammograms obtained from 1996 to 2007 in women 40-80 years old in the Breast Cancer Surveillance Consortium were examined. Inclusion criteria were a recommendation for immediate follow-up at screening, or subsequent imaging, and observed follow-up within 180 days of the recommendation. Recommendations for additional imaging (AI) and biopsy or surgical consultation (BSC) were analyzed separately. The distribution of time to follow-up care was estimated by using the Kaplan-Meier estimator. RESULTS: Data were available on 214,897 AI recommendations from 118 facilities and 35,622 BSC recommendations from 101 facilities. The median time to subsequent follow-up care after recommendation was 14 days for AI and 16 days for BSC. Approximately 90% of AI follow-up and 81% of BSC follow-up occurred within 30 days. Facilities with higher recall rates tended to have longer AI follow-up times (P < .001). Over the study period, BSC follow-up rates at 15 and 30 days improved (P < .001). Follow-up times varied substantially across facilities. Timely follow-up was associated with larger volumes of the recommended procedures but not notably associated with facility type nor observed facility-level characteristics. CONCLUSION: Most patients with follow-up returned within 3 weeks of the recommendation.

Accuracy of screening mammography varies by week of menstrual cycle.

PURPOSE: To investigate sensitivity, specificity, and cancer detection rate of screening mammography according to week of menstrual cycle among premenopausal women. MATERIALS AND METHODS: In this institutional review board-approved HIPAA-compliant study, sensitivity, specificity, and cancer detection rate of 387,218 screening mammograms linked to 1283 breast cancers in premenopausal women according to week of menstrual cycle were studied by using prospectively collected information from the Breast Cancer Surveillance Consortium. Logistic regression analysis was used to test for differences in mammography performance according to week of menstrual cycle, adjusting for age and registry. RESULTS: Overall, screening mammography performance did not differ according to week of menstrual cycle. However, when analyses were subdivided according to prior mammography, different patterns emerged. For the 66.6% of women who had undergone regular screening (mammography had been performed within the past 2 years), sensitivity was higher in week 1 (79.5%) than in subsequent weeks (week 2, 70.3%; week 3, 67.4%; week 4, 73.0%; P = .041). In the 17.8% of women who underwent mammography for the first time in this study, sensitivity tended to be lower during the follicular phase (week 1, 72.1%; week 2, 80.4%; week 3, 84.6%; week 4, 93.8%; P = .051). Sensitivity did not vary significantly by week in menstrual cycle in women who had undergone mammography more than 3 years earlier. There were no clinically meaningful differences in specificity or cancer detection rate. CONCLUSION: Premenopausal women who undergo regular screening may benefit from higher sensitivity of mammography if they schedule screening mammography during the 1st week of their menstrual cycle. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100974/-/DC1.

Influence of annual interpretive volume on screening mammography performance in the United States.

PURPOSE: To examine whether U.S. radiologists' interpretive volume affects their screening mammography performance. MATERIALS AND METHODS: Annual interpretive volume measures (total, screening, diagnostic, and screening focus [ratio of screening to diagnostic mammograms]) were collected for 120 radiologists in the Breast Cancer Surveillance Consortium (BCSC) who interpreted 783 965 screening mammograms from 2002 to 2006. Volume measures in 1 year were examined by using multivariate logistic regression relative to screening sensitivity, false-positive rates, and cancer detection rate the next year. BCSC registries and the Statistical Coordinating Center received institutional review board approval for active or passive consenting processes and a Federal Certificate of Confidentiality and other protections for participating women, physicians, and facilities. All procedures were compliant with the terms of the Health Insurance Portability and Accountability Act. RESULTS: Mean sensitivity was 85.2% (95% confidence interval [CI]: 83.7%, 86.6%) and was significantly lower for radiologists with a greater screening focus (P = .023) but did not significantly differ by total (P = .47), screening (P = .33), or diagnostic (P = .23) volume. The mean false-positive rate was 9.1% (95% CI: 8.1%, 10.1%), with rates significantly higher for radiologists who had the lowest total (P = .008) and screening (P = .015) volumes. Radiologists with low diagnostic volume (P = .004 and P = .008) and a greater screening focus (P = .003 and P = .002) had significantly lower false-positive and cancer detection rates, respectively. Median invasive tumor size and proportion of cancers detected at early stages did not vary by volume. CONCLUSION: Increasing minimum interpretive volume requirements in the United States while adding a minimal requirement for diagnostic interpretation could reduce the number of false-positive work-ups without hindering cancer detection. These results provide detailed associations between mammography volumes and performance for policymakers to consider along with workforce, practice organization, and access issues and radiologist experience when reevaluating requirements.

Performance of diagnostic mammography differs in the United States and Denmark.

Diagnostic mammography is the primary imaging modality to diagnose breast cancer. However, few studies have evaluated variability in diagnostic mammography performance in communities, and none has done so between countries. We compared diagnostic mammography performance in community-based settings in the United States and Denmark. The performance of 93,585 diagnostic mammograms from 180 facilities contributing data to the US Breast Cancer Surveillance Consortium (BCSC) from 1999 to 2001 was compared to that of all 51,313 diagnostic mammograms performed at Danish clinics in 2000. We used the imaging workup's final assessment to determine sensitivity, specificity and an estimate of accuracy: area under the receiver-operating characteristics (ROCs) curve (AUC). Diagnostic mammography had slightly higher sensitivity in the United States (85%) than in Denmark (82%). In contrast, it had higher specificity in Denmark (99%) than in the United States (93%). The AUC was high in both countries: 0.91 in United States and 0.95 in Denmark. Denmark's higher accuracy may result from supplementary ultrasound examinations, which are provided to 74% of Danish women but only 37% to 52% of US women. In addition, Danish mammography facilities specialize in either diagnosis or screening, possibly leading to greater diagnostic mammography expertise in facilities dedicated to symptomatic patients. Performance of community-based diagnostic mammography settings varied markedly between the 2 countries, indicating that it can be further optimized.

Identifying minimally acceptable interpretive performance criteria for screening mammography.

PURPOSE: To develop criteria to identify thresholds for minimally acceptable physician performance in interpreting screening mammography studies and to profile the impact that implementing these criteria may have on the practice of radiology in the United States. MATERIALS AND METHODS: In an institutional review board-approved, HIPAA-compliant study, an Angoff approach was used in two phases to set criteria for identifying minimally acceptable interpretive performance at screening mammography as measured by sensitivity, specificity, recall rate, positive predictive value (PPV) of recall (PPV(1)) and of biopsy recommendation (PPV(2)), and cancer detection rate. Performance measures were considered separately. In phase I, a group of 10 expert radiologists considered a hypothetical pool of 100 interpreting physicians and conveyed their cut points of minimally acceptable performance. The experts were informed that a physician's performance falling outside the cut points would result in a recommendation to consider additional training. During each round of scoring, all expert radiologists' cut points were summarized into a mean, median, mode, and range; these were presented back to the group. In phase II, normative data on performance were shown to illustrate the potential impact cut points would have on radiology practice. Rescoring was done until consensus among experts was achieved. Simulation methods were used to estimate the potential impact of performance that improved to acceptable levels if effective additional training was provided. RESULTS: Final cut points to identify low performance were as follows: sensitivity less than 75%, specificity less than 88% or greater than 95%, recall rate less than 5% or greater than 12%, PPV(1) less than 3% or greater than 8%, PPV(2) less than 20% or greater than 40%, and cancer detection rate less than 2.5 per 1000 interpretations. The selected cut points for performance measures would likely result in 18%-28% of interpreting physicians being considered for additional training on the basis of sensitivity and cancer detection rate, while the cut points for specificity, recall, and PPV(1) and PPV(2) would likely affect 34%-49% of practicing interpreters. If underperforming physicians moved into the acceptable range, detection of an additional 14 cancers per 100000 women screened and a reduction in the number of false-positive examinations by 880 per 100000 women screened would be expected. CONCLUSION: This study identified minimally acceptable performance levels for interpreters of screening mammography studies. Interpreting physicians whose performance falls outside the identified cut points should be reviewed in the context of their specific practice settings and be considered for additional training.

Screening-detected breast cancers: discordant independent double reading in a population-based screening program.

PURPOSE: To analyze discordant and concordant screening-detected breast cancers in a nationwide population-based screening program by using independent double reading with consensus. MATERIALS AND METHODS: The study is a part of the evaluation of the Norwegian Breast Cancer Screening Program and is covered by the Cancer Registry regulation. Analyses were based on prospective initial interpretation scores of 1 033 870 screenings that included 5611 breast cancers. A five-point scale for probability of cancer was used in the initial interpretation. Screening mammograms with a score of 2 or higher by either radiologist were discussed at consensus meetings where the decision whether to recall was made. A score of 1 by one reader and 2 or higher by the other was defined as a discordant interpretation and discordant cancer, whereas a score of 2 or higher by both readers was defined as a concordant recall and cancer. RESULTS: Discordant interpretation was present in 5.3% (54 447 of 1 033 870) of the screenings, whereas 2.1% (21 928 of 1 033 870) were concordant positive interpretations. Of the screening-detected cancers, 23.6% (1326 of 5611) were diagnosed in women who were recalled because of screenings with discordant interpretation. One hundred seventeen interval breast cancers were diagnosed among the 40 312 screenings that were dismissed at consensus; these were 6.5% of all interval cancers. A significantly higher proportion of microcalcifications alone was present in discordant cancers (24.9% [304 of 1219]) compared with concordant cancers (17.7% [704 of 3972]) (P < .001). CONCLUSION: Independent double reading with consensus at mammography screening has the potential to increase the cancer detection rate compared with single reading. Mammograms with microcalcifications alone are significantly more common among discordant cancers.

When radiologists perform best: the learning curve in screening mammogram interpretation.

PURPOSE: To examine changes in screening mammogram interpretation as radiologists with and radiologists without fellowship training in breast imaging gain clinical experience. MATERIALS AND METHODS: In an institutional review board-approved HIPAA-compliant study, the performance of 231 radiologists who interpreted screen-film screening mammograms from 1996 to 2005 at 280 facilities that contribute data to the Breast Cancer Surveillance Consortium was examined. Radiologists' demographic data and clinical experience levels were collected by means of a mailed survey. Mammograms were grouped on the basis of how many years the interpreting radiologist had been practicing mammography, and the influence of increasing experience on performance was examined separately for radiologists with and those without fellowship training in breast imaging, taking into account case-mix and radiologist-level differences. RESULTS: A total of 1 599 610 mammograms were interpreted during the study period. Performance for radiologists without fellowship training improved most during their 1st 3 years of clinical practice, when the odds of a false-positive reading dropped 11%-15% per year (P < .015) with no associated decrease in sensitivity (P > .89). The number of women recalled per breast cancer detected decreased from 33 for radiologists in their 1st year of practice to 24 for radiologists with 3 years of experience to 19 for radiologists with 20 years of experience. Radiologists with fellowship training in breast imaging experienced no learning curve and reached desirable goals during their 1st year of practice. CONCLUSION: Radiologists' interpretations of screening mammograms improve during their first few years of practice and continue to improve throughout much of their careers. Additional residency training and targeted continuing medical education may help reduce the number of work-ups of benign lesions while maintaining high cancer detection rates.

Disclosing harmful mammography errors to patients.

PURPOSE: To assess radiologists' attitudes about disclosing errors to patients by using a survey with a vignette involving an error interpreting a patient's mammogram, leading to a delayed cancer diagnosis. MATERIALS AND METHODS: We conducted an institutional review board-approved survey of 364 radiologists at seven geographically distinct Breast Cancer Surveillance Consortium sites that interpreted mammograms from 2005 to 2006. Radiologists received a vignette in which comparison screening mammograms were placed in the wrong order, leading a radiologist to conclude calcifications were decreasing in number when they were actually increasing, delaying a cancer diagnosis. Radiologists were asked (a) how likely they would be to disclose this error, (b) what information they would share, and (c) their malpractice attitudes and experiences. RESULTS: Two hundred forty-three (67%) of 364 radiologists responded to the disclosure vignette questions. Radiologists' responses to whether they would disclose the error included "definitely not" (9%), "only if asked by the patient" (51%), "probably" (26%), and "definitely" (14%). Regarding information they would disclose, 24% would "not say anything further to the patient," 31% would tell the patient that "the calcifications are larger and are now suspicious for cancer," 30% would state "the calcifications may have increased on your last mammogram, but their appearance was not as worrisome as it is now," and 15% would tell the patient "an error occurred during the interpretation of your last mammogram, and the calcifications had actually increased in number, not decreased." Radiologists' malpractice experiences were not consistently associated with their disclosure responses. CONCLUSION: Many radiologists report reluctance to disclose a hypothetical mammography error that delayed a cancer diagnosis. Strategies should be developed to increase radiologists' comfort communicating with patients.

Variability in interpretive performance at screening mammography and radiologists' characteristics associated with accuracy.

PURPOSE: To identify radiologists' characteristics associated with interpretive performance in screening mammography. MATERIALS AND METHODS: The study was approved by institutional review boards of University of Washington (Seattle, Wash) and institutions at seven Breast Cancer Surveillance Consortium sites, informed consent was obtained, and procedures were HIPAA compliant. Radiologists who interpreted mammograms in seven U.S. regions completed a self-administered mailed survey; information on demographics, practice type, and experience in and perceptions of general radiology and breast imaging was collected. Survey data were linked to data on screening mammograms the radiologists interpreted between January 1, 1998, and December 31, 2005, and included patient risk factors, Breast Imaging Reporting and Data System assessment, and follow-up breast cancer data. The survey was returned by 71% (257 of 364) of radiologists; in 56% (205 of 364) of the eligible radiologists, complete data on screening mammograms during the study period were provided; these data were used in the final analysis. An evaluation of whether the radiologists' characteristics were associated with recall rate, false-positive rate, sensitivity, or positive predictive value of recall (PPV(1)) of the screening examinations was performed with logistic regression models that were adjusted for patients' characteristics and radiologist-specific random effects. RESULTS: Study radiologists interpreted 1 036 155 screening mammograms; 4961 breast cancers were detected. Median percentages and interquartile ranges, respectively, were as follows: recall rate, 9.3% and 6.3%-13.2%; false-positive rate, 8.9% and 5.9%-12.8%; sensitivity, 83.8% and 74.5%-92.3%; and PPV(1), 4.0% and 2.6%-5.9%. Wide variability in sensitivity was noted, even among radiologists with similar false-positive rates. In adjusted regression models, female radiologists or fellowship-trained radiologists had significantly higher recall and false-positive rates (P < .05, all). Fellowship training in breast imaging was the only characteristic significantly associated with improved sensitivity (odds ratio, 2.32; 95% confidence interval: 1.42, 3.80; P < .001) and the overall accuracy parameter (odds ratio, 1.61; 95% confidence interval: 1.05, 2.45; P = .028). CONCLUSION: Fellowship training in breast imaging may lead to improved cancer detection, but it is associated with higher false-positive rates.

The principal neuronal gD-type 3-O-sulfotransferases and their products in central and peripheral nervous system tissues.

Within the nervous system, heparan sulfate (HS) of the cell surface and extracellular matrix influences developmental, physiologic and pathologic processes. HS is a functionally diverse polysaccharide that employs motifs of sulfate groups to selectively bind and modulate various effector proteins. Specific HS activities are modulated by 3-O-sulfated glucosamine residues, which are generated by a family of seven 3-O-sulfotransferases (3-OSTs). Most isoforms we herein designate as gD-type 3-OSTs because they generate HS(gD+), 3-O-sulfated motifs that bind the gD envelope protein of herpes simplex virus 1 (HSV-1) and thereby mediate viral cellular entry. Certain gD-type isoforms are anticipated to modulate neurobiologic events because a Drosophila gD-type 3-OST is essential for a conserved neurogenic signaling pathway regulated by Notch. Information about 3-OST isoforms expressed in the nervous system of mammals is incomplete. Here, we identify the 3-OST isoforms having properties compatible with their participation in neurobiologic events. We show that 3-OST-2 and 3-OST-4 are principal isoforms of brain. We find these are gD-type enzymes, as they produce products similar to a prototypical gD-type isoform, and they can modify HS to generate receptors for HSV-1 entry into cells. Therefore, 3-OST-2 and 3-OST-4 catalyze modifications similar or identical to those made by the Drosophila gD-type 3-OST that has a role in regulating Notch signaling. We also find that 3-OST-2 and 3-OST-4 are the predominant isoforms expressed in neurons of the trigeminal ganglion, and 3-OST-2/4-type 3-O-sulfated residues occur in this ganglion and in select brain regions. Thus, 3-OST-2 and 3-OST-4 are the major neural gD-type 3-OSTs, and so are prime candidates for participating in HS-dependent neurobiologic events.

Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis.

Endothelial cell production of anticoagulant heparan sulfate (HS(act)) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1). In vitro, HS(act) dramatically enhances the neutralization of coagulation proteases by antithrombin. The in vivo role of HS(act) was evaluated by generating Hs3st1(-/-) knockout mice. Hs3st1(-/-) animals were devoid of 3-OST-1 enzyme activity in plasma and tissue extracts. Nulls showed dramatic reductions in tissue levels of HS(act) but maintained wild-type levels of tissue fibrin accumulation under both normoxic and hypoxic conditions. Given that vascular HS(act) predominantly occurs in the subendothelial matrix, mice were subjected to a carotid artery injury assay in which ferric chloride administration induces de-endothelialization and occlusive thrombosis. Hs3st1(-/-) and Hs3st1(+/+) mice yielded indistinguishable occlusion times and comparable levels of thrombin.antithrombin complexes. Thus, Hs3st1(-/-) mice did not show an obvious procoagulant phenotype. Instead, Hs3st1(-/-) mice exhibited genetic background-specific lethality and intrauterine growth retardation, without evidence of a gross coagulopathy. Our results demonstrate that the 3-OST-1 enzyme produces the majority of tissue HS(act). Surprisingly, this bulk of HS(act) is not essential for normal hemostasis in mice. Instead, 3-OST-1-deficient mice exhibited unanticipated phenotypes suggesting that HS(act) or additional 3-OST-1-derived structures may serve alternate biologic roles.

Benign breast biopsy diagnosis and subsequent risk of breast cancer.

BACKGROUND: We examine benign breast biopsy diagnoses as reported by community pathologists in New Mexico and investigate associations with future breast cancer development. METHODS: Using data collected between 1992 and 2000 by the New Mexico Mammography Project and cancer data through 2003 from the New Mexico Tumor Registry, we calculated breast cancer rates following 14,602 benign breast biopsies for women ages 30 to 89 years. For comparison, we also calculated the breast cancer rate following 215,283 normal screening mammograms. Hazard ratios (HR) are presented. RESULTS: We identified 480 subsequent breast cancer diagnoses among 14,602 women with benign breast biopsies and 4,402 breast cancer diagnoses among 215,283 women with mammograms assigned a "negative" or "benign finding" assessment. Histologic diagnoses in absence of atypia had an age-adjusted HR of 1.95 [95% confidence interval (95% CI), 1.77-2.15]. Among low-risk histologic diagnoses, the strongest associations with subsequent breast cancer development included adenosis, apocrine metaplasia, calcifications, and ductal hyperplasia. Fibroadenoma, inflammation, and cysts did not exhibit an association with breast cancer development. Women with low-risk diagnoses and breast tissue characterized as fatty or with scattered densities had a HR of 2.09 (95% CI, 1.68-2.60), whereas women with low-risk histologic diagnoses and dense breasts had a HR of 3.36 (95% CI, 2.83-3.99). CONCLUSIONS: The observed breast cancer occurrence contributes to evidence of increased risk following benign biopsy. The risk associated with histologic diagnoses in absence of atypia was twice the risk experienced by women with normal mammogram evaluations and may be modified by breast density.