Magnetic Resonance Imaging Screening Study Research Articles

Re-attendance in supplemental breast MRI screening rounds of the DENSE trial for women with extremely dense breasts.

Supplemental MRI screening improves early breast cancer detection and reduces interval cancers in women with extremely dense breasts in a cost-effective way. Recently, the European Society of Breast Imaging recommended offering MRI screening to women with extremely dense breasts, but the debate on whether to implement it in breast cancer screening programs is ongoing. Insight into the participant experience and willingness to re-attend is important for this discussion. We calculated the re-attendance rates of the second and third MRI screening rounds of the DENSE trial. Moreover, we calculated age-adjusted odds ratios (ORs) to study the association between characteristics and re-attendance. Women who discontinued MRI screening were asked to provide one or more reasons for this. The re-attendance rates were 81.3% (3458/4252) and 85.2% (2693/3160) in the second and third MRI screening round, respectively. A high age (> 65years), a very low BMI, lower education, not being employed, smoking, and no alcohol consumption were correlated with lower re-attendance rates. Moderate or high levels of pain, discomfort, or anxiety experienced during the previous MRI screening round were correlated with lower re-attendance rates. Finally, a plurality of women mentioned an examination-related inconvenience as a reason to discontinue screening (39.1% and 34.8% in the second and third screening round, respectively). The willingness of women with dense breasts to re-attend an ongoing MRI screening study is high. However, emphasis should be placed on improving the MRI experience to increase the re-attendance rate if widespread supplemental MRI screening is implemented. For many women, MRI is an acceptable screening method, as re-attendance rates were high - even for screening in a clinical trial setting. To further enhance the (re-)attendance rate, one possible approach could be improving the overall MRI experience. • The willingness to re-attend in an ongoing MRI screening study is high. • Pain, discomfort, and anxiety in the previous MRI screening round were related to lower re-attendance rates. • Emphasis should be placed on improving MRI experience to increase the re-attendance rate in supplemental MRI screening.

Improving the diagnostic accuracy of a stratified screening strategy by identifying the optimal risk cutoff.

The American Cancer Society (ACS) suggests using a stratified strategy for breast cancer screening. The strategy includes assessing risk of breast cancer, screening women at high risk with both MRI and mammography, and screening women at low risk with mammography alone. The ACS chose their cutoff for high risk using expert consensus. We propose instead an analytic approach that maximizes the diagnostic accuracy (AUC/ROC) of a risk-based stratified screening strategy in a population. The inputs are the joint distribution of screening test scores, and the odds of disease, for the given risk score. Using the approach for breast cancer screening, we estimated the optimal risk cutoff for two different risk models: the Breast Cancer Screening Consortium (BCSC) model and a hypothetical model with much better discriminatory accuracy. Data on mammography and MRI test score distributions were drawn from the Magnetic Resonance Imaging Screening Study Group. A risk model with an excellent discriminatory accuracy (c-statistic [Formula: see text]) yielded a reasonable cutoff where only about 20% of women had dual screening. However, the BCSC risk model (c-statistic [Formula: see text]) lacked the discriminatory accuracy to differentiate between women who needed dual screening, and women who needed only mammography. Our research provides a general approach to optimize the diagnostic accuracy of a stratified screening strategy in a population, and to assess whether risk models are sufficiently accurate to guide stratified screening. For breast cancer, most risk models lack enough discriminatory accuracy to make stratified screening a reasonable recommendation.

Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study.

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.

Baseline screening and psychosocial results from the UK SIGNIFY study: A whole-body MRI screening study in TP53 mutation carriers and matched controls.

1520 Background: In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. Some centres employ family specific screening with most centres having an “open-door” policy. Recent evidence suggests there may be a survival benefit with more intensive screening, including whole-body MRI. There are no published data on the psychological impact of such screening programmes. Methods: This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers aged over 18 years. Clinical and psychological endpoints were assessed. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. A series of questionnaires is used to assess the psychological impact of screening. Results: 44 TP53 mutation carriers and 44 population controls were recruited. In TP53 mutation carriers, six of 44 (13.6%, 95% CI: 5.2%-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1%, 95% CI: 20.5%-49.9%) and 7 controls (15.9%, 95% CI: 6.6%-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). To date, there is no evidence of clinically significant adverse psychosocial effects. Conclusions: The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. Clinical trial information: NCT01737255.

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2–27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5–49.9%) and seven controls (15.9, 95% CI 6.7–30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.

Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC).

Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1 matched controls. Controls, unscreened if<50 years, and screened with biennial mammography if ≥50 years, were matched on risk category (BRCA1, BRCA2, familial risk), year and age of diagnosis. Of 2,308 MRISC participants, breast cancer was detected in 93 (97 breast cancers), who received MRI <2 years before breast cancer diagnosis; 33 BRCA1 mutation carriers, 18 BRCA2 mutation carriers, and 42 with familial risk. MRISC patients had smaller (87% vs. 52% <T2, p < 0.001), more often node negative (69% vs. 44%, p = 0.001) tumors and received less chemotherapy (39% vs. 77%, p < 0.001) and hormonal therapy (14% vs. 47%, p < 0.001) than controls. Median follow-up time was 9 years (range 0-14). Breast cancer metastasized in 9% (8/93) of MRISC patients and in 23% (21/93) of controls (p = 0.009). MFS was better in MRISC patients overall (log-rank p = 0.008, HR 0.36, 95% CI 0.16-0.80), with familial risk (log-rank p = 0.024, HR: 0.21, 95% CI 0.04-0.95), and in BRCA1 mutation carriers (log-rank p = 0.055, HR 0.30, 95% CI 0.08-1.13). MFS remained better in MRISC patients after lead time correction (log-rank p = 0.020, HR 0.40, 95% CI 0.18-0.90). Overall survival was non-significantly better in MRISC patients (log-rank p = 0.064, HR 0.51, CI 0.24-1.06). Annual screening with MRI and mammography improves metastasis free survival in women with BRCA1 mutation or familial predisposition.

Semi-automatic region-of-interest segmentation based computer-aided diagnosis of mass lesions from dynamic contrast-enhanced magnetic resonance imaging based breast cancer screening.

Cancer screening with magnetic resonance imaging (MRI) is currently recommended for very high risk women. The high variability in the diagnostic accuracy of radiologists analyzing screening MRI examinations of the breast is due, at least in part, to the large amounts of data acquired. This has motivated substantial research towards the development of computer-aided diagnosis (CAD) systems for breast MRI which can assist in the diagnostic process by acting as a second reader of the examinations. This retrospective study was performed on 184 benign and 49 malignant lesions detected in a prospective MRI screening study of high risk women at Sunnybrook Health Sciences Centre. A method for performing semi-automatic lesion segmentation based on a supervised learning formulation was compared with the enhancement threshold based segmentation method in the context of a computer-aided diagnostic system. The results demonstrate that the proposed method can assist in providing increased separation between malignant and radiologically suspicious benign lesions. Separation between malignant and benign lesions based on margin measures improved from a receiver operating characteristic (ROC) curve area of 0.63 to 0.73 when the proposed segmentation method was compared with the enhancement threshold, representing a statistically significant improvement. Separation between malignant and benign lesions based on dynamic measures improved from a ROC curve area of 0.75 to 0.79 when the proposed segmentation method was compared to the enhancement threshold, also representing a statistically significant improvement. The proposed method has potential as a component of a computer-aided diagnostic system.

Cost-Effectiveness of Screening Women With Familial Risk for Breast Cancer With Magnetic Resonance Imaging

To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear. We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided. Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (€93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (€102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (€41 390) per LYG with mammography only. Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories.

Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk

Women from high-risk families consider preventive measures for breast cancer including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected relatives is predictive for age at diagnosis. We analyzed the age of breast cancer detection of 1,304 first- and second-degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within- and between-family variance in the relative's age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK-MARIBS study. Mean age at diagnosis in the relatives varied between families; 95% range of mean family ages was 35-55 in BRCA1-, 41-57 in BRCA2- and 44-60 in high-risk families. In all, 14% of the variance in age at diagnosis, in BRCA1 even 23%, was explained by family history, 7% by risk group. Determining start of screening based on the model and on risk-group gave similar results in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and the United Kingdom data sets. Age at breast cancer diagnosis is partly dependent on family history which may assist planning starting age for preventive measures.

Utility of Limited Protocol Magnetic Resonance Imaging Lumbar Spine for Nerve Root Compression in a Developing Country, Is It Accurate and Cost Effective?

Study DesignCross sectional study.PurposeTo determine the accuracy of the screening magnetic resonance study of the lumbar spine in the diagnosis of nerve root compression in cases of low back pain as compared to the routine magnetic resonance imaging (MRI) study of the lumbar spine.Overview of LiteratureNo local study has been conducted for this purpose. In an international study, the reported sensitivity and specificity of screening MRI lumbar spine protocol in the detection of nerve root compression are 54% and 100% respectively.MethodsPatients of both genders older than 20 years of age with low back pain of any duration or any severity who were referred to the radiology department of Aga Khan University Hospital for MRI of their lumbar spine were evaluated. Two sets of MRI imaging were recruited for each patient: one labeled as 'screening' and the other labeled as 'routine'. The findings of screening MRI were compared with the findings of the routine MRI study.ResultsA total of 109 patients fulfilling the inclusion criteria were included in this study. The diagnostic accuracy, specificity and sensitivity of the screening protocol in our study was 100%, 100% and 100%, respectively in comparison with the routine MRI lumbar spine study for the detection of nerve root compression.ConclusionsOur data proved that the MRI screening study is a highly accurate tool, and its findings are comparable to the routine study for the detection of nerve root compression especially in cases of lumbar spondylosis.

Abstract P3-02-09: Cost-effectiveness of screening with additional MRI for women with familial risk for breast cancer without a genetic predisposition

Abstract Background: To reduce mortality risk, women with a family history of breast cancer are often screened with mammography before 50 years of age. Additional Magnetic Resonance Imaging (MRI) can improve sensitivity. MRI screening is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history of breast cancer without a proven mutation cost-effectiveness is not clear. We evaluated the cost-effectiveness of additional MRI for women with a familial risk in the largest prospective MRI screening study: the Dutch MRI Screening Study (MRISC). Materials &amp; Methods: Between 1999 and 2007 a total of 1597 women (8370 women years at risk) between 25–70 years, with an estimated cumulative lifetime risk of 15–50% for breast cancer participated in the MRISC. Women were screened with clinical breast examination (CBE) every six months and annual mammography and MRI. We calculated the costs per detected breast cancer. In addition, MRISC data were incorporated into a micro simulation screening analysis model: MISCAN. This model simulates screening programs with different screening modalities and time intervals. Different screening schemes were evaluated and the cost per life-year gained (CLYG) estimated. Results: Forty-seven breast cancers, including 9 Ductal Carcinoma in Situ, were detected. Screening with additional MRI leads to a cost per detected breast cancer treated of €101,962. In increasing age-cohorts the cost decreased, probably due to the higher breast cancer incidence. The cost per detected and treated breast cancer in age group 40–50 years doubled in the age group &amp;gt;60 years. We will demonstrate these results more extensively. With MISCAN modeling we predicted that screening with this scheme from age 35 to 60 years reduces breast cancer mortality by 30% at a CLYG of €119,945 (3.5% discounting), compared to 21% estimated mortality reduction at €45,707 CLYG with mammography and CBE alone. Conclusion: Screening with MRI may improve survival for women with familial risk for breast cancer, but is expensive. However, it may be cost-effective for a select group. We will discuss subgroups that may benefit from MRI screening and in which age category MRI was most effective in our study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-09.

Abstract P4-11-05: Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk

Abstract Background: Women from high risk breast cancer families consider preventive measures including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected family members is predictive for age at diagnosis of a relative. Methods: We analyzed the age of breast cancer detection of 1304 first and second degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within and between family variance in age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK- MARIBS study. Results: Mean age at diagnosis in the family varied between families; 95% range of mean family ages was 35–55 in BRCA1−, 41–57 in BRCA2− and 44–60 in high-risk families.14% of the variance in age at diagnosis was explained by family history, 7% by risk group. Approaches to determining start of screening based on the model and on risk-group were similar in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and UK datasets. Conclusion: Age at breast cancer diagnosis is in part dependent on family history which may assist planning starting age for preventive measures. Keywords: BRCA1, BRCA2, breast cancer, prevention, age at onset Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-05.

BRCA1-Associated Breast Cancers Present Differently From BRCA2-Associated and Familial Cases: Long-Term Follow-Up of the Dutch MRISC Screening Study

The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition

In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study(MRISC), a non-randomized prospective multicenter study,women with high familial risk or a genetic predisposition for breast cancer were screened once a year by mammography and MRI and every 6 months with a clinical breast examination (CBE). The false-negative MR examinations were subject of this study and were retrospectively reviewed by two experienced radiologists. From November 1999 until March 2006, 2,157 women were eligible for study analyses. Ninety-seven malignant breast tumors were detected, including 19 DCIS (20%). In 22 patients with a malignant lesion, the MRI was assessed as BI-RADS 1 or 2. One patient was excluded because the examinations were not available for review. Forty-three percent (9/21) of the false-negative MR cases concerned pure ductal carcinoma in situ (DCIS) or DCIS with invasive foci, in eight of them no enhancement was seen at the review. In six patients the features of malignancy were missed or misinterpreted.Small lesion size (n = 3), extensive diffuse contrast enhancement of the breast parenchyma (n = 2),and a technically inadequate examination (n = 1) were other causes of the missed diagnosis. A major part of the false-negative MR diagnoses concerned non-enhancing DCIS, underlining the necessity of screening not only with MRI but also with mammography. Improvement of MRI scanning protocols may increase the detection rate of DCIS. The missed and misinterpreted cases are reflecting the learning curve of a multicenter study.

Psychological impact of recall in high-risk breast MRI screening

To address the widespread concern that false-positive results during breast MRI screening may have adverse psychological effects. Impact of Event Scale measurements in 103 high-risk women enrolled in a longitudinal MRI screening study and comparison of subjects with normal results vs. those with prior recall events. Of 189 MRI scans performed, 64 (34%) prompted further evaluation. Subjects with previously abnormal results had significantly higher Avoidance scores at the time of their second MRI. Multivariate analysis showed this was driven by the greater number of BRCA1/2 carriers in that group but was not related to screening recall. Practitioners' concerns about the high false positive rate of breast MRI may not be matched by actual psychological effects in most high-risk women.

Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier

Homozygous loss of activity at the breast cancerpredisposing genes BRCA1 and BRCA2 (FANCD1) confers increased susceptibility to DNA double strand breaks, but this genotype occurs only in the tumor itself, following loss of heterozygosity at one of these loci. Thus, if these genes play a role in tumor etiology as opposed to tumor progression, they must manifest a heterozygous phenotype at the cellular level. To investigate the potential consequences of somatic heterozygosity for a BRCA1 mutation demonstrably associated with breast carcinogenesis on background somatic mutational burden, we applied the two standard assays of in vivo human somatic mutation to blood samples from a manifesting carrier of the Q1200X mutation in BRCA1 whose tumor was uniquely ascertained through an MRI screening study. The patient had an allele-loss mutation frequency of 19.4 x 10(-6) at the autosomal GPA locus in erythrocytes and 17.1 x 10(-6) at the X-linked HPRT locus in lymphocytes. Both of these mutation frequencies are significantly higher than expected from age-matched disease-free controls (P < 0.05). Mutation at the HPRT locus was similarly elevated in lymphoblastoid cell lines established from three other BRCA1 mutation carriers with breast cancer. Our patient's GPA mutation frequency is below the level established for diagnosis of homozygous Fanconi anemia patients, but consistent with data from obligate heterozygotes. The increased HPRT mutation frequency is more reminiscent of data from patients with xeroderma pigmentosum, a disease characterized by UV sensitivity and deficiency in the nucleotide excision pathway of DNA repair. Therefore, this BRCA1-associated breast cancer patient manifests a unique phenotype of increased background mutagenesis that likely contributed to the development of her disease independent of loss of heterozygosity at the susceptibility locus.

Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition

Within the Dutch MRI Screening (MRISC) study, a Dutch multicenter screening study for hereditary breast cancer, the authors investigated whether previously reported increased diagnostic accuracy of magnetic resonance imaging (MRI) compared with mammography would be maintained during subsequent screening rounds. From November 1999 to October 2003, 1909 eligible women were included in the study. Screening parameters and tumor characteristics of different rounds were calculated and compared. The authors defined 3 different types of imaging screening rounds: first round in women never screened by imaging before, first round in women screened by imaging (mainly mammography) before, and subsequent rounds. The difference in sensitivity for invasive cancers between mammography and MRI was largest in the first round of women previously screened with mammography (20.0 vs. 93.3%; P=.003), but also in subsequent rounds, there was a significant difference in favor of MRI (29.4 vs. 76.5%; P=.02). The difference in false-positive rate between mammography and MRI was also largest in the first round of women previously screened with mammography (5.5 vs. 14.0%; P<.001), and it remained significant in subsequent rounds (4.6 vs. 8.2%; P<.001). Screen-detected tumors were smaller and more often lymph node negative than symptomatic tumors in age-matched control patients, but no major differences in tumor stage were found between tumors detected at subsequent rounds compared with those in the first round. In subsequent rounds, a significantly higher sensitivity and better discriminating capacity of MRI compared with mammography was maintained, and a favorable tumor stage compared with age-matched symptomatic controls. As results of these subsequent screening rounds were most predictive for long-term effects, the authors expect that this screening program will contribute to a decrease of breast cancer mortality in these high-risk women.

The prevalence of osteonecrosis in severe acute respiratory syndrome patients: an MRI screening study

目的 采用MRI对康复的严重急性呼吸综合征(SARS)患者骨缺血性坏死进行筛查,探讨康复SARS患者骨缺血性坏死的患病率,及与激素使用的关系.方法用MRI对448例感染SARS的康复患者进行骨缺血性坏死筛查.所有受试者都做了双髋和双膝关节MR扫描,其中192例还扫描了肩和踝关节.采用体线圈同时扫描双侧关节,扫描序列常规做冠状面T1WI, 如发现有骨缺血性坏死征象,加扫短时反转恢复(STIR)序列.178例在MR检查的同一天还行双髋关节正位和蛙式位数字X线摄影(DR)片.所有MR图像由3位高年资医生阅片,诊断有无骨缺血性坏死.由2位医生在不知道MRI结果的情况下阅读双髋关节正位和蛙式位DR片,判断有无骨缺血性坏死.448例中在SARS临床研究数据库有用药记载者386例,其中361人在治疗过程中使用激素并记载了剂量和时间;SARS临床研究数据库无用药记载的其余62例中有59例自述治疗时使用激素.结果骨缺血性坏死的MRI表现为关节面下骨髓内出现弧形或线形异常信号带,T1WI为低信号,在STIR序列上为高信号,与临床上所见的因其他疾病而使用激素或饮酒等原因引起的骨缺血性坏死表现相同.MRI筛查发现在448例中共有138例(30.8%)出现1处以上骨缺血性坏死.28例未用激素的患者中有1例出现有股骨干骨梗死征象(1/28),420例使用激素患者的MRI筛查发现137例(32.6%)出现至少1处骨缺血性坏死MRI表现,两组间差异有统计学意义(P<0.05).股骨头缺血性坏死101例,均有使用激素史,占激素使用者的24.0%(101/420).膝关节骨缺血性坏死84例,占激素使用者的20.0%(84/420).同时累及股骨头和膝关节者48例,占激素使用者的11.4%(48/420),仅发生在股骨头者53例,占激素使用者的12.6%(53/420),而仅发生于膝关节者36例,占激素使用者的8.6%(36/420).192例双侧肩关节和踝关节MR扫描发现肱骨头缺血性坏死26例(13.5%),踝关节骨缺血性坏死13例(6.8%).178例DR和MRI诊断股骨头坏死的阳性符合率为14.1%,DR诊断的敏感度为11.0%,特异度为97.0%.秩和检验显示骨缺血性坏死组的激素总剂量,甲泼尼龙(甲强龙)的使用时间、平均日剂量和总剂量均大于无坏死组(P<0.05).多因素Logistic回归分析表明甲泼尼龙日平均剂量和平均使用时间是发生骨坏死的危险因素(P<0.05).结论 MRI筛查发现北京地区使用激素治疗的SARS患者的骨缺血性坏死患病率较高,主要发生在股骨头、膝、肩和踝关节,常累及多个部位,多数为双侧同时受累.是否使用激素、激素使用剂量和时间是发生骨坏死的危险因素。

Haploinsufficiency for BRCA1is associated with normal levels of DNA nucleotide excision repair in breast tissue and blood lymphocytes

BackgroundScreening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied. A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links.Case presentationWe describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis (UDS) assay revealed no deficiency in NER.ConclusionAs new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in breast epithelial cells from this patient which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis.

Impact of screening for breast cancer in high-risk women on health-related quality of life.

The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample (n=334) showed significant changes over time. The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population.