Adrian K. Dixon

Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)

BACKGROUND Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. METHODS We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. FINDINGS We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p<0.0001), and 77% (75-79) with both methods. The difference between CE MRI and mammography sensitivities was particularly pronounced in BRCA1 carriers (13 cancers; 92%vs 23%, p=0.004). INTERPRETATION Our findings indicate that CE MRI is more sensitive than mammography for cancer detection. Specificity for both procedures was acceptable. Despite a high proportion of grade 3 cancers, tumours were small and few women were node positive. Annual screening, combining CE MRI and mammography, would detect most tumours in this risk group.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Aortic Calcification Is Associated With Aortic Stiffness and Isolated Systolic Hypertension in Healthy Individuals

Arterial stiffening is an independent predictor of mortality and underlies the development of isolated systolic hypertension (ISH). A number of factors regulate stiffness, but arterial calcification is also likely to be important. We tested the hypotheses that aortic calcification is associated with aortic stiffness in healthy individuals and that patients with ISH exhibit exaggerated aortic calcification compared with controls. A total of 193 healthy, medication-free subjects (mean age±SD: 66±8 years) were recruited from the community, together with 15 patients with resistant ISH. Aortic pulse wave velocity (PWV) was measured noninvasively, and aortic calcium content was quantified from high-resolution, thoraco-lumbar computed tomography images using a volume scoring method. In healthy volunteers, calcification was positively and significantly associated with aortic PWV (r=0.6; P<0.0001) but was not related to augmentation index or brachial PWV. Calcification was significantly higher in treatment-resistant and healthy subjects with ISH compared with controls (mean [interquartile range]: 1.92 [1.14 to 3.66], 0.84 [0.35 to 1.75], and 0.19 [0.1 to 0.78] cm3, respectively; P<0.0001 for both). In a multiple regression model, aortic calcium was independently associated with aortic PWV along with age, mean arterial pressure, heart rate, and estimated glomerular filtration rate (R2=0.51; P<0.0001). Only age, calcium phosphate product, and aortic PWV were independently associated with calcification. These data suggest that calcification may be important in the process of aortic stiffening and the development of ISH. Calcification may underlie treatment resistance in ISH, and anticalcification strategies may present a novel therapy.

Evaluation of early abdominopelvic computed tomography in patients with acute abdominal pain of unknown cause: prospective randomised study

Abstract Objectives: To evaluate the impact of early abdominopelvic computed tomography in patients with acute abdominal pain of unknown cause on length of hospital stay and accuracy of diagnosis. Design: Randomised, prospective controlled trial. Setting: Teaching hospital in England. Participants: 120 patients admitted with acute abdominal pain for which no immediate surgical intervention or computed tomography was indicated. Intervention: 55 participants were prospectively randomised to early computed tomography (within 24 hours of admission) and 65 to standard practice (radiological investigations as indicated). Main outcome measures: Length of hospital stay, accuracy of diagnosis, and, owing to a possible effect on inpatient mortality, deaths during the study. Results: Early computed tomography reduced the length of hospital stay by 1.1 days (geometric mean 5.3 days (range 1 to 31) v 6.4 days (1 to 60)), but the difference was non-significant (95% confidence interval, 8% shorter stay to 56% longer stay, P=0.17). Early computed tomography missed significantly fewer serious diagnoses. Seven inpatients in the standard practice arm died. Only 50% (59 of 118) of diagnoses on admission were correct at follow up at 6 months, but this improved to 76% (90) of diagnoses after 24 hours. Conclusions: Early abdominopelvic computed tomography for acute abdominal pain may reduce mortality and length of hospital stay. It can also identify unforeseen conditions and potentially serious complications. What is already known on this topic Computed tomography improves the accuracy of diagnosis of several acute abdominal conditions Uncontrolled studies have shown improvements in accuracy of diagnosis after computed tomography; none have described an effect on mortality What this study adds Early abdominopelvic computed tomography for acute abdominal pain can identify unforeseen serious abdominal conditions It may also reduce length of hospital stay and might reduce inpatient mortality

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

Abdominal fat assessed by computed tomography: Sex difference in distribution

Abdominal fat distribution has been compared in 25 men and 25 women by computed tomography (CT) at the level of the umbilicus. Men have significantly more fat within the abdominal cavity. Women have similar total fat, but store a greater proportion of it in their subcutaneous tissues. For this reason, abdominal CT may prove to be more accurate in males than in females.

Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1–7 individual annual screening events. Women aged 35–49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was £28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to £11 731 (CE MRI vs mammography) and £15 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

Magnetic resonance imaging of the knee: Diagnostic performance statistics

Abstract Objectives: To review and reassess the published diagnostic performance statistics for MRI of the menisci and cruciate ligaments. To illustrate the potential sources and effects of bias in the evaluation of this widely accepted diagnostic technique. Methods: Published evaluations of knee MRI were identified from the literature. Criteria for inclusion in the review were a total sample size ≥ 35, arthroscopic correlation of MRI findings and presentation of complete results. Diagnostic performance statistics were then recalculated for each published study. Results: Twenty-two studies were identified with sample sizes between 35 and 1014. The overall sensitivity for MRI of the menisci and cruciates was 0.88 (95% confidence interval 0.86–0.90). The overall specificity was 0.94 (0.93–0.94). Sampling error varied widely amongst studies and was rarely quantified. Conclusions: Diagnostic performance statistics are widely used. It is still not well appreciated that these are subject to sampling error. Such errors make meaningful comparisons between published studies more difficult. Nevertheless, the results for meniscal and cruciate lesions are consistently high and support the use of MRI for these common problems. The diagnostic performance of other applications of MRI should be subjected to similar critical review.

Predicting composition of leg sections with anthropometry and bioelectrical impedance analysis, using magnetic resonance imaging as reference.

Magnetic resonance imaging (MRI) was used to evaluate and compare with anthropometry a fundamental bioelectrical impedance analysis (BIA) method for predicting muscle and adipose tissue composition in the lower limb. Healthy volunteers (eight men and eight women), aged 41 to 62 years, with mean (S.D.) body mass indices of 28.6 (5.4) kg/m2 and 25.1 (5.4) kg/m2 respectively, were subjected to MRI leg scans, from which 20-cm sections of thigh and 10-cm sections of lower leg (calf) were analysed for muscle and adipose tissue content, using specifically developed software. Muscle and adipose tissue were also predicted from anthropometric measurements of circumferences and skinfold thicknesses, and by use of fundamental BIA equations involving section impedance at 50 kHz and tissue-specific resistivities. Anthropometric assessments of circumferences, cross-sectional areas and volumes for total constituent tissues matched closely MRI estimates. Muscle volume was substantially overestimated (bias: thigh, -40%; calf, -18%) and adipose tissue underestimated (bias: thigh, 43%; calf, 8%) by anthropometry, in contrast to generally better predictions by the fundamental BIA approach for muscle (bias: thigh, -12%; calf, 5%) and adipose tissue (bias: thigh, 17%; calf, -28%). However, both methods demonstrated considerable individual variability (95% limits of agreement 20-77%). In general, there was similar reproducibility for anthropometric and fundamental BIA methods in the thigh (inter-observer residual coefficient of variation for muscle 3.5% versus 3.8%), but the latter was better in the calf (inter-observer residual coefficient of variation for muscle 8.2% versus 4.5%). This study suggests that the fundamental BIA method has advantages over anthropometry for measuring lower limb tissue composition in healthy individuals.

Evidence-based diagnostic radiology

The radiological community has a long track record of self-examination, starting well before evidence-based medicine came of age. It had to produce such evidence to prove the need for and win funds for its expensive gadgets. The assessment of new tests is easier than proving the value of well-established ones, and in scrutinising the evidence base for an imaging technique a balance must be struck between apparent (eg, diagnostic) benefit and real benefit to the patient. And even when there is a wealth of good evidence healthy debate continues. So radiology may be ahead of some other disciplines in considering the evidence for its daily practice. For example, where is the evidence for the routine clinical examination-and might the radiologist with a chest X-ray and abdominal ultrasound do better?