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 pound28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to pound11 731 (CE MRI vs mammography) and pound15 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.

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.

How significant is detection of ductal carcinoma in situ in a breast screening programme?

PURPOSE: To compare the histological grades of screen detected and non-screen detected ductal carcinoma in situ (DCIS) and to identify any differences that might support the contention that DCIS found by breast screening represents an over-diagnosis. The aim was also to establish whether any particular mammographic features of DCIS can be used to predict tumour grade reliably. MATERIALS AND METHODS: Biopsy proven cases of DCIS (n=153) were reviewed with respect to grade and subdivided into high, intermediate and low grades using the Van Nuys classification. A more aggressive subset of DCIS (microinvasive and interval cancers) were similarly analysed. Mammograms were reviewed with regard to abnormal features and distribution, and the appearances correlated with grade. RESULTS: Fifty-four percent (53/98) of screen detected and 62% (34/52) of non-screen detected DCIS were high grade. The rest were equally intermediate and low grade, with no statistical difference between the two groups. Eighty-four percent of the aggressive subset of tumours were high grade. Micro-calcification was present in 90% and in 10% there were soft tissue changes alone. Seventy-six percent of linear branching calcification was associated with high grade DCIS. Only 13% of high grade DCIS demonstrated punctate micro-calcification; however, 38% of cases of punctate micro-calfication were associated with high grade tumours and there was a great deal of overlap between the groups. CONCLUSION: Most cases of DCIS in both screen and non-screen detected groups were high grade. Only one in five was low grade. Analysis of the aggressive subgroup underlines the significance of high grade DCIS. Mammographic patterns are not always reliable in the prediction of tumour grade. The detection of DCIS in screening programmes is important and should not be regarded as over-diagnosis.

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS).

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

A method of coil localization for breast lesions seen only on MRI.

Breast lesions may be identified on MRI that are not shown on mammography or ultrasound owing to the high sensitivity and relatively poor specificity of contrast enhanced MRI. Techniques for diagnostic biopsy of such lesions are not widely available. A method is described that uses standard mammographic localization methods to place an MR compatible cerebral coil at the site of the suspect lesion. Confirmatory MRI can then be obtained before the lesion is surgically removed using a mammographic hook wire. This method is described and illustrated in detail for one case, and in summary for three further cases, to show the potential flexibility of application. The method is commended because it is simple and cheap, uses standard breast procedures and can be undertaken outside the MRI suite. The procedure will make full use of breast MRI possible to those who do not have dedicated localization equipment.

Predictors of positive margins after local excision of ductal carcinoma in situ.

BACKGROUND: This study aimed to examine the association between clinicopathologic parameters and positive margins in women with ductal carcinoma in situ (DCIS) treated by breast-conserving surgery (BCS). METHODS: We retrospectively reviewed the clinical, radiologic, and pathologic data of 100 women who had undergone BCS for DCIS in our center. RESULTS: Sixty-seven percent of patients presented via breast screening and 55% of all cases were diagnosed preoperatively on fine needle aspiration cytology ([FNAC] ie, C5). Overall, 45% of patients had clear margins after initial local excision. Positive margins showed a nonsignificant trend of association with distribution of microcalcifications (MCC), nonconsultant operating surgeon, inconclusive preoperative FNAC, presence of necrosis, and low specimen weight. There was a highly significant association between low grade DCIS (P = 0.003) and incomplete excision. There was no significant association with age, associated invasive focus, morphology of MCC, or with mode of presentation. CONCLUSION: Positive margins after local excision of DCIS are significantly associated with low nuclear grade, and preoperative determination of nuclear grade by core biopsy may have surgical implications.

Turbo STIR magnetic resonance imaging as a whole-body screening tool for metastases in patients with breast carcinoma: preliminary clinical experience.

This study was undertaken to assess the utility of whole-body turbo short tau inversion recovery (STIR) magnetic resonance imaging (MRI) to detect metastases to liver, brain, and bone as a single examination in women with breast cancer. Seventeen patients with biopsy-proven breast cancer and suspected metastatic disease attending over a 12-month period referred for both conventional imaging and whole-body MRI were included in the study. Three patients were found to be free of metastases at both conventional and MR imaging. Appendicular or axial skeletal metastases were identified in 11 of 17 patients, with correlation between findings at whole-body MRI and scintigraphy in 15 of the 17 patients. Five patients had evidence of hepatic metastases on whole-body MRI, of which metastases were identified in only three patients at CT despite contrast enhancement. Four patients had brain abnormalities (metastases in three patients, meningioma in one patient) detected on both whole-body and dedicated brain MRI. Preliminary clinical experience suggests that turbo STIR whole-body MRI may represent a convenient and cost-effective method of total body screening for metastases in patients with breast carcinoma.

CT appearances of mucosa-associated lymphoid tissue (MALT) lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade lymphoma that differs from high-grade non-Hodgkin lymphoma both clinically and histologically. The CT appearances of MALT lymphoma are described. Of 40 patients referred with biopsy-proven MALT lymphoma, only seven had not had gastrectomy or chemotherapy prior to CT examination. The CT scans of these seven cases were analysed for the degree and extent of gastric wall thickening, enlargement of abdominal and extra-abdominal lymph nodes, and presence of extra-nodal disease. In all patients the stomach was distended with oral contrast medium and scans performed at narrow collimation, after intravenous administration of 20 mg hyoscine butylbromide. In six patients focal thickening of the gastric wall was 1 cm or less. One patient had thickening of over 4 cm. There was no enlargement of abdominal or extra-abdominal lymph nodes or extension to adjacent organs. Thus on CT, at presentation, MALT lymphoma results in minimal gastric wall thickening, unlike high-grade non-Hodgkin lymphoma, which typically causes bulky gastric disease, nodal enlargement and extension into adjacent organs. CT is therefore of limited value in monitoring response to treatment. With disease greater than minimal thickening, transformation to a higher grade should be considered.

The alpha-adrenergic-mediated activation of the cardiac mitochondrial Ca2+ uniporter and its role in the control of intramitochondrial Ca2+ in vivo.

Administration of methoxamine (10 microM, 2 min) to perfused rat hearts increased the rate at which subsequently isolated mitochondria accumulated Ca2+. Methoxamine did not change significantly the development of delta phi with time or the basal rates of Ca2+ flux on inhibition of the uniporter with Ruthenium Red. With 200 microM-Pi, the rates of Ca2+ uptake at constant delta phi were unaffected by the small variations in endogenous [Pi] between mitochondrial preparations, and were also unaffected by changes in internal Ca2+ over the approximate range 8-43 nmol of Ca2+/mg. At low internal Ca2+ (about 8 nmol/mg of protein) the rates of Ca2+ uptake at constant delta phi were unaffected by addition of 200 microM-Pi. Under these conditions, the uniporter activity and the uniporter conductance were increased by 38-40% by methoxamine pretreatment. The endogenous Ca2+ content of mitochondria from control heart was about 1.8 nmol of Ca2+/mg of protein. Perfusion with agonist increased the Ca2+ content as follows: 10 microM-methoxamine (2 min), 48%; 1 microM-isoprenaline (2 min), 100%; 1 microM-adrenaline (2 min), 140%. The implications of the data for the adrenergic control of oxidative metabolism by intramitochondrial Ca2+ is discussed.

The sequestration of Ca2+ by mitochondria in rat heart cells.

Rat heart ventricular cells, purified by Percoll density gradient centrifugation, were incubated in the presence of 1.3 mM CaCl2. After 20 min incubation, samples of the cells were lysed in medium containing 0.3 mM digitonin, ruthenium red and EGTA, and a mitochondrial fraction was isolated at intervals thereafter. Extrapolation of the mitochondrial 45Ca2+ contents to zero time enabled the endogenous 45Ca2+ to be estimated at the time of cell lysis. The lysis conditions yielded essentially complete release of lactate dehydrogenase from the cells, but caused negligible damage to the mitochondria as judged by their retention of glutamate dehydrogenase, and their ability to accumulate and retain Ca2+ in the absence of ruthenium red and EGTA. The data indicate that about 13% of total cell Ca2+ only may be mitochondrial in vivo.

The alpha-adrenergic-mediated activation of Ca2+ influx into cardiac mitochondria. A possible mechanism for the regulation of intramitochondrial free CA2+.

Mitochondria isolated from rat hearts perfused with adrenaline, and from hearts excised from adrenaline-treated rats, showed an enhanced rate of respiration-dependent Ca2+ uptake. Adrenaline pretreatment did not change the activity of the Na+/Ca2+-antiporter of isolated heart mitochondria. Simultaneous measurements of the membrane potential revealed that perfusion with adrenaline has no significant effect on this parameter during Ca2+ accumulation. The activation of Ca2+ uptake was induced also by the alpha-adrenergic agonist, methoxamine, but not by the beta-adrenergic agonist, isoprenaline. Methoxamine pretreatment also increased the sensitivity of alpha-oxoglutarate dehydrogenase in intact mitochondria to 10 nM--300 nM extramitochondrial Ca2+ during steady-state Ca2+ recycling across the inner membrane. Possible implications of these data for the adrenergic regulation of oxidative metabolism are discussed.

Evidence that catecholamines stimulate renal gluconeogenesis through an alpha 1-type of adrenoceptor.

1. Noradrenaline stimulates gluconeogenesis through an alpha-adrenoceptor in renal cortical tubule fragments from fed rats incubated with 5 mM-lactate. 2. The selective alpha 1-adrenoreceptor agonist methoxamine stimulated gluconeogenesis, but the selective alpha 2-adrenoceptor agonist clonidine was ineffective. 3. The selective alpha 1-adrenoceptor antagonist thymoxamine blocked the stimulatory effects on gluconeogenesis of noradrenaline and of oxymetazoline (a synthetic alpha-agonist). The selective alpha 2-adrenoceptor antagonist yohimbine was ineffective in this respect. 4. It is concluded that noradrenaline and oxymetazoline stimulate gluconeogenesis in rat kidney via an alpha 1-rather than an alpha 2-type of adrenoceptor.