Contrast-enhanced spectral mammography improves diagnostic accuracy in the symptomatic setting.

AIM: To assess the diagnostic accuracy of contrast-enhanced spectral mammography (CESM), and gauge its "added value" in the symptomatic setting. MATERIALS AND METHODS: A retrospective multi-reader review of 100 consecutive CESM examinations was performed. Anonymised low-energy (LE) images were reviewed and given a score for malignancy. At least 3 weeks later, the entire examination (LE and recombined images) was reviewed. Histopathology data were obtained for all cases. Differences in performance were assessed using receiver operator characteristic (ROC) analysis. Sensitivity, specificity, and lesion size (versus MRI or histopathology) differences were calculated. RESULTS: Seventy-three percent of cases were malignant at final histology, 27% were benign following standard triple assessment. ROC analysis showed improved overall performance of CESM over LE alone, with area under the curve of 0.93 versus 0.83 (p<0.025). CESM showed increased sensitivity (95% versus 84%, p<0.025) and specificity (81% versus 63%, p<0.025) compared to LE alone, with all five readers showing improved accuracy. Tumour size estimation at CESM was significantly more accurate than LE alone, the latter tending to undersize lesions. In 75% of cases, CESM was deemed a useful or significant aid to diagnosis. CONCLUSION: CESM provides immediately available, clinically useful information in the symptomatic clinic in patients with suspicious palpable abnormalities. Radiologist sensitivity, specificity, and size accuracy for breast cancer detection and staging are all improved using CESM as the primary mammographic investigation.

Does the insertion of a gel-based marker at stereotactic breast biopsy allow subsequent wire localizations to be carried out under ultrasound guidance?

AIM: To investigate whether the insertion of a gel-based marker at the time of stereotactic breast biopsy allows subsequent preoperative localization to be performed under ultrasound guidance. MATERIALS AND METHODS: One hundred consecutive women who underwent either a 10 G stereotactic vacuum-assisted breast biopsy or 14 G stereotactic core biopsy with marker placement, followed by wire localization and surgical excision were identified. All had mammographic abnormalities not initially visible with ultrasound. The method of preoperative localization was recorded and its success judged with reference to the wire position on the post-procedure films relative to the mammographic abnormality and the marker. Histopathology data were reviewed to ensure the lesion had been adequately excised. RESULTS: Eighty-three women (83%) had a successful ultrasound-guided wire localization. Successful ultrasound-guided localization was more likely after stereotactic vacuum biopsy (86%) compared to stereotactic core biopsy (68%), although this did not quite reach statistical significance (p=0.06). CONCLUSION: The routine placement of a gel-based marker after stereotactic breast biopsy facilitates preoperative ultrasound-guided localization.

Can computerised tomography replace bone scintigraphy in detecting bone metastases from breast cancer? A prospective study.

BACKGROUND: The aim of this study was to determine whether bone scans (BS) can be avoided if pelvis was included in CT thorax and abdomen to detect bony metastases from breast cancer. MATERIALS AND METHODS: Results of 77 pairs of CT (thorax, abdomen, and pelvis) and BS in newly diagnosed patients with metastatic breast cancer (MBC) were compared prospectively for 12 months. Both scans were blindly assessed by experienced radiologists and discussed at multidisciplinary team meetings regarding the diagnosis of bone metastases. RESULTS: CT detected metastatic bone lesions in 43 (98%) of 44 patients with bone metastases. The remaining patient had a solitary, asymptomatic bony metastasis in shaft of femur. BS was positive in all patients with bone metastases. There were 11 cases of false positive findings on BS. CONCLUSION: Our findings suggest routine BS of patients presenting with MBC is not required if CT (thorax, abdomen, and pelvis) is performed.

NHSBSP type 1 interval cancers: a scientifically valid grouping?

AIM: To assess whether there are differences in the pathological features or survival between the new National Health Service Breast Screening Programme (NHSBSP) interval cancer classification system category of type 1 interval cancers, and the previously used, separate categories of occult, unclassified, and true interval cancers. MATERIALS AND METHODS: The prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor status, and histological type) and survival of 428 type 1 interval invasive breast cancers were analysed by subgroup (occult, unclassified and true interval). RESULTS: Occult cancers compared with other type 1 interval cancers were of significantly lower grade [38 of 52 (73%) versus 151 of 340 (44%) grade 1 or 2, p=0.0005], more likely to be smaller size [37 of 51 (73%) versus 158 of 341 (46%) <20mm, p=0.0003] and more frequently of lobular type at histology [14 of 42 (32%) versus 50 of 286 (17%), p=0.03]. There was no significant difference in pathological features of unclassified tumours compared with other type 1 tumours. There was no significant survival difference between different type 1 subgroups (p=0.12). CONCLUSION: The NHSBSP type 1 interval cancers are a heterogeneous grouping with markedly differing pathological features. However, no significant survival difference is seen between the different type 1 subgroups.

Interval breast cancers: prognostic features and survival by subtype and time since screening.

OBJECTIVES: To investigate the hypothesis that interval cancers arising soon after the previous screen and true interval cancers are biologically aggressive and have a relatively poor prognosis compared with other interval cancers, and to assess which prognostic features are relevant to interval cancers. METHODS: Analysis of prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor [ER] status and histological type), radiological features (comedo/non-comedo calcification and spiculation) and survival for 538 invasive interval breast cancer cases by type and time since previous screen. RESULTS: Late interval cancers were less likely to be lymph node positive (13 versus 43%, P = 0.003). Type 1 interval cancers were more likely to be histological grade 3 than type 2 (minimal signs) and type 3 (false-negative) intervals (52 versus 35%, P = 0.05). Type 3 interval cancers were more likely to have lobular features than other intervals (47 versus 20%, P < 0.0001). There was no significant survival difference by interval cancer type (P = 0.64) or interval year (P = 0.83). At univariate analysis of all interval cancers, tumour size, grade, nodal stage, ER status, vascular invasion and comedo calcification were associated with survival. On multivariate analysis of prognostic features significant at univariate analysis, nodal stage (P value = 0.009), tumour size (P = 0.001), ER status (P < 0.0001) and vascular invasion (P < 0.0001) maintained independent significance. CONCLUSIONS: Our study shows that true intervals and interval cancers arising quickly after screening do not have a worse prognosis than other interval cancers, and that interval cancers have a unique set of prognostic features.

Effects of hypoxia, anoxia, and metabolic inhibitors on KATP channels in rat femoral artery myocytes.

Vascular ATP-sensitive potassium (KATP) channels have an important role in hypoxic vasodilation. Because KATP channel activity depends on intracellular nucleotide concentration, one hypothesis is that hypoxia activates channels by reducing cellular ATP production. However, this has not been rigorously tested. In this study we measured KATP current in response to hypoxia and modulators of cellular metabolism in single smooth muscle cells from the rat femoral artery by using the whole cell patch-clamp technique. KATP current was not activated by exposure of cells to hypoxic solutions (Po2 approximately 35 mmHg). In contrast, voltage-dependent calcium current and the depolarization-induced rise in intracellular calcium concentration ([Ca2+]i) was inhibited by hypoxia. Blocking mitochondrial ATP production by using the ATP synthase inhibitor oligomycin B (3 microM) did not activate current. Blocking glycolytic ATP production by using 2-deoxy-D-glucose (5 mM) also did not activate current. The protonophore carbonyl cyanide m-chlorophenylhydrazone (1 microM) depolarized the mitochondrial membrane potential and activated KATP current. This activation was reversed by oligomycin B, suggesting it occurred as a consequence of mitochondrial ATP consumption by ATP synthase working in reverse mode. Finally, anoxia induced by dithionite (0.5 mM) also depolarized the mitochondrial membrane potential and activated KATP current. Our data show that: 1) anoxia but not hypoxia activates KATP current in femoral artery myocytes; and 2) inhibition of cellular energy production is insufficient to activate KATP current and that energy consumption is required for current activation. These results suggest that vascular KATP channels are not activated during hypoxia via changes in cell metabolism. Furthermore, part of the relaxant effect of hypoxia on rat femoral artery may be mediated by changes in [Ca2+]i through modulation of calcium channel activity.

The pathological and radiological features of screen-detected breast cancers diagnosed following arbitration of discordant double reading opinions.

AIM: To compare the mammographic background pattern, the mammographic and the pathological features of screen-detected cancers diagnosed following arbitration of discordant double reading opinions with screen-detected cancers diagnosed following concordant double reading. METHODS: Between April 2002 and December 2003, 249 patients were diagnosed with screen-detected malignancies following concordant double reading. In the same period 38 patients were diagnosed with screen-detected malignancies after their mammograms had undergone arbitration prior to recall. Mammograms of both groups of patients were reviewed retrospectively and the mammographic features documented. Histological data for both groups were also compared. RESULTS: Cancers detected following arbitration were more likely to manifest as parenchymal distortions (44 versus 8%, p<0.001) and less likely to manifest as spiculate masses (19 versus 42%, p=0.014). Arbitration cancers were less likely to be detected in fatty breasts (4 versus 29%, p=0.01). Arbitration cancers were smaller (p=0.045). Lobular cancers were commoner in the arbitration group, although this was of borderline significance (19 versus 8%, p=0.057) There was no significant difference in patient age, tumour grade or lymph node stage between the two groups. CONCLUSION: Cancers detected following arbitration are smaller and more likely to manifest as a parenchymal distortion compared with cancers detected by both readers. Arbitration cancers have broadly similar prognostic features to cancers detected by concordant double reading. It is estimated that approximately 11% more cancers are detected as a result of double reading with arbitration compared with single reading alone, after taking into consideration second reader bias.

The use of a short-acting benzodiazepine to reduce the risk of syncopal episodes during upright stereotactic breast biopsy.

The use of sublingual lorazepam provides a safe and effective means of reducing the risk of syncopal episodes during upright stereotactic breast biopsy. Sublingual lorazepam, 2-4mg, was received by 19 women undergoing a total of 20 stereotactic procedures. Of 14 women who had previously fainted during upright stereotactic biopsy, 13 had a successful repeat biopsy following administration of sublingual lorazepam. All 4 women who received lorazepam for significant anxiety had successful biopsies. Stereotactic guided wire localization also was performed in 2 cases.

Patterns of metastatic breast carcinoma: influence of tumour histological grade.

AIM: To assess if the pattern of metastatic spread of carcinoma of the breast varies according to tumour histological grade. MATERIALS AND METHODS: The clinical details, histological features of the primary tumour, and imaging findings at presentation of patients with metastatic breast cancer have been recorded prospectively since 1997. The pattern of metastatic spread, age at metastasis, metastasis-free interval (MFI), and length of survival with metastases were analysed by tumour grade. RESULTS: There was a significant association between histological high-grade tumours and high frequency of intra-pulmonary metastases (p=0.013); liver metastases (p=0.039); para-aortic lymphadenopathy (p=0.022) and metastatic presentation under 50 years of age (p=0.003). A significant correlation was also demonstrated between histological low-grade tumours and increased frequency of pleural disease (p=0.020); increased frequency of bone metastases (p=0.004); prolonged MFI (MFI>5 years; p<0.0001); and increased length of survival (p<0.0001). CONCLUSION: There is a correlation between patterns of metastatic spread and tumour histological grade. This partly explains the negative prognostic value of high tumour grade, as metastases from grade 3 tumours more commonly occur at sites associated with a worse prognosis. This finding may also prove useful in interpreting imaging in patients who have a history of breast cancer and undergo subsequent imaging because of new symptoms.

Randomized clinical trial comparing radioisotope occult lesion localization and wire-guided excision for biopsy of occult breast lesions.

BACKGROUND: Accurate localization of impalpable breast lesions that require biopsy is important. This randomized trial compared radioisotope occult lesion localization (ROLL) with the standard hooked-wire technique. METHODS: Ninety-five patients were randomized to receive either ROLL or wire localization of an occult breast lesion. Correct placement of isotope was confirmed by mammography and a hand-held gamma probe was used to guide the surgical excision. Radiological, surgical and pathological data were compared for accuracy, duration and ease of technique, and histopathological diagnosis. Procedure-related pain was also assessed. RESULTS: Of the 95 patients entered, 48 were randomized to ROLL and 47 to wire localization. Two ROLL procedures failed. Marking was accurate in 46 of 48 ROLL procedures and 44 of 47 of wire localizations (P = 0.242). Difficulty in localization (Likert score 2.6 for ROLL versus 4.4 for wire localization; P < 0.001) and the degree of surgical difficulty (2.6 versus 4.0; P < 0.001) were significantly less for ROLL. ROLL was associated with less pain (score 2.7 versus 3.6; P = 0.012). There were no significant differences in mean duration of operation, specimen weight, need for intraoperative re-excision or second therapeutic operation. CONCLUSION: ROLL and wire-guided localization were similarly effective for breast biopsy, but ROLL was easier for both radiologist and surgeon, and less painful for the patient.

Brain metastases from breast cancer: identification of a high-risk group.

AIMS: Brain metastases from breast cancer are an uncommon initial presentation of metastatic breast cancer, but brain metastases commonly occur later in women's metastatic illness. The aims of this study were to document the type, frequency, and temporal occurrence of brain metastases from breast cancer as well as the survival of women with such metastases, and to attempt to identify a subgroup of women at high risk of brain metastases who may benefit from pre-emptive medical intervention. MATERIALS AND METHODS: The radiological reports of all women presenting with metastases aged under 70 years who had subsequently died were examined. The type, frequency, temporal occurrence and survival with brain metastases were documented. Correlations were sought between the frequency of brain metastases and age at metastatic presentation, tumour grade, histological type and oestrogen receptor (ER) status. RESULTS: Of 219 patients who had died with metastatic disease and who were under 70 years of age at metastatic presentation, 49 (22%) developed brain metastases. The development of brain metastases was related to young age (P = 0.0002), with 43% of women under 40 years developing brain metastases. Brain metastases were more common in women whose tumours were ER negative (38%) compared with women with ER-positive disease (14%) (P = 0.0003). By combining age and ER status, it is possible to identify a group of women (age under 50 years and ER negative) with a 53% risk of developing brain metastases. This group included many women who had chemotherapy for visceral metastases, and 68% had either stable disease or disease response at other sites at the time of brain metastases presentation. CONCLUSION: It is possible to identify a subgroup of women with metastatic breast cancer at high risk of brain metastases who may benefit from pre-emptive medical intervention, such as screening or prophylactic treatment.

Woman feels breast lump--surgeon cannot: the role of ultrasound in arbitration.

The role of ultrasound scanning (USS) in patients complaining of a breast lump where the clinical examination (CE) is normal is not clearly defined. To determine this in greater detail, all patients complaining of a breast lump underwent CE. Where no lump could be found, but was still reported by the patient, an USS was performed. All lesions underwent biopsy and/or aspiration, as well as mammography in suspicious cases or those over 40 years of age. This cohort represented 5% of all referrals in the study period. Four hundred and twenty women were prospectively studied in this way. Median follow up is 3.4 years (range 2.5-4.2 years). Twenty two had solid lumps (of which 3 were cancers) and 48 had cysts. Nineteen patients re-presented with symptoms in the same breast (median time = 12 months (range 4.5-20 months), all of which were imaged on USS: 15 cysts and 4 further cancers (3 in the same quadrant as the original lump, one contralateral) were identified. Women with symptomatic breast lumps and a normal CE can be considered a reliable indication that cancer is very unlikely to be present (negative predictive value = 0.98). Ultrasound may be a suitable complimentary investigation, which will relieve symptoms in those with cysts and can detect small clinically--and sometimes mammographically--occult breast cancers.

Metastatic carcinoma of the breast with tubular features: differences compared with metastatic ductal carcinoma of no specific type.

AIMS: To compare the metastatic pattern at presentation and the prognosis with metastases of 48 patients with carcinomas with tubular features (45 tubular mixed and three pure tubular) and 302 patients with tumours of ductal of no special type (DNST). MATERIALS AND METHODS: We carried out a retrospective study from a prospectively maintained database of all patients who developed metastatic disease from carcinoma of the breast in Nottingham, U.K., since 1997. We recorded site of first presentation with metastatic disease, radiological features, histological features and characteristics of the primary tumour. RESULTS: The group of patients with tubular features were older at metastatic presentation (63.9 years vs 59.6 years; P=0.012), had a longer disease-free interval (87 months vs 34 months: P<0.001) and a longer survival with metastases (P<0.002). This group were less likely to have liver metastases (23% vs 41%; P=0.028), in particular multiple liver metastases (50% vs 71%; P=0.015) than the patients with DNST. Other factors known to be associated with prolonged survival, such as low histological grade of the primary invasive tumour and positive oestrogen receptor (ER) status, were more common in the group of patients with tumours with tubular features (Grade 1: 33% vs 3%; Grade 2: 42% vs 25%; Grade 3: 25% vs 72%; P<0.001), (ER positivity 76% vs 52%; P=0.009). When patients with grade 2 tumours were compared, the age at metastatic presentation, disease-free interval and the presence of multiple liver metastases were still significantly different between the two groups. CONCLUSION: Patients with metastatic breast carcinoma with tubular features have a longer survival with metastases than patients with metastatic DNST carcinoma. This improved survival can be explained by better well-recognised prognostic features, such as metastatic site pattern, histological grade, ER status and disease-free interval.

Radioisotope for occult lesion localisation (ROLL) of the breast does not require extra radiation protection procedures.

AIM OF STUDY: Dosimetry data from patients and hospital personnel involved in the use of radioisotope for occult lesion localisation (ROLL) of the breast were collected to determine the need for extra radiation protection procedures. METHODS: Sixty-three patients have been enrolled to date into a randomised trial evaluating ROLL. Two megabecquerels of (99m)Tc- MAA in a syringe was mixed with X-ray contrast medium; this was injected directly into the lesion under image guidance. A gamma-detecting probe (Neo-Probe) was used to locate the area of radioactivity. Radiation doses to all staff groups were estimated using time and motion studies and dose rate measurements at a range of distances during each stage of ROLL. RESULTS: The finger dose [FD](+/-95% CI) was considered to be the critical variable for surgeons and radiologists. Surgeon FD=9.3+/-3.3 microSv, Radiologist FD=0.5+/-0.13 microSv. Whole body doses [WBD](+/-95% CI) were estimated for other staff groups. Nurse WBD=0.4+/-0.4 microSv, porter WBD: nil, contamination and waste: nil. CONCLUSIONS: In the case of a surgeon performing 100 procedures per annum, a FD dose of approximately 1 mSv is received, well within the annual dose limit of 150 mSv. Annual WBD to assisting staff may reach 0.04 mSv, compared to an annual limit of 6 mSv. These low doses and the lack of contamination of radioactive waste indicate that no additional radiation protection measures are required.

Diagnosis of axillary nodal metastases by ultrasound-guided core biopsy in primary operable breast cancer.

The purpose of this study was to examine the use of ultrasound (US)-guided core biopsy of axillary nodes in patients with operable breast cancer. The ipsilateral axillae of 187 patients with suspected primary operable breast cancer were scanned. Nodes were classified based on their shape and cortical morphology. Abnormal nodes underwent US-guided core biopsy/fine needle aspiration (FNA), and the results correlated with subsequent axillary surgery. The nodes were identified on US in 103 of 166 axillae of patients with confirmed invasive carcinoma. In total, 54 (52%) met the criteria for biopsy: 48 core biopsies (26 malignant, 20 benign node, two normal) and six FNA were performed. On subsequent definitive histological examination, 64 of 166 (39%) had axillary metastases. Of the 64 patients with involved nodes at surgery, preoperative US identified nodes in 46 patients (72%), of which 35 (55%) met the criteria for biopsy and 27 (42%) of these were diagnosed preoperatively by US-guided biopsy. In conclusion, US can identify abnormal nodes in patients presenting with primary operable breast cancer. In all, 65% of these nodes are malignant and this can often be confirmed with US-guided core biopsy.

The structure of S100A12 in a hexameric form and its proposed role in receptor signalling.

S100A12 is a member of the S100 subfamily of EF-hand calcium-binding proteins; it has been shown to be one of the ligands of the 'receptor for advanced glycation end products' (RAGE) that belongs to the immunoglobulin superfamily and is involved in diabetes, Alzheimer's disease, inflammation and tumour invasion. The structure of the dimeric form of native S100A12 from human granulocytes in the presence of calcium in space group R3 has previously been reported. Here, the structure of a second crystal form in space group P2(1) (unit-cell parameters a = 53.9, b = 100.5, c = 112.7A, beta = 94.6 degrees) solved at 2.7A resolution by molecular replacement using the R3 structure as a search model is reported. Like most S100 proteins, S100A12 is a dimer. However, in the P2(1) crystal form dimers of S100A12 are arranged in a spherical hexameric assembly with an external diameter of about 55 A stabilized by calcium ions bound between adjacent dimers. The putative target-binding sites of S100A12 are located at the outer surface of the hexamer, making it possible for the hexamer to bind several targets. It is proposed that the S100A12 hexameric assembly might interact with three extracellular domains of the receptor, bringing them together into large trimeric assemblies.

Detecting which invasive cancers at mammographic screening saves lives?

OBJECTIVES: Assessment of the features of primary operable breast carcinomas arising in women known to subsequently develop metastatic disease, to show for which invasive breast cancers earlier detection by mammographic screening is potentially beneficial. These data were applied to a separate series of screen detected cancers. METHODS: Features associated with the development of metastatic disease after a previous operable breast cancer were ascertained from examination of histological sections of the initial primary carcinoma and in particular the incidence of nodal positivity and definite vascular invasion. Trends in the frequency of nodal involvement and vascular invasion according to histological grade, invasive size, and tumour type were then examined in a further group of 573 screen detected invasive cancers to predict the likelihood of development of systemic disease in these women. RESULTS: Of 173 women who developed metastatic disease after a previous operable breast cancer, 79 (72%) had nodal metastases and 62 (59%) had definite vascular invasion. A high proportion (84%) had either lymph node metastases or vascular invasion or both. The absence of vascular invasion and nodal involvement in invasive breast cancer indicated a low risk of subsequent development of metastatic disease. In the screen detected group, grade 1 invasive cancers <20 mm in size and grade 2 and 3 cancers <10 mm in size had low rates of nodal involvement and vascular invasion. There was a gradual trend to small size, lymph node negativity, and less vascular invasion when comparing screen detected ductal carcinoma of no special type, tubular mixed carcinoma, and tubular carcinoma. Cancers with a lobular component tended to be larger and more often lymph node positive than ductal and no specific type carcinomas. CONCLUSIONS: These data suggest that identification of grade 1 cancers less than 20 mm in size and grade 2 and 3 cancers less than 10 mm in size at screening is likely to be beneficial, with a lower likelihood of developing metastatic disease from these lesions. The detection of tubular mixed carcinomas and ductal carcinomas of no specific type also appears beneficial. However the detection of tumours with lobular features at breast screening does not seem to significantly benefit the patient.