Role of circulating endothelial progenitor cells in the reparative mechanisms of stable ischemic myocardium.

BACKGROUND: Mobilization of endothelial progenitor cells (EPCs) into circulation from bone marrow in patients with acute myocardial infarction has strong scientific evidence; less is known about EPC mobilization in patients with stable coronary artery disease (CAD). The aim of this study was to investigate the association of stable ischemic heart disease with EPC levels in tissue and blood. METHODS: Fifty-five consecutive patients admitted to a single treatment center for valve or coronary artery bypass grafting (CABG) surgeries were included in the study. Blood samples were collected in the morning before surgery and analyzed by flow-cytometry to determine peripheral EPC levels (EPC/ml). Tissue EPC (CD34+VEGFR2+) levels were assessed on a right atrial appendage segment. RESULTS: Mean age was 76±5years, 48% were men, and 53% had CAD The number of CD34+ VEGFR2+ cells in the tissue of patients with CAD was significantly higher (p<0.005) and circulating EPC showed a tendency to be reduced by approximately 20% in peripheral blood of patients with CAD when compared to those without CAD. CONCLUSION: Patients with stable CAD had higher EPC density values (EPC/mm2) and were more likely to have lower EPC blood levels when compare with normal controls.

Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks.

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub-populations grouped by age, race, and sex. Methods: Study-level data were combined from 27 double-blind, placebo-controlled or active-comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6-24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first-/second-line therapy (first line = drug-naïve or rendered drug-naïve by washout at study entry; second line = ongoing statin at study entry or statin run-in), trial within first-/second-line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first-/second-line subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug-related, hepatitis-related and gastrointestinal-related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first-line vs. second-line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second-line studies, ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. These results describe the safety profiles of widely used lipid-lowering therapies and encourage their appropriate and judicious use in certain subpopulations.

Indications for breast magnetic resonance imaging. Consensus document "Attualità in senologia", Florence 2007.

The clinical use of breast magnetic resonance (MR) imaging is increasing, especially for applications requiring paramagnetic contrast-agent injection. This document presents a synthetic list of acceptable indications with potential advantages for women according to evidence from the literature and the expert opinion of the panel that developed this statement. We generally recommend that breast MR imaging be performed in centres with experience in conventional breast imaging [mammography and ultrasonography (US)] and needle-biopsy procedures (under stereotactic or US guidance) as well as in breast MR imaging and second-look US for findings not revealed by conventional imaging performed before MR imaging. In our opinion, there is no evidence in favour of breast MR imaging as a diagnostic tool to characterise equivocal findings at conventional imaging when needle-biopsy procedures can be performed, nor for the study of asymptomatic, non-high-risk women with negative conventional imaging. After a description of technical and methodological requirements, we define the indications and limitations of breast MR imaging for surveillance of high-risk women, local staging before surgery, evaluation of the effect of neoadjuvant chemotherapy, breast previously treated for carcinoma, carcinoma of unknown primary syndrome, nipple discharge and breast implants.

Analysis of the results of a proficiency test in screening mammography at the CSPO of Florence: review of 705 tests.

PURPOSE: The aim of this study was to evaluate the performance of a sample of Italian radiologists undergoing a proficiency test of screening mammography. MATERIALS AND METHODS: We retrospectively analysed the results of 705 tests (537 first tests, 168 repeat tests) taken during 1997-2005 by 537 Italian radiologists. The test, consisting of 17 screen-detected cancer cases and 133 negative controls, was validated by a panel of expert readers defining a minimum standard as to sensitivity for cancer and recall rate of negative controls. Success rates were assessed as a function of previous experience in mammography (years of experience, total mammograms read, mammograms read in the last year). RESULTS: A total of 176 radiologists successfully passed the test at their first attempt (32.7%). Success correlated with experience, measured in terms of years of experience (5-year cutoff: chi(2) for trend=4.17, p=0.04), total mammograms read (chi(2) for trend =11.8, p=0.002) or mammograms read in the last year (chi(2) for trend=6.27, p=0.04). Training improves performance at repeat testing: after a first negative attempt, a second attempt was successful in 50.6% of cases (74/146) and a third in 68.1% (15/22). CONCLUSIONS: A substantial proportion of Italian radiologists taking the test showed limited proficiency in screening mammography. This finding is consistent with several reports of poor performance of service screening compared with reference standards. As expected, test performance is associated with experience, suggesting that the current policy of employing non-dedicated, untrained, general radiologists in screening should be reconsidered. Test performance improves with training (courses, consultation of teaching atlases). Several screening programmes in Italy have been implemented without prior adequate radiologist training. Radiologist training needs to be considered a priority, at least in those screening programmes that are still to be implemented in one third of the country.

The role of arbitration of discordant reports at double reading of screening mammograms.

OBJECTIVE: To asses the effectiveness of arbitration of discordant double readings in mammography screening. DESIGN: A retrospective study of 1217 consecutive arbitrations. SETTING: A subset of discordant double readings from the Florence screening programme underwent arbitration by a third reader. RESULTS: Positive arbitration of 1217 discordant double readings prompted assessment in 476 cases (39.2%), detecting 30 cancers (6.3%). Of 741 negative arbitrations (60.8%), 311 have been followed up thus far, and two cancers (0.64%) occurred in the site previously suspected at one of the two independent readings. Arbitration had a sensitivity of 86.3% and a negative predictive value of 99.3%. Arbitration reduced the overall referral rates from 3.82% to 2.59% (relative decrease 32.1%). Due to false-negative arbitration, cancers detected per 1000 women screened would decrease from 4.58 to 4.50 (relative decrease 1.7%). For every cancer missed due to false-negative arbitration, 151 unnecessary recalls and 21,248 euro would have been saved, whereas the saved cost per screened woman due to arbitration was 1.72 euro. DISCUSSION: Arbitration of discordant double reading would substantially reduce referral rates with a limited reduction in cancer detection rate, and may be recommended as a routine procedure. Greater benefit from arbitration might be expected in the presence of high referral rates at independent double reading, a common scenario in a newly implemented service screening.

[Assessment of diagnostic accuracy of mammography carried out for secondary prevention. Results of a test with a sample caseload conducted by 75 Italian radiologists]. / Valutazione dell'accuratezza diagnostica nella mammografia eseguita con fini di prevenzione secondaria. Risultati di una prova su casistica campione sostenuta da 75 radiologi italiani.

PURPOSE: To report the results of a test performed by 75 volunteer radiologists involved in screening program in Italy. MATERIAL AND METHODS: The test includes 12 screening detected cancers and 6 cancers (4 screening detected and 2 interval lesions) with minimal signs at review of a previous negative mammogram. Data on previous experience in mammography (years of activity, years of screening activity, total number of mammograms read and number of mammograms read per year) were also collected. RESULTS: Standards for passing the test were at least 83.3% for sensitivity for screening detected cancers and at most 30% for recall rate among negative cases. Mean sensitivity was 83.9% (median 83.3%, range 50-100%) and mean recall rate was 16.3 (median 14.4%, range 3.8-42.4%). In all, 44 radiologists (58.7%) passed the test. On average 1.4 of 6 cancers with minimal signs were correctly identified. According to readers' experience (at least 5 years in mammographic activity, at least 3 years in screening mammography, at least 10,000 total mammograms read, at least 5,000 per year) radiologists were classified as expert (13) or not (62): no difference in test performance was observed between the two groups. The only significant association occurred for years of mammographic activity and sensitivity. DISCUSSION AND CONCLUSIONS: Test results suggest the need for proper training of radiologists prior to involvement in a screening program. Seeding proficiency tests with cancers with minimal signs was of no benefit as far as evaluation is concerned.

[Radiologic analysis of interval cancers in the screening program called Florence Woman Project]. / Analisi radiologica dei carcinomi di intervallo nel programma di screening Progetto Firenze Donna.

PURPOSE: The aim of the present study was to provide data on interval cancer incidence after the first round of the screening program in the city of Florence, and to provide and discuss the results of the review of previous screening mammograms. MATERIAL AND METHODS: The screening program "Progetto Firenze Donna" involves all women age 50 to 69 years resident in the city of Florence. In the interval from the end of the first and the start of the second screening round 51 interval cancers were identified, of which 41 were available for radiological review. Films were reviewed by expert screening radiologists, not involved in the program and blinded to the final diagnosis, according to the review criteria recommended by the UK Guidelines for radiologists (blind and informed review). RESULTS: Sensitivity (screening errors/total) was different among blind reviewers (reader A = 7.3%, reader B = 14.6%), as well as specificity which shows an inverse pattern (reader A = 98.4%, reader B = 97.6%). Informed review classified 5 cases as "screening error" (12.2%), 11 as "minimal sign" (26.8%) and 25 as "occult" (61%). Informed review classified a higher proportion of cases as "minimal sign" (minimal abnormalities are better perceived with the knowledge of the site and the pattern of subsequent cancer). DISCUSSION AND CONCLUSIONS: Analysis of interval cancers is fundamental for the quality control of a screening program. According to this experience, informed review tends to overestimate "minimal signs" in the cancer site and should not be used (or "minimal signs" should be anyhow assumed as negative). Identification of interval cases as "minimal signs" may be influenced by individual variability. Standard criteria should be adopted to identify and review/classify interval cancers to allow comparisons between different programs.

Proficiency test for screening mammography: results for 117 volunteer Italian radiologists.

OBJECTIVE: To analyse the performance of a large sample of Italian radiologists undergoing a proficiency test for screening mammography. DESIGN: Evaluation of performance indicators according to reference standards determined by a panel of experts (sensitivity (reference standard > or = 80%), recall rate (reference standard < or = 15%)). SETTING: 117 Italian radiologists of varying experience (years of practice 0.5-18, average 5.9; mammograms read 500-51,000, average 13,000), all currently reporting clinical mammography and planning to take part in screening in the near future. RESULTS: Eighty four of 117 (72%) radiologists reached the standard for sensitivity, 88 (75%) reached the standard for recall rate, and only 59 (50%) reached both standards and passed the proficiency test. The probability of passing the test was significantly correlated with mammographic practice (p = 0.015), mammograms read (p = 0.024), and mammograms read/year (p = 0.043). DISCUSSION: The performance of a large sample of Italian radiologists currently reporting clinical mammography was disappointing, indicating the need for proper training of at least 50% of the tested subjects. When implementing organised screening the health authority should set up a proper process for training and accrediting radiologists, and a proficiency test should be part of such a process.

Solid nonpalpable breast lesions. Success and failure of guided fine-needle aspiration cytology in a consecutive series of 2444 cases.

PURPOSE: To evaluate the contribution of guided fine-needle aspiration cytology in reducing unnecessary biopsies of benign solid nonpalpable breast lesions with low suspicion of malignancy at mammography. MATERIAL AND METHODS: An evaluation was made of a consecutive series of 2444 solid nonpalpable breast lesions detected by mammography and undergoing guided (sonography or stereotaxy) fine-needle aspiration cytology. Surgical biopsy was made in the presence of strong suspicion of malignancy at mammography and/or of abnormal cytology. RESULTS: The sensitivity was 96.7% and the specificity 77.7% (average follow-up 2.77 years). False-negative/inadequate cytology associated with low suspicion of malignancy at mammography resulted in a diagnostic delay in 27 cancer cases (invasive 20, intraductal 7). On the other hand, cytology led to surgical biopsy in 53 cancer cases which might not otherwise have been biopsied because of low radiological suspicion of cancer. Surgical biopsy of all cases, to avoid diagnostic delays, would have increased the benign biopsy rate by a factor of 4.5, with a rise in the benign: malignant biopsy ratio from 0.44:1 to 1.93:1. CONCLUSION: Stereotaxy- or ultrasound-guided fine-needle aspiration cytology of nonpalpable mammographic abnormalities can achieve a sharp reduction in unnecessary benign biopsies in cases of low suspicion of malignancy at mammography.

[Test for the assessment of the diagnostic accuracy of mammography. Results of 103 tests carried out by Italian radiologists]. / Test per la valutazione dell'accuratezza diagnostica nella mammografia. Risultati di 103 test sostenuti da radiologi italiani.

This study reports the results of some voluntary Italian radiologists performing 103 proficiency tests in clinical (100 patients, 32 cancers) and screening mammography (150 patients, 17 cancers). Relative to the average accuracy of a panel of expert radiologists, 12 of 49 readers (27%) and 32 of 54 readers (56%) passed the clinical and screening mammography test, respectively. The results were significantly correlated with the readers' previous experience (years of mammographic practice [< 2, 2-4, > 4] and number of mammograms read [< 5,000, 5-10,000, > 10,000]). The rate of passed test was: < 2 years = 0%, 2-4 years = 40%, > 4 years = 66.6% (P = 0.002); < 5,000 mammograms read = 15.3%, 5-10,000 = 28.5%, > 10,000 = 69.2% (P = 0.02). The best results were achieved by the readers with a previous reading experience of at least 10,000 mammograms, a figure which might be used as the reference for a future criterion of accreditation on a national basis. Proper training before reporting mammography is fundamental to ensure a good diagnostic performance. The low number of tests performed in most Italian mammographic practice facilities makes local training highly questionable and requires quite a long time. Reference centers, adequately equipped for training, should be identified for this purpose. Proficiency tests such as those described in the present study are useful to assess individual performance and should be a part of a training program.

[The procedures and results of a quality control program in mammography carried out on a regional basis]. / Procedure e risultati di un programma di controllo di qualità in mammografia svolto su base regionale.

In 1990 the region of Tuscany instituted a quality control program for mammography, in order to check the working conditions of mammography centers in the region, to investigate the feasibility of applying some working standards in line with European recommendations, and to promote the training of personnel. The program involves the following: a test of newly acquired mammographic equipment to establish that it meets the required standards; an annual test of generators, X-ray beams, grid, AEC, screen-film system, film processing, dose and image quality; daily test (phantom radiography and film sensitometry) performed by the personnel of each mammographic Unit; and a sustained advisory service for the technical problems occurring between checks. Thirty-nine of 57 centers participated on a voluntary basis, and 135 checks were performed annually. The results of the program show a performance below the recommended standard in relation to AEC, film sensitometry and the adequacy of lights in dark rooms in 40%, 50% and 63%, respectively, of the centers. Entrance exposure was over 1500 mR, with a maximum value of 3450 mR, in 6 cases in the first round. 5 cases in second, and only 1 case in the third. In general, the results are slightly improving, but mammography optimization is still a long way off. It is necessary to carry out suitable programs for quality control in mammography on a regional basis and to establish precise guidelines for individual mammographic Units to follow in order to meet the European standards.

Independent double reading of screening mammograms.

OBJECTIVE: To evaluate the cost effectiveness of independent double reading of screening mammograms. SETTING: Prospective study of 18,817 women undergoing first or repeat screening in a population based programme in the Florence district. METHODS: Mammograms were independently double read by experienced radiologists. Subjects with mammographic abnormalities reported by at least one reader were recalled for diagnostic assessment. The mean increase in recall rate, cancer detection rate, and screening costs attributable to double reading was calculated. RESULTS: Eleven of 125 cancers were detected by only one reader. The mean increase in cancer detection rate attributable to double reading compared with single reading was 4.6% (95% confidence interval (CI) 1.1 to 8.9). From a total of 748 cases referred for diagnostic assessment, 196 subjects were referred by one reader only. The mean increase in referral rate attributable to double reading compared with single reading was 15.1% (CI 12.3 to 17.8). Double reading caused a marked increase in the cost for each woman screened -8.5% at the first screening and 6.2% at repeat screening and a more limited increase in the cost for each cancer detected -3.5% at the first screening and 2.7% at repeat screening. Cancers detected by only one screener were at an earlier stage than those detected by both screeners (P = 0.6, not significant). CONCLUSIONS: Independent double reading results in only a modest increase in the detection of cancers and therefore may not be cost effective.

[The diagnostic role of breast echography]. / Ruolo diagnostico dell'ecografia mammaria.

The authors reviewed a consecutive series of 4,160 breast lesions (511 carcinomas and 3,649 benign lesions) studied with 10-MHz US in 1990-1991. US sensitivity was 72.6%, specificity was 97.3% and positive predictive value was 78.9%. Sensitivity was independent of age whereas it strongly depended on tumor size (pT1a = 54.2%, pT1b = 70.6%, pT1c = 80.6%, pT2-4 = 90.2%) (81.1% palpable masses and 41.3% nonpalpable masses) and histologic type (11.4% intraductal carcinomas and 69.4% special types). The association was confirmed of the classic US signs with carcinoma (irregular margins and posterior shadowing) and benign lesions (lateral shadowing, no echogenicity and posterior acoustic enhancement) patterns, even though the former are not accurate enough for diagnostic purposes. US demonstrated 376 of 402 palpable carcinomas (50 diagnosed as benign and 326 as suspicious) and 58 of 109 nonpalpable carcinomas (13 diagnosed as benign and 45 as suspicious). US was the only imaging method to yield findings suggestive of cancer in 13 of 511 total cases and contributed to final diagnosis in 6 more clinically and radiologically negative cases in which US findings suggested a benign lesion but indicated the need for aspiration cytology. If on the one hand US was the only method responsible for unnecessary biopsy in 21 of 141 surgical benign lesions, on the other hand negative or benign US findings helped avoid unnecessary biopsy in 277 cases diagnosed as suspicious at palpation or mammography. US should be used as the routine examination in the assessment of clinical and mammographic abnormalities. Its contribution to cancer detection is limited but it allows the number of unnecessary biopsies to be markedly reduced as well as a more accurate guide for fine needle aspiration in most palpable cancers and in approximately half of nonpalpable ones.

Assessment of lesions detected at mammographic screening: performance at first or repeat screening in the Florence programme.

OBJECTIVE: To evaluate the assessment criteria and the results achieved in the detection of breast lesions at mammographic screening. SETTING: Review of cases assessed in the last screening round of Florence city (FC--first screening round: 29,522 subjects) and Florence district (FD --repeat screening round: 13,268 subjects) programmes. METHODS: Referral and biopsy rates, predictive values, and prevalence of cancers detected by screening were determined, as well as the frequency of the diagnostic procedures used at assessment, and their contribution to the final diagnosis according to the mammographic appearance of the suspected lesion. Assessment costs were estimated. RESULTS: Referral rate (FC 4.2%; FD 1.8%), referral positive predictive value (FC 18.7%; FD 28.3%), surgical biopsy rate (FC 0.96%; FD 0.6%), benign/malignant biopsy ratio (FC 0.20; FD 0.13), and prevalence of cancers detected by screening (FC 0.78%; FD 0.5%) were all within the European Community (EC) recommended standards for screening performance. The benign biopsy rate was considerably lower than that of recommended standards. The cost for each subject assessed was 179,000 Italian lire at the first and 116,000 lire at repeat screening. The cost for each subject screened that was attributable to assessment was 7600 lire at the first or 2100 lire at repeat screening. CONCLUSIONS: Limited referral rates and costs were achieved and the proportion of cancers detected by screening was high. The number of referrals was further reduced at repeat screening, and assessment had a limited impact on total screening costs. Detail or magnification mammography, palpation, sonography, and fine needle aspiration cytology all contributed to the final diagnosis and should be immediately available at the assessment clinic. The observed benign biopsy rate was particularly low and suggests that EC recommended standards should be modified.

[The mammographic aspect and the prognosis of breast carcinoma]. / Aspetto mammografico e prognosi del carcinoma mammario.

The authors report on 354 consecutive cases of invasive breast carcinoma followed up 3 to 13 years. The prognostic value of the mammographic appearance of cancer, determined according to Broberg, was studied, as well as that of other indicators, such as pT, pN and estrogen receptor content. An association was found between the mammographic appearance and the other prognostic indicators, but such an association was at the limits of statistical significance (pT p = 0.033, pN p = 0.039, ER p = 0.033) and the mammographic patterns associated with more favorable indicators were not consistent across the three variables. Ten-year actuarial overall survival was significantly associated with pT (p < 0.0001), pN (p < 0.0001) or estrogen receptor content (p < 0.001), but not with mammographic appearance. Multivariate analysis confirmed such results. We found no evidence, as suggested in some literature reports, of any association of the mammographic appearance of breast cancer with survival, and we believe that this indicator has no practical use in predicting prognosis in breast cancer patients.

The contribution of ultrasonography to the differential diagnosis of breast cancer.

Overall consecutive breast abnormalities (259 carcinomas, 1820 benign) examined with breast ultrasonography (US) are reported. US sensitivity, specificity and positive predictive value were 67.6, 97.7 and 81.0%, resp. (the corresponding values were 57.9, 97.9 and 77.2% for palpation, 79.9, 93.5 and 73.7% for mammography, and 97.6, 92.6 and 87.6% for cytology). US sensitivity was unaffected by age, whereas it was strongly influenced by tumor size (pT1-76.1%; pT2-87.1%) and histologic type (intraductal-7.4%; invasive ductal/lobular-83.4%; invasive special types-64.1%). The features of the lesions at US were significantly associated with cancer (irregular margins, posterior acoustic shadowing) or benign lesions (anechoic structure, lateral shadowing, posterior acoustic enhancement) but had a limited diagnostic accuracy. Overall, US visualized 174 (benign-24, suspicious-150) of 188 palpable, and 32 (benign-7, suspicious-25) of 71 nonpalpable cancers. US contribution was determinant to final diagnosis in 4 of 7 cancers, missed at palpation and mammography, but was at least partially responsible for 8 unnecessary biopsies of benign lesions. A negative/benign US report contributed to avoid unnecessary biopsy in 71 suspicious cases at palpation/mammography. Routine US examination of clinical/mammographic abnormalities is recommended for the advantages of US-guided aspiration and to reduce the frequency of unnecessary biopsies.

Fine-needle aspiration cytology of nonpalpable breast lesions: US versus stereotaxic guidance.

The authors evaluated ultrasound (US)-guided fine-needle aspiration cytology (FNAC) in 270 patients with suspicious findings at mammography. FNAC with a 10-MHz transducer and real-time scanner was performed when a lesion seen mammographically was unequivocally depicted at US. The needle was inserted with variable obliquity to the scanning plane. Stereotaxically guided FNAC was performed when lesions were not visible at US. High suspicion at mammography and positive cytologic reports led to surgical biopsy. Of the 270 lesions, 120 (44.4%) were visible at US. Opacities were the most frequently visualized lesions. Inadequate samplings were most frequently reported for opacities with smooth margins. Differences in accuracy and inadequacy rate between the two modalities were not significant. Cancer was surgically confirmed in 86 of 110 cases. The other 160 lesions were considered benign, and mammographic follow-up in 120 has shown no change. Because FNAC with US guidance was faster and less expensive, it is recommended as the technique of choice in lesions detectable with US.

Radial scars of the breast: review of 38 consecutive mammographic diagnoses.

The authors report 38 consecutive cases of histologically proved breast radial scars (RSs) detected at mammography. In a retrospective review of mammograms in 30 matched cases of nonpalpable RS and nonpalpable scirrhous cancer, the characteristic mammographic features of RS were confirmed: (a) the absence of a central opacity, often substituted by a radiolucent area; (b) the presence of multiple elongated thin spicules radiating from the center of the lesion; (c) the infrequency of any palpable finding, even for superficial lesions of relatively large size. Microcalcifications with aspecific structure were found in the lesions on mammograms of 14 of the 38 cases and in 24 of the histologic specimens. The typical mammographic features of RS were not specific to RS, being present in a minority of cancer cases. For two blinded readers, sensitivity was 86.7% and 76.7% and specificity was 78% and 80%, respectively. Although some specific mammographic features may suggest the presence of RS, the final differential diagnosis from scirrhous cancer should be based on histologic evidence, and surgical biopsy should be advised for any stellate lesion detected at mammography.