Early detection of second breast cancers improves prognosis in breast cancer survivors.

BACKGROUND: The impact of early detection of second breast cancers in women who have survived a primary breast cancer is unknown. We examined the prognostic effect of detection of ipsilateral breast relapse (IBR) or contralateral breast cancer (CBC) in the asymptomatic relative to symptomatic phase. PATIENTS AND METHODS: Subjects were women with histology-verified second (invasive or in situ) breast cancer (N = 1044) in a breast centre in Florence (1980-2005). Symptom status, test, tumour stage, and outcomes data were obtained from clinical records and linkage with mortality registry. Disease-specific survival was measured from first cancer diagnosis to avoid lead-time bias. Sensitivity analysis was used to allow for length-time bias. RESULTS: Second cancers (IBR = 455; CBC = 589; median age 60 years) were diagnosed in 699 asymptomatic and 345 symptomatic women (67% versus 3%, P < 0.0001). Mammography was more sensitive than clinical examination (86% versus 57%, P < 0.0001); however, 13.8% of cases were only identified clinically. Asymptomatic cancers were smaller than symptomatic for both IBR (P < 0.001) and CBC (P < 0.001). Early-stage tumours were more frequent in asymptomatic (58.1%) than symptomatic (22.6%) women (P < 0.0001). Fewer women with asymptomatic than symptomatic CBC had node metastases (P = 0.0001). Hazard ratio (HR) for asymptomatic (relative to symptomatic) detection was 0.51 (0.32-0.80) for IBR, 0.53 (0.36-0.78) for CBC, and 0.53 (0.40-0.72) in all subjects (P < 0.0001). Length bias-adjusted HRs ranged from 0.53 to 0.73. CONCLUSION: Detection of second breast cancers in the asymptomatic phase leads to detection of early-stage cancer and improves relative survival by between 27% and 47%.

Severe HDL deficiency due to novel defects in the ABCA1 transporter.

OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.

Second breast cancers in a Tuscan case series: characteristics, prognosis, and predictors of survival.

Little is known about long-term outcomes following a second breast cancer diagnosis. We describe the epidemiology, characteristics and prognosis of second breast cancers in an Italian cohort. We identified women with two breast cancer diagnoses from 24 278 histology records at a Tuscan breast cancer service between 1980 and 2005, and determined their survival status. Disease-specific survival from second diagnosis was examined using Cox regression analyses. Second cancers were identified in 1044 women with a median age of 60 years. In all 455 were ipsilateral relapses and 589 were contralateral cancers. Median time between first and second diagnosis was 63.4 months. The majority of second cancers was small invasive or in situ tumours. Estimated 10-year survival from a second cancer diagnosis was 78%. Survival was poorest when the second cancer was large (HR=2.26) or node-positive (HR=3.43), when the time between the two diagnoses was <5 years (HR=1.45), or when the diagnosis was in an earlier epoch (HR=2.20). Second tumours were more likely to be large or node-positive if the first breast cancer had these features. Prognosis following a second breast cancer in this cohort was generally good. However, large or node-positive second tumours, and shorter intervals between diagnoses were indicators of poorer survival.

Efficacy and safety of oral beclomethasone dipropionate for ileal or ileal-right colon Crohn's disease of mild-to-moderate activity or in remission: Retrospective study.

Although conventional glucocorticosteroids are the main treatments for active Crohn's disease, several problems are associated with steroid dependence and steroid-related adverse events. To assess the efficacy and safety of oral beclomethasone dipropionate (BDP) coated tablets in adults with mild-to-moderate Crohn's disease. Thirty-four patients (age 18-70years) with a diagnosis of Crohn's disease confirmed by conventional criteria (barium enema, clinical criteria, colonoscopy, histology) were retrospectively evaluated in the study. All subjects received a treatment schedule with BDP 5-10mg/day for 24weeks. BDP significantly (p=0.005) reduced mean Crohn's Disease Activity Index (CDAI) score from 169.6 at baseline to 123.2 after 24weeks. Clinical success was evident at 24weeks in 66.7% of patients with initial active disease, and remission was maintained at week 24 in 93.8% of patients with remission at baseline. Overall, female non-smokers had the best response to treatment. BDP was well tolerated and the only adverse events observed were nausea (n=1), facial erythema (n=1) and one patient with raised fasting blood glucose level. These results clearly suggest that oral BDP coated tablets are effective and safe for treatment of mild-to-moderate Crohn's disease of ileal or ileal-right colonic localisation.

Assessment of liver fibrosis in the clinical setting: something is changing?

Clinical management of compensated chronic liver diseases (CLD) requires precise definition of the stage of liver fibrosis which is the key histologic predictor of progression to cirrhosis. Several methods are used to assess liver fibrosis. Among those, percutaneous liver biopsy is still the gold standard. However, the recent introduction of liver imaging techniques, the rising of statistical tests able to classify CLD noninvasively, and a reconsideration of its potential complications, have contributed to an audit of the evolving role of liver biopsy. At present, there is an increasing interest for noninvasive approaches to evaluate the stage of liver fibrosis in the clinical work-up of patients with CLD. Transient elastography (FibroScan) is a new, noninvasive method to assess liver stiffness and, consequently, the degree of liver fibrosis. Since its use in the clinical setting is of great interest, further studies should define the exact role of this procedure.

Hepatocellular carcinoma complicating primary sclerosing cholangitis in Crohn's disease. A case report.

The prevalence of primary sclerosing cholangitis (PSC) in Crohn's disease (CD) patients is up to 8.5%. Although cholangiocarcinoma may complicate long-standing PSC in one third of the cases if follow-up is extended long enough, hepatocellular carcinoma (HCC) is a rare complication of PSC. The concomitant presence of PSC, HCC and CD have been reported sporadically. We discuss here a case of association of these three conditions.

[Gastroenterology outpatient clinic of the Molinette Hospital (Turin, Italy): the 2003-2006 report]. / Poliambulatori specialistici di gastroenterologia: l'esperienza 2003-2006 dell'Ospedale Molinette di Torino.

AIM: Given the demographic shifts and needs of cost rationalization, it is of high priority to organize health care on the basis of ambulatory outpatients models. The aim of this study was to examine activity at the gastro-hepatology outpatients clinic of the Molinette Hospital. In this facility, the management is based on a work team organization that follows cohorts of patients with specific pathologies. METHODS: All services, consultations and urea breath test (UBT) for the diagnosis of Helicobacter pylori infection, carried out from January 2003 to December 2006, were extrapolated from the computerized system. Consultations were divided into first examination and controls. Furthermore, the destination of the patients after each consultation was considered. RESULTS: During the year 2003, 8 842 consultations and 4 071 UBT were carried out, in the year 2004, 11 342 consultations and 2 409 UBT, in the year 2005, 12 474 consultations and 2 510 UBT, in the year 2006, 12 249 consultations and 2 357 UBT. No further specialistic management was required for 25% of patients, while 2% had been hospitalized in the bed unit, 3% in the short hospitalization unit or the day-hospital. The remaining 70% were included in work teams or monitored thereafter. The comparison with consultations from 1994 shows an increase due to both first examination (+300%) and controls (+83%). CONCLUSIONS: The burden of the requests from the population and primary care structures addressed to the outpatients clinic of gastro-hepatology is relevant. The activity of this facility leads to a low rate of hospitalization as well as of cost reduction.

[Non-invasive diagnosis of Helicobacter pylori infection in the 2006 clinical practice]. / La diagnosi "non invasiva" dell'infezione da Helicobacter pylori nella pratica clinica del 2006.

At present, 2 approaches are used to detect Helicobacter pylori (H. pylori): invasive, if based on biopsies taken during endoscopy, and non-invasive, if they do not rely on endoscopic approach. A 3rd option is offered by the string test, that employs an invasive non-endoscopic strategy. The present review attempts to update on the diagnostic non-invasive approaches to patients in the clinical setting. Non-invasive tests include urea breath test (UBT), antigen stool assay, serology, and ''doctor's tests''. The choice of the methods depends on the situation, for example, the clinical circumstances, the diagnostic accuracy, the costs of the testing strategy, and the availability of the tests in the respective area. According to European guidelines, UBT and antigen stool assay are recommended in patients without alarm symptoms or under 45 years of age, at low risk of malignancy in the test and treat strategy. Confirmation of H. pylori eradication following treatment should be tested by UBT; the stool antigen assay is the alternative if the former is not available.

Second reading of screening mammograms increases cancer detection and recall rates. Results in the Florence screening programme.

OBJECTIVE: To assess double reading effectiveness in mammography screening. DESIGN: Retrospective study of 177,631 consecutive mammograms double read during 1998-2003. SETTING: The Florence screening programme, involving 11 trained radiologists. Abnormalities reported by at least one reader prompted assessment. RESULTS: The referral rate was 2.89% for the first reader, 3.15% for the second reader, and 3.59% for either reader. Of 713 total cancers detected, 43 were suspected only by the second reader (6.4% relative, 0.024% increase in absolute detection rate) and had a lower stage compared to the first reader (pTis-pT1b = 65.7 versus 52.0%): 41 were reviewed and classified (error type) as "minimal sign" in six, and "screening error" in 35 cases, or as BI-RADS 3 in one, 4a in 20, 4b in 13, and 4c in three cases. The second reading cost was 2.70 per woman examined, or 11,168 per additional cancer detected (versus 11,585 at a single reading). DISCUSSION: Second reading is effective in detecting a limited number of additional cancer cases. Tumour stage (one-third over 1 cm in diameter) and review findings (high rate of "screening errors" and BI-RADS R4b-c categories) suggest that second reading detects small "difficult cases" as well as larger cancers missed due to fatigue or loss of attention. Second reading reduces screening specificity to a minor extent, and since cancer detection at second reading seems cost-effective the procedure is recommendable in routine practice.

Autoimmune manifestations during interferon therapy in patients with chronic hepatitis C: the hepatologist's view.

In face of numerous benefits induced by therapy based on interferon (IFN) associated with ribavirin for the treatment of chronic hepatitis C, there is an increasing concern regarding its tolerance, which can, in some cases, reduce the quality of life as well as compliance of patients. Among the less common side effects, there are the autoimmune ones which can be globally divided into appearance or increase in titres of auto-antibodies and/or manifestation of overt autoimmune pathologies. Whereas the former may concern more than 50% of treated subjects, the latter is reported in only 1-2% of patients under therapy. Thyroid dysfunction represents the well-studied autoimmune disorder. The presence of pre-existing anti-thyroid antibodies and being of female sex, constitute relevant risk factors for the development of a disease involving this gland. Often the treatment of thyropathy must be continuous in spite of IFN discontinuation because the disturbance usually does not abate with stopping antiviral therapy. Some observations have pointed out to the fact that IFN can lead to the development of insulin-dependent diabetes mellitus. Sometimes, during, as well as after IFN treatment, the appearance of anti-islet cell antibodies has been shown, but its interrelationship with the development of disease is uncertain. While being treated with IFN for chronic hepatitis C, the finding of non-organ specific antibodies at baseline can increase the likelihood of the development of autoimmune hepatitis. However, their presence does not constitute an absolute contraindication to the treatment, except in case of high titre. Other disorders, such as a lupus erythematosus-like syndrome, haemolytic anaemia, and immune-mediated thrombocytopenia have been reported. In conclusion, although the presence of auto-antibodies is considered to be an epiphenomenon without pathogenic significance in most patients suffering from chronic hepatitis C, it poses a problem when they need to be treated with IFN. This antiviral drug can induce or exacerbate a multitude of autoimmune-related disorders, however, clinically overt immune-mediated diseases are rare and affect a subset of subjects who have an underlying autoimmune diathesis.

Prostate cancer screening: the problem of overdiagnosis and lessons to be learned from breast cancer screening.

Screening for prostate cancer is a relatively new procedure, still under experimental evaluation within prospective randomised trials. The design of prospective studies has been mainly based on the experience of other cancer screenings, particularly breast cancer, for which data of several controlled studies are available. Unfortunately, breast cancer is very different from prostate cancer, particularly for aspects such as early diagnosis and, thus the screening process, originally modelled on the basis of the lesson taught by breast cancer screening, needs continuous re-evaluation and adjustment, based on data which are now being produced from ongoing screening experiences. In this paper, we will consider the most controversial aspects of prostate cancer screening and compare prostate screening with breast cancer screening in order to promote a better understanding of the current problems and lessons to be learned.

Trends in cervical cancer incidence in the district of Florence.

The trend in cervical cancer incidence in the District of Florence from 1975 to 1989 was investigated. Tuscany Cancer Registry data were available since 1985. Incidence data from 1975 to 1985 were obtained through a retrospective survey of all the Departments of Pathology and Gynaecology in the district. Cytological screening for cervical cancer has been available in the district since 1973, and since 1980 active invitation of residents aged 25 to 59 years has been in use. A significant trend in decreasing incidence was evident for the overall population (P = 0.003) and for 40-49 (P = 0.028), 50-59 (P < 0.001) and 60-69 (P = 0.002) year age groups, whereas no significant trend was observed for the age group 30-39 years. An association between attendance to screening and reduced incidence was evident, in that a greater reduction was evident for those cohorts (ages 50-59 and 60-69) who had a higher compliance to screening 10-15 years before. If the decrease in cervical cancer incidence was spontaneous, a parallel decrease of CIN3, which is commonly assumed to be the precursor of invasive carcinoma, would be expected. On the contrary, the detection rate of CIN3 at first Pap test showed a significant increase in the study period. All these findings suggest that the observed reduction in cervical cancer incidence was mostly due to the effect of screening, and stress the need for optimising the coverage of the invited population.

Non-palpable lesions of the breast detected by mammography--review of 1182 consecutive histologically confirmed cases.

We report on 1182 consecutive histologically confirmed non-palpable breast lesions detected by mammography (infiltrating carcinoma 427, in situ carcinoma 121, benign 634). The proportion of cancer cases varied according to age (< 50 years = 33%; 50-59 years = 46%; > 59 years = 63%), mammographic pattern (regular opacities = 8%, parenchymal distortions = 20%, isolated calcifications = 42%, irregular opacities = 62%, stellate opacities = 73%), and calendar period (1970-1985 = 29%, 1986-1989 = 56%; 1990-1992 = 69%). A sharp decrease of the benign/malignant biopsy ratio was evident after routine fine-needle aspiration cytology (sonography-guided or stereotaxic) was introduced in 1986. The independent significant association of cancer frequency to age, calendar period and mammographic pattern was confirmed by multivariate analysis. A significant trend over time in favour of conservative surgery was also observed for cancer cases (1970-1979 = 6%, 1980-1985 = 41%, 1986-1992 = 83%). Among invasive cancers, node involvement was observed in 11.5% of cases, being associated with tumour size (pT1a = 0%, pT1b = 7%, pT1c = 13%, pT2a = 33%). Five-, ten- and fifteen-year overall survivals of invasive cancers were 98.1, 95.7 and 87.3%, respectively.

Loop electrosurgical excision procedure of the transformation zone and colposcopically directed punch biopsy in the diagnosis of cervical lesions.

OBJECTIVE: To estimate the disagreement between the histologic reports at colposcopically directed punch biopsy of the cervix and subsequent loop excision of the transformation zone, and to assess the indications for loop excision in current practice. METHODS: The histologic diagnoses from loop electrosurgical excision procedures and concurrent colposcopically directed punch biopsies were compared in 337 consecutive women undergoing loop excision in a 5-year period. RESULTS: Disagreement between punch biopsy and loop excision was recorded in 190 cases (56.4%). The undercall and overcall rates for punch biopsy were 14 and 42.4%, respectively. Undercall at punch biopsy occurred in 24 of 46 cases of cervical intraepithelial neoplasia (CIN) III and in one microinvasive cancer diagnosed at loop excision, and disagreement was within one grade of CIN in 16 cases. CONCLUSIONS: Loop electrosurgical excision allows further and more accurate histologic examination of the transformation zone and should be the standard assessment procedure in all cases of CIN II detected at punch biopsy and whenever cytology or colposcopy suggests the risk of punch biopsy undercall. Immediate treatment by local destruction should not be performed, to avoid underestimation of the severity of the lesion.

Monitoring interval cancers in mammographic screening: the Florence District programme experience.

The aim of the present study was to monitor the occurrence of interval (breast) cancers (IC) as an interim outcome measure of quality assurance in the mammographic screening programme of the District of Florence. IC were identified by linking breast screening data with registrations of breast cancers from the Tuscany Tumour Registry. The main outcome measures were the numbers, rates, and the proportionate incidence of IC. Overall, 90 invasive IC were observed among women who attended the breast screening programme in the District of Florence from 1 January 1985 to 31 December 1993, respectively, 23, 50, on 17 cases, at 1, 2, and 3 years after the last negative screening test. Expressed as a proportion of underlying incidence, the figures are 16, 44, and 46%. As to risk factors for IC, mammographic density was the most important one in the present survey, whereas no effect of age emerges from the present study.

Felbamate in refractory partial epilepsy.

This open-label study was performed to evaluate efficacy and safety of Felbamate (FBM) add-on therapy in drug-refractory partial epilepsy. We evaluated 36 patients (12 males) aged 11-68 years (mean 29.8) in which FBM was titrated gradually from 300 mg/day to a mean total maintenance daily dose of 1936 mg. Patients were monitored according to clinical practice and performed regularly laboratory tests. Mean follow-up of FBM therapy was 10 months (range 2-27). In this study, 5% of patients resulted to be seizure-free, 11% showed a seizure reduction more than 75%, 23% decreased their seizure frequency between 50% and 75% (P = 0.0001). The adverse events which were reported more frequently were: nausea, vomiting, anorexia and weight loss. Even if the patients sample is small FBM proves its efficacy in partial epilepsy, showing a relatively well tolerated profile.

Phyllodes tumor of the breast: a multicenter series of 59 cases. Coordinating Center and Writing Committee of FONCAM (National Task Force for Breast Cancer), Italy.

A series of 59 phyllodes tumors of the breast was retrospectively reviewed (average follow-up = 3.9 years). Clinical features (age, size of tumor) and diagnostic tests (palpation, mammography, sonography and cytology) were found to be inaccurate in predicting benign (n = 22), borderline (n = 12) or malignant (n = 25) histological type. Limited surgery was associated with a relatively high proportion of local recurrence (enucleation/enucleoresection = 3/5, wide resection = 12/30) compared with mastectomy (2/24). No significant association was observed between the probability of local recurrence and patient's age, histological type or lesion size. Although the study confirms that limited surgery may cure phyllodes tumor, careful follow-up of all patients is needed, since no reliable risk factors for recurrence are available. In malignant cases, axillary node involvement was nil and distant metastases were infrequently observed (3/25). Axillary dissection and search for asymptomatic metastases is not recommended.

Reliability of volume or age-adjusted prostate specific antigen to improve diagnostic accuracy.

Prostate Specific Antigen (PSA), PSA density, PSA excess, and PSA age-specific range have been compared in 331 subjects (35 cancers, 296 benign) with equivocal findings at screening by PSA or palpation+transrectal ultrasonography. The specificity of PSA using a cut-off of 4 ng/ml was only 0.49. A cutoff of 10 ng/ml improved the specificity to 0.88 but the sensitivity decreased from 0.97 to 0.63. The sensitivity and specificity for PSA density (cutoff 0.15), PSA excess (cutoff -5), and age-specific range were 0.86 and 0.80, 0.80 and 0.82, and 0.91 and 0.67, respectively. Avoided benign biopsies vs missed cancers on the basis of PSA density, PSA excess and PSA age-specific range would have been 19 and 5, 26 and 7, and 16 and 3, respectively. Methods adjusting for prostate volume allow a better interpretation of PSA values and may reduce the benign biopsy rate, but the consequent cost of delayed cancer diagnoses when the choice of biopsy is based only on these methods seems unacceptable.

Analysis of PSA velocity in 1666 healthy subjects undergoing total PSA determination at two consecutive screening rounds.

The study purpose was to assess PSA velocity (PSAV) in healthy subjects in order to establish a reliable cutoff for the differential diagnosis of prostate cancer in a screening setting. We studied a series of 1666 healthy men aged 55 to 74 years undergoing two total PSA determinations at a four-year interval within a population-based randomized screening trial at the Centro per lo Studio e la Prevenzione Oncologica of Florence. First and second screening round PSA assays (PSA1 and PSA2) were carried out with the same method and by the same laboratory. PSAV (PSA1-PSA2/year) was determined in non-cancer subjects in the overall series or in specific age and PSA subgroups, and in subjects with cancer detected at the second screening round. Average PSAV in 1648 non-cancer subjects was 0.07 ng/mL/year (range -2.18+5.99, 95% CI 0.05-0.09); at least one third of subjects showed a decrease in PSA (negative PSAV), mostly of limited magnitude and in the low PSA range. Average PSAV in the 18 cancer patients was 1.16 ng/mL/year (range 0.10-5.6, 95% CI 0.56-1.77), which is significantly higher (p<0.01) than in non-cancer subjects. None of the cancer patients showed a PSA decrease over time. Whatever cutoff was taken for PSAV, its power to discriminate cancer was limited: in particular the previously used PSAV cutoff of 0.75 ng/mL/year would have included only 42 of the 1648 non-cancer subjects (specificity 97.5%) but excluded eight of the 18 cancer patients (sensitivity 55.5%). At best, with the adopted screening protocol PSAV (cutoff 0.10 ng/mL/year) could have spared 27.9% of non-cancer subjects with PSA > or =2.5 ng/mL further diagnostic assessment and 22.7% of non-cancer subjects with PSA > or =4 ng/mL random sextant biopsy, while missing no cancers. This study provides a reliable estimate of PSAV based on a large unbiased population sample. PSAV is widely variable over time, particularly at low PSA values. PSAV might be of value as an indicator for diagnostic assessment and random sextant biopsy in a screening setting.

Predicting prostate biopsy outcome by findings at digital rectal examination, transrectal ultrasonography, PSA, PSA density and free-to-total PSA ratio in a population-based screening setting.

The study offers a retrospective analysis of the positive predictive value (PPV) of several variables, i.e. digital rectal examination (DRE), transrectal ultrasonography (TRUS), PSA value, PSA density (PSAD), and free/total PSA ratio (F/T), for the histologic outcome of 179 prostate biopsies performed within a population-based screening trial. The ratio of spared benign biopsies to missed cancers (SBB/MC) if biopsy results had been decided on the basis of single variables was also evaluated. PPV was 82.9% for DRE, 56.3% for TRUS, 26.6% for PSA (cutoff > or =4 ng/mL), 47.4% for PSA (cutoff > or =10 ng/mL), 42.0% for PSAD (cutoff 0.15), 59.2% for PSAD (cutoff 0.20), 34.9% for F/T (cutoff 0.20) and 40.0% for F/T (cutoff 0.15). SBB/MC was 121/23 for DRE, 96/12 for TRUS, 11/10 for PSA (cutoff > or =4 ng/mL), 107/34 for PSA (cutoff > or =10 ng/mL), 87/23 for PSAD (cutoff 0.15), 109/26 for PSAD (cutoff 0.20), 45/8 for F/T (cutoff 0.20) and 70/14 for F/T (cutoff 0.15). Multivariate analysis of the association with biopsy outcome showed the highest odds ratio for TRUS (13.24, 95% CI=4.4-30.7), and considerably lower values for DRE (4.17, 95% CI=2.0-8-9), PSAD (cutoff 0.20: 3.24, 95% CI=-1.8-5.7) and F/T (cutoff <0.15: 3.16, 95% CI=1.7-1.8). None of the possible variable combinations was clinically useful: the highest PPV (83.3%) was obtained with a combination of suspicious DRE/TRUS, PSAD >0.20 and F/T <0.15, which nevertheless missed 20 of 52 cancers.