Immunochemical faecal occult blood test: number of samples and positivity cutoff. What is the best strategy for colorectal cancer screening?

Immunochemical faecal occult blood tests have shown a greater sensitivity than guaiac test in colorectal cancer screening, but optimal number of samples and cutoff have still to be defined. The aim of this multicentric study was to evaluate the performance of immunochemical-based screening strategies according to different positivity thresholds (80, 100, 120 ng ml(-1)) and single vs double sampling (one, at least one, or both positive samples) using 1-day sample with cutoff at 100 ng ml(-1) as the reference strategy. A total of 20 596 subjects aged 50-69 years were enrolled from Italian population-based screening programmes. Positivity rate was 4.5% for reference strategy and 8.0 and 2.0% for the most sensitive and the most specific strategy, respectively. Cancer detection rate of reference strategy was 2.8 per thousand, and ranged between 2.1 and 3.4 per thousand in other strategies; reference strategy detected 15.6 per thousand advanced adenomas (range=10.0-22.5 per thousand). The number needed to scope to find a cancer or an advanced adenoma was lower than 2 (1.5-1.7) for the most specific strategies, whereas it was 2.4-2.7, according to different thresholds, for the most sensitive ones. Different strategies seem to have a greater impact on adenomas rather than on cancer detection rate. The study provides information when deciding screening protocols and to adapt them to local resources.

PSA doubling time as a predictor of the outcome of random prostate biopsies prompted by isolated PSA elevation in subjects referred to an outpatient biopsy facility in a routine clinical scenario.

AIM: To assess the validity of PSA doubling time (PSADT) as a predictor of prostate sextant biopsy outcome in patients with PSA levels in the 4-10 ng/mL range. MATERIAL AND METHODS: A consecutive series of 355 sextant biopsies performed during 2001-2007 in subjects with negative digital rectal examination and transrectal ultrasonography was considered. Variables tested as possible predictors were age, total and free/total PSA value, PSA velocity and PSA doubling time. While PSA at time of biopsy and free/total PSA were determined with a standardized method undergoing strict quality control, previous PSA values used to assess velocity/doubling time came from other labs using different assays over widely varying intervals of time. The association with biopsy outcome (cancer vs non-cancer) was investigated by univariate and multivariate analysis. RESULTS: Apart from free/total PSA ratio, no other studied variable showed a statistically significant and independent association with biopsy outcome, either at univariate or multivariate analysis. No studied variable had a good performance as a biopsy indicator. Depending on the variable considered, 1.17 to 1.97 cancers would be missed to spare 10 benign biopsies. CONCLUSION: When based on PSA data determined with different assays over widely varying intervals and in the absence of an underlying protocol for PSA surveillance, PSA velocity and doubling time should never discount a biopsy prompted by total PSA elevation.

Sensitivity of latex agglutination faecal occult blood test in the Florence District population-based colorectal cancer screening programme.

We evaluated the sensitivity for colorectal cancer (CRC) of the latex agglutination test (LAT), an immunochemical test routinely used in the Florence District screening programme since 2000. Sensitivity was calculated by the proportional interval cancer incidence method in a population of 27,503 consecutive subjects screened in 2000-2002, interval cancers being identified by linkage to the Tuscany Cancer Registry files. Sensitivity was calculated overall and by gender, age, time since last negative LAT, CRC site, and rank of screening. Overall 1- and 2-year sensitivity estimates were 80.7 and 71.5%, respectively, suggesting that faecal occult blood testing screening sensitivity may be suboptimal due to testing or programme quality problems. Increasing screening sensitivity might be achieved if the detection rate of advanced adenomas could be increased without unacceptable loss in specificity.

Gastric cancer after positive screening faecal occult blood testing and negative assessment.

BACKGROUND: Gastric cancer may be suspected with otherwise unexplained positive faecal occult blood testing. AIMS: To assess the frequency of gastric cancer following positive faecal occult blood testing and negative colonoscopy. SUBJECTS: Age 40-74 cohort at first screening (1985-2001) with (a) faecal occult blood testing- (83,489), (b) faecal occult blood testing +/colonoscopy+ (2025), or faecal occult blood testing+/colonoscopy- (3555). METHODS: Gastric cancer incidence in faecal occult blood testing subsets, compared with expected standardized incidence rates. RESULTS: Gastric cancer risk was increased (standardized incidence rate=146.7; 95% confidence interval: 105.8-203.4) in faecal occult blood testing+/colonoscopy- subjects. A four-fold excess incidence occurred during first year (observed cases=10, standardized incidence rate=408.3; 95% confidence interval: 219.7-758.8), irrespective of faecal occult blood testing type (guaiac, immunological). No excess risk occurred in faecal occult blood testing- (observed cases=53, standardized incidence rate=91.2; 95% confidence interval: 84.1-98.8) or in faecal occult blood testing+/colonoscopy+ subjects (observed cases=2, standardized incidence rate=101.9; 95% confidence interval: 25.5-407.4). Assuming a 100% 3-year study sensitivity for gastric cancer, faecal occult blood testing positive predictive value would be 0.4% (40-74 years) or 0.7% (> or =60 years) in faecal occult blood testing+/colonoscopy- subjects. CONCLUSIONS: Data suggest an association of faecal occult blood testing+/colonoscopy- and excess gastric cancer incidence in the following year. Due to low faecal occult blood testing+ positive predictive value, routine upper digestive tract endoscopy in these subjects is questionable.

Association of FOBT-assessed faecal Hb content with colonic lesions detected in the Florence screening programme.

We assessed the correlation between quantitative results of immunological faecal occult blood testing (I-FOBT) and colonic lesions (191 colorectal cancers, 890 adenomas) detected at colonoscopy in 2597 FOBT+ (cutoff 100 ng ml(-1) Hb) subjects. At univariate analysis, a higher average faecal Hb content was significantly associated with male gender (P=0.003), age (P=0.02), and colonoscopy findings (P=0.000). Among adenomas, higher faecal Hb content was significantly associated with size (P=0.0000), presence of severe dysplasia (P=0.0001), presence of villous component (P=0.0002), and location in the left colon (P=0.003). At multivariate analysis adjusting for potential confounders, age (P=0.03), size (P=0.0000), and location in the left colon (P=0.0005) were confirmed as having an independent association with higher faecal Hb content. Immunological FOBT is confirmed to be a specific screening test to detect cancer and adenoma, with a low positivity rate (3.7%) and a high positive predictive value (41.5%). Faecal Hb content is significantly higher for those lesions (cancer and high-risk adenomas) screening is aimed at detecting.

Evaluation of diagnostic accuracy of screening by fecal occult blood testing (FOBT). Comparison of FOB Gold and OC Sensor assays in a consecutive prospective screening series.

We evaluated a new immunological fecal occult blood testing assay (FOB Gold, Sentinel = SENT) compared to the assay currently employed in the Florence screening program (OC-Hemodia, Eiken = OC). A total of 4,133 subjects were screened with both tests and underwent colonoscopy if positive (100 ng/mL Hb cutoff) to either test: 190 (4.59%) were positive (OC =140 (3.4%); SENT = 131 (3.2%)). The relative sensitivity for 7 cancers was 100% with OC and 67.9% with SENT, and for 48 high-risk adenomas (HRAs) it was 77.0% with OC and 66.6% with SENT. The positive predictive value (PPV) for cancer+HRA was 31.4% for OC and 28.2% for SENT and the specificity was 97.7 for both. The differences were not statistically significant. Adding SENT to OC increased the positivity rate by 32% and the cancer+HRA detection rate by 25%, and decreased the PPV by 10%. Both tests were performed on the same tubes in 1,601 cases, and in 18 of 47 cases they differed on different tubes but not on the same tube, suggesting inhomogeneous Hb content or varying fecal matrix influence in different samples. SENT has practical advantages for screening [corrected] (fully automated, high output, requires no dedicated instrument), a comparable specificity and a lower sensitivity, though the latter difference may be partially ascribed to differences in sampling and not to the assay itself [corrected] Because of the statistical insignificance of the differences, further studies are needed for confirmation.

On the clinical usefulness of the free-to-total prostate-specific antigen ratio.

The free-to-total prostate-specific antigen ratio (F/T PSA) is associated with the presence of prostate cancer and is thus used as an indicator for suspicion of prostate cancer and as a determinant for biopsy. We reviewed a recent retrospective series of 966 consecutive prostate biopsies where F/T PSA was blindly determined and did not influence biopsy indication. We simulated the association of F/T PSA with biopsy outcome and its impact as a biopsy determinant. When adopting an F/T PSA cutoff of 10%, 13%, 16% or 20% among random sextant biopsies in the 4-10 ng/mL total PSA range, the sensitivity was 15%, 37%, 55% and 72% and the specificity 89%, 80%, 64% and 44%, respectively. Using F/T PSA as a biopsy determinant, from 1.7 to 2.6 cancer biopsies would have been delayed to avoid 10 benign biopsies. As this balance is not acceptable, F/T PSA has no role as a biopsy indicator and its clinical use is questionable.

Predictors of random sextant biopsy outcome in screened men with PSA > 4 ng/mL and a negative sextant biopsy at previous screening. Experience in a population-based screening program in Florence.

The aim of this study was to evaluate possible pedictors of the outcome of repeat random sextant biopsy of the prostate prompted by a rise in prostate-specific antigen (PSA). Random biopsies performed for PSA elevation (>4 ng/mL) in the course of a randomized study of screening efficacy were reviewed, and 87 consecutive biopsies (carcinoma = 13, high-grade prostatic intraepithelial neoplasia = 6, negative = 68) performed in subjects with a negative random biopsy at the previous screening round were considered. Findings at digital rectal examination or transrectal ultrasonography and total PSA value were not useful predictors of repeat biopsy outcome, whereas PSA velocity was significantly associated with biopsy outcome. The positive predictive value for a cancer biopsy was 2.7% (1/36), 28.5% (2/7), and 22.7% (10/44) for PSA velocity values of <0.1, 0.1-0.19, and >0.19 ng/mL/yr, respectively. A cutoff of 0.1 ng/mL/yr for PSA velocity would have allowed to avoid approximately half (35/74 = 47.2%) of the benign biopsies while decreasing the sensitivity by 7.6% (1/13), and is thus suggested as a possible criterion for the indication of repeat random biopsy for persistent PSA elevation.

Colorectal cancer screening programme by faecal occult blood test in Tuscany: first round results.

Screening with faecal occult blood test (FOBT) has been shown to be effective in reducing mortality from colorectal cancer. Tuscany was the first region in Italy in which a screening programme for colorectal cancer by FOBT was initiated region-wide. The aim of the paper was to describe organizational aspects, a quality control model and the results of this experience. From June 2000 to December 2001, 192583 subjects aged 50-70 were invited to undergo a 1-day immunochemical test without any dietary restriction. A total of 78505 subjects (41%) performed the screening test, of whom 4537 responders had a positive test result (5.8%). Among them, 1122 refused any form of assessment or underwent a colonoscopy outside the screening referral centres, with an overall assessment compliance of 75.3%. Malignancies were found in 193 patients and at least a high-risk adenomatous polyp in 692 patients. In about a quarter of the positive subjects who underwent assessment, cancer or high-risk adenoma was detected. In conclusion, data from this experience supported the feasibility of biennial colorectal screening programme by FOBT, particularly regarding invitation compliance and positivity rate. Further efforts are necessary to implement screening extension and to improve data collection.

Clinical impact (cost-effectiveness) of qualifying atypical squamous cells of undeterminate significance (ASCUS) in cases favoring a reactive or dysplastic process.

The cost-effectiveness of qualifying ASCUS cases into two different subcategories, favoring a reactive (ASCUS-R) or dysplastic process (ASCUS-S), was evaluated at the Centro per lo Studio e la Prevenzione Oncologica of Florence in a prospective study. The study determined the positive predictive value (PPV) for histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2) or more (CIN>) severe lesion of the two ASCUS subgroups. ASCUS-S had a PPV (10.78%) comparable to low-grade squamous intraepithelial lesions (LSIL) (11.40%). For ASCUS-R cases, the recommendation of 6-mo repeat cytology prompting colposcopy in cases of persistent ASCUS or more severe cytology was also effective, as it selected a subgroup with a relatively high PPV (10.34%). The cost-effectiveness of a protocol based on ASCUS qualification was compared with two other possible options for nonqualified ASCUS cases: immediate colposcopy and colposcopy in persistent ASCUS at 6-mo repeat cytology. The detection rate of CIN2> was substantially higher using ASCUS qualification (35.9 vs 14.8 or 17.1). The cost per ASCUS subject was euro 24.99, 27.11, or 25.14 and that per CIN2> detected was euro 697, 1,831 or 1,470 for the three options, respectively. The evidence that ASCUS detection option implies a higher detection rate of CIN2> and subsequently a lower cost per CIN2> detection must be considered with caution and deserves confirmation by other comparative studies.

Basic variables at different positivity thresholds of a quantitative immunochemical test for faecal occult blood.

OBJECTIVES: Screening by faecal occult blood testing (FOBT) is effective in decreasing mortality and incidence of colorectal cancer (CRC). Immunochemical tests have proved to be more cost effective than guaiac FOBTs. The latex agglutination test (LAT) has the advantage of being a fully automated, quantitative test. The aim of this study is to interpret the overall experience with LAT according to different positivity thresholds. SETTING: A population based screening programme is currently running involving subjects aged 50-70, invited every 2 years to have an FOBT. LAT is the standard screening test and has a positivity threshold for further diagnostic tests of 100 ng haemoglobin/ml of sample solution. METHODS: Positivity rates, detection rates for CRC high risk adenomas, and positive predictive values for CRC, high risk adenomas, and low risk adenomas were calculated for several positivity thresholds. RESULTS: 19,132 attendances at screening were recorded (11,774 at first screening, 7358 at subsequent screenings). Progressively increasing the positivity threshold from 100 to 200 ng/ml showed (a) a decrease in positivity rate; (b) a decrease in detection rates for CRC or high risk adenomas; (c) an increase in positive predictive values for cancer; (d) an increase in positive predictive value for high risk adenomas. CONCLUSIONS: Increasing the positivity threshold of the LAT reduces recall rate and improves positive predictive value for cancer or high risk adenomas but substantially decreases the detection rate of CRC and high risk adenomas. For this reason increasing the positivity cut off for LATs is not advisable. On the other hand decreasing the positivity threshold would increase recall rate and sensitivity of screening. Careful evaluation of sensitivity of the quantitative results of the LAT for interval cancers is needed to definitively assess the optimal positivity threshold for LATs in population based screening programmes.

Measuring interval cancers in population-based screening using different assays of fecal occult blood testing: the District of Florence experience.

The fecal occult blood test (FOBT) has demonstrated its efficacy in reducing mortality from colorectal cancer (CRC). The guaiac-based FOBT has been criticized for its low sensitivity. In this study, two different assays for FOBT (guaiac or an immunochemical test based on reversed passive hemagglutination [RPHA]) were tested for comparison within a population-based screening program for colorectal cancer in the province of Florence (Italy). The proportional incidence method was used to calculate sensitivity for both FOBTs, according to rank of screening (first or repeat), age at entry (two groups of 50 to 59 and 60 to 70 years old) and lesion site (colon or rectum). When comparing FOBTs, the sensitivity multivariate Poisson regression was used to adjust for other variables. The sensitivity after the first 2 years was 50% (95% confidence interval [CI] 34% to 63%) for the guaiac test versus 82% (95% CI 67% to 92%) for RPHA. At multivariate analysis the risk of developing an interval cancer after a guaiac test is almost 3 times that after RPHA (rate ratio = 2.64; 95% CI 1.3 to 5.4). Our study confirms that RPHA is more sensitive than the guaiac test. The assumption that FOBT screening for CRC has to be based on a guaiac test should be reconsidered, and RPHA should be recommended as the standard FOBT for screening purposes.

Colorectal cancer screening by fecal occult blood testing: results of a population-based experience.

AIMS AND BACKGROUND: The study evaluated the results of an experimental screening protocol for colorectal cancer by fecal occult blood testing in a municipality of the Province of Florence. METHODS: A total of 15,235 subjects aged 50-70 years were invited to perform a 1-day immunochemical fecal occult blood testing without any dietary restrictions. All eligible subjects were sent a personal invitation letter, followed by a postal reminder to non-responders. Subjects with a negative stool test were advised to repeat screening after 2 years. Subjects with a positive screening test were invited to undergo full colonoscopy or a combination of left colonoscopy and a double contrast barium enema. RESULTS: A total of 6,418 subjects performed the screening test, with an overall compliance of 42.1%. A total of 268 compliers had positive test results. The positivity rate was 4.2%. Detection rate for cancer and for adenomas was 5.1% and 11.6%, respectively. The positive predictive value was 14.3% for cancer and 32.5% for adenoma. A higher compliance was recorded in subjects born in the province of Florence or living in the centre of the town, in married subjects, and in women. The best results in compliance were associated with the direct distribution of fecal occult blood testing kits by general practitioners to their outpatients. CONCLUSIONS: The study provides useful information about the efficiency and feasibility of a screening program for colorectal cancer using fecal occult blood testing. Compliance results confirm the importance of GP involvement in oncological screening.

Screening for colorectal cancer by faecal occult blood test: comparison of immunochemical tests.

OBJECTIVE: To compare two immunochemical faecal occult blood tests based on reversed passive haemagglutination (RPHA) or latex agglutination (Hdia) in a population based screening setting. METHOD: Hdia was interpreted according to three positivity thresholds: 100, 150, or 200 ng of haemoglobin/mg of specimen solution. A total of 5844 subjects were recruited into the study, from 17432 invited subjects aged 50-70. RESULTS: Positivity rates were 3.3% for RPHA, Hdia100 3.5%, Hdia150 2.5%, Hdia200 2.0%. Among subjects complying with the diagnostic work up, colorectal cancer (CRC) was detected in 19 subjects (17 RPHA positive, 16 Hdia100 positive, 15 Hdia150 positive, 14 Hdia200 positive) and high risk adenoma/s in 41 subjects (28 RPHA positive, 32 Hdia100 positive, 29 Hdia150 positive, 25 Hdia200 positive). The prevalence of screen positive CRC in the population was for RPHA 2.9 per thousand, Hdia100 2.7 per thousand, Hdia150 2.6 per thousand, Hdia200 2.4 per thousand. The prevalence of screen positive high risk adenomas in the population was for RPHA 4.8 per thousand, Hdia100 5.5 per thousand, Hdia150 5.0 per thousand, Hdia200 4.3 per thousand. CONCLUSION: Hdia100 was as sensitive as RPHA for cancer and high risk adenomas. As Hdia is less technically complex than RPHA, it is a valid alternative to the latter, provided that full automation of the development procedure is available. Increasing the positivity threshold of Hdia up to 150 or 200 ng of haemoglobin/mg of specimen solution is not advisable as the increase in specificity is too small to justify the corresponding decrease in the detection of screen positive cancers in the population.

Analysis of false-negative and underreported smears in the Florence district screening program for cervical carcinoma.

AIMS AND BACKGROUND: To review false-negative or underreported (reactive changes, squamous or glandular atypia) smears performed in women developing histologically proven CIN2 or more severe lesions within 24 months and evaluate error causes. The study setting was the Florence District cervical cancer population-based screening: about 60,000 women age 25-60 years screened per year. METHODS: 118 false-negative or underreported cases were identified at screening files-cancer Registry matching, and the original smears were reviewed by six independent readers to judge smear adequacy and error type. RESULTS: Sampling errors (reported as inadequate, negative or less severe than CIN1 at review) accounted for 74% and screening/interpretation errors (reported as CIN1 or more severe at review) accounted for 26% of studied cases. Screening/interpretation errors were more likely ascribed to misinterpretation and underreporting than to misperception of cellular abnormalities. CONCLUSIONS: Quality control should above all address the problem of sampling adequacy. Due to the rarity of misperceived abnormalities (true screening errors), manual or automated rescreening of negative smears would not be an effective procedure for quality control.

[Thyroid carcinoma as cystic nodule. The diagnostic role of cytology by needle aspiration]. / Il carcinoma tiroideo su nodulo cistico. Ruolo diagnostico della citologia per agoaspirazione.

195 patients affected by a cystic thyroid lesion were studied by a Fine Needle Aspiration biopsy (FNAb). 42 patients were operated on account of clinical data, compressive phenomena or cytologic results suggesting a neoplasia. Out of the operated patients, 3 were affected by a carcinoma in the cystic lesion (one "pure" cystic nodule and two "mixed" ones), while three more patients with multinodular goiters showed a carcinomatous lesion in a nodule different from the cystic one. Macroscopic characteristics of the aspirated fluid (quantity and quality) didn't affect the cytologic diagnosis. Cytology was useful in the preoperative diagnosis of benign thyroid nodules (only two false positives out of 42 patients) and was diagnostic in all the three patients affected by a carcinoma in the cystic nodule.