Clinical Epidemiology of Microinvasive Cervical Carcinoma in an Italian Population Targeted by a Screening Programme.

(1) Background: This population-based study aimed at identifying the factors associated with the likelihood of detection of stage IA cervical carcinoma-versus the detection of stage IB through IV cervical carcinoma-and the patterns of surgical treatment. (2) Methods: Between 1995-2016, 3750 patients living in the Emilia-Romagna Region (northern Italy) were registered with cervical carcinoma, including 2942 eligible patients (median age, 53). Multivariate analysis was performed using binary logistic regression models. (3) Results: The likelihood of stage IA cervical carcinoma (n = 876, 29.8%) did not change over time, decreased with increasing patient age, and was lower for patients with adenocarcinoma and grade 3-4 disease. Three hundred and fifty (40.0%) patients had a conservative treatment, 317 (36.2%) had hysterectomy, 197 (22.5%) had hysterectomy with lymph node dissection (LND), and 12 (1.4%) had a conservative treatment with LND. The proportion of hysterectomy decreased from 70.6% in 1995-1999 to 46.9% in 2011-2016. The likelihood of hysterectomy increased above the age of 40. Among screening-aged (25-64 years) patients, the likelihood of hysterectomy did not differ between screen-detected and non-screen-detected ones. Hysterectomy was increasingly combined with LND. High tumour grade was the strongest determinant of LND during hysterectomy. (4) Conclusions: This study provided a multifaceted overview of stage IA cervical carcinoma over the last decades.

How a faecal immunochemical test screening programme changes annual colorectal cancer incidence rates: an Italian intention-to-screen study.

BACKGROUND: This study aimed to evaluate the effectiveness of a biennial faecal immunochemical test (FIT) screening programme in reducing annual colorectal cancer (CRC) incidence in its dynamic target population. METHODS: The target population included over 1,000,000 persons aged 50-69 living in a region of northern Italy. The average annual response rate to invitation was 51.4%. Each observed annual age-standardised (Europe) rate per 100,000 persons between 2005, the year of introduction of the programme, and 2016 was compared with each expected annual rate as estimated with age-period-cohort (men) and age-period (women) models. RESULTS: For both sexes, the rates observed in 1997-2004 and those expected in 2005-2016 were stable. Observed rates increased in 2005, peaked in 2006 (the first full year of screening), dropped significantly below the expected level in 2009, and continued to decrease until 2013 (the eighth full year), after which no further significant changes occurred. In the pooled years 2013-2016, the observed incidence rate per 100,000 persons was 102.2 [95% CI: 97.4, 107.1] for men, 75.6 [95% CI: 71.6, 79.7] for women and 88.4 [95% CI: 85.3, 91.5] for both sexes combined, with an observed:expected incidence rate ratio of 0.68 [95% CI: 0.65, 0.71], 0.79 [95% CI: 0.76, 0.82] and 0.72 [95% CI: 0.66, 0.81], respectively. DISCUSSION: The study provided multiple consistent proofs of a causal relationship between the introduction of screening and a stable 28% decrease in annual CRC incidence after eight years.

Effects of Attendance to an Organized Fecal Immunochemical Test Screening Program on the Risk of Colorectal Cancer: An Observational Cohort Study.

BACKGROUND & AIMS: This cohort study compared colorectal cancer (CRC) incidence and mortality between people who participated in an Italian regional biennial fecal immunochemical test (FIT) screening program and people who did not. METHODS: The program started in 2005. The target population included over 1,000,000 people aged 50 to 69 years. The FIT was a one-sample OC-Sensor (Eiken Chemical Co, Tokyo, Japan) (cutoff, ≥20 µg hemoglobin/g feces). The average annual response rate to invitation was 51.4%. The records of people invited up to June 2016 were extracted from the screening data warehouse. Attenders were subjects who responded to the first 2 invitations or to the single invitation sent them before they became ineligible. Non-attenders were subjects who did not respond to any of these invitations. The records were linked with the regional CRC registry. People registered up to December 2016 were identified. Self-selection-adjusted incidence rate ratios (IRRs) and incidence-based CRC mortality rate ratios (MRRs) for attenders to non-attenders, with 95% confidence intervals (CIs), were calculated. RESULTS: The cohort generated 2,622,131 man-years and 2,887,845 woman-years at risk with 4490 and 3309 CRC cases, respectively. The cohort of attenders was associated with an IRR of 0.65 (95% CI, 0.61-0.69) for men, 0.75 (95% CI, 0.70-0.80) for women and 0.69 (95% CI, 0.66-0.72) for both sexes combined. The self-selection-adjusted IRR was 0.67 (95% CI, 0.62-0.72) for men and 0.79 (95% CI, 0.72-0.88) for women. The IRR for stage I, II, III, and IV CRC was 1.35 (95% CI, 1.20-1.50), 0.61 (95% CI, 0.53-0.69), 0.60 (95% CI, 0.53-0.68) and 0.28 (95% CI, 0.24-0.32) for men and 1.64 (95% CI, 1.43-1.89), 0.60 (95% CI, 0.52-0.69), 0.73 (95% CI, 0.63-0.85) and 0.35 (95% CI, 0.30-0.42) for women. The overall incidence-based CRC MRR was 0.32 (95% CI, 0.28-0.37) for men, 0.40 (95% CI, 0.34-0.47) for women and 0.35 (95% CI, 0.31-0.39) for both sexes combined. The adjusted MRR was 0.35 (95% CI, 0.29-0.41) for men and 0.46 (95% CI, 0.37-0.58) for women. CONCLUSIONS: Attendance to a FIT screening program is associated with a CRC incidence reduction of 33% among men and 21% among women, and a CRC mortality reduction of 65% and 54%, respectively.

Five-year annual incidence and clinico-molecular features of breast cancer after the last negative screening mammography at age 68-69.

OBJECTIVE: The European Commission Initiative on Breast Cancer recommendation for triennial screening of women aged 70-74 is based on very weak evidence. A cohort of Italian women who had their last biennial screening mammography at age 68-69 was followed up for 5 years, assumed to represent the interval to another hypothetical screening mammography, in order to determine the annual proportional incidence of interval breast cancer. METHODS: The cohort included 118,370 women. They had their last mammography between 1997 and 2008. Incident breast cancers were identified by record-linking the cohort with the regional breast cancer registry. The expected incidence in the age range 65-74 was estimated with an age-period-cohort model. The number of interval cancers was divided by the expected number to obtain their proportional incidence. RESULTS: Overall, there were 298,658 woman-years at risk with 371 interval cancers versus 988.8 expected. In the first, second, third, fourth, and fifth interval year, the proportional incidence was 0.09 (95% confidence interval, 0.06-0.13), 0.32 (0.25-0.39), 0.60 (0.49-0.73), 0.75 (0.60-0.92), and 0.81 (0.60-1.07), respectively. Between the second and the fifth year, tumour stage and molecular subtype did not change significantly. CONCLUSION: Though not supported by these findings, the proposal of triennial screening for women aged 70-74 merits further research, because the 95% confidence interval of the third-year proportional incidence of interval cancer included 0.50-the maximum limit considered acceptable for women aged 50-69. KEY POINTS: • The third-year incidence of breast cancer relative to the expected one was 0.60 (95% confidence interval, 0.49-0.73). • Between the second and the fifth year, tumour stage and molecular subtype did not change significantly (p >0.10). • The proposal of a 3-year screening interval at age 70-74 merits further evaluation.

Results of Compliant Participation in Five Rounds of Fecal Immunochemical Test Screening for Colorectal Cancer.

BACKGROUND & AIMS: We investigated the magnitude and temporal patterns of the decreasing trend in main performance measures of fecal immunochemical test (FIT) screening for colorectal cancer (CRC) observed in second and subsequent rounds. METHODS: We followed up 494,187 participants from the first round of a regional biennial FIT screening program in Italy (cut-off value for positivity, 20 µg hemoglobin/g feces) for 5 total rounds (2005-2016). At each round, only compliant participants were eligible. Performance measures from the first, third, fourth, and fifth rounds were compared with those from the second round (the first incidence round) using rate ratios from multivariate Poisson regression models and relative risk ratios from multinomial logistic regression models. RESULTS: Between the second and the third rounds, a significant 20% to 30% decrease was found in the proportion of men with a positive FIT result (from 5.2% to 4.3%) and in detection rates of advanced adenoma (from 13.4 to 10.2 per 1000), CRC (from 1.7 to 1.4 per 1000), and advanced neoplasia (from 15.1 to 11.6 per 1000). Positive predictive values (PPVs) decreased by 10% or less between the second and third rounds. Detection rates and PPVs for adenoma stabilized by the fourth and fifth rounds. The PPVs for advanced adenoma, CRC, and advanced neoplasia decreased slightly in men and women by the fourth and fifth rounds. The detection rate of proximal colon cancer stabilized after the second round, whereas the detection rate of distal colon cancer decreased until the fourth round in men (from 0.7 to 0.3 per 1000), and the fifth round in women. CONCLUSIONS: These findings support the notion that FIT screening prevents progression of a subset of advanced adenomas. Screening intensity could be modulated based on results from previous rounds, with a risk-based strategy.

Proportional incidence of interval colorectal cancer in a large population-based faecal immunochemical test screening programme.

BACKGROUND: The European guidelines for quality assurance in colorectal cancer (CRC) screening recommend that interval cancer rate be expressed as a proportion of background incidence rate. AIM: To determine the crude and adjusted proportional incidence of interval CRC in an Italian regional two-yearly faecal immunochemical test (FIT) screening programme. METHODS: The programme (year of implementation, 2005) is targeted at over 1,000,000 people aged 50-69 years. The test is a one-sample OC-Sensor (Eiken Chemical Co., Tokyo, Japan). The study covered one-third of the regional area. Excerpts of 434,295 eligible negative FIT records dated 2005-2012 from 193,193 subjects were retrieved from the regional CRC screening data warehouse. By 31 December 2013, the cohort accumulated 198,302 man-years and 235,370 woman-years. Interval CRCs were identified by record-linkage with the local population-based cancer registry. Their number was divided by the expected number, estimated with age-period-cohort models, to obtain the proportional incidence. RESULTS: The proportional incidence of interval CRC for men and women was, respectively, 0.06 (95% confidence interval (CI), 0.04-0.09) and 0.17 (95% CI, 0.13-0.23) in the first interval year, and 0.21 (95% CI, 0.16-0.26) and 0.28 (95% CI, 0.22-0.36) in the second year. CONCLUSIONS: The results were acceptable and in line with previous studies.

A regional population-based hereditary breast cancer screening tool in Italy: First 5-year results.

BACKGROUND: Up to 10% of individuals with breast cancer (BC) belong to families with hereditary syndromes. The aim of this study was to develop an instrument to identify individuals/families at high-hereditary risk for BC and offer dedicated surveillance programs according to different risks. METHODS: The instrument consisted of a primary questionnaire collecting history of BC and ovarian cancer (OC). This questionnaire was applied to women enrolled in the Emilia-Romagna Breast Cancer Screening Program. General practitioners (GPs) and specialists could propose the same questionnaire too. Women with a score of ≥ 2, were invited to complete an oncogenetic counseling. According to the Tyrer-Cuzick evaluation, women considered at high risk were invited to involve the most representative alive individual of the family affected with BC/OC for BRCA1/2 genetic testing. RESULTS: Since January 2012 and December 2016, 660 040 women were evaluated by the regional screening program, of which 22 289 (3.5%) were invited to the Spoke evaluation, but only 5615 accepted (25.2%). Totally, also considering women sent by GPs and specialists, 11 667 were assessed and 5554 were sent to the Hub evaluation. Finally, 2342 (42.8%) women fulfilled the criteria for genetic testing, and 544 (23.2%) resulted BRCA1/2 mutation carriers. CONCLUSIONS: To our knowledge, this is the first regional population-based multistep model that is aimed to identify individuals with BRCA1/2 mutations and to offer an intensive surveillance program for hereditary-high risk women. This tool is feasible and effective, even if more efforts must be performed to increase the acceptance of multiple assessments by the study population.

Changes in the incidence of cervical tumours by disease stage in a cytology-based screening programme.

OBJECTIVES: To report changes in incidence of cervical tumours by disease stage, following the introduction of an organized cytology-based screening programme. METHODS: An intention-to-screen study of a cytology-based screening programme targeting 1,219,000 women aged 25-64 in northern Italy was carried out. Based on the previously reported trend in total incidence of cervical cancer, the study period 1995-2014 was divided into 1995-1996 (pre-screening, or reference, years), 1997-1998 (screening implementation phase), 1999-2006 (transition phase, when incidence decreased), and 2007-2014 (steady-state phase, when incidence stabilized again). Tumour stage was categorized as preinvasive (cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ), early (pT1a), advanced (pT1b or greater, ypT), and unknown (pT1 not otherwise specified, pTx, missing information). Average annual incidence rates observed in each phase were compared with the expected (reference) rates, using the incidence rate ratio, calculated with a Poisson regression model. RESULTS: In the steady-state phase, incidence rate ratios were: CIN3, 1.55 (95% confidence interval, 1.41-1.70); early-stage squamous carcinoma, 0.49 (0.36-0.67); advanced-stage squamous carcinoma, 0.44 (0.33-0.57); unknown-stage squamous carcinoma, 0.69 (0.48-0.99); adenocarcinoma in situ, 1.44 (0.72-2.88); early-stage adenocarcinoma, 2.65 (0.82-8.53); advanced-stage adenocarcinoma, 1.03 (0.56-1.91); and unknown-stage adenocarcinoma, 0.46 (0.23-0.92). CONCLUSIONS: After stabilization, changes in incidence by tumour stage included a 55% increase for CIN3 and a 50-55% decrease both for early- and advanced-stage squamous carcinoma, but no significant changes for glandular tumours. These data will serve to quantify the incremental impact of the implementation of human papillomavirus-based screening, introduced in 2015.

Annual mammography at age 45-49 years and biennial mammography at age 50-69 years: comparing performance measures in an organised screening setting.

OBJECTIVE: To compare the results of 5 years of annual mammography screening at age 45-49 with the results of 5 years of biennial screening at age 50-54 and 55-69. METHODS: In an Italian screening programme, data from 1,465,335 mammograms were analysed. Recall rates, invasive assessment rates, surgical biopsy (including excisional biopsy and definitive surgical treatment) rates, and cancer detection rates were calculated for the first screen (first) and, cumulatively, for the second and subsequent screens (second+). RESULTS: The rate ratios between younger women and the two groups of older ones were (in parentheses, original figures per 1000 mammograms if not otherwise specified): recall rate: first 1.11 (103.6 vs. 93.5) and 1.11 (vs. 93.2), second+ 2.10 (208.9 vs. 99.7) and 2.77 (vs. 75.5); invasive assessment rate: first 0.94 (23.0 vs. 24.5) and 0.94 (vs. 24.6), second+ 1.63 (35.8 vs. 22.0) and 1.56 (vs. 23.0); surgical biopsy rate: first 0.68 (5.9 vs. 8.6) and 0.45 (vs. 13.2), second+ 1.35 (11.5 vs. 8.5) and 0.88 (vs. 13.0); total detection rate: first 0.63 (4.3 vs. 6.7) and 0.37 (vs. 11.7), second+ 1.30 (8.9 vs. 6.8) and 0.74 (vs. 12.0); total positive predictive value of surgical biopsy: first 0.93 (72.8% vs. 78.0%) and 0.82 (vs. 88.9%), second+ 0.96 (77.2% vs. 80.5%) and 0.83 (vs. 92.7%). CONCLUSION: Younger women experienced two to threefold higher cumulative recall rates at second+ screens and limited differences in surgical biopsy rate. Albeit encouraging, these results must be completed with further investigation, especially on interval cancer incidence. KEY POINTS: • At repeated screens, cumulative recall rate was two- to threefold higher for younger women. • Differences in cumulative surgical referral and surgical biopsy rates were moderate. • Differences in positive predictive value of surgical biopsy were particularly small.

Estimating the impact of an organised screening programme on cervical cancer incidence: A 26-year study from northern Italy.

The impact of the organised cervical cancer (CC) screening programmes implemented in Europe since the 1990s has been insufficiently evaluated. We investigated the changes in CC incidence following the introduction of a screening programme in the Emilia-Romagna Region (northern Italy). The study period was 1988-2013. The programme, targeting women aged 25-64 years (1,219,000 in 2018), started in 1998. The annual incidence rates that would be expected in 1998-2013 in the absence of screening were estimated, first, by analysing the annual rates in 1988-1997 with a log-linear model and, second, by analysing the annual rates in 1988-2013 with an age-period model in which the period effect was enforced to be linear. Cervical adenocarcinoma incidence trend over the entire period was used to validate both estimates. Observed annual rates were compared to the two series of expected ones with the incidence rate ratio (IRR). Incidence remained stable during 1988-1997, peaked in 1998 and then decreased until 2007, when it stabilised. The two series of expected rates were virtually coincident and their trends roughly paralleled the stable adenocarcinoma incidence trend. After 2007, the median IRR was 0.60 (95% confidence interval, 0.45-0.81) based on the log-linear model and 0.58 (95% confidence interval, 0.34-0.97) based on the age-period model. Thirty-six to seventy-five CC cases were prevented annually for an average annual frequency of 6.5 per 100,000 women in the target population. In summary, consistent circumstantial evidences were obtained that the organised screening programme brought about a 40% reduction in annual CC incidence after 10 years.

Diets contaminated with Bisphenol A and Di-isononyl phtalate modify skeletal muscle composition: A new target for environmental pollutant action.

In the last years, an increasing number of studies reported that food pollution represents a significant route of exposure to environmental toxicants, able to cause mild to severe food illnesses and health problems, including hormonal and metabolic diseases. Pollutants can accumulate in organisms and biomagnify along the food web, finally targeting top consumers causing health and economic problems. In this study, adults of gilthead sea bream, Sparus aurata, were fed with diets contaminated with Bisphenol A (BPA) (4 and 4000 µg BPA kg-1 bw day-1) and Di-isononyl phthalate (DiNP) (15 and 1500 µg DiNP kg-1 bw day-1), to evaluate the effects of the contamination on the muscle macromolecular composition and alterations of its texture. The analysis conducted in the muscle using infrared microspectroscopy, molecular biology and biochemical assays, showed, in fish fed BPA contaminated diets, a decrease of unsaturated lipids and an increase of triglycerides and saturated alkyl chains. Conversely, in fish fed DiNP, a decrease of lipid content, caused by a reduction of both saturated and unsaturated chains and triglycerides was measured. Protein content was decreased by both xenobiotics evidencing a novel macromolecular target affected by these environmental contaminants. In addition, in all treated groups, proteins resulted more phosphorylated than in controls. Calpain and cathepsin levels, orchestrating protein turnover, were deregulated by both xenobiotics, evidencing alterations of muscle composition and texture. In conclusion, the results obtained suggest the ability of BPA and DiNP to modify the muscle macromolecular building, advising this tissue as a target of Endocrine-Disrupting Chemicals (EDCs) and providing a set of biomarkers as possible monitoring endpoints to develop novel OEDC test guidelines.

Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy.

BACKGROUND: The objective of this study was to evaluate if mammography screening attendance is associated with a reduction in late-stage breast cancer incidence. METHODS: The cohort included over 400,000 Italian women who were first invited to participate in regional screening programmes during the 1990s and were followed for breast cancer incidence for 13 years. We obtained individual data on their exposure to screening and correlated this with total and stage-specific breast cancer incidence. Socio-economic status and pre-screening incidence data were used to assess the presence of self-selection bias. RESULTS: Overall, screening attendance was associated with a 10% excess risk of in situ and invasive breast cancer (IRR = 1.10; 95% confidence interval (CI): 1.06-1.14), which dropped to 5% for invasive cancers only (IRR = 1.05; 95% CI: 1.01-1.09). There were significant reductions among attenders for specific cancer stages; we observed a 39% reduction for T2 or larger (IRR = 0.61; 95% CI: 0.57-0.66), 19% for node positives (IRR = 0.81; 95% CI: 0.76-0.86) and 28% for stage II and higher (IRR = 0.72; 95% CI: 0.68-0.76). Our data suggest that the presence of self-selection bias is limited and, overall, invited women experienced a 17% reduction of advanced cancers compared with pre-screening rates. CONCLUSIONS: Comparing attenders' and non-attenders' stage-specific breast cancer incidence, we have estimated that screening attendance is associated with a reduction of nearly 30% for stages II+.

Neural Analyses Validate and Emphasize the Role of Progesterone Receptor in Breast Cancer Progression and Prognosis.

Oestrogen receptor (ER) expression is routinely measured in breast cancer management, but the clinical merits of measuring progesterone receptor (PR) expression have remained controversial. Hence the major objective of this study was to assess the potential of PR as a predictor of response to endocrine therapy. We report on analyses of the relative importance of ER and PR for predicting prognosis using robust multilayer perceptron artificial neural networks. Receptor determinations use immunohistochemical (IHC) methods or radioactive ligand binding assays (LBA). In view of the heterogeneity of intratumoral receptor distribution, we examined the relative merits of the IHC and LBA methods. Our analyses reveal a more significant correlation of IHC-determined PR than ER with both nodal status and 5-year disease-free survival (DFS). In LBA, PR displayed higher correlation with survival and ER with nodal status. There was concordance of correlation of PR with DFS by both IHC and LBA. This study suggests a clear distinction between PR and ER, with PR displaying greater correlation than ER with disease progression and prognosis, and emphasizes the marked superiority of the IHC method over LBA. These findings may be valuable in the management of patients with breast cancer.

Information provided by Italian breast cancer screening programmes: a comparison between 2001 and 2014.

Debate on efficacy, benefits, and risks of breast cancer screening continues to rage, and scientific controversy surrounding overdiagnosis, false positives/false negatives, raises questions about communication to women attending screening programmes. The study compares information provided by invitation letters and leaflets of Italian breast screening programmes in 2001 (N=47) and 2014 (N=80). At both times, nearly all programmes provided adequate practical information and details about screening objectives and test procedures. Information regarding epidemiology/figures was scarce or absent in 2001, while in 2014 a number of programmes began to inform women about screening risks (false negative and positive results and overdiagnosis, 65%, 16%, and 21% respectively) although actual figures were rarely supplied. Despite this small improvement, Italian programmes are still far from giving balanced information. Further efforts should be addressed to providing accurate and transparent information, enabling women to make an informed choice.

Invitation strategies for colorectal cancer screening programmes: The impact of an advance notification letter.

AIM: To estimate the impact of an advance notification letter on participation in sigmoidoscopy (FS) and fecal immunochemical test (FIT) screening. METHODS: Eligible subjects, invited in 3 Italian population based programmes using FS and in 5 using FIT, were randomised (1:1:1), within GP, to: A) standard invitation letter; B) advance notification followed after 1month by the standard invitation; and C) B+indication to contact the general practitioner (GP) to get advice about the decision to be screened. We calculated the 9-month attendance and the incremental cost of each strategy. We conducted a phone survey to assess GP's utilization and predictors of participation. RESULTS: The advance notification was associated with a 20% increase in the attendance among 15,655 people invited for FS (B vs A - RR: 1.17, 95% CI: 1.10-1.25; C vs A - RR: 1.19, 95% CI: 1.12-1.27); the incremental cost ranged between 10 and 9 Euros. Participation in FIT screening (N=23,543) was increased only with simple pre-notification (B vs A - RR: 1.06, 95% CI: 1.02-1.10); the incremental cost was 22.5 Euros. GP consultation rate was not increased in group C. CONCLUSIONS: An advance notification represents a cost-effective strategy to increase participation in FS screening; its impact on the response to FIT screening was limited.

Prediction of nodal metastasis and prognosis of breast cancer by ANN-based assessment of tumour size and p53, Ki-67 and steroid receptor expression.

BACKGROUND: Tumour stage and the appropriate course of treatment in patients with breast cancer are primarily characterized by the state of metastasis in the axillary lymph nodes. In recent years, substantial research has focused on the prediction of lymph node status based on various pathological and molecular markers in order to obviate the necessity to carry out axillary dissection. In the present study, artificial neural network (ANN) is employed as the analysis platform to examine the prognostic significance of a group of well-established prognostic markers for breast cancer outcome prediction in terms of nodal status. Furthermore, we investigated existing interactions between these markers. PATIENTS AND METHODS: The data set contained 66 patient records, where 5 pathological and molecular markers including tumour size, oestrogen receptor status (ER), progesterone receptor status (PR), Ki-67 and p53 expression had been assessed for each patient. The spread of metastasis to the axillary lymph nodes was clinically diagnosed and patients were accordingly categorized into node-positive and node-negative groups. The aforementioned markers were analyzed using a probabilistic neural network (PNN) for nodal status prediction which was considered as the network output. Furthermore, the interactions between these markers were evaluated using different marker combinations as the network input for finding the best marker arrangement for nodal predication. RESULTS: The best prediction accuracy was obtained by a 3-marker combination including tumour size, PR and p53 with 71% accuracy for nodal prediction. Leaving out ER and PR from the full marker set showed approximately the same variations in the results, which is an indication of the direct correlation of these two markers. Furthermore, tumour size was proved to be the most significant individual marker for predicting nodal metastasis. However, when used in combination with Ki-67 the prediction results drop significantly. CONCLUSION: The results presented here indicate that molecular and pathological markers can provide useful information for early-stage prognosis. However, the interactions between these markers must be considered in order to achieve accurate and reliable prediction.

Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report.

INTRODUCTION: Small cell neuroendocrine cancer of the breast is a rare tumor with less than 30 cases reported in the literature. The morphological and immunohistochemical patterns of this tumor are similar to small cell neuroendocrine cancer of the lung. For this reason, it is often difficult to distinguish a primary small cell neuroendocrine cancer of the breast from a metastatic lesion from other sites. CASE PRESENTATION: We report and characterize with immunohistochemical techniques a case of primary small cell neuroendocrine cancer of the breast occurring in a 40-year-old Caucasian woman. A palpable and mobile 3.0 cm tumor was located in the upper-outer quadrant of her right breast. Lumpectomy and subsequent radical mastectomy with axillary lymph node resection were performed. Microscopically, the tumor consisted predominantly of a diffuse proliferation of small oat cells. The tumor cells were positive for neuroendocrine markers chromogranin A and synaptophysin. One of 16 lymph nodes was metastatic. A correct treatment needs to be chosen. CONCLUSIONS: It has recently been demonstrated that early small cell neuroendocrine cancer of the breast shows a good prognosis with adjuvant treatments with high disease free survival. Our patient is alive and well without disease eight years after treatment. We performed an adjuvant therapy with the classic scheme doxorubicin and cyclophosphamide, followed by carboplatin and etoposide. A more extensive review is required to define a standard treatment protocol for this rare neoplasm.

Risk of cancer of the prostate and of the kidney parenchyma following bladder cancer.

AIMS AND BACKGROUND: A registry-based cohort study of male patients with bladder cancer was conducted to determine the relative risk of second primary cancer of the prostate and kidney, the uni-/multivariate differences in relative risk according to patient characteristics, the cumulative risk by duration of the follow-up, and the prevalence:incidence ratio of prostate and kidney cancer cases detected in the first 6 months after the diagnosis of bladder cancer. METHODS: The complete case records of all male patients (n = 2025) diagnosed with bladder cancer between 1986 and 2002 were extracted from the database of the Romagna Cancer Registry: 1539 patients were eligible for analysis of the incidence of following prostate and kidney cancers, of the relative risk and the standardized incidence ratio specific for the time interval of follow-up. RESULTS: A total of 108 prostate cancer cases and 23 kidney cancer cases were observed during the follow-up. The relative risk of second primary cancer of the prostate and kidney was respectively 3.52 (95% CI, 2.89-4.25) and 3.90 (95% CI, 2.47-5.85). The absolute excess risk was 11.8 x 1000 for prostate cancer and 2.5 x 1000 for kidney cancer. The number of prevalent cases of prostate and kidney cancer detected was approximately 10 times greater than the expected number based on incidence rates from the general population. During the follow-up, incidence of prostate cancer stabilized at a level that was 3- to 4-fold greater than that expected. Despite fluctuations, a decrease was also observed for incidence of kidney cancer. CONCLUSIONS: In summary, our study showed the relatively constant high incidence of prostate and kidney cancers in bladder cancer patients over time. The possibility of subsequent cancer implies that an appropriate long surveillance is required. The pertinence depends on the duration of the follow-up as well as the degree of surveillance.

Quality of life assessment of randomized controlled trials.

AIMS AND BACKGROUND: According to the USA Food and Drug Administration, quality of life (QOL) and/or survival are a priority for new anticancer drug approval. This study was performed to review approaches to QOL in randomized controlled clinical trials (RCCTs) and to survey the use of such measures in trials. MATERIAL AND METHODS: A literature survey was carried out using the Medline/Medscape, Embase, Cochrane Library, and Ovid databases. Included in the survey were all publications in the set period (from 1966 to June 2005) with "quality of life" in the title or in the abstract in the field of "randomized, controlled clinical trials". Each trial was evaluated according to the level of importance of QOL as a measure of outcome (primary, important and secondary) and was analyzed using the quality scoring system reported by Nicolucci et al. with some items regarding QOL. RESULTS: Four hundred and five RCCT articles in the oncology setting were found. Fifty-six of the 405 (13.8%) publications had QOL as primary end point. The overall quality score of these trials ranged from 40% to 100%, with a median overall score of 80%. The overall score was correlated with the year of publication (P = 0.007), the type of journal (P = 0.05), the presence of a biostatistician among the authors (P = 0.001), and the number of participating institutions (P = 0.009). CONCLUSIONS: More attention to QOL in all components of RCCTs (design, choice of instruments, data management and processing) is required from both clinicians and statisticians.