Proportional incidence and radiological review of large (T2+) breast cancers as surrogate indicators of screening programme performance.

OBJECTIVES: Surrogate measures of screening performance [e.g. interval cancer (IC) proportional incidence] allow timely monitoring of sensitivity and quality. This study explored measures using large (T2+) breast cancers as potential indicators of screening performance. METHODS: The proportional incidence of T2+ cancers (observed/expected cases) in a population-based screening programme (Trento, 2001-2009) was estimated. A parallel review of 'negative' preceding mammograms for screen-detected T2+ and for all ICs, using 'blinded' independent readings and case-mixes (54 T2+, 50 ICs, 170 controls) was also performed. RESULTS: T2+ cancers were observed in 168 screening participants: 48 at first screen, 67 at repeat screening and 53 ICs. The T2+ estimated proportional incidence was 68% (observed/expected = 168/247), corresponding to an estimated 32% reduction in the rate of T2+ cancers in screening participants relative to that expected without screening. Majority review classified 27.8% (15/54) of T2+ and 28% (14/50) of ICs as screening error (P = 0.84), with variable recall rates amongst radiologists (8.8-15.2%). CONCLUSIONS: T2+ review could be integrated as part of quality monitoring and potentially prove more feasible than IC review for some screening services. KEY POINTS: • Interval breast cancers, assumed as screening failures, are monitored to estimate screening performance • Large (T2+) cancers at screening may also represent failed prior screening detection • Analysis of T2+ lesions may be more feasible than assessing interval cancers • Analysis of T2+ cancers is a potential further measure of screening performance.

Analysis of proportional incidence and review of interval cancer cases observed within the mammography screening programme in Trento province, Italy.

PURPOSE: The aim of this study was to assess the performance of the mammography screening programme in Trento Province, Italy, by analysing the interval cancers (IC) observed from 2001 to 2008. MATERIAL AND METHODS: IC were identified by linking screening archives with local cancer registry and pathology archives as well as with hospital discharge records. Proportional incidence was determined according to breast cancers expected in the absence of screening, estimated on the basis of patients/year at risk and age-specific incidence. The review of screening mammograms preceding ICs was performed by an external (three radiologists) and an internal (five radiologists) panel and aimed at assessing the proportion of IC reviewed as screening errors. Results were compared with European Community (EC) recommended standards. RESULTS: IC proportional incidence was 15.90% for the first year (EC standard <30%) and 25.77% for the second year (EC standard <50%) of the interval. At external review, 18.4% of cases were reviewed as screening errors (identified by at least two of three reviewers), whereas at internal review (identified by at least three of five reviewers) it was 17.4% (EC standard <20%). No significant difference was observed between external and internal review (mean recall rate 8.3% vs. 9.0%; mean identification rate 19.7% vs 19.6%). CONCLUSIONS: The study confirms good performance of the mammography screening programme in Trento Province, Italy. Comparable results of external and internal reviews suggest that the latter, no doubt easier to be implemented, might be adopted as a routine procedure to assess this early efficacy indicator.

"CADEAT": considerations on the use of CAD (computer-aided diagnosis) in mammography.

Computer-aided diagnosis (CAD) has been extensively reported to increase sensitivity by about 10% when added to a single reading while increasing recall rate by 12%, and its current use can be safely recommended in clinical practice. CAD has been suggested as a possible alternative to conventional double reading in screening. Uncontrolled comparison is consistent and suggests that CAD is comparable to double reading in incremental cancer detection rate (CAD +10.6%, double reading +9.1%) and possibly better in recall rate (CAD +12.5%, double reading +28.8%). However, controlled studies comparing single reading + CAD to conventional double reading are not consistent and on average suggest a lower cancer detection rate (-5.1%) and a lower recall rate (-9.8%) for CAD. Scientific evidence is not sufficient for a safe recommendation of single reading + CAD as a current alternative to conventional double reading.

The biological underpinnings of perinatal depressive symptoms: A multi-systems approach.

BACKGROUND: Well-established evidence exists of an association between depressive symptoms and alterations in the stress and inflammatory response systems; however, the picture is far less coherent during the perinatal period. This study combines the assessment of multiple stress and inflammatory biomarkers in late pregnancy and after delivery in order to investigate cross-sectional and prospective associations with perinatal depressive symptoms. METHODS: One-hundred-ten healthy women were assessed in late pregnancy (mean gestational age=34.76; SD=1.12) and 89 were re-evaluated after delivery (mean hours after delivery=52.36; SD=19.70) for depressive and anxiety symptoms through the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory. Serum Interleukin-6 (IL-6), C-Reactive Protein (CRP) and diurnal salivary cortisol levels were measured on both occasions, while diurnal salivary alpha amylase (sAA) levels were assessed in late pregnancy. RESULTS: Using Hierarchical Linear Models, higher depressive symptoms were found to be associated with higher IL-6 levels, lower morning cortisol levels and a flatter cortisol diurnal slope during pregnancy, while adjusting for potential confounders. No significant associations were found after delivery or with change in biomarker levels from pre- to post-partum. Furthermore, preliminary evidence of a positive association between inflammation and stress markers in women with higher antenatal depressive symptoms was found. LIMITATIONS: The sample was relatively small and highly selected, thus limiting generalizability of the findings. CONCLUSIONS: Results emphasize the need for an integrated multi-systems approach to the understanding of the biological underpinnings of perinatal depression and suggest that the stress-immune interactions represent a promising avenue for future endeavor.

Beyond the HPA-axis: Exploring maternal prenatal influences on birth outcomes and stress reactivity.

Accumulating evidence suggests that antenatal maternal stress is associated with altered behavioral and physiological outcomes in the offspring, however, whether this association is causal and the underlying biological mechanisms remain largely unknown. While the most studied mediator of maternal stress influences on the fetus has generally been cortisol, alternative novel markers of stress or inflammation warrant further consideration. The current investigation explored the influence of variations in self-reported symptoms of distress, stress hormones and inflammatory markers on infant birth outcomes and early stress regulation. The sample consisted of 104 pregnant women (mean gestational age = 34.76; SD = 1.12) and their healthy newborns. Maternal self-reported symptoms of depression and anxiety were evaluated through the Edinburgh Postnatal Depression Scale and the State-Trait Anxiety Inventory and levels of serum Interleukine-6 (IL-6), C-Reactive Protein (CRP), salivary cortisol and alpha amylase (sAA) were measured in late pregnancy. Newborns' cortisol and behavioral response to the heel-stick was assessed 48-72 hours after birth. The associations between maternal stress measures and infant birth outcomes and stress reactivity, adjusted for potential confounders, were examined through hierarchical linear regressions and hierarchical linear models. Higher maternal IL-6 levels were associated with smaller head circumference at birth, while diurnal sAA levels were positively associated with birthweight. Maternal diurnal cortisol was related to newborn's stress reactivity: a flatter infant cortisol response to the heel-stick was associated with greater maternal cortisol increases after awakening during pregnancy, while greater infant behavioural reactivity was related to a flatter maternal diurnal cortisol profile. The observational nature of these data does not allow for causal inferences but the current findings illustrate that antenatal factors related to alterations in maternal stress and immune response systems are associated with fetal growth and neonatal stress reactivity. This may have implications for later health and psychological outcomes.

Inter-observer and intra-observer variability of mammogram interpretation: a field study.

To evaluate the performance of radiologists in mammographic mass screening, seven radiologists read blindly the mammograms of 45 women (two views for each breast). The films included 12 normal, 24 benign disease and 9 cancers. The readings were repeated after 2 years. As expected, variability was higher among radiologists than between the two readings of the same radiologist, but general reproducibility was moderate. Kappa values for a positive/negative classification were 0.45 at the first and 0.44 at the second reading (inter-observer comparisons). For the intra-observer comparisons, Kappa values ranged from 0.35 to 0.67 (mean 0.56). Generally, accuracy was low partly due to the difficulty of the cases. A slight increase in sensitivity was observed at the second reading. The level of agreement is a good indicator of accuracy. Proper training and standardization of criteria are essential before mass breast screening is implemented.

Mammographically detected in situ lobular carcinomas of the breast.

We present ten cases of mammographically detected lobular carcinoma in situ (LCIS), involving a single area of variable size (up to a quadrant) in seven cases and the entire gland in three cases. Histologically, calcifications were associated with necrotic central areas within the in situ carcinomatous foci. Multiple foci of LCIS were observed in all five cases in which mastectomy had been performed. Cytologically, the lesions were characterized by a solid proliferation of round noncohesive cells with nuclei of intermediate size. Immunocytochemically, all cases were E-cadherin and p53 negative, and c-ErbB-2, GCDFP-15 and estrogen receptor positive. The proliferation index, evaluated with Ki67, was in the low range. Four cases were associated with foci of infiltrating lobular carcinoma (ILC). These findings contradict the commonly held opinion that LCIS is not mammographically detectable because of its lack of necrosis and calcification. This study documents the existence of a variant of LCIS exhibiting the mammographic features and central necrosis classically associated with ductal carcinoma in situ (DCIS), while retaining the spatial distribution, cytological composition and immunocytochemical features of lobular carcinoma.

Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents.

OBJECTIVE: To investigate possible associations between serotonin transporter (5-HTT) promoter genotypic variants (l/l, l/s, and s/s) and differential regulation of platelet 5-HTT functionality parameters in a group of drug-naive depressed children and adolescents and healthy controls. METHOD: Children and adolescents with major depression (n = 18) defined by DSM-III-R criteria and normal controls (n = 21) were assessed both for platelet serotonin functionality and for genotypic variants on 5-HTT promoter region. Four parameters were considered: (1) serotonin uptake rate (Vmax); (2) serotonin dissociation constant (K(m)); (3) paroxetine binding and density of site (Bmax); and (4) paroxetine dissociation constant (Kd). RESULTS: Depressed children had lower Vmax and K(m). Control subjects with l/l genotype had significantly higher Vmax than control subjects with l/s and s/s genotype. Control subjects with l/l genotype also had significantly higher Vmax than their depressed homologs. In contrast, Vmax was not significantly different between depressed and nondepressed subjects who carried the other 2 genotypes. The 5-HTT promoter genotype, diagnoses, or their interaction had no effect on the other serotonin parameters. CONCLUSIONS: While showing a significant decrease of Vmax and K(m) in a group of drug-naive depressed children and adolescents, these data suggest that l/l genotype has a substantial effect on the decrease of Vmax during a depressive episode.

Cimetropium bromide as a relaxant for the radiological examination of the stomach and duodenum.

A study was carried out to evaluate the efficacy of two different doses of a new hypotonizing agent, cimetropium bromide, as a premedication for X-ray of the stomach and duodenum. Forty consecutive patients were allocated at random to two groups and treated intravenously in double-blind fashion with 5 mg or 10 mg cimetropium bromide. The drug was administered immediately after the first phase of an upper gastro-intestinal series had been completed. Duration of the drug-induced hypokinesia was recorded fluoroscopically. The hypotonizing effect was evaluated by measuring the diameters of the gastric antrum, duodenal bulb and loop on the pre-injection and post-injection radiographs. In both groups, the relaxant effect started promptly (within 1 minute of injection) and lasted for an average of 10 minutes, which was considered adequate for the study. There were no statistically significant differences between the two groups in relaxant activity. The treatments were scored arbitrarily as 'excellent' in 75% of the examinations after the 10 mg dose and in 60% after the 5 mg dose. The difference between the two groups was not significant. Side-effects were few, of mild entity and not dose-related.

Isolation of 10, 11-epoxide of protriptyline in rat urine after protriptyline administration.

The 10, 11-epoxide, 10-hydroxy, and 10, 11-dihydrodiol metabolites of protriptyline were identified in rat urine collected after the administration of 40 mg/kg ip of protriptyline. Mass spectrometric characterization confirmed the structure of these metabolites.

Identification of 10, 11-epoxide and other cyclobenzaprine metabolites isolated from rat urine.

Cyclobenzaprine (40 mg/kg ip) was administered to rats, and six urinary metabolites of this drug were identified. They were the 10, 11-epoxide, the N -oxide, the desmethyl derivative, the hydroxylated and desmethylhydroxylated compounds, and the N-oxide hydroxylated at the 10- or 11-position. Mass spectrometric analysis confirmed their structures.

Depressive symptoms as measured by the CDI in a population of northern Italian children.

The aim of this study was to evaluate some Children's Depression Inventory (CDI) psychometric properties and the prevalence of depressive symptoms in an unselected Italian sample of two hundred and eighty-four children aged 8 years. The CDI internal consistency was adequate (Cronbach's alpha:.80). The mean and standard deviation of CDI and the percentage of children at risk of depression (10.6%) in this sample are consistent with the figures reported by other studies carried out in northern Europe and North America. There were differences in gender and socioeconomic level in that boys scored higher than girls, and in the lower socioeconomic level there were more children at risk of depression. Ten items best discriminated children at risk for depression with 94% of correct classification. Most of these items consisted of observable signs. It is suggested that the CDI has noteworthy consistency across samples of relatively different cultures, that it can reliably be employed in the assessment of young children, and that observable signs outnumber internalizing symptoms of depression among children at risk

Inter-observer variability in the interpretation of mammograms.

Inter-observer agreement was tested in the interpretation by 8 radiologists of mammograms from 45 women (for a total of 180 films per radiologist). The radiologists were representative of the whole range of those involved in mammography in the town of Torino, with a number of films read per year ranging from 100 to 4000. Out of the 45, 9 women were affected by breast cancer (histologically proved), 25 had benign disease (diagnosed with fine-needle aspiration) and 11 had normal breasts. Weighted kappa values were in the range 0.27-0.82 (median 0.60) for parenchymal patterns; 0.33-0.67 (0.48) for diagnosis in five categories; and 0.22-0.57 (0.38) for indications for further diagnostic tests. These values are comparable with those reported from other investigations.

MOv18 monoclonal antibody in diagnostic applications: capability to recognize the histotype of the original tumor.

Cells from 52 ascitic fluids and 28 abdominopelvic cavity washings, obtained from 46 ovarian cancer patients, 17 patients bearing malignancies of non ovarian sites and 17 patients with non-malignant ovarian diseases, were tested using 2 methods: traditional cytology and monoclonal antibody immunofluorescence. The immunologic test using the MOv18 MAb, raised against ovarian carcinoma, revealed immunoreactive cells in 83% of the 36 cytologically positive fluids and in one of the 8 negative fluids from ovarian carcinoma patients and in 18% of the 17 fluids from patients with non-malignant ovarian disease. Forty six cytologically positive ascitic fluids from malignant patients were analyzed in order to evaluate the ability of this MAb to identify the histotype of metastatic cells. Ninety-three percent (26/28) of the effusions from nonmucinous ovarian carcinomas contained MOv18-positive cells, whereas no reactive cells were found in cytologically malignant fluids from patients with ovarian tumors of other oncotypes or with carcinomas of non-ovarian origin. The MOv18 reagent, used as an adjuvant in cytological analysis, can help in the identification of the histotype of metastatic cells of unknown origin.

[Metastasis to the penis from carcinoma of the rectum. A clinical case]. / Metastasi al pene da carcinoma del retto. Caso clinico.

Penile metastases are extremely uncommon, with less than 300 reported cases. The primary sites of the responsible carcinoma have been bladder, rectum, prostate, kidney, testis, lung, nasopharynx and melanoma in that order. We report a case confirming the same data: no therapy has been shown to be helpful, the prognosis is very poor, with an average survival of less than one year. On the other hand we pointed out the importance of CT scan as a diagnostic tool for assessing the spread of neoplasm.

In vivo studied on the metabolism of dibenzo [c,f]-[1,2] diazepine.

The in vivo metabolism of dibenzo [c,f]-[1,2] diazepine (I) was studied after i.p. administration to rats, in order to observe the influence of the heteroatom on the metabolic pathway. Metabolites were separated by chromatography and their structures elucidated by mass spectrometry, by both gas chromatography coupled with mass spectrometry and the direct inlet system. Six metabolites were identified, some of them by direct comparison with authentic samples.

In vitro studies on the metabolism of dibenzo[c,f]-[1,2]diazepine.

Dibenzo [c,f]-[1,2] diazepine is a new compound with a tricyclic structure and a double bond between two nitrogen atoms in positions 1 and 2 of the molecule. Its in vitro metabolism has been studied, incubating the compound with rat liver microsomes. Two metabolites have been identified: dibenzo [c,f] - [1,2]diazepine-1-N-oxide and a monohydroxyderivative in the aromatic ring.

[Cost analysis of a mammographic screening program]. / Analisi dei costi di un programma di screening mammografico.

In this paper we evaluate the principal direct costs (staff, capital and maintenance equipment, supplies, hardware and software system, mail, advertising campaign) of the mammographic screening programme "Prevenzione Serena" (Torino), from the recruitment time to the diagnostic assessments of screen positive cases. On the basis of the annual situation of a screening Unit which supplies two-view mammographies, read by two radiologists, and of a 60% attendance rate and a 5% recall rate, we estimate a total annual cost of 1.4 thousand million lire (875,000$), a cost per invited woman of 38,600 lire (24$), per tested woman of 64,400 lire (40$) and per breast cancer detected of 9.2 million lire (5,750$). Staff accounts for about 60% of the total cost. We evaluate also some alternative scenarios, with different hypothesis about the useful life of the equipment, the discount rate, the attendance and the recall rate.

Leisure and occupational physical activity at different ages and risk of endometriosis.

OBJECTIVE: Cohort and case-control studies have suggested that adult physical activity (PA) may lower endometriosis risk and improve symptoms, but evidence is still controversial. To add information on leisure and occupational PA impact, if any, on endometriosis risk, we have analyzed data from a small case-control study conducted in Milan (Italy). STUDY DESIGN: Ninety cases and 90 controls (median age 35 years, range 18-76) were compared. Endometriosis was laparoscopically diagnosed within the year before interview. Information on demographic variables, menstrual and reproductive history, occupational and recreational physical activity was collected. RESULTS: A consistent protective effect emerged between leisure PA and endometriosis risk. For <2-4 and ≥5h/week (reference no PA), the estimated odds ratios (ORs) were, respectively: 0.36 (95% CI 0.18-0.74) and 0.83 (95% CI 0.27-2.53) as regards PA in early adolescence; 0.31 (95% CI 0.15-0.63) and 0.78 (95% CI 0.25-2.38) as regards PA in teenage years; 0.34 (95% CI 0.12-0.94) and 0.33 (95% CI 0.08-1.28) for PA in adulthood. However, no significant trend was seen according to hours spent in leisure PA. Occupational PA did not show statistical significant differences among different types or across age classes. CONCLUSIONS: These results suggest that leisure PA in early adolescence, teenage years and adulthood may, to some extent, decrease the risk of endometriosis. In the interpretation of these results, however, the role of potential biases cannot be totally ruled out.

The requirements of a specialist Breast Centre.

INTRODUCTION: In recognition of the advances and evidence based changes in clinical practice that have occurred in recent years and taking into account the knowledge and experience accumulated through the voluntary breast unit certification programme, Eusoma has produced this up-dated and revised guidelines on the requirements of a Specialist Breast Centre (BC). METHODS: The content of these guidelines is based on evidence from the recent relevant peer reviewed literature and the consensus of a multidisciplinary team of European experts. The guidelines define the requirements for each breast service and for the specialists who work in specialist Breast Centres. RESULTS: The guidelines identify the minimum requirements needed to set up a BC, these being an integrated Breast Centre, dealing with a sufficient number of cases to allow effective working and continuing expertise, dedicated specialists working with a multidisciplinary approach, providing all services throughout the patients pathway and data collection and audit. It is essential that the BC also guarantees the continuity of care for patients with advanced (metastatic) disease offering treatments according to multidisciplinary competencies and a high quality palliative care service. The BC must ensure that comprehensive support and expertise may be needed, not only through the core BC team, but also ensure that all other medical and paramedical expertise that may be necessary depending on the individual case are freely available, referring the patient to the specific care provider depending on the problem. CONCLUSIONS: Applying minimum requirements and quality indicators is essential to improve organisation, performance and outcome in breast care. Efficacy and compliance have to be constantly monitored to evaluate the quality of patient care and to allow appropriate corrective actions leading to improvements in patient care.