Reduction of Advanced Breast Cancer Stages at Subsequent Participation in Mammography Screening.

PURPOSE: The decline in advanced breast cancer stages is presumably the most relevant surrogate parameter in mammography screening. It represents the last step in the causal cascade that is expected to affect breast cancer-related mortality. To assess the effectiveness of population-based screening, we analyzed the 2-year incidence rates of advanced breast cancers between women participating in the initial and in the first subsequent round. MATERIALS AND METHODS: The study included data from 19,563 initial and 18,034 subsequent examinations of one digital screening unit (2008 - 2010). Data on tumor stages, detected by screening or within the following interval of two years (2-year incidence), were provided by the epidemiological cancer registry. Rates of all and combined UICC stages 2, 3 and 4 (advanced stages) were reported for a two-year period. Proportions were tested for significance by using chi-square tests (p < 0.001). RESULTS: The 2-year incidence rate of all stages was significantly lower in participants in subsequent screening than in initial screening (0.85 vs. 1.29 per 100 women (%); p < 0.0001). A significantly lower 2-year incidence of advanced stages was observed for subsequent screening compared to initial screening (0.26 % vs. 0.48 %; p = 0.0007). Among women aged 50 to 59 years, the incidence of advanced stages was less clearly different (0.21 % vs. 0.35 %; p = 0.07) than in women aged 60 to 69 years (0.31 % vs. 0.70 %; p = 0.0008). CONCLUSION: During the change from prevalent to incident phase mammography screening, a program impact is seen by a lower 2-year incidence of advanced breast cancers within subsequent compared to initial participants, predominately in women aged 60 to 69 years. KEY POINTS: • The incidence of advanced tumor stages represents the most relevant surrogate parameter for screening effectiveness. • For the first time the 2-year incidence of advanced breast cancer stages after subsequent mammography screening was analyzed. • We observed a significant effect of screening on the 2-year incidence of advanced stages, predominately in the age group 60 to 69 years.

Rates of presurgical underestimation of breast cancer after standardized assessment of breast calcifications.

PURPOSE: To determine the frequency of histopathological underestimation of breast cancer after vacuum-assisted biopsy (VAB) in standardized assessment of breast calcifications compared to postsurgical diagnosis. MATERIALS AND METHODS: The retrospective study included acquired data of 506 consecutively examined women, who underwent VAB for the assessment of pure calcifications after standardized digital mammographic and sonographic imaging. 119/506 (24.5 %) women underwent further surgical procedures: 37 women had a surgical diagnostic excision biopsy, 82 women a surgical procedure based on a therapeutic concept. Presurgical results of VAB were compared with the postsurgical histopathological reports. RESULTS: In 91/119 women (76.5 %) the final histology was malignant. The rate of ductal carcinoma in situ (DCIS) was 79.1 % (72/91) and the rate of invasive carcinoma was 20.9 % (19/91). In 9/37 women with diagnostic excision biopsy, the presurgical status of benign or uncertain changed to a postsurgical diagnosis of malignant (24.3 %). In eight cases underestimation included DCIS (21.6 %) and in one case invasive cancer (2.7 %). Seven of the nine underestimated cases (77.8 %) resulted from excision biopsy of atypical epithelial proliferation of ductal type (AEPDT, positive predictive value 30.4 % (7/23)). After surgery due to DCIS in 7/71 women invasive breast cancer was diagnosed (9.9 %). In 11/82 women with oncological surgery, invasive cancer was already diagnosed by VAB. CONCLUSION: Underestimation of invasive cancer in terms of presurgical DCIS diagnosis can be minimized by the standardized assessment protocol to about 10 %. Underestimation of DCIS is mainly related to presurgical diagnosis of AEPDT. KEY POINTS: • The standardized use of digital mammographic and sonographic imaging prior to vacuum-assisted biopsy is suitable for minimizing underestimation of invasive breast cancer. AEPDT represents a high risk diagnosis for underestimation of DCIS.

Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress.

In Alzheimer's disease (AD), different types of neurons and different brain areas show differential patterns of vulnerability towards neurofibrillary degeneration, which provides the basis for a highly predictive profile of disease progression throughout the brain that now is widely accepted for neuropathological staging. In previous studies we could demonstrate that in AD cortical and subcortical neurons are constantly less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are basically composed of large aggregating chondroitin sulphate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R (TN-R). Under experimental conditions in mice, PN-ensheathed neurons are better protected against iron-induced neurodegeneration than neurons without PN. Still, it remains unclear whether these neuroprotective effects are directly mediated by the PNs or are associated with some other mechanism in these neurons unrelated to PNs. To identify molecular components that essentially mediate the neuroprotective aspect on PN-ensheathed neurons, we comparatively analysed neuronal degeneration induced by a single injection of FeCl3 on four different mice knockout strains, each being deficient for a different component of PNs. Aggrecan, link protein and TN-R were identified to be essential for the neuroprotective properties of PN, whereas the contribution of brevican was negligible. Our findings indicate that the protection of PN-ensheathed neurons is directly mediated by the net structure and that both the high negative charge and the correct interaction of net components are essential for their neuroprotective function.

Minimal invasive biopsy results of "uncertain malignant potential" in digital mammography screening: high prevalence but also high predictive value for malignancy.

PURPOSE: To evaluate the rate, the histological spectrum and the positive predictive value (PPV) for malignancy of minimally invasive biopsies with "uncertain malignant potential (B3)" in digital mammography screening. METHODS AND MATERIALS: Consecutive data of 37,178 participants of one digital unit of the German screening program were included. RESULTS: The B 3 rate was 15.1 % (148 / 979). The frequencies of lesion subtypes were as follows: atypical epithelial proliferation of ductal type (AEPDT) 35.1 % (52 / 148), radial scar (RS) 28.4 % (42 / 148), papillary lesions (PAP) 20.3 % (30 / 148), lobular carcinoma in situ 8.8 % (13 / 148), flat epithelial atypia 5.4 % (8 / 148), and mucocele-like lesions 2.0 % (3 / 148). The PPV for malignancy in surgical excisions was overall 0.28 (25 / 91); in detail 0.40 (19 / 47) for AEPDT, 0.20 (5 / 25) for RS, 0.08 (1 / 12) for PAP. CONCLUSION: Despite a higher B 3 rate of minimally invasive biopsies with "uncertain malignant potential" in digital screening, the benign surgical biopsy rate is not disproportionally increased compared with analog screening programs. Together with defined management protocols, this results in an increased cancer detection rate per screening participant with surgical excision.

First epidemiological analysis of breast cancer incidence and tumor characteristics after implementation of population-based digital mammography screening.

PURPOSE: To epidemiologically evaluate the impact of digital mammography screening on incidence rates and tumor characteristics for breast cancer. MATERIALS AND METHODS: The first German digital screening units in the clinical routine were evaluated during the implementation period by using data from the cancer registry to compare the incidence rate of breast cancers and prognostic characteristics. 74 % of women aged 50 - 69 within the region of Muenster/Coesfeld/Warendorf were invited between 10 / 2005 and 12 / 2007 for initial screening; 55 % participated (n = 35 961). RESULTS: In 2002 - 2004 the average breast cancer incidence rate (per 100,000) was 297.9. During the implementation of screening, the rate rose to 532.9 in 2007. Of the 349 cancers detected with screening, 76 % (265 / 349) were invasive compared to 90 % (546 / 608) of cases not detected with screening during the same period. 37 % (97 / 265) of cancers detected in the screening program had a diameter of

[Immunohistochemistry in breast pathology: differential diagnosis of epithelial breast lesions]. / Immunhistochemie in der Mammapathologie: Zur Differenzialdiagnose epithelialer Mammaläsionen.

Proliferative epithelial breast lesions include a wide variety of benign hyperplastic and noninvasive neoplastic lesions, as well as invasive carcinomas. Mammographically these lesions may show microcalcifications, architectural distortions or mass lesions. The task of the pathologist begins with a preoperative diagnosis by means of minimally invasive biopsy. His diagnosis forms the basis for not only the radiological-pathological correlation diagnosis, but also for the management of benign proliferative breast disease lesions, as well as therapeutic decisions in the case of malignant lesions.In daily practice, immunohistochemistry is the method of choice for clarifying difficult cases. The aim of this chapter is to describe the relevant markers in breast pathology and to provide an algorithmic approach to different proliferative breast disease lesions.

[Diagnostics of microcalcifications from minimally invasive biopsies in mammography screening: results from the prevalence phase]. / Mikrokalkdiagnostik an minimal-invasiven Biopsien im Mammographie-Screening: Ergebnisse aus der Prävalenzphase.

BACKGROUND: In mammography screening programmes carried out according to European guidelines, minimally invasive biopsies (MIB) are performed on up to 3% of participants. The aim of this study was to analyse the spectrum of histopathological findings including B categories in MIBs with microcalcifications compared to MIBs without microcalcifications. MATERIAL AND METHODS: Prospectively collected histological findings of MIBs taken during the period July 2006 to June 2007 were analysed using the Breast Screening Pathology Database of the Reference Centre in Münster. RESULTS: Of the 4,326 MIBs investigated, 2,161 were benign (B1-B3) whereas 2,165 were malignant (B4-B5) resulting in an overall malignancy rate of 50.04%. Of the MIBs 1,809 contained microcalcifications and 2,517 did not. Cases with microcalcifications showed a different distribution of B categories: B2 was found in 44.5% versus 24.2%, B3 in 18.2% versus 5.5% and the malignancy rate of cases with microcalcifications was 36.8% versus 59.5%. Of all cases of ductal carcinoma in situ (DCIS) detected in the screening programme, 83.35% were diagnosed in MIBs containing microcalcifications. CONCLUSIONS: MIBs containing microcalcifications showed a different spectrum of diagnoses, especially higher rates of B3 lesions. Even though MIBs without microcalcifications showed a higher overall malignancy rate, most cases of DCIS were diagnosed in MIB containing microcalcifications.

[Atypical ductal hyperplasia and atypical epithelial proliferation of ductal type]. / Atypische duktale Hyperplasie und atypische epitheliale Proliferation vom duktalen Typ.

The definition of atypical ductal hyperplasia (ADH) encompasses qualitative and quantitative criteria. Qualitative criteria include cytological and architectural features similar to those of low grade ductal carcinoma in situ (DCIS), the quantitative criteria are characterized by metric features (2 mm or 2 ductules) or by the confines of lobules. In this article we discuss the morphology of ADH, the status of ADH in the low grade pathway of breast carcinoma development and its clinical significance. Furthermore, we comment some special forms of atypical epithelial proliferations of the ductal type.

[Flat epithelial atypia]. / Flache epitheliale Atypie.

According to the WHO, flat epithelial atypia (FEA) is defined as a neoplastic epithelial proliferation of ductal type in either a single or in multiple terminal duct lobular unit(s) limited to the periphery of the ductules in a clinging growth pattern. The atypical cells may form between one and several layers of epithelial cells that show low grade cytologic atypia. FEA most often presents as mammographic microcalcifications, which are typically round (secretory type and psammomatous calcification in an eosinophilic matrix, so-called ossifying calcifications). Clinical relevance is dependent on whether the lesion appears in isolation or whether it is an excision biopsy or a minimally invasive biopsy. Currently available data suggest that the risk of subsequent breast carcinoma in the ipsilateral breast is very low following the diagnosis of FEA. The differential diagnosis should include atypical ductal hyperplasia, low-grade clinging ductal carcinoma in situ, blunt duct adenosis and apocrine metaplasia.

Digital mammography screening: average glandular dose and first performance parameters.

PURPOSE: The Radiation Protection Commission demanded structured implementation of digital mammography screening in Germany. The main requirements were the installation of digital reference centers and separate evaluation of the fully digitized screening units. Digital mammography screening must meet the quality standards of the European guidelines and must be compared to analog screening results. We analyzed early surrogate indicators of effective screening and dosage levels for the first German digital screening unit in a routine setting after the first half of the initial screening round. MATERIALS AND METHODS: We used three digital mammography screening units (one full-field digital scanner [DR] and two computed radiography systems [CR]). Each system has been proven to fulfill the requirements of the National and European guidelines. The radiation exposure levels, the medical workflow and the histological results were documented in a central electronic screening record. RESULTS: In the first year 11,413 women were screened (participation rate 57.5 %). The parenchymal dosages for the three mammographic X-ray systems, averaged for the different breast sizes, were 0.7 (DR), 1.3 (CR), 1.5 (CR) mGy. 7 % of the screened women needed to undergo further examinations. The total number of screen-detected cancers was 129 (detection rate 1.1 %). 21 % of the carcinomas were classified as ductal carcinomas in situ, 40 % of the invasive carcinomas had a histological size

Maintenance immunotherapy by repetitive low-dose donor lymphocytes infusions in a child with relapse state aml after allogeneic stem cell transplantation.

The treatment of a child with a relapsed state acute leukemia after allogeneic stem cell transplantation (allo-SCT) is a challenge. The authors report about a child with an acute myelogenous leukemia (AML), which relapsed after allo-SCT despite immunological intervention. It was further treated with a second line chemotherapy followed by an infusion of stem cells and donor lymphocytes. Because of an immense risk for a further relapse, an immunological maintenance therapy was also performed, consisting of repetitive infusions of low doses of donor lymphocytes combined with low-dose chemotherapy. Presently, the child is in continuous complete remission and has a good quality of life.

[The "EVA" Trial: Evaluation of the Efficacy of Diagnostic Methods (Mammography, Ultrasound, MRI) in the secondary and tertiary prevention of familial breast cancer. Preliminary results after the first half of the study period]. / Die "EVA"-Studie: Evaluierung der Leistungsfähigkeit diagnostischer Verfahren (Mammographie, Sonographie, MRT) zur sekundären und tertiären Prävention des familiären Mammakarzinoms -- Zwischenergebnisse nach der ersten Hälfte der Förderungsperiode.

PURPOSE: To investigate the respective diagnostic accuracies of the different breast imaging modalities, i. e., mammography (Mx), high-frequency breast ultrasound (US), and dynamic contrast-enhanced breast (MRI) regarding the early diagnosis of familial (hereditary) breast cancer. MATERIALS AND METHODS: A prospective, non-randomized controlled clinical multi-center trial is performed at 4 academic tertiary care centers in Germany (Ulm, Munchen/Grosshadern, Munster and Bonn) for a total period of 4 years, sponsored by the German Cancer Aid. The protocol consists of semiannual clinical visits and breast ultrasound, and annual bilateral two-view Mx, US and MRI. Imaging studies were first analyzed independently, then Mx was read in conjunction with US, followed by Mx combined with MRI, and finally, all three imaging modalities were read in synopsis. We present the concept and first results of this trial. RESULTS: So far, 748 screening rounds are available for analysis in 613 women. A total of 12 breast cancers have been identified, with 11/12 cases in the pTis or pT1/N0 stage. The mean size of detected invasive cancers was 7 mm. A total of 19 benign lesions were biopsied due to false-positive imaging diagnoses. The breast cancer detection rates were: Mx: 5/12 (42 %), US 3/12 (25 %), MRI 10/12 (83 %), and the positive predictive values: Mx 5/17 (29 %), US 3/15 (30 %), and MRI 10/23 (43 %). CONCLUSION: The preliminary data suggest that early diagnosis of familial breast cancer is feasible by intensified surveillance, in particular with the addition of MRI.

New method for rapid solid-phase extraction of large-volume water samples and its application to non-target screening of North Sea water for organic contaminants by gas chromatography-mass spectrometry.

A method has been developed that allows the solid-phase extraction of microorganic compounds from large volumes of water (10 l) for non-target analysis of filtered seawater. The filtration-extraction system is operated with glass fibre filter candles and the polymeric styrene-divinylbenzene sorbent SDB-1 at flow-rates as high as 500 ml/min. Recovery studies carried out for a couple of model substances covering a wide range of polarity and chemical classes revealed a good performance of the method. Especially for polar compounds (log Kow 3.3-0.7) quantitative recovery was achieved. Limits of detection were between 0.1 and 0.7 ng/l in the full scan mode of the MS. The suitability of the method for the analysis of marine water samples is demonstrated by the non-target screening of water from the German Bight for the presence of organic contaminants. In the course of this screening a large variety of substances was identified including pesticides, industrial chemicals and pharmaceuticals. For some of the identified compounds their occurrence in marine ecosystems has not been reported before, such as dichloropyridines, carbamazepine, propyphenazone and caffeine.

Intensive chemotherapeutic regimens against acute leukemia transiently suppress asthma symptoms but do not lead to long-term relief.

In some very rare cases children suffer from a combination of asthma and a malignant disease. This study investigated whether intensive chemotherapy might have a positive effect on asthma in these special cases and whether asthma generally relapses after completion of chemotherapy. The authors monitored clinical outcome and lung function of 43 children with acute lymphoblastic leukemia and non-Hodgkin lymphoma who received chemotherapy at the University Children's Hospital of Greifswald between 1993 and 1998. Cytostatic chemotherapy was administered according to the German treatment protocols. Two of the 43 patients had asthma before leukemia was diagnosed. During the course of chemotherapy, asthma symptoms diminished promptly after beginning of chemotherapy but asthma was rediagnosed after completion of chemotherapy in both cases. The third patient developed asthmatic symptoms shortly after completion of chemotherapy for the first time. It can be stated that chemotherapy does not essentially cure asthma. Therefore, it seems mandatory to perform follow-up lung testings after chemotherapy, especially in patients with asthma.

Ectopic cervical thymus in a 12-year-old boy: a case report.

The case of a 12-year-old boy with ectopic cervical thymus is reported. This is a rare differential diagnosis in cervical tumors in childhood. The clinical symptoms might present as complications; in rare cases malignant transformations have been reported. The diagnosis ectopic cervical thymus can be achieved only histologically. Due to possible malignant transformation, it is mandatory to excise this thymus tumor totally.

Geographic information systems. A new tool in environmental epidemiology.

PURPOSE: Geographic Information Systems (GIS) are useful tools for identifying populations with potential exposure to environmental contaminants. Using a GIS, features of the local environment around an individual's home, work, or school can be described. We present two examples illustrating methods and issues in identifying populations potentially exposed to agricultural pesticides and to toxic releases from the Toxic Release Inventory (TRI).METHODS: We used USDA Farm Service Agency records as ground reference data to classify a late summer 1984 satellite image into crop species in 3 counties in Nebraska. We located residences from a case-control study of non-Hodgkin's lymphoma (NHL) on the crop maps and calculated the distance to crop fields. Residences from a 4-center study of NHL were mapped and the distance to TRI sites was determined.RESULTS: Twenty-two percent of residences had crop fields within 500 meters of the home, an intermediate distance for the range of drift effects from pesticide applications. After accounting for the extent of primary drift from ground applications of pesticides, we estimated that 30 percent of residences were potentially exposed to crop pesticides. In the 4-center study, residence locations determined by address-matching methods and by a global positioning system were compared; the population 1 mile from specific TRI sites is described.CONCLUSIONS: These examples demonstrate the utility of a GIS in environmental epidemiology studies. A GIS can be a useful addition to questionnaire and other methods of exposure assessment in health studies.

Antibiotic sequential therapy for febrile neutropenia in pediatric patients with malignancy.

Children suffering malignant diseases can experience phases of bone marrow depression during intensive chemotherapy. The influence of antibiotic sequence therapy on the course of diseases was examined in 41 pediatric patients with malignant diseases. Inclusion criteria were neutropenia (ANC < 500/microL), rectal body temperature over 38.5 degrees C, and increased C-reactive protein (CRP, cutoff > 5.0 mg/L). The first stage of therapy comprised the following antibiotics: piperacillin, teicoplanin, and gentamicin. In stage 2 imipenem, teicoplanin, and tobramycin were administered. Fluconazole was the antifungal drug of choice in stages 1 and 2. In the first level of antibiotic therapy 68% of the patients showed a positive reaction. The C-reactive protein was a sensitive parameter, which significantly decreased with 3 days of therapy. A total of 72% of the bacteriological smears were sterile. All patients survived the septic phase.

Identifying populations potentially exposed to agricultural pesticides using remote sensing and a Geographic Information System.

Pesticides used in agriculture may cause adverse health effects among the population living near agricultural areas. However, identifying the populations most likely to be exposed is difficult. We conducted a feasibility study to determine whether satellite imagery could be used to reconstruct historical crop patterns. We used historical Farm Service Agency records as a source of ground reference data to classify a late summer 1984 satellite image into crop species in a three-county area in south central Nebraska. Residences from a population-based epidemiologic study of non-Hodgkin lymphoma were located on the crop maps using a geographic information system (GIS). Corn, soybeans, sorghum, and alfalfa were the major crops grown in the study area. Eighty-five percent of residences could be located, and of these 22% had one of the four major crops within 500 m of the residence, an intermediate distance for the range of drift effects from pesticides applied in agriculture. We determined the proximity of residences to specific crop species and calculated crop-specific probabilities of pesticide use based on available data. This feasibility study demonstrated that remote sensing data and historical records on crop location can be used to create historical crop maps. The crop pesticides that were likely to have been applied can be estimated when information about crop-specific pesticide use is available. Using a GIS, zones of potential exposure to agricultural pesticides and proximity measures can be determined for residences in a study.

The nuclear export signal within the E4orf6 protein of adenovirus type 5 supports virus replication and cytoplasmic accumulation of viral mRNA.

During the late phase of adenovirus infection, viral mRNA is efficiently transported from the nucleus to the cytoplasm while most cellular mRNA species are retained in the nucleus. Two viral proteins, E1B-55 kDa and E4orf6, are both necessary for these effects. The E4orf6 protein of adenovirus type 5 binds and relocalizes E1B-55 kDa, and the complex of the two proteins was previously shown to shuttle continuously between the nucleus and cytoplasm. Nucleocytoplasmic transport of the complex is achieved by a nuclear export signal (NES) within E4orf6. Mutation of this signal sequence severely reduces the ability of the E1B-55 kDa-E4orf6 complex to leave the nucleus. Here, we examined the role of functional domains within E4orf6 during virus infection. E4orf6 or mutants derived from it were transiently expressed, followed by infection with recombinant adenovirus lacking the E4 region and determination of virus yield. An arginine-rich putative alpha helix near the carboxy terminus of E4orf6 contributes to E1B-55 kDa binding and relocalization as well as to the synthesis of viral DNA, mRNA, and proteins. Further mutational analysis revealed that mutation of the NES within E4orf6 considerably reduces its ability to support virus production. The same effect was observed when nuclear export was blocked with a competitor. Further, a functional NES within E4orf6 contributed to the efficiency of late virus protein synthesis and viral DNA replication, as well as total and cytoplasmic accumulation of viral late mRNA. Our data support the view that NES-mediated nucleocytoplasmic shuttling strongly enhances most, if not all, intracellular activities of E4orf6 during the late phase of adenovirus infection.