[Therapy Goals for Children and Adolescents with ADHD and their Primary Caregivers. A Content Analysis and Examination of Agreement of ADHD Patients and their Primary Caregivers]. / Therapieziele von Kindern und Jugendlichen mit ADHS und ihren Hauptbezugspersonen. Eine inhaltsanalytische Auswertung und Prüfung der Übereinstimmung zwischen Betroffenen und Bezugspersonen.

OBJECTIVE: The aim of this study was to identify individual therapy goals (ITGs) of children and adolescents with ADHD and their primary caregivers. METHODS: Within the evaluation of the selective contract for children and adolescents with ADHD in Bremerhaven, Germany, ITGs of 42 study participants (aged 8-17) and their primary caregivers were collected with the psychotherapy basis documentation for children and adolescents (Psy-BaDo-KJ). ITGs were analysed following the classification of categories for individual therapy goals (KITZ) and their modification for children and adolescents. Analysis focused on the most frequently named ITGs and the agreement of patients and primary caregivers ITGs on the individual level. RESULTS: 235 ITGs were named. The greatest proportion of ADHD patients and their caregivers (47%) focused on interactional, psychosocial conflicts. In 19% of the cases (n=8) patients and their caregivers had the same main goal. 38% of patients and of caregivers (n=16) named the other ones main goal in one of his/her ITGs as well. CONCLUSIONS: ADHD patients and their primary caregivers both pursue ITGs related to ADHD symptoms. Few ITGs address medication related aspects. In case of differences in the ITGs of a patient and his/her primary caregivers, therapists should check whether differing ITGs address the same problem from different perspectives.

Insulin-like growth factor 1-coated sutures improve anastomotic healing in an experimental model of colitis.

BACKGROUND: : Exogenously applied insulin-like growth factor (rhIGF-1) may improve normal intestinal healing. This study examined the effect of rhIGF-1-coated sutures on anastomotic healing in experimental colitis. METHODS: : Acute colitis was induced in rats by dextran sodium sulphate (DSS). Inflammation was assessed by clinical Disease Activity Index (DAI), myeloperoxidase (MPO) measurement and histological examination. A distal colonic anastomosis was performed using sutures coated with rhIGF-1 dissolved in poly(D,L-lactide) (PDLLA) under general anaesthetic. Anastomotic healing was evaluated histologically, and by hydroxyproline measurement and bursting parameters after 1, 3 and 7 days, and compared with healthy, DSS and DSS + PDLLA controls. RESULTS: : DAI, MPO and histological inflammation scores were significantly increased in all animals treated with DSS. Bursting occurred less often within the anastomotic line on day 3 in the IGF group than in DSS controls (three versus eight of ten). On day 7, the IGF group had significantly increased histological healing scores (mean(s.e.m.) 12.5(0.7) versus 9.2(0.8) (P < 0.050)) and hydroxyproline content (4.6(0.3) versus 3.6(0.1) mg/g tissue; P < 0.050) compared with DSS controls. CONCLUSION: : IGF-1-coated sutures improve important aspects of anastomotic healing in rats with experimental colitis.

Expression of aromatase and estrogen sulfotransferase in preinvasive and invasive breast cancer.

PURPOSE: Intratumoral estradiol levels in postmenopausal women with breast cancer are thought to be mainly regulated by the aromatase-mediated conversion from androgens and estrogen sulfotransferase (EST)-mediated reduction of bioavailability. While in invasive breast cancer (IBC) the role of both enzymes has been extensively studied and has led to the use of aromatase inhibitors as a key therapeutic strategy, comparably little is still known about their role in the local regulation of estradiol in ductal carcinoma in situ (DCIS). METHODS: We have performed immunohistochemistry to investigate the expression of aromatase and sulfotransferase in custom-made breast cancer tissue arrays containing 96 samples of pure DCIS and in 104 tumor biopsies which contain both, DCIS and invasive components. RESULTS: We found that aromatase was equally detectable in epithelial components of both, DCIS and IBC (P = 0.884, Chi square test). However, stromal aromatase expression was significantly higher in IBC compared to adjacent DCIS components (P = 0.034, Chi square test). Whereas no significant difference was observed for epithelial aromatase expression in high versus non-high grade DCIS (P = 0.735 Chi square test), epithelial EST levels were found to be significantly down-regulated in high-grade DCIS compared to non-high grade cases (P = 0.042). CONCLUSION: We have demonstrated the presence of both aromatase and EST in malignant epithelium and adjacent stromal fibroblasts in DCIS. Lower stromal aromatase expression in preinvasive breast cancer and lower EST levels in high-grade DCIS suggest that the net effect of intratumoral estradiol (E2)-modulating enzymes results in lower local E2 levels in earlier stages of breast tumorigenesis.

Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion.

Tumour hypoxia, being widespread in solid tumours, is related to an increased risk of invasion and metastasis as well as to resistance to chemotherapy and radiotherapy. Hypoxia-inducible factor-1alpha (HIF-1alpha) has emerged as the key regulator of the cellular response to hypoxia. In primary breast cancers, HIF-1alpha is overexpressed, and high levels of HIF-1alpha predict for early relapse and increased metastasis. The endothelin (ET) axis, comprising the peptides ET-1, -2, -3 and their receptors A (ETAR) and B (ETBR), is another regulatory system of major relevance in human breast cancer. However, little is known about the interaction of HIF-1alpha and the ET axis in breast carcinomas. Therefore, we analysed expression of HIF-1alpha and the ET axis in 600 breast cancer tissue samples by immunohistochemistry, observing a significant correlation between expression of HIF-1alpha and ET-1 (P<0.001). In vitro, hypoxia was found to double ET-1 secretion of MCF-7 breast cancer cells (203.5% of controls; P<0.001), thereby promoting an invasive phenotype. Of note, real-time PCR analysis revealed that the increase of ET-1 was not due to enhanced transcription of the ET-1 gene. In invasion assays, breast cancer cell invasiveness was strongly increased by hypoxia (150.0% of controls; P=0.007). Most important, this increase was completely inhibited by the selective ETAR antagonist atrasentan. In conclusion, we provide evidence for a relevant interaction between hypoxia and the ET axis in breast cancer cells. Our data suggest that tumour hypoxia induces breast carcinoma invasiveness by releasing intracellularly stored ET-1. However, induction of invasiveness may be inhibited by selective ETAR antagonism, thus emphasising the promising status of the ET axis as a therapeutic target in breast cancer.

Expression of beta-catenin and p53 are prognostic factors in deep aggressive fibromatosis.

AIMS: To determine the prognostic significance of beta-catenin in aggressive fibromatosis and to identify potential molecular markers for new targeted therapies. METHODS AND RESULTS: A tissue microarray of 37 cases of deep aggressive fibromatosis was constructed and subjected to immunohistochemical analysis for beta-catenin, p53, smooth muscle actin (SMA), desmin, Ki67, c-erbB2, epidermal growth factor receptor (EGFR), c-kit, CD34 and S100. Complete clinical follow-up was available for 23 patients. Nuclear beta-catenin expression was associated with an increased rate of local tumour recurrence (60.0% 1-year and 0% 5-year event-free survival; P < 0.05). Furthermore, p53 expression was associated with an increased risk of tumour recurrence (50% 1-year event-free survival rate and 0% 5-years event-free survival rate, P < 0.05). The coexpression of p53 and beta-catenin was significantly correlated (P < 0.05). No statistically significant association was seen between MIB1 and p53 or beta-catenin expression, respectively. No expression of EGFR, c-erbB2 or c-kit was seen. CONCLUSIONS: The overexpression of beta-catenin and p53 is associated with a decreased event-free survival in deep aggressive fibromatosis. Further studies are required to establish whether these findings can lead to an improvement in the treatment of this rare neoplasm.

[The significance of "normal tissue" in the development of breast cancer: new concepts of early carcinogenesis]. / Bedeutung des "Normalgewebes" in der Brustkrebsentstehung: Neue Vorstellungen zur frühen Pathogenese des Mammakarzinoms.

Only little information on the primary molecularbiological events involved in early breast is available. In particular, the definition of postulated precursor lesions of invasive breast cancer, such as ductal hyperplasia or ductal carcinoma in situ, is under an intense, controversial discussion in terms of pathogenesis and tumor biology. The most recent research on biological regulation mechanisms and genetic alterations in morphologically normally appearing breast tissue give rise for a reinterpretation for the most common progression models of breast cancer. The detection of genetic alterations within normal breast tissue in particular challenges the commonly postulated relationship between invasive and in situ breast carcinomas on the one hand, and benign, proliferative breast lesions on the other. The concerns about these relationship are further supported by the description of different cellular compartments within the normal female breast, including a "progenitor cell compartment" with different cytokeratin expression patterns, which can be transferred towards well known or suspected precursor lesions of invasive and in situ breast cancer. The aim of this manuscript is to provide an overview of the most recent results and developments in breast pathology, and to describe the consequences of our changing understanding of breast carcinogenesis.

[Papillary tumors of the breast]. / Papilläre Tumoren der Mamma.

The term papilloma applies to benign proliferative epithelial breast lesions with a papillary architecture. The papillae in such lesions contain an arborizing fibrovascular core, glandular surface epithelium and a basal myoepithelial layer. A basement membrane encloses these structures. Papilloma may occur at any site in the ductal lobular system and according to its localization is subdivided into two types: solitary (central) papilloma which are located in the major nipple/subareolar ducts or large segmental ducts and multiple (peripheral) papillomas in cystically dilated terminal ductal lobular units (TDLU). Stromal changes, epithelial metaplasia and/or proliferations and neoplasia may alter the prototypical architecture. In a significant number of papillomas atypia can be identified which have to be classified as atypical proliferates of the ductal type. These lesions must be distinguished from the papillary type of ductal carcinoma in situ. Some 17% of all papilloma are associated with (synchronous) intraductal or invasive carcinoma, but these also act as an indicator for subsequent (metachronous) carcinoma. As a consequence, in minimally invasive biopsy papilloma has to be classified as B3 and usually has to be followed by surgical excision.

Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer.

The aim of this study was to investigate the expression of the protein tyrosine phosphatases (PTP) PRL-1, PRL-2, and PRL-3 in human breast cancer and to evaluate its clinical and prognostic significance. PRL-PTP mRNA expression was examined in malignant (n = 7) and nonmalignant (n = 7) cryoconserved breast tissue samples as well as in eight breast cancer cell lines by RT-PCR. Furthermore, protein expression of PRL-3 was analysed semiquantitatively by immunohistochemistry in ductal breast carcinoma in situ (n = 135) and invasive breast cancer (n = 147) by use of tissue microarray technology (TMA). In 24 lymph node-positive patients we selected the corresponding lymph node metastases for analysis of PRL-3 expression, and a validation set (n = 99) of invasive breast cancer samples was examined. Staining results were correlated with clinicopathological parameters and long-term follow-up. PRL-3 mRNA expression was significantly higher in malignant compared to benign breast tissue. For PRL-1 and PRL-2 expression no significant differences were observed. Staining of TMAs showed PRL-3 expression in 85.9% ductal carcinoma in situ and 75.5% invasive breast carcinomas. Analysis of survival parameters revealed a shorter disease-free survival (DFS) in patients with PRL-3-positive carcinomas, and in particular a significantly shorter DFS in nodal-positive patients with PRL-3 overexpressing tumours as compared to PRL-3-negative breast carcinomas (66+/-7 months (95% CI, 52-80) vs 97+/-9 months (95% CI, 79-115); P = 0.032). Moreover, we found a more frequent expression of PRL-3 in lymph node metastases as compared to the primary tumours (91.7 vs 66.7%; P = 0.033). Our results suggest that PRL-3 might serve as a novel prognostic factor in breast cancer, which may help to predict an adverse disease outcome.

Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas.

BACKGROUND: New targeted cancer treatments acting against growth factor receptors such as the epidermal growth factor receptor (EGFR) necessitate selecting patients for treatment with these drugs. Besides carcinomas, soft tissue sarcomas (STS) express EGFR and might thereby be a promising target for this new therapeutic strategy. OBJECTIVE: To test and compare different EGFR antibodies to determine the frequency of EGFR expression in STS. METHODS: 302 consecutive specimens of STS were examined using the tissue microarray technique. EGFR expression levels were assessed by immunohistochemistry using five different commercially available antibodies. Gene amplification status was measured by fluorescence in situ hybridisation (FISH). Immunoreactivity and amplification status were correlated with clinicopathological features and follow up data available in 163 cases. RESULTS: EGFR expression frequency ranged between 0.3% and 52.9%, depending on the antibody and scoring method used. In all, 3.5% of the tumours showed egfr gene amplification by FISH, which correlated with EGFR expression for three antibodies. Only one antibody had independent prognostic value in multivariate analysis and correlated with an unfavourable outcome; egfr gene amplification status showed no correlation with clinical features. CONCLUSIONS: Frequency of EGFR immunopositivity in STS strongly depends on the antibody used, and only one of five antibodies tested predicted an unfavourable clinical outcome. This indicates that choice of primary antibody and scoring system have a substantial impact on the determination of EGFR immunoreactivity.

Expression of early placenta insulin-like growth factor in breast cancer cells provides an autocrine loop that predominantly enhances invasiveness and motility.

Early placenta insulin-like growth factor (EPIL) is expressed by a subpopulation of the Her2-positive SKBR3 breast cancer cell line displaying high motility and transendothelial invasiveness in vitro, as recently shown by our group. As a consequence of this, we established cellular models by generating an EPIL-overexpressing SKBR3 cell line, knocked down EPIL by adding specific small interfering RNA (siRNA) to those cells and produced EPIL-enriched and depleted serum-free culture media. EPIL-expressing cells as well as EPIL-induced SKBR3 cells acquired a high capacity for transendothelial invasiveness. We observed a thin and outspread morphology caused by enhanced formation of lamellipodia, i.e. protrusions in the initial phase of motility. In parallel, Her2-positive MDAHer2 breast cancer cells also showed increased invasiveness when induced by EPIL-conditioned medium. A downstream signaling impact of EPIL could be observed in the form of reduced phosphorylation of Her2, erk1/2 and akt, while phospholipase Cgamma1 phophorylation remained unaffected. As an in vivo model for highly motile tumor cells, Paget's disease of the nipple showed simultaneous EPIL and Her2 expression upon immunohistochemical examination using specific antibodies. Such experimental data have been translated to a clinical setting by using a prognostic tissue microarray established from 603 breast cancer cases. Survival data analysis found a significant association between expression levels of EPIL and 5-year overall survival that was dose dependent: EPIL (negative) 84%, EPIL (moderately positive) 77%, EPIL (strongly positive) 48% (P < 0.005). One particular subgroup (7.6% of the cases with full clinical records) that comprised tumors simultaneously expressing EPIL and Her2 represented patients with the poorest 5-year overall survival. The results suggested that EPIL might be a cancer cell-produced growth factor that influences lateral Her2 signaling. Moreover, EPIL may be induced by factors apart from Her2 and may independently provide signaling for cancer invasion and motility.

Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ.

The objective of this study was to investigate expression of various growth factors associated with angiogenesis and lymphangiogenesis and of their receptors in ductal carcinomas in situ of the breast (DCIS). We studied protein expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)-A, endothelin (ET)-1, and VEGF-C, and their receptors bFGF-R1, Flt-1, KDR, ET(A)R, ET(B)R, and Flt-4 immunohistochemically in 200 DCIS (pure DCIS: n=96; DCIS adjacent to an invasive component: n=104) using self-constructed tissue microarrays. Basic fibroblast growth factor-R1, VEGF-C, Flt-4, and ET(A)R were expressed in the tumour cells in the majority of cases, whereas bFGF and Flt-1 expression was rarely observed. VEGF-A, KDR, ET-1, and ET(B)R were variably expressed. The findings of VEGF-C and its receptor Flt-4 as lymphangiogenic factors being expressed in tumour cells of nearly all DCIS lesions and the observed expression of various angiogenic growth factors in most DCIS suggest that in situ carcinomas are capable of inducing angiogenesis and lymphangiogenesis. Moreover, we found a higher angiogenic activity in pure DCIS as compared to DCIS with concomitant invasive carcinoma. This association of angiogenic factors with pure DCIS was considerably more pronounced in the subgroup of non-high-grade DCIS (n=103) as compared with high-grade DCIS (n=94). Determination of these angiogenic markers may therefore facilitate discrimination between biologically different subgroups of DCIS and could help to identify a particularly angiogenic subset with a potentially higher probability of recurrence or of progression to invasiveness. For these DCIS, targeting angiogenesis may represent a feasible therapeutic approach for prevention of progression of DCIS to invasion.

Primary left atrial angiosarcoma mimicking severe mitral valve stenosis.

Primary cardiac tumours are quite rare and most of these tumours are benign. In this report, a patient presented with heart failure symptoms attributable to severe mitral valve stenosis. Echocardiography showed a dense left atrial mass causing functional mitral valve obstruction. The morphological and intraoperative presentation was highly suggestive of a myxoma but histopathological examination found a primary pedunculated cardiac angiosarcoma. The role of two dimensional and transoesophageal echocardiography in the assessment of cardiac masses and tumours is discussed.

Immunohistochemical differentiation of eosinophilic heart diseases using antibodies against eosinophil activation markers.

AIMS: Eosinophilic heart syndromes are rare in Western countries and include endocarditis parietalis fibroplastica (EPF) and hypersensitivity myocarditis (HM). There are striking differences in natural history and morphological findings. Since diagnosis can be difficult when analysing small myocardial biopsies lacking the characteristic histological features, we studied a set of immunohistochemical markers in order to characterize the activation status of the infiltrating eosinophils to distinguish between these two entities. METHODS AND RESULTS: This study is based on the investigation of seven explanted hearts and one left ventricular specimen collected during implantation of a left ventricular assist device from a total of seven patients with HM. Also investigated were three right and three left ventricular specimens from five patients with EPF. We used antibodies (Ab) against EG1, and EG2, CD44, and CD69 which have been described as markers to distinguish between resting and activated eosinophils. The EG1 to EG2 ratio of eosinophils and the immunoreactivity against CD44 showed no differences between the two entities. However, eosinophils in the EPF were completely negative for CD69, whereas eosinophils reacted positively within the HM group. CONCLUSION: The immunohistochemical investigation of eosinophilic heart diseases using antibodies against CD69 can be a useful tool to distinguish between hypersensitivity myocarditis and endocarditis parietalis fibroplastica.

[Two cystic retroperitoneal lesions mimicking adrenal cysts]. / Retroperitoneale Zysten, die Nebennierenzysten imitieren können.

Adrenal cysts are uncommon lesions and most of them are found incidentally during abdominal imaging. We report on two benign extraadrenal lesions mimicking adrenal tumors in abdominal imaging. The histopathological investigation of the lesions revealed a foregut duplication cyst of the lesser gastric curvature and an epithelial inclusion cyst (epidermoid cyst) in an intrapancreatic accessory spleen respectively.

Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature.

Erdheim-Chester disease is a rare non-Langerhans' cell histiocytosis with characteristic radiological and histological features. This entity is defined by a mononuclear infiltrate consisting of lipid laden, foamy histiocytes that stain positively for CD68. About half of those affected have extraskeletal manifestations, including involvement of the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen, and orbit. This report describes the case of a 50 year old white man who presented with hypogonadism and diabetes insipidus. At necropsy, extensive organ involvement was found, including the testes, thyroid, and lymph nodes. This is the first report of thyroid and lymph node infiltration in this disease. Because of the endocrinological symptoms, neurosarcoidosis and hypophysitis are important diseases in the differential diagnosis. This report also includes a review of the literature concerning rare organ manifestations and patients presenting primarily with similar symptoms.

Expression of endothelin-A-receptor predicts unfavourable response to neoadjuvant chemotherapy in locally advanced breast cancer.

Endothelin-1 (ET-1) and its receptors (ETAR and ETBR), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas and appear to influence tumour growth and progression. The objective of this study was to determine the effect of expression of the ET axis in breast carcinomas on response to cytotoxic chemotherapy. The study included 44 patients with locally advanced breast cancer participating in a prospective phase III study evaluating high-dose neoadjuvant chemotherapy of epirubicin and cyclophosphamide. Expression of ET-1, ETAR and ETBR was determined by semiquantitative immunohistochemical analysis of breast cancer tissue from prechemotherapy tru-cut biopsies. Immunohistochemical staining was positive for ET-1 in 61.5%, for ETAR in 35% and for ETBR in 35.9% of breast carcinomas. Pathological response to chemotherapy was significantly decreased in ETAR-positive patients (P=0.002). In total, 50% of ETAR-positive patients as compared to 7.7% of ETAR-negative patients attained pathologically 'no change'. Logistic regression confirmed ETAR as an independent predictive marker for pathological response (P=0.009). These data indicate that increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. Determination of ETAR status may serve as a predictive marker for identifying patients less likely to be responsive to conventional chemotherapy.

Deciphering a subgroup of breast carcinomas with putative progression of grade during carcinogenesis revealed by comparative genomic hybridisation (CGH) and immunohistochemistry.

Distinct parallel cytogenetic pathways in breast carcinogenesis could be identified in recent years. Nevertheless, it remained unclear as to which tumours may have progressed in grade or which patterns of cytogenetic alteration may define the switch from an in situ towards an invasive lesion. In order to gain more detailed insights into cytogenetic mechanisms of the pathogenesis of breast cancer, the chromosomal imbalances of 206 invasive breast cancer cases were characterised by means of comparative genomic hybridisation (CGH). CGH data were subjected to hierarchical cluster analysis and the results were further compared with immunohistochemical findings on tissue arrays from the same breast cancer cases. The combined analysis of immunohistochemical and cytogenetic data provided evidence that carcinomas with gains of 7p, and to a lesser extent losses of 9q and gains of 5p, are a distinct subgroup within the spectrum of ductal invasive grade 3 breast carcinomas. These aberrations were associated with a high degree of cytogenetic instability (16.6 alterations per case on average), 16q-losses in over 70% of these cases, strong oestrogen receptor expression and absence of strong expression of p53, c-erbB2 and Ck 5. These characteristics provide strong support for the hypothesis that these tumours may develop through stages of well- and perhaps intermediately differentiated breast cancers. Our results therefore underline the existence of several parallel and also stepwise progression pathways towards breast cancer.

Pentanucleotide short tandem repeat locus DXYS156 displays different patterns of variations in human populations.

AIM: To establish a database for the pentameric short tandem repeat locus DXYS156 from worldwide populations for routine genotyping in forensic identity testing and evolutionary biology. METHODS: Using polymerase chain reaction with a newly designed primer pair, we analyzed 1,408 male and female samples from 28 populations representing four major geographic groups. RESULTS: We observed 11 different alleles, which we sequenced and used to construct an allelic ladder. CONCLUSION: DXYS156 displays a contrasting pattern of X-linked and Y-linked variation among geographic regions, and between X and Y chromosomes. This complex allele distribution may be forensically useful for the ethnic differentiation of unknown stains.

Prior exposure of the entrance wound region from clothing is uncommon in firearm suicides.

According to an old rule still in use, gunshot suicides will rarely shoot through the clothing but will pull it aside to bare the skin. Thus, a bullet defect in the clothing would be an indicator for homicide or an accident. A total of 138 clearly defined gunshot suicides were analysed with regard to this topic. The thorax, which is commonly covered by textile, was the target for 27 suicides (19.5%). Of these 27 persons, 25 had fired through the clothing and 2 had placed the muzzle directly on the exposed skin, which represents a relative frequency of only 7%. Special features such as thick clothing or an affected state of mind did not appear to influence this behavior. Consequently, the perforation of textile does not suggest homicide or an accident - it is not applicable as a criterion for distinguishing different modes of death. Only in the rare cases when a gunshot victim is found with intact clothing covering the entrance wound can this finding be interpreted as an indication for suicide.