Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells.

PURPOSE: EMMPRIN (extracellular matrix metalloprotease inducer) is a glycosylated member of the immunoglobulin superfamily known to stimulate the production of matrix metalloproteases (MMPs) 1, 2, and 3 and MT1-MMP in peritumoral fibroblasts. We here evaluated whether EMMPRIN expression is related to tumor progression in human breast cancer. EXPERIMENTAL DESIGN: An immunohistochemical study using high-density tissue microarrays (n = 2222 breast cancer samples) and EMMPRIN-specific antibodies HIM6 and MEM-M6/1 was performed, and staining results were statistically correlated with various clinicopathological parameters. To analyze the putative association between EMMPRIN expression and bone marrow (BM) micrometastasis, an additional set of 55 breast tumors from patients with or without micrometastatic cells as determined with anti-cytokeratin antibody A45-B/B3 were included in our study. Cytokeratin-positive cells in BM were costained with EMMPRIN-specific antibody 1G6.2. RESULTS: Positive EMMPRIN staining correlated significantly with various histopathological risk factors (higher tumor grade, increased tumor size, negative estrogen receptor status and progesterone receptor status, and higher mitotic index) as well as decreased tumor-specific survival (log-rank, P = 0.0027). In particular, in patients > 50 years (i.e., postmenopausal women), EMMPRIN expression was an independent prognosticator as shown by Cox regression analysis (relative risk = 1.7, 95% confidence interval 1.4-4.3, P = 0.036). An involvement of EMMPRIN in tumor progression was also supported by the fact that it was expressed on approximately 90% of micrometastatic cells in BM. CONCLUSIONS: EMMPRIN expression in primary tumor predicts an unfavorable prognosis in breast cancer, suggesting a crucial role of EMMPRIN in progression of human mammary carcinomas.     

Transvenous occlusion of dural cavernous sinus fistulas through the thrombosed inferior petrosal sinus: report of four cases and review of the literature

BACKGROUND: The aim of this study is to describe the technique and results of the endovascular approach through the thrombosed inferior petrosal sinus (IPS) for occlusion of dural cavernous sinus fistulas (DCSFs). METHODS: In four patients presenting with clinically symptomatic DCSFs, the angiogram did not show opacification of the IPS, indicating that it neither drained the arteriovenous fistula nor the cerebral venous outflow. A large volume biplane phlebogram of the jugular bulb was obtained to identify a thrombosed remnant of the IPS. We were able to navigate small hydrophilic catheters and microguide wires through the thrombosed IPS into the ipsi- or contralateral CS. After reaching the fistula site the CS was packed with detachable platinum coils. RESULTS: We were able to reach the fistula site and to achieve a dense packing of coils within the arteriovenous shunting zone in all of the patients. The final angiogram showed subtotal or complete occlusion of the arteriovenous fistula. All four patients recovered completely and showed disappearance of the fistula on follow-up arteriograms. One patient developed a transient sixth nerve palsy. No complications related to the approach were observed. CONCLUSIONS: For endovascular treatment, transvenous occlusion of DCSFs via the IPS is a feasible approach, even when this sinus is partially or completely thrombosed. Gentle handling of recently available, improved hydrophilic microguide wires and microcatheters allows effective and safe catheter navigation into the CS. A phlebogram of the jugular bulb is very useful for identification of a thrombosed IPS.     

Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 promotes progression of non-small cell lung cancer.

PURPOSE: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) has recently been implicated in cancer development and progression. This study was performed to assess whether CEACAM-1 expression in primary tumors is correlated to long-term survival in patients with operable non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Primary tumors of 145 consecutive patients with completely resected NSCLC (pT(1-4) pN(0-2) M(0) R(0)) were stained immunohistochemically using the monoclonal anti-CEACAM-1 antibody 4D1/C2. The prognostic relevance of CEACAM-1 expression was evaluated by univariate Kaplan-Meier and multivariate Cox regression analysis. The median follow-up period was 72 months (range, 10-130 months). RESULTS: Normal bronchiolar epithelium present in all sections exhibited no immunostaining. In contrast, 73 tumors (50.4%) showed between 1 and 66% CEACAM-1 positive tumor cells, and 72 tumors (49.6%) exhibited even a higher percentage of positive tumor cells. A high CEACAM-1 expression rate (i.e., >/=66% positive tumor cells) was more frequent in adenocarcinomas than in squamous cell carcinomas (61.9 versus 35.7%, respectively). Multivariate Cox regression analysis demonstrated that CEACAM-1 represents an independent prognosticator for cancer-related survival (P = 0.018; relative risk, 1.8; 95% confidence interval, 1.1-2.8). Subgroup analysis revealed that a high CEACAM-1 expression rate was of significant prognostic impact in pN(1)-pN(2) patients (n = 60; P = 0.024), pT(3)-pT(4) patients (n = 22; P = 0.009), and stage IIa-IIIa patients (n = 69; P = 0.012). CONCLUSIONS: The absence of CEACAM-1 in normal lung tissue and its expression in tumor cells argues against a tumor-suppressive role of CEACAM-1 in NSCLC. The correlation between elevated CEACAM-1 expression and an unfavorable prognosis indicates rather that CEACAM-1 might promote lung cancer progression.     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

Diagnosis: toxic!--trying to apply approaches of clinical diagnostics and prevalence in toxicology considerations.

The assessment of relevance of toxicological testing was compared with approaches of diagnostic medicine, a discipline that faces a comparable situation. Considering the work of a toxicologist as setting a diagnosis for compounds, assessment tools for diagnostic tests were transferred to toxicological tests. In clinical diagnostics, test uncertainty is well accepted and incorporated in this assessment. Furthermore, prevalence information is considered to evaluate the gain in information resulting from the application of a test. Several common toxicological scenarios, in which test uncertainty and prevalence are combined, are discussed including the interdependence of test accuracy, prevalence and predictive values or the sequential application of a screening and a confirmatory test. In addition, real prevalences derived from prevalences determined by an imperfect test are presented. We conclude that information on prevalences of toxic health effects is required to allow a complete assessment of the relevance of toxicological test. In this process, lessons can be learned from evidence-based approaches in clinical diagnostics.     

Variation in the structure of Toxoplasma gondii and the roles of selfing, drift, and epistatic selection in maintaining linkage disequilibria.

Previous studies of Toxoplasma gondii, based on samples dominated by clinical isolates, have concluded that its population structure is clonal, despite the sexual reproduction that occurs in cats. To determine whether this applies to non-clinical isolates, we compared patterns of linkage disequilibrium (LD) among seven loci in samples of T. gondii from Brazil and the US. LD was detected in both locations, but it was substantially lower in Brazil. The lower LD in Brazil can be explained by a higher rate of sexual reproduction between different genotypes (outcrossing) because of a higher rate of transmission. The extent of LD between pairs of physically unlinked loci varied significantly in each location. Moreover, the magnitude of LD between corresponding locus pairs in Brazil and the US was correlated, despite minimal gene exchange between the continents (mean FST = 0.19). The heterogeneity among locus pairs and the correlation in LD between physically unlinked locus pairs from different continents suggests that locus-specific factors, such as epistatic selection are involved in maintaining LD in T. gondii. Possibly, the unique life cycle of T. gondii with its unpredictable transmission among diverse host species and distinct ecological habitats requires specific combinations of alleles from multiple loci. The usefulness of typing isolates based on physically unlinked loci is questioned not only by the geographic variation in the reproductive population structure, but mainly by the low overall predictability of the genotype of one locus based on the genotype in another (unlinked) locus. This predictability ranged between 23 and 45%, but was close to nil for a considerable fraction of locus pairs.     

Brain electric correlates of strong belief in paranormal phenomena: intracerebral EEG source and regional Omega complexity analyses

The neurocognitive processes underlying the formation and maintenance of paranormal beliefs are important for understanding schizotypal ideation. Behavioral studies indicated that both schizotypal and paranormal ideation are based on an overreliance on the right hemisphere, whose coarse rather than focussed semantic processing may favor the emergence of 'loose' and 'uncommon' associations. To elucidate the electrophysiological basis of these behavioral observations, 35-channel resting EEG was recorded in pre-screened female strong believers and disbelievers during resting baseline. EEG data were subjected to FFT-Dipole-Approximation analysis, a reference-free frequency-domain dipole source modeling, and Regional (hemispheric) Omega Complexity analysis, a linear approach estimating the complexity of the trajectories of momentary EEG map series in state space. Compared to disbelievers, believers showed: more right-located sources of the beta2 band (18.5-21 Hz, excitatory activity); reduced interhemispheric differences in Omega complexity values; higher scores on the Magical Ideation scale; more general negative affect; and more hypnagogic-like reveries after a 4-min eyes-closed resting period. Thus, subjects differing in their declared paranormal belief displayed different active, cerebral neural populations during resting, task-free conditions. As hypothesized, believers showed relatively higher right hemispheric activation and reduced hemispheric asymmetry of functional complexity. These markers may constitute the neurophysiological basis for paranormal and schizotypal ideation.     

Psychosoziale Anpassung bei chronischen Arthritiden

We sought to measure psychosocial adaptation in children and adolescents with different forms of chronic arthritis and to determine associated factors. Mothers of 68 children aged 8–17 years with juvenile idiopathic arthritis (JIA) or reactive arthritis reported behaviour problems (CBCL), children reported their actual stress level (SSK), functional disability in conducting activities of daily living (CHAQ) and health-related quality of life (HRQOL) including self-esteem (KINDL-R). Children and adolescents with JIA or reactive arthritis reported lower self-esteem compared to normative data. Almost 20% of the samples were reported to have serious behaviour problems, mostly social isolation and depression/anxiety. Children with lower HRQOL, more functional limitations and a higher stress level showed more behaviour problems. Self-esteem and behaviour problems may be relevant outcome measures in children and adolescents with chronic arthritis and useful to monitor psychosocial support in this population.     

Mood state and brain electric activity in ecstasy users

Resting EEG during open and closed eyes and subsequent mood ratings were obtained from 15 Ecstasy users and 14 Ecstasy-naive controls. Absolute spectral power on the scalp, and the three-dimensional, intracerebral distribution of neuroelectric activity using low resolution brain electromagnetic tomography (LORETA) were computed. LORETA revealed global increases of theta, alpha 1 and beta 2/3 power during eyes open in Ecstasy users, and spectral analyses revealed a right-posterior increase of alpha 2 power (confirmed by LORETA) and increased beta band activity during open eyes. Ecstasy users had higher levels of state depressiveness, emotional excitability and a trend-level increase in state anxiety. The observed differences may be related to regular exposure to Ecstasy or other illicit drugs, or may be pre-existing.