First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas-a single-centre experience in 61 patients.

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

[Severe respiratory insufficiency as manifestation of a pulmonary metastasized Ewing's sarcoma]. / Schwerste Atemnot als Manifestation eines pulmonal metastasierten Ewing-Sarkoms.

A previously unknown tumor led to respiratory failure due to pulmonary metastasis in a young male. The shortness of breath began gradually and then rapidly progressed within 2 weeks. With the cause of respiratory failure still unclear, extracorporeal membrane oxygenation (ECMO) treatment was initiated to gain time for the definitive diagnosis. After the exclusion of infectious lung diseases the diagnosis could be made by a biopsy. Surprisingly, a Ewing's sarcoma was diagnosed and chemotherapy was initiated. This led to tumor regression within about 3 weeks, so that the patient could be successfully weaned from ECMO treatment.

[Communication with Migrant Patients and their Parents in Inpatient General Pediatric Care]. / Verständigung mit Patienten und Eltern mit Migrationshintergrund in der stationären allgemeinpädiatrischen Versorgung.

OBJECTIVES: Depending on the ethnic background of patients, the quality of communication between the parents of pediatric patients and clinicians, as well as the type and frequency of interpreter services was studied in an inpatient setting. METHODS: As part of a questionnaire-based survey, data from parents, doctors and nurses with reference to 220 pediatric patients treated in the Department of Pediatrics at the University Hospital Leipzig from February to May 2013 were analyzed; 18,2% of patients were migrants. RESULTS: No differences were found in the assessment of the quality of communication with clinic staff by migrant and non-migrant parents. Physicians as well as nurses rated the communication with migrant parents compared to non-migrant parents significantly lower. In up to 19,2% (data provided by nursing staff) and 15,3% (data provided by doctors) of the cases characterized by insufficient language skills on the part of migrant parents, interpreter services had to be procured. No professional interpreters were used. CONCLUSION: The results highlight once more the difficulties in communication between clinicians and migrant patients with insufficient language skills. More attention should be paid to the impact of the use of professional interpreters in the health care services.

[Home Treatment]. / Home Treatment.

Home Treatment (HT) means acute psychiatric treatment in the patient's usual environment. Conceptually, HT is to be differentiated from other home-based services: It is limited with regard to duration and multiprofessional (e. g. psychiatrist plus psychiatric nursing staff plus social worker); the "24/7"-accessibility is frequently provided by the corresponding background hospital infrastructure. Target group are acutely mentally ill persons with an indication to inpatient treatment, who are willing to cooperate, and absence of endangerment to self and others. In contrast to the Scandinavian and many Anglophone countries where nationwide HT services are delivered, there are not many HT sites in Germany so far. Consequently, empirical data concerning HT in Germany is scarce. In summary, international studies show equivalent effects on psychopathological measures compared to inpatient treatment, reductions with regard to inpatient days, higher patient satisfaction and a trend towards cost-effectivity.

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro.

AIMS/HYPOTHESIS: In steroid diabetes insulin secretion does not adequately compensate for enhanced hepatic gluconeogenesis and peripheral insulin resistance. Previous studies suggest that activation of the transcription factor forkhead box O1 (FOXO1) contributes to glucocorticoid-induced beta cell death. This study examines the role and regulation of FOXO1 in insulin-secreting cells. METHODS: INS-1E cells and mouse islet cells were cultured in the presence of dexamethasone. Signalling pathways were modified pharmacologically or by small interfering (si)RNA-mediated inhibition of protein synthesis. Changes in protein abundance and phosphorylation were analysed by western blotting, and subcellular localisation was assessed using confocal microscopy. Transcript levels were examined by RT-PCR. RESULTS: Surprisingly, downregulation of FOXO1 by siRNA did not affect dexamethasone-induced apoptosis or Bim expression, but it prevented the effects of the pan protein kinase B (AKT) inhibitor (Akti-1/2). Indeed, dexamethasone and Akti-1/2 synergistically increased beta cell death and Bim expression. Akti-1/2 triggered dephosphorylation and nuclear translocation of FOXO1. Glucocorticoid-receptor activation stimulated Foxo1 transcription, but FOXO1 phosphorylation was unchanged and the cytosolic concentration of FOXO1 remained high in relation to its nuclear concentration. However, subcellular fractionation revealed a significant increase in both cytosolic and nuclear FOXO1 compared with untreated cells. Dexamethasone diminished Pdx1 mRNA level, an effect which was not reversed by siRNA against Foxo1. Downregulation of AKT isoforms and serum/glucocorticoid-regulated kinase 1 (SGK1) suggests that only sustained suppression of all three AKT isoforms caused dephosphorylation and nuclear accumulation of FOXO1. CONCLUSIONS/INTERPRETATION: This study reveals that FOXO1 is not the main mediator of glucocorticoid-receptor-induced beta cell apoptosis, but rather that it escalates beta cell death when AKT activity is inhibited by distinct pathways.

Functional inactivation but not structural mutation of p53 causes liver cancer.

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

ERPs reveal an iconic relation between sublexical phonology and affective meaning.

Classical linguistic theory assumes that formal aspects, like sound, are not internally related to the meaning of words. However, recent research suggests language might code affective meaning such as threat and alert sublexically. Positing affective phonological iconicity as a systematic organization principle of the German lexicon, we calculated sublexical affective values for sub-syllabic phonological word segments from a large-scale affective lexical German database by averaging valence and arousal ratings of all words any phonological segment appears in. We tested word stimuli with either consistent or inconsistent mappings between lexical affective meaning and sublexical affective values (negative-valence/high-arousal vs. neutral-valence/low-arousal) in an EEG visual-lexical-decision task. A mismatch between sublexical and lexical affective values elicited an increased N400 response. These results reveal that systematic affective phonological iconicity - extracted from the lexicon - impacts the extraction of lexical word meaning during reading.

Sunlight and skin cancer: inhibition of p53 mutations in UV-irradiated mouse skin by sunscreens.

UV-induced mutations in the p53 tumor suppressor gene play an essential role in skin cancer development. We report here that such mutations can be detected in UV-irradiated mouse skin months before the gross appearance of skin tumors. Application of SPF-15 sunscreens to mouse skin before each UV irradiation nearly abolished the frequency of p53 mutations. These results indicate that p53 mutation is an early event in UV skin carcinogenesis and that inhibition of this event may serve as an early end point for assessing protective measures against skin cancer development.

Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.

Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the host's immune system in controlling the devastating course of metastatic renal cell carcinoma. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a 'mixed response', and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens.

CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes.

Whereas CD40-CD40 ligand interactions are important for various dendritic cell (DC) functions in vitro, their in vivo relevance is unknown. We analyzed the DC status of CD40 ligand -/- mice using a contact hypersensitivity (CHS) model system that enables multiple functions of DCs to be assessed in vivo. Immunohistochemistry of skin sections revealed no differences in terms of numbers and morphology of dendritic epidermal Langerhans cells (LCs) in unsensitized CD40 ligand -/- mice as compared with wild-type C57BL/6 mice. However, after contact sensitization of CD40 ligand -/- mice, LCs failed to migrate out of the skin and substantially fewer DCs accumulated in draining lymph nodes (DLNs). Furthermore, very few antigen-bearing DCs could be detected in the paracortical region of lymph nodes draining sensitized skin. This defect in DC migration after hapten sensitization was associated with defective CHS responses and decreased cutaneous tumor necrosis factor (TNF)-alpha production and was corrected by injecting recombinant TNF-alpha or an agonistic anti-CD40 monoclonal antibody. Thus, CD40-CD40 ligand interactions in vivo regulate the migration of antigen-bearing DCs from the skin to DLNs via TNF-alpha production and play a vital role in the initiation of acquired T cell-mediated immunity.

E-/P-selectins and colon carcinoma metastasis: first in vivo evidence for their crucial role in a clinically relevant model of spontaneous metastasis formation in the lung.

BACKGROUND: Interactions of endothelial selectins with tumour cell glycoconjugates have been shown to have a major role in tumour cell dissemination in previous experiments. However, experiments validating this observation were limited in value, as 'metastases' in these experiments were artificially induced by i.v. injection rather than developed spontaneously as in true metastases. METHODS: Endothelial (E) and platelet (P)-selectin-deficient severe combined immunodeficient (scid) mice were generated and human HT 29 colon cancer cells were subcutaneously inoculated in these mice and in wild-type scid mice. Tumour growth, spontaneous metastasis formation in the lung and adherence of HT29 cells to E- and P-selectin under flow were determined. RESULTS: The number of metastases decreased by 84% in E- and P-selectin-deficient scid mice, compared with wild-type scid mice. The remaining 16% metastases in the E- and P-selectin-deficient scid mice grew within the pulmonary artery and not in the alveolar septae as they did in wild-type scid mice. Flow experiments indicate that tumour cells roll and tether on an E- and P-selectin matrix similar to leukocytes; however, firm adhesion is mainly mediated in E-selectin. CONCLUSION: Our results indicate that E- and P-selectins have a crucial role in spontaneous metastasis formation. As the human HT 29 colon cancer cells are positive for the lectin Helix pomatia agglutinin (HPA), which identified the metastatic phenotype in earlier clinical studies, these results are of particular clinical relevance.

Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors.

BACKGROUND: Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. MATERIALS AND METHODS: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors. RESULTS: Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected. CONCLUSIONS: Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.

Severe impaired respiratory ciliary function in Wegener granulomatosis.

OBJECTIVE: The pathogenesis of granulomatous inflammation in the respiratory tract and autoimmunity in Wegener granulomatosis (WG) are poorly understood. Since mucociliar clearance represents the first major line of defence in the respiratory tract and its breakdown facilitates chronic inflammation, we investigated ciliary beat frequency (CBF) in WG. METHODS: Nasal epithelial cells were obtained from 30 patients with WG with involvement of the upper respiratory tract, 12 patients with other inflammatory rheumatic disease and 10 healthy controls. CBF was measured at 5 and 24 h after collection. RESULTS: were correlated with clinical data. Results: CBF was significantly reduced in WG compared to disease and healthy controls after 5 and 24 h. In WG, CBF almost stagnated after 24 h. Reduction of CBF correlated with the cumulative number of immunosuppressive agents in WG, but not in disease controls. No correlation was found between CBF impairment and cyclophosphamide levels, disease extent, disease activity, disease duration, serological and microbiological findings, or inflammation markers. CONCLUSION: CBF is severely impaired in WG, potentially influenced by immunosuppressive treatment. To what extent CBF impairment and subsequent barrier dysfunction are caused by other factors still has to be elucidated. Supportive measures to improve mucociliary clearance should be discussed in patients with WG.

Borderline personality disorder: health service use and social functioning among a national household population.

BACKGROUND: It is unclear whether Axis II psychopathology or co-morbid clinical syndromes result in the treatment-seeking behaviour and social impairment of patients with borderline personality disorder (BPD). This study examined the independent associations between social functioning and service use and Axis I and Axis II disorders in persons with BPD in the national household population of Britain. METHOD: The study was a cross-sectional survey of adults aged 16-74 years in households (n=8397). Data included self-reported consultations with health-care professionals and behavioural problems. Diagnosis was determined by computer-assisted interviews. Analyses included logistic regression adjusting for demography, co-morbid Axis I clinical syndromes and other Axis II disorders. RESULTS: Consultation in the past year was reported by 57.5% of persons with BPD but only 13.4% reported lifetime psychiatric admission. BPD was not independently associated with impaired functioning but was associated with co-morbid psychotic, depressive and anxiety disorders. Only general practitioners (GPs) were consulted for problems independently due to BPD. CONCLUSIONS: Functional effects of BPD are mediated through co-morbid clinical syndromes, not Axis II psychopathology. A subgroup do not have co-morbid disorders or seek treatment, and are high functioning.

Adequate connexin-mediated coupling is required for proper insulin production.

To assess whether connexin (Cx) expression contributes to insulin secretion, we have investigated normal and tumoral insulin-producing cells for connexins, gap junctions, and coupling. We have found that the glucose-sensitive cells of pancreatic islets and of a rat insulinoma are functionally coupled by gap junctions made of Cx43. In contrast, cells of several lines secreting insulin abnormally do not express Cx43, gap junctions, and coupling. After correction of these defects by stable transfection of Cx43 cDNA, cells expressing modest levels of Cx43 and coupling, as observed in native beta-cells, showed an expression of the insulin gene and an insulin content that were markedly elevated, compared with those observed in both wild-type (uncoupled) cells and in transfected cells overexpressing Cx43. These findings indicate that adequate levels of Cx-mediated coupling are required for proper insulin production and storage.

Antigen-specific helper function of cell-free T cell products bearing TCR V beta 8 determinants.

Although the T cell receptor (TCR) alpha beta heterodimer and its encoding genes have been characterized, a cell-free form of this receptor, which is needed for the study of functional or ligand-binding properties of the receptor, has not previously been isolated. When the cell-free supernatant products of activated cloned T helper (TH) cells were found to mediate helper activity with antigen specificity identical to that of intact T cells, experiments were carried out to determine whether this functional activity was mediated by a cell-free form of TCR-related material. A disulfide-linked dimer indistinguishable from the T cell surface alpha beta heterodimer was precipitated from cell-free supernatants of cloned TH cells with F23.1, a monoclonal antibody specific for a TCR V beta 8 determinant. Moreover, when cell-free TH products were bound to and eluted from immobilized F23.1, these affinity-purified materials had antigen-specific and major histocompatibility complex-restricted helper activity that synergized with recombinant lymphokines in the generation of B cell antibody responses. These findings suggest that the factor isolated from T cell supernatants is a cell-free form of the TCR alpha beta dimer.

Virtual reality-based simulator for training in regional anaesthesia.

BACKGROUND: The safe performance of regional anaesthesia (RA) requires theoretical knowledge and good manual skills. Virtual reality (VR)-based simulators may offer trainees a safe environment to learn and practice different techniques. However, currently available VR simulators do not consider individual anatomy, which limits their use for realistic training. We have developed a VR-based simulator that can be used for individual anatomy and for different anatomical regions. METHODS: Individual data were obtained from magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) without contrast agent to represent morphology and the vascular system, respectively. For data handling, registration, and segmentation, an application based on the Medical Imaging Interaction Toolkit was developed. Suitable segmentation algorithms such as the fuzzy c-means clustering approach were integrated, and a hierarchical tree data structure was created to model the flexible anatomical structures of peripheral nerve cords. The simulator was implemented in the VR toolkit ViSTA using modules for collision detection, virtual humanoids, interaction, and visualization. A novel algorithm for electric impulse transmission is the core of the simulation. RESULTS: In a feasibility study, MRI morphology and MRA were acquired from five subjects for the inguinal region. From these sources, three-dimensional anatomical data sets were created and nerves modelled. The resolution obtained from both MRI and MRA was sufficient for realistic simulations. Our high-fidelity simulator application allows trainees to perform virtual peripheral nerve blocks based on these data sets and models. CONCLUSIONS: Subject-specific training of RA is supported in a virtual environment. We have adapted segmentation algorithms and developed a VR-based simulator for the inguinal region for use in training for different peripheral nerve blocks. In contrast to available VR-based simulators, our simulation offers anatomical variety.

MRI and FDG-PET in the assessment of inflammatory aortic arch syndrome in complicated courses of giant cell arteritis.

OBJECTIVES: To evaluate the use of MRI and FDG-PET for the diagnosis and measurement of disease activity of inflammatory aortic arch syndrome in patients with complicated giant cell arteritis. METHODS: MRI and FDG-PET were performed for 25 patients with giant cell arteritis who presented with a complicated disease course despite immunosuppressive therapy. Disease activity of the thoracic aorta and the supra-aortic arteries as assessed by both modalities was compared with serological (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical findings (Birmingham vasculitis activity score (BVAS.2)). Additionally, the usefulness of MRI for assessment of vessel wall thickening, aneurysms and stenoses was evaluated. RESULTS: In 17/25 patients, MRI disclosed structural vessel lesions suspicious for vasculitis. Active disease was detected by MRI, thoracic PET, and whole body PET in 22, 14 and 20 patients, respectively. While serological and clinical findings correlated significantly with each other, there was no concordance with MRI and only low, non-significant correlation of PET with CRP (r(s) = -0.158, 0.136), ESR (r(s) = -0.232, 0.320) and BVAS.2 (r(s) = -0.064, 0.221) for disease activity. CONCLUSIONS: MRI and PET are unreliable for assessing large-vessel inflammation in patients with giant cell arteritis and pre-existing immunosuppressive therapy. MRI is valuable for its ability to detect morphological vessel lesions, such as aneurysms and stenoses.

The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study.

BACKGROUND: Recent research has convincingly shown that the ability to work mainly depends on the cognitive status in multiple sclerosis (MS). An international committee of experts recommended a brief neuropsychological battery to evaluate cognitive performance in MS. BICAMS comprises three tests, the Symbol Digit Modalities Test (SDMT), the learning trials of the California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). OBJECTIVE: To validate BICAMS on a sample of German MS patients and healthy controls (HCs). METHODS: According to the international guidelines for validation, examiner's instructions were standardized and translated into German. Due to the availability of better normative data for future applications in routine clinical care and classification of individual performance degree, the Rey Auditory Verbal Learning Test (RAVLT) (German version: Verbaler Lern- und Merkfähigkeits-Test, VLMT) was chosen instead of CVLT-II. 172 MS patients and 100 HCs entered the study. BICAMS was administered at baseline and retest (after 3-4 weeks). RESULTS: The groups did not differ in age, gender or education. Mean age of MS patients was 43.33 years (SD 11.64); 68% were female and 86.9% had relapsing-remitting MS. Patients performed significantly worse than HCs on the SDMT (p < 0.01) and on BVMT-R (p < 0.05) but not on VLMT. In addition, BICAMS was shown to be reliable over time: r = 0.71 for BVMT-R, r = 0.72 for VLMT and r = 0.85 for SDMT. SDMT z-score proved to be a good predictor for the ability to work in a full-time (p < 0.001) as well as in a part-time job (p < 0.001). VLMT z-score turned out to be a significant predictor only for the ability to work in a part-time job, while BVMT-R z-score showed no significant predictive value. CONCLUSION: In this German validation study with the VLMT, the modified BICAMS (BICAMS-M) turned out to reliably detect cognitive problems in MS patients and to monitor cognitive performance over time. SDMT revealed the best predictive value for working ability. Moreover, only the SDMT was able to predict the ability to work in a part-time or full-time job. Following these results, application of the SDMT is recommended for medical statements on working ability of MS patients.