Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus.

Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell-targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell-suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.

Candida in the Respiratory Tract Potentially Triggers Galactomannan Positivity in Nonhematological Patients.

BAL fluid samples from critically ill patients shared a rate of 29% false-positive galactomannan results. We aimed to determine whether Candida species abundance in BAL fluid causes galactomannan (GM) positivity. A total of 89 Candida culture-positive BAL fluid samples from patients without suspicion of invasive aspergillosis (IA) were analyzed. GM results were correlated with Candida species abundance, Candida species quantity, and patient data. Candida species quantities of ≥104/ml and Candida glabrata abundance were significantly associated with positive GM results. The added diagnostic value of GM in BAL fluid for diagnosing IA in critically ill patients is limited.

A prospective international Aspergillus terreus survey: an EFISG, ISHAM and ECMM joint study.

OBJECTIVES: A prospective international multicentre surveillance study was conducted to investigate the prevalence and amphotericin B susceptibility of Aspergillus terreus species complex infections. METHODS: A total of 370 cases from 21 countries were evaluated. RESULTS: The overall prevalence of A. terreus species complex among the investigated patients with mould-positive cultures was 5.2% (370/7116). Amphotericin B MICs ranged from 0.125 to 32 mg/L, (median 8 mg/L). CONCLUSIONS: Aspergillus terreus species complex infections cause a wide spectrum of aspergillosis and the majority of cryptic species display high amphotericin B MICs.

Psychopathology among parents of children and adolescents with separation anxiety disorder.

OBJECTIVE: To examine psychopathology among parents of children and adolescents with separation anxiety disorder (SAD). METHOD: A case-control design was applied: parents of children and adolescents suffering from SAD (n = 30; age: 10.7 ± 1.8 a) were compared with parents of youth without any psychiatric disease (n = 30; age: 11.2 ± 1.8 a). The SCID-I, a structured clinical interview to assess psychopathology, was applied among the parents group. RESULTS: Parents of children and adolescents suffering from SAD exhibited a significantly higher prevalence of psychopathology, mainly anxiety disorders and mood disorders, in comparison with the control group. Within anxiety disorders, mothers predominantly suffered from social phobia and specific phobia. Fathers most frequently suffered from obsessive-compulsive disorder and social phobia. Maternal anxiety disorder (current and lifetime) and maternal affective disorder (lifetime) proved to be significant predictors of SAD in youth. CONCLUSIONS: The associations between parents' psychopathology and the development of SAD in their children are discussed in the light of clinical implications, both in terms of psychotherapeutic care as well as treatment outcome.

Psychosis in neurosyphilis -- clinical aspects and implications.

BACKGROUND: The World Health Organization estimates that 10-12 million new syphilis infections occur each year. Without treatment, years to decades after initial infection, 30% of affected individuals may develop tertiary syphilis, which can manifest as neurosyphilis. The aim of this review is to evaluate the research literature examining the psychopathological manifestations of psychosis in association with neurosyphilis. METHOD: The authors performed a systematic electronic search for published studies (1995-2012). The following databases were used: Medline, Embase and the Cochrane Library as well as the search engines Scopus and Google Scholar. RESULTS: 61 articles were used for detailed analysis. Psychotic symptoms due to neurosyphilis are numerous and can inform differential diagnosis for many psychotic manifestations according to ICD-10 or DSM-IV. CONCLUSION: Due to our results, current epidemiological data, and the difficulties in differential diagnosis of neurosyphilis, routine screening tests are still recommended in the psychiatric field. Long-term psychiatric input, with periodic syphilis titre controls, seems indicated in individuals affected by neurosyphilis with psychiatric symptoms. Furthermore, individuals with mental health problems may be at higher risk of acquiring syphilis.

T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct.

Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N=23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E:T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E:T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.

[Efficacy of antipsychotic augmentation therapy in treatment-resistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomised, placebo-controlled trials]. / Effektivität einer Augmentationstherapie mit Antipsychotika bei therapieresistenten Zwangsstörungen - eine Metaanalyse doppelblinder, randomisierter, placebokontrollierter Studien.

Only 40 - 60 % of all patients with obsessive-compulsive disorder (OCD) respond to serotonin reuptake inhibitors (SRIs). Therefore, the evaluation of additive treatment in the presence of treatment resistance has high clinical relevance. All double-blind, randomised, placebo-controlled trials that evaluated the efficacy of a combination therapy of SRIs and antipsychotics in treatment-resistant OCD were identified by systematic literature searches and combined in a meta-analysis. 11 studies with a total of 356 treatment-resistant patients were included. After the augmentation, significantly more subjects in the intervention groups (SRI + antipsychotic) fulfilled the response criterion (reduction in the Yale-Brown obsessive compulsive scale [Y-BOCS] ≥ 35 %) than in the control groups (SRI + placebo) (relative risk = 2.16). The subgroup analysis showed significant efficacy only for risperidone. Further significant differences have been found regarding the antipsychotic dosage and the SRI-treatment duration before the augmentation.

Anidulafungin for the treatment of invasive candidiasis.

Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide, with a particularly strong impact and high incidence in the intensive-care unit, where there is a need for new treatment options and strategies. The echinocandin anidulafungin has broad in vitro activity against a wide range of Candida species, along with favourable pharmacokinetics that allow administration in hepatic and renal impairment and with any comedication without the need for dose adjustments. The efficacy and safety of anidulafungin for the treatment of C/IC were demonstrated in a number of clinical studies and by some limited data from clinical practice. In a randomized comparative trial for the treatment of C/IC in adults, 76% of patients receiving anidulafungin and 60% of those given fluconazole were treated successfully (95% CI for difference: 4-27; p 0.01). Post hoc analyses suggest that anidulafungin is significantly more effective than standard-dose fluconazole for the treatment of candidaemia in critically ill patients. Anidulafungin is generally well tolerated, with commonly reported side effects including headache, hypokalaemia, gastrointestinal symptoms, abnormal liver function test results, and rash. In pharmaco-economic analyses, anidulafungin compared favourably with fluconazole (in terms of overall costs and hospital resource use) as well as with other echinocandins. Echinocandins, including anidulafungin, are now generally recommended as first-line therapy in moderately to severely ill patients, those with prior azole exposure, and patients with C/IC caused by Candida glabrata or Candida krusei.

Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain.

BACKGROUND AND AIMS: Liver metastases are the leading cause of death in colorectal cancer. To gain better insight into the biology of metastasis and possibly identify new therapeutic targets we systematically investigated liver-metastasis-specific molecular aberrations. METHODS: Primary colorectal cancer (pCRC) and matched liver metastases (LMs) from the same patients were analysed by microarray-based comparative genomic hybridisation in 21 pairs and gene expression profiling in 18 pairs. Publicly available databases were used to confirm findings in independent datasets. RESULTS: Chromosome aberration patterns and expression profiles of pCRC and matched LMs were strikingly similar. Unsupervised cluster analysis of genomic data showed that 20/21 pairs were more similar to each other than to any other analysed tumour. A median of only 11 aberrations per patient was found to be different between pCRC and LM, and expression of only 16 genes was overall changed upon metastasis. One region on chromosome band 11p15.5 showed a characteristic gain in LMs in 6/21 patients. This gain could be confirmed in an independent dataset of LMs (n=50). Localised within this region, the growth factor IGF2 (p=0.003) and the intestinal stem cell specific transcription factor ASCL2 (p=0.029) were found to be over-expressed in affected LM. Several ASCL2 target genes were upregulated in this subgroup of LM, including the intestinal stem cell marker OLFM4 (p=0.013). The correlation between ASCL2 expression and four known direct transcriptional targets (LGR5, EPHB3, ETS2 and SOX9) could be confirmed in an independent expression dataset (n=50). CONCLUSIONS: With unprecedented resolution a striking conservation of genomic alterations was demonstrated in liver metastases, suggesting that metastasis typically occurs after the pCRC has fully matured. In addition, we characterised a subset of liver metastases with an ASCL2-related stem-cell signature likely to affect metastatic behaviour of tumour cells.

Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse.

BACKGROUND: ALCAM (activated leucocyte cell adhesion molecule, synonym CD166) is a cell adhesion molecule, which belongs to the Ig superfamily. Disruption of the ALCAM-mediated adhesiveness by proteolytic sheddases such as ADAM17 has been suggested to have a relevant impact on tumour invasion. Although the expression of ALCAM is a valuable prognostic and predictive marker in several types of epithelial tumours, its role as a prognostic marker in pancreatic cancer has not yet been reported. METHODS: In this study, paraffin-embedded samples of 97 patients with pancreatic cancer undergoing potentially curative resection were immunostained against ALCAM, ADAM17 and CK19. Expression of ALCAM and ADAM17 was semiquantitatively evaluated and correlated to clinical and histopathological parameters. RESULTS: We could show that in normal pancreatic tissue, ALCAM is predominantly expressed at the cellular membrane, whereas in pancreatic tumour cells, it is mainly localised in the cytoplasm. In addition, univariate and multivariate analyses show that increased expression of ALCAM is an adverse prognostic factor for recurrence-free and overall survival. Overexpression of ADAM17 in pancreatic cancer, however, failed to be a significant prognostic marker and was not coexpressed with ALCAM. CONCLUSIONS: Our findings support the hypothesis that the disruption of ALCAM-mediated adhesiveness is a relevant step in pancreatic cancer progression. Moreover, ALCAM overexpression is a relevant independent prognostic marker for poor survival and early tumour relapse in pancreatic cancer.

In situ analysis of the antigen-processing machinery in acute myeloid leukaemic blasts by tissue microarray.

Altered expression of major histocompatibility complex (MHC) class I molecules can be caused by defects in genes of the antigen-processing machinery (APM), and is often correlated to progression in solid tumours. However, little is known about expression of the APM components in blasts from patients with acute myeloid leukaemia (AML). In this study, we investigated the expression of the APM components large multifunctional peptidases (LMP) 2 and 7, transporter-associated with antigen processing (TAP) 1 and 2, beta-2-microglobulin (beta2m) and MHC class I heavy chain in situ by tissue microarray from bone marrow biopsies of 30 AML patients. APM components were heterogeneously expressed in all AML samples tested, but no significant correlation with the AML subtype according to the French-American-British classification was found. Depending on the APM component tested, up to 90% of the trephines showed no or weak expression, whereas the LMP7 protein was detected in 66% of all samples. By following disease progression in individual AML patients, we found severe downregulation of APM components in two out of four patients from initial diagnosis to relapse. We conclude that downregulation of APM components may play a role in the failure of immuno-surveillance and may therefore contribute to relapse in acute leukaemia.

How depressive symptoms correlate with stigma perception of mental illness.

INTRODUCTION: The aim of this study was to survey the attitudes of 115 patients with the diagnosis of somatoform pain disorder, toward anticipated discrimination and mental illness stigma and how it is influenced by depressive symptoms. METHOD: 115 consecutive in- and outpatients with somatoform pain disorder (mean age: 50 +/- 11 years; 62% female) from the Department of Psychiatry and Psychotherapy, Medical University of Vienna, were administered a modified 12-item version of Link's Perceived Stigma Questionnaire and the Beck Depression Inventory. RESULTS: With regard to close personal relationships, such as taking care of children or dating, somatoform pain patients showed a rather high perceived stigma score (over 70% for both items). Also nearly 70% think that 'most employers' would pass over the application of a psychiatric patient in favour of another applicant. The overall results show a significant correlation with depressive symptoms (r = 0.228 and p = 0.014). CONCLUSION: Fear of stigma increases with depressive symptoms and both are a risk for treatment delay. The goal of future research should be the question how to reduce subjective stigma experiences of the patients affected in order to help them enter psychiatric treatment early and gain self-confidence and mental health back again.

The stigma of mental illness: anticipation and attitudes among patients with epileptic, dissociative or somatoform pain disorder.

The aim of this study was to survey the attitudes of 101 consecutive in- and out-patients with epileptic, dissociative or somatoform pain disorders (mean age: 43 [+/-11] years; 58% female) from either the Department of Psychiatry or Neurology toward anticipated mental illness stigma. The patients were administered a modified 12-item version of Links Stigma Questionnaire. Nearly 60% of all 101 patients believe that "most people" would not allow a mental patient "to take care of their children", "most young women" would be "reluctant to date a man" who has been treated for a mental illness and "most employers would pass over" the application of a psychiatric patient in favour of another applicant. Fifty five percent of the respondents assume that "most people think less of a person who has been in a mental hospital" and over a half of all patients interviewed assert that the general population thinks that psychiatric patients are "less intelligent, less trustworthy and that their opinion is taken less seriously by others". Gender, age and education had no influence on the overall results. There is a high stigmatisation concerning psychiatry even in patients with epilepsy and somatoform/dissociative symptoms with psychiatric comorbidity. Fear of being stigmatized is more pronounced among somatoform pain patients as compared to patients suffering from epileptic or dissocative disorders, with particular reference to close personal relationships.

[Chemoprevention of breast cancer: a literature review and report on the current status in Germany]. / Medikamentöse Prävention des Mammakarzinoms: eine Ubersicht über die Literatur und den Stand in Deutschland.

The prevention of breast cancer is increasingly of focus in health-politics policies and has gained a valid position in the area of medical intervention. Data from a current meta-analysis of all four randomised Tamoxifen prevention studies illustrate a reduction of 38 % (Odds ratio 0.62; 95 % CI 0.42-0.89) in the incidence of breast cancer. This observation lead to registration of this drug in the USA for the prevention of breast cancer in women with a calculated 5-year risk of > 1.66 %. In addition to Tamoxifen, further substances are currently being tested with the aim of improving the therapeutic index whilst reducing incidence and mortality rates. These are primarily substances which have proven efficacy in the treatment of breast cancer (other antioestrogens, aromatase inhibitors and GnRH-analogues) or those whose mechanism of action predict a preventative effect (retinoids, phytooestrogens, substitution preparations e. g. Tibolone). In Germany, chemoprevention is currently only to be recommended within study protocols, as to date no substance is approved in the indication 'prevention of breast cancer'. A essential contribution to the accrual of valid data is the conduct of breast cancer prevention trials. The participation of women with high risk of breast cancer in Germany is, in contrast to comparable international studies, problematic. Data on the current knowledge and attitude of the female population towards such trials (gathered via a questionnaire of the DACH in 7 000 women) show that only 19.5 % of the women questioned during a consultation with a gynaecologist were aware of the possibility of active chemoprevention. However, 55.3 % stated that they would be prepared to take such a substance, were chemoprevention possible. Studies for both pre- and post-menopausal women with increased risk of breast cancer are currently active in Germany (GISS and IBIS-II of the study group GABG - German Adjuvant Breast cancer Group). An intensive information campaign to raise public awareness of breast cancer risk amongst women and their physicians is planned in conjunction with the IBIS-II study (www.brustkrebsvorbeugen.de). Latest literature recommendations for prevention of breast cancer (Chlebowski et al.) have been assessed.

Invasive intrauterine treatment of pulmonary atresia/intact ventricular septum with heart failure.

The mortality and morbidity of children with pulmonary atresia/intact ventricular septum (PA/IVS) are linked to the degree of right ventricular (RV) hypoplasia. Opening up the pulmonary valve (PV) in fetal life could result in improved growth of the RV making it amenable to biventricular repair postnatally. Successful valvulotomy of the PV was performed in a fetus with heart failure at 28 weeks. Following the procedure there was significant growth of the tricuspid valve and RV. The neonate was delivered at 38 weeks with a RV suitable for biventricular repair. In utero pulmonary valvulotomy is feasible and may change the natural history of the condition in affected fetuses with PA/IVS.

Characterizing voltage-dependent Ca(2+) channels coupled to VIP release and NO synthesis in enteric synaptosomes.

In enteric synaptosomes of the rat, the role of voltage-dependent Ca(2+) channels in K(+)-induced VIP release and nitric oxide (NO) synthesis was investigated. Basal VIP release was 39 +/- 4 pg/mg, and cofactor-substituted NO synthase activity was 7.0 +/- 0.8 fmol. mg(-1). min(-1). K(+) depolarization (65 mM) stimulated VIP release Ca(2+) dependently (basal, 100%; K(+), 172.2 +/- 16.2%; P < 0.05, n = 5). K(+)-stimulated VIP release was reduced by blockers of the P-type (omega-agatoxin-IVA, 3 x 10(-8) M) and N-type (omega-conotoxin-GVIA, 10(-6) M) Ca(2+) channels by ~50 and 25%, respectively, but not by blockers of the L-type (isradipine, 10(-8) M), Q-type (omega-conotoxin-MVIIC, 10(-6) M), or T-type (Ni(2+), 10(-6) M) Ca(2+) channels. In contrast, NO synthesis was suppressed by omega-agatoxin-IVA, omega-conotoxin-GVIA, and isradipine by ~79, 70, and 70%, respectively, whereas Ni(2+) and omega-conotoxin-MVIIC had no effect. These findings are suggestive of a coupling of depolarization-induced VIP release primarily to the P- and N-type Ca(2+) channels, whereas NO synthesis is presumably dependent on Ca(2+) influx not only via the P- and N- but also via the L-type Ca(2+) channel. In contrast, none of the Ca(2+) channel blockers affected VIP release evoked by exogenous NO, suggesting that NO induces VIP secretion by a different mechanism, presumably involving intracellular Ca(2+) stores.

[Real time 3D sonography of the normal fetal heart--clinical evaluation]. / Klinische Evaluierung der Realtime-3D-Sonographie beim normalen fetalen Herzen.

AIM: Aim of the study was to determine the clinical feasibility of real time 3D ultrasound in the examination of the normal fetal heart compared to conventional 2D fetal echocardiography. METHOD: Twenty fetuses with normal hearts at 20 to 38 weeks of gestation underwent real time 3D ultrasound. Examination data were stored on an external notebook. Later analysis and interpretation was done by a different sonographer using a special software. RESULTS: In the assessment of the four chamber view and the out flow tracts real time 3D ultrasound was equivalent to conventional ultrasound. Advantages of realtime 3D ultrasound were the possibility of later time-independent off-line analysis and post-processing of volume data and generation of new views not available in 2D imaging. Disadvantages included low frame rate (16 frames/s), low lateral resolution and the lack of Doppler and colour information. CONCLUSION: Simultaneous display of 3 different views of the fetal heart as well as the construction of spatial perspectives ("new views") provide additional useful information to conventional fetal echocardiography. Later off-line analysis of 3D volume data can be used for sequential analysis of the normal fetal heart with good diagnostic results. Currently it remains unclear whether this new method may provide additional important information in the assessment of fetal congenital heart defects.

Alexithymia in DSM-IV disorder: comparative evaluation of somatoform disorder, panic disorder, obsessive-compulsive disorder, and depression.

The purpose of this study was a direct comparative evaluation of alexithymia in patients with somatoform disorder, panic disorder, obsessive-compulsive disorder, and depression, taking into account the multidimensionality of the alexithymia construct. The authors administered the Structured Clinical Interview for DSM-IV (SCID) and the Toronto Alexithymia Scale (TAS-20) to a sample of 234 subjects. Panic disorder, but no other diagnosis, was significantly related to lower TAS-20 total scores (P=0.000). Regarding TAS-20 subfactors, Factor 1 was significantly associated with somatoform disorder (P=0.006) and depression (P=0.002), Factor 2 was significantly associated with depression (P=0.025), and Factor 3 was significantly associated with obsessive-compulsive disorder (P=0.001), whereas panic disorder showed a significant negative correlation with Factor 3 (P=0.001). The relationships of the three subfactors with various DSM-IV diagnoses and sociodemographic variables emphasize the multidimensionality of alexithymia.

Clinical validity of ICD-10 neurasthenia.

BACKGROUND: Neurasthenia was defined over a century ago. In view of a questionable clinical validity, it was omitted from the 3rd edition of the American Psychiatric Association's DSM, while it remains as an own diagnostic category in the WHO's ICD-10. The purpose of this study was, therefore, to examine the clinical validity of ICD-10 neurasthenia in a consecutive sample of chronic pain patients. PATIENTS AND METHODS: We included 193 patients (mean age 45.1, SD +/- 10.2, 63% females) in the study. Psychiatric diagnoses were established by the use of ICD-10 Diagnostic Criteria for Research. In addition, the Screening List for Somatization Symptoms was administered: self-rating of 53 medically unexplained somatic symptoms, and 11 additional screening questions concerning weakness after slight mental or physical exertion and disease conviction. RESULTS: Thirty-three percent of the patients who fulfilled the criteria of ICD-10 neurasthenia also fulfilled the criteria of ICD-10 somatization disorder, 69% the criteria of ICD-10 undifferentiated somatoform disorder, 14% the criteria of ICD-10 hypochondriacal disorder, 66% the criteria of ICD-10 somatoform autonomic dysfunction, 85% the criteria of ICD-10 persistent somatoform pain disorder and 14% the criteria for sexual dysfunction not caused by organic disorder or disease. The symptom profile of ICD-10 neurasthenia was not clearly distinguishable from the symptom profiles of ICD-10 somatoform disorders and ICD-10 sexual dysfunction. DISCUSSION: Due to this substantial diagnostic overlap, the clinical validity of ICD-10 neurasthenia remains questionable.