[Implementation of the principle of supported employment in Germany : Position paper of a task force of the DGPPN]. / Umsetzung der Prinzipien des Supported Employment in Deutschland : Positionspapier einer Task-Force der DGPPN.

The effects of mental diseases on the employment and working situation can be substantial. They are one of the main reasons for inability to work and reduced earning capacity. Against this background the question arises about suitable occupational reintegration measures for people with severe mental illnesses. In recent years, the principle of supported employment has been internationally shown to be increasingly more successful. In this context mentally ill people are primarily placed at a position of the first employment market and supported on-site by a job coach. This concept is inclusive, individual and evidence based. Despite proven effectiveness, it has so far been insufficiently implemented in German-speaking regions. In the future it will be a matter of considering the individual needs for assistance of mentally ill people more intensively than previously and to respond with functional and in a best-case scenario, multiprofessional and flexible offers.

Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII.

INTRODUCTION: Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with 177Lu as an agent for RIT. METHODS: 6A10 Fab fragment was modified and radiolabelled with 177Lu and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts. RESULTS: The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy. CONCLUSION: The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab.

[Standards for treatment in forensic committment according to § 63 and § 64 of the German criminal code : Interdisciplinary task force of the DGPPN]. / Standards für die Behandlung im Maßregelvollzug nach §§ 63 und 64 StGB : Interdisziplinäre Task-Force der DGPPN.

People who have been convicted of a crime due to a severe mental disorder and continue to be dangerous as a result of this disorder may be placed in a forensic psychiatric facility for improvement and safeguarding according to § 63 and § 64 of the German Criminal Code (StGB). In Germany, approximately 9000 patients are treated in clinics for forensic psychiatry and psychotherapy on the basis of § 63 of the StGB and in withdrawal centers on the basis of § 64 StGB. The laws for treatment of patients in forensic commitment are passed by the individual States, with the result that even the basic conditions differ in the individual States. While minimum requirements have already been published for the preparation of expert opinions on liability and legal prognosis, consensus standards for the treatment in forensic psychiatry have not yet been published. Against this background, in 2014 the German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology (DGPPN) commissioned an interdisciplinary task force to develop professional standards for treatment in forensic psychiatry. Legal, ethical, structural, therapeutic and prognostic standards for forensic psychiatric treatment should be described according to the current state of science. After 3 years of work the results of the interdisciplinary working group were presented in early 2017 and approved by the board of the DGPPN. The standards for the treatment in the forensic psychiatric commitment aim to initiate a discussion in order to standardize the treatment conditions and to establish evidence-based recommendations.

[DGPPN recommendations on quality indicators for schizophrenia]. / Aktuelle Empfehlungen der DGPPN für Schizophrenie-Qualitätsindikatoren.

BACKGROUND: In Germany, several quality indicators have been proposed for the measurement of quality of mental healthcare. Some of these quality indicators have been tested in feasibility studies. The German Association for Psychiatry and Psychotherapy (DGPPN) established the "Task Force Quality Indicators (QI)" that, based on previous experience in the development and pilot testing of indicators, considered the further development and practical realization of QI for schizophrenia. AIM: The aim was to select a set of QI for schizophrenia that can also be applied to other diagnoses or used in generic measurements. Another goal was to focus on high feasibility of indicators. METHODS: In a multistage selection process, the DGPPN Task Force selected QI that focus on essential quality aspects from an inventory of 161 existing QI developed by national and international research groups. Indicators were adapted in consultation with the "trialogic forum" of the DGPPN. RESULTS: The DGPPN proposes the following ten indicators for quality measurement in mental healthcare for schizophrenia: QI1 Long-term treatment/Monitoring of side effects, QI2 Seclusion and restraint, QI3 Number of suicides, QI4 Psychoeducational-oriented intervention for significant others, QI5 Timely beginning of outpatient treatment after discharge from inpatient treatment, QI6 Aggression management - inpatient treatment, QI7 Diagnostic procedures/Physical examination, QI8 Antipsychotic polypharmacy, QI9 Rehabilitation/Vocational rehabilitation, QI10 Diagnostic procedures/Psychosocial functioning. DISCUSSION: Most of our proposed QI have to be measured by means of additional data documentation. Based on prior experience in the pilot testing of QI, the DGPPN estimates that the additional efforts in data documentation would be manageable, but have to be refinanced. The indicators will be tested in feasibility studies in different mental healthcare hospitals in Germany.

[Innovations in biomarker development: a pathway towards individualized cancer therapy?]. / Moderne Methoden der Biomarkerentwicklung: eine Chance für die individualisierte Tumortherapie?

Despite multiple medical and scientific achievements, cancer remains a leading cause of death worldwide. Next to imaging technologies, molecular methods for early detection and for monitoring of the course of disease are of increasing interest. Thus, over the past years numerous studies have focused on the identification of biomarkers for cancer diagnosis, prognosis and response to therapy. The study of biomarkers seems to pose a high degree of complexity because many different types of molecules may, in principle, serve as potential biomarkers. In addition, these molecules can be produced either by the tumor or by the tumor-host in response to the presence of cancer. In this review the authors will address several major topics encompassed by the field of biomarker research. They will discuss the primary sources from which biomarker candidates can be 'mined' as well as the technological or methodological challenges associated with identification of biomarkers. Furthermore, the review will focus on current biomarker candidates for head and neck squamous cell carcinoma (HNSCC), with particular interest on several molecules yielding potential relevance for detection and prognosis of this type of cancer. Finally, several biomarker candidates with predictive potential for the response to therapy of HNSCC patients will be discussed, since identifying such molecules is crucial for developing individually-tailored and improved therapeutic strategies.

[Diagnostic and prognostic biomarkers in head and neck squamous cell carcinoma]. / Tumormarker und Prognosefaktoren bei Plattenepithelkarzinomen der Kopf-Hals-Region.

Classical prognostic factors for squamous cell carcinoma of the head and neck (HNSCC) are based on general parameters such as tumor stage or histological grading and only allow for a rough estimation of the clinical course. However, predicting individual responses to treatment remains challenging and diverging clinical courses of same-stage HNSCC stage remain obscure. The need for a better understanding of the individual genomic or proteomic signature of HNSCC resulted in a great number of publications on novel biomarkers. Still, in most cancer centres therapy planning and risk appraisal are solely based on the classical factors with only a few exceptions such as HPV status in oropharyngeal carcinoma. Future improvements in biomarker research will probably be achieved with sets of various genomic and proteomic markers as provided by microarray technology. This review highlights the criteria for a successful biomarker candidate, gives an overview on the most important new biomarkers, and introduces the principles of genomic and proteomic biomarker chips.

COX-inhibitors relieve the immunosuppressive effect of tumor cells and improve functions of immune effectors.

A common phenomenon in cancer patients is a suppressed cell-mediated immunity, characterized by the inability of immune effector cells to mount efficient anti-tumor responses. Immunosuppressive factors, released by the tumor, contribute to this phenomenon and thus to tolerance. Prostaglandins, catalyzed by the cyclooxygenases (COX-1 and COX-2) from arachidonic acid, are one class of these factors. Since at least one of the COX enzymes is often expressed at high level in human cancers, the enzymes were ascribed a causal role in tumor etiology and progression. Non-steroidal antiinflammatory drugs (NSAIDs) like aspirin, which block COX activity, have demonstrated their antitumor effects in preclinical and clinical trials. Pro-apoptotic and anti-angiogenic effects in tumor cells may account for this activity. In addition, by inhibiting the release of prostaglandins from the tumor and by blocking COX activity in immune effector cells, NSAIDs may also bias the function of immune cells towards a more tumoricidal phenotype. We show here that tumor cells inhibit the physiological function of immune cells, and that NSAIDs restore this function. These data contribute to an understanding of the antineoplastic effect ascribed to NSAIDs and support the prophylactic use of these drugs in high-risk patients.

Genetic design of an optimized packaging cell line for gene vectors transducing human B cells.

Viral gene vectors often rely on packaging cell lines, which provide the necessary factors in trans for the formation of virus-like particles. Previously, we reported on a first-generation packaging cell line for gene vectors, which are based on the B-lymphotropic Epstein-Barr virus (EBV), a human gamma-herpesvirus. This 293HEK-derived packaging cell line harbors a helper virus genome with a genetic modification that prevents the release of helper virions, but efficiently packages vector plasmids into virus-like particles with transducing capacity for human B cells. Here, we extended this basic approach towards a non-transforming, virus-free packaging cell line, which harbors an EBV helper virus genome with seven genetic alterations. In addition, we constructed a novel gene vector plasmid, which is devoid of a prokaryotic antibiotic resistance gene, and thus more suitable for in vivo applications in human gene therapy. We demonstrate in this paper that EBV-based gene vectors can be efficiently generated with this much-improved packaging cell line to provide helper virus-free gene vector stocks with transducing capacity for established human B-cell lines and primary B cells.

Profile identification of disease-associated humoral antigens using AMIDA, a novel proteomics-based technology.

We describe AMIDA (autoantibody-mediated identification of antigens), a novel target identification technology based on the immunoprecipitation of disease-specific antigens by autologous serum antibodies followed by two-dimensional electrophoretic separation, and their identification via mass spectrometry. Twenty-seven potential carcinoma antigens were identified including proteins of hitherto unknown function. Validation of one of the identified antigens, cytokeratin 8, revealed its de novo expression in hyperplastic tissue, gradual overexpression with increasing malignancy, and ectopic localization on the cell surface. Furthermore, a strong prevalence of CK8-specific antibodies occurred in the serum of cancer patients already at early disease stages. In situ hybridization for one marker of unknown function, KIAA1273/TOB3, demonstrated its strong overexpression in head and neck carcinomas, thus making it a likely tumor antigen candidate. Eventually, AMIDA could foster significant improvements for the diagnosis and therapy of human diseases eliciting a humoral immune response, and allows for the rapid identification of new target molecules.

Immune restoration in head and neck cancer patients via cyclooxygenase inhibition: an update.

Most carcinomas overexpress cyclooxygenase, especially COX-2, thus secreting large amounts of immunosuppressive prostaglandins. Epidemiological data and animal models have provided evidence that inhibition of cyclooxygenase and thus prostaglandin E2 synthesis via non-steroid antiinflammatory drugs (NSAIDs) inhibits tumor growth in vitro and in vivo. Moreover, it could be demonstrated that chemoprevention, i.e. the long-term use of NSAIDs, significantly reduced the risk of developing certain types of cancer. However, the molecular mechanisms underlying these antineoplastic effects are not entirely understood. This review focuses on prostaglandin-mediated immunosuppressive mechanisms in head and neck cancer and presents immunorestorative strategies via cyclooxygenase inhibition in vitro and in vivo with special emphasis on COX-2. A better understanding of the interaction of tumors with the immune system and how the process of carcinogenesis can be antagonized by selectively modulating the activity of specific enzymes such as COX-2 will provide the rationale for the use of NSAIDs for chemoprevention or immunoadjuvant cancer therapies.

[Giant Madelung's disease. Report of a case and review of the literature]. / Der Madelung-Fetthals. Aktuelle Diagnostik und Therapie.

Madelung's disease, also known as benign symmetrical lipomatosis, is a rare proliferative disorder of unknown etiology that was first mentioned by Brodie in 1846. Characterized by multiple symmetrical deposits of unencapsulated fat in the head and neck region, the disease is most common in middle-aged men with a history of alcohol abuse. The only effective therapy in cases of dyspnea and dysphagia, indicating the necessity of treatment, is the surgical resection of the adipose tissue. The authors report on the evaluation and therapy in a case of giant Madelung's disease.

Tumor necrosis factor alpha negatively regulates the expression of the carcinoma-associated antigen epithelial cell adhesion molecule.

BACKGROUND: The epithelial cell adhesion molecule (EpCAM) is a homophilic and Ca2+ independent adhesion molecule that is expressed de novo in squamous cell carcinoma (SCC) but is absent in the majority of healthy squamous epithelia. EpCAM expression correlates with cell proliferation and dedifferentiation along with a progression in tumorigenicity. To date, nothing is known about the molecular mechanisms responsible for the regulation of the EpCAM gene. METHODS: The authors analyzed the regulation of a fragment of the EpCAM promoter. RESULTS: The analyzed fragment has significant activity in EpCAM positive cells, and it is regulated negatively by tumor necrosis factor alpha (TNFalpha). This negative regulation results in diminished mRNA expression and in the down-regulation of EpCAM protein at the cell surface in SCC cells. Both effects can be mimicked by the treatment of cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). TNFalpha-induced inhibition of the EpCAM expression is mediated by TNF receptor 1 through the TNF receptor-associated death domain protein (TRADD) and by the activation of nuclear factor kappaB (NF-kappaB), and it can be blocked by dominant-negative variants of TRADD and the NF-kappaB inhibitor, IkappaB. The authors provide further evidence that NF-kappaB represses EpCAM expression by competing for the transcriptional coactivator p300/CREB binding protein (p300/CBP). CONCLUSIONS: The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects.

[IL-2 gene therapy in ENT carcinomas]. / IL-2 Gentherapie bei HNO-Karzinomen.

Suppressed cellular immunity is common in patients with squamous cell carcinoma of the head and neck (HNSCC). It was demonstrated in previous studies that administration of interleukin 2 (IL-2) results in enhanced antitumoral immunity in vitro as well as in vivo. Since the serum half-life of IL-2 is relatively short, repeated applications are necessary to achieve therapeutically effective serum concentrations, but this strategy might cause severe side effects. Therefore, methods that provide high local cytokine levels over a prolonged period of time without the need for repeated injections are desirable. Gene therapy as an innovative treatment approach using tumor cells stably transduced to produce IL-2 might meet these criteria. In vitro manipulated tumor cells, if readministered in the vicinity of non-manipulated tumor cells, may enhance a specific anti-tumor response in vivo without systemic side effects. The present manuscript reviews the current literature dealing with IL-2-protein and -gene therapy with special emphasis on head and neck cancer. Our own in vitro results with IL-2 gene therapy in conjunction with published data from other authors argue in favour of an in vivo approach for this therapeutic strategy that is currently in progress in our department.

TNFalpha contributes to the antitumor activity of a bispecific, trifunctional antibody.

Immunological cancer therapies focus on the activation of immune effector cells yielding a specific antitumor activity. Disseminated tumor cells are regarded as the origin of metastases and consequently their elimination is the central objective of adjuvant immune therapies. The use of bispecific antibodies is an approach that is regarded as promising in order to fight those disseminated tumor cells. Unfortunately, the efficiency of these antibodies is limited by the fact that they usually activate a single class of effector cell, thus not yielding optimal immune response. In addition, tumor cells may down-regulate the antibody's target molecule and escape recognition. We have recently described results with an intact bispecific molecule, BiUII, that represents a new class of intact antibodies. These antibodies, termed "triomab", provide an excellent antitumor activity in vitro, a fact that most probably is attributable to the simultaneous activation of different classes of immune effector cells. We have now investigated this antitumor activity in more detail and demonstrate here that at least a dual mechanism accounts for triomab-mediated killing of tumor cells: besides direct cell-mediated killing, triomab induces the production of TNFalpha in PBMCs at concentrations that induce apoptosis in target cells. This bystander effect may be of special interest for the clinical application of triomab in terms of killing of target antigen-negative tumor cells.

The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells.

Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.

The PKC targeting protein RACK1 interacts with the Epstein-Barr virus activator protein BZLF1.

Phorbol esters reactivate Epstein-Barr virus (EBV) from latently infected cells via transcriptional activation of the viral immediate-early gene BZLF1. BZLF1 is a member of the extended AP-1 family of transcription factors that binds to specific BZLF1-binding motifs within early EBV promoters and to consensus AP-1 sites. Regulation of BZLF1's activity is achieved at the transcriptional level as well as through post-translational modifications. Recently, we reported that the transcriptional activity of BZLF1 is augmented by TPA [Baumann, M., Mischak, H., Dammeier, S., Kolch, W., Gires, O., Pich, D., Zeidler, R., Delecluse, H. J. & Hammerschmidt, W., (1998) J. Virol. 72, 8105-8114]. The increase of BZLF1's activity depends on a single serine residue (S186) that is phosphorylated by protein kinase C (PKC) in vitro and in vivo after stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA). Here, we identified RACK1 as a binding partner of BZLF1 in a yeast interaction trap assay. RACK stands for receptor of activated C-kinase and is involved in targeting activated PKCs and other signaling proteins. In vivo, RACK1 binds directly to the transactivation domain of BZLF1. Although a functional relationship between BZLF1 and PKC could be mediated by RACKs, RACK1 did not have a detectable effect on the phosphorylation status of BZLF1 in in vitro or in vivo phosphorylation assays. We suggest that RACK1 may act as a scaffolding protein on BZLF1 independently of activated PKCs.

Tumor cell-derived prostaglandin E2 inhibits monocyte function by interfering with CCR5 and Mac-1.

The cyclooxygenases (COX)-1 and COX-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. Whereas COX-1 is expressed ubiquitously, COX-2 is an immediate-early gene often associated with malignant transformation, and a role for the COX enzymes in tumor initiation and promotion is discussed. Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and indomethacin that block COX-1 and -2 have been shown to have beneficial effects for tumor patients. Therefore, these compounds have gained interest also among oncologists. However, the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood. The prostaglandin-dependent and -independent effect may both account for their antineoplastic action. We show here that tumor cells derived from different tumors regularly produce prostaglandin E(2) (PGE(2)) interfering with the function of monocytes. In particular, PGE(2) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell. This inhibition is most probably due to a modulation of the chemokine receptor CCR5 and the beta2-integrin Mac-1. Both down-regulation of CCR5 and reduced expression of Mac-1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues. Since both dysfunctions can be restored with NSAIDs, our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression.

Ep-CAM--a marker for the detection of disseminated tumor cells in patients suffering from SCCHN.

Disseminated tumor cells are considered as the origin of metastases. Since the number of circulating tumor cells in the bone marrow or the peripheral blood of patients correlates well with the tumor stage, their early detection is an important feature for the identification of high risk patients. We therefore investigated the pan-carcinoma antigen Ep-CAM for its suitability to serve as a specific marker for disseminated tumor cells in patient with squamous cell carcinoma of the head and neck (SCCHN). In order to detect small numbers of tumor cells in early tumor stages, we developed and describe here a RT-PCR assay that detects a single tumor cell within 10(5) normal cells. We examined bone marrows from patients and healthy donors and demonstrate that Ep-CAM can be used as a tumor marker for the diagnosis of single tumor cells in patients with SCCHN.

Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing.

Bispecific Abs (bsAb) are promising immunological tools for the elimination of tumor cells in minimal residual disease situations. In principle, they target an Ag on tumor cells and recruit one class of effector cell. Because immune reactions in vivo are more complex and are mediated by different classes of effector cell, we argue that conventional bsAb might not yield optimal immune responses at the tumor site. We therefore constructed a bsAb that combines the two potent effector subclasses mouse IgG2a and rat IgG2b. This bispecific molecule not only recruits T cells via its one binding arm, but simultaneously activates FcgammaR+ accessory cells via its Fc region. We demonstrate here that the activation of both T lymphocytes and accessory cells leads to production of immunomodulating cytokines like IL-1beta, IL-2, IL-6, IL-12, and DC-CK1. Thus this new class of bsAb elicits excellent antitumor activity in vitro even without the addition of exogenous IL-2, and therefore represents a totally self-supporting system.

Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins.

Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required for B cell immortalization by Epstein-Barr virus. Molecular and biochemical approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in the induction of NF-kappaB and AP-1 via two C-terminal activating regions. We demonstrate here that a third region encompassing a proline rich sequence within the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation of Janus kinase 3 (JAK3). The interaction of LMP1 and JAK3 leads to the enhanced tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT transcription factors. These results reveal a novel activating region in the LMP1 C-terminus and identify the JAK/STAT pathway as a target of this viral integral membrane protein in B cells.