Wolfram Jung

Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell non-Hodgkin's lymphoma

Reduced intensity conditioning and allogeneic stem cell transplantation after salvage therapy integrating alemtuzumab for patients with relapsed peripheral T-cell non-Hodgkins lymphoma

Test-enhanced learning of clinical reasoning: a crossover randomised trial

Clinical reasoning is an essential skill, the foundations of which should be acquired during undergraduate medical education. Student performance in clinical reasoning can be assessed using key feature examinations. However, within a paradigm of test‐enhanced learning, such examinations may also be used to enhance long‐term retention of procedural knowledge relevant to clinical reasoning.

Resistance Against Natural Killer Cell Cytotoxicity: Analysis of Mechanisms

Target cell resistance against natural killer (NK) cell‐mediated cytotoxicity obstructs NK cell‐based immunotherapy of leukaemia. Several mechanisms of resistance have been described. Because of lack of simple assays for analysing these mechanisms, their relative impact on a given effector–target pair is mostly unknown. We here analysed the combination of the Granzyme B (GrB) enzyme‐linked immunospot assay (ELISPOT) for the assessment of NK cell reactivity and cytotoxicity assays to estimate target cell escape mechanisms. Target cell recognition failure leads to negative GrB ELISPOT results, whereas target cell resistance shows positive GrB ELISPOT results in the absence of cytotoxicity. We confronted NK cells with the sensitive target cell line K562, and with the resistant cell lines ML2, SupB15 and Raji. ML2 cells sufficiently activated GrB‐release whilst being resistant against cytotoxic granules of NK cells. Partial resistance of Raji results from the interaction of HLA class I with inhibitory killer immunglobulin‐like receptors (KIR) on the NK cells. Failure of target recognition by HLA class I–KIR interaction, lacking ligands to stimulatory NK cell receptors and partial resistance to cytotoxic granules all contributed to resistance of SupB15. In conclusion, revealing the mechanisms of resistance against NK cell‐mediated cytotoxicity may allow improving the results of NK‐based immunotherapy.

Self-tolerance of Human Natural Killer Cells Lacking Self-HLA-specific Inhibitory Receptors

Natural killer (NK) cells identify cells with altered human leucocyte antigen (HLA) expression as targets through lacking engagement of self‐HLA‐specific inhibitory receptors (e.g. killer cell immunoglobulin‐like receptor, KIR). Thus, they eliminate cells with ‘missing self’ because of viral or malignant transformation. We performed analysis of HLA, KIR genotypes and KIR receptor expression patterns at single cell level in NK cells in 17 donors. The function of NK cell subsets is determined by degranulation assays using target cells expressing self, cognate, control or no HLA class I. Donors could be grouped into three groups: their NK cells possess potential for alloreactivity, autoreactivity based on the presence of NK cells expressing particular KIR only (mono‐KIR) in the absence of its ligand or lack alloreactivity. All donors possess NK cells lacking all detectable inhibitory receptors. Both potential autoreactive subpopulations did not respond to HLA class I‐positive target cells. They retain partial reactivity against HLA class I‐negative tumour target cells. Mono‐KIR NK cells without the corresponding ligands in the individuals and NK cells lacking all inhibitory receptors behave self‐tolerant. Our results suggest alternative mechanisms than HLA‐specific inhibitory receptors to control NK cell activity. But HLA seems to be involved in shaping effector function of the NK cell repertoire.

Differenzialdiagnose und -abklärung von Lymphknotenvergrößerungen

Besides acute inflammatory swelling of a lymph node, acute lymphadenitis, enlarged lymph nodes occur in conjunction with various benign and malignant diseases. Lymphadenopathy can appear in a localized or generalized form and requires further diagnostic measures. Possible causes are primarily infectious, immunological, neoplastic, and metabolic disorders. The medical history and physical examination provide the first clues to the diagnosis. Localized swollen glands often have an infectious etiology so that the first step is to identify the possible focus of infection. Generalized lymphadenopathy is frequently a sign of a hematological systemic disease, particularly in adults. Therefore, in every case of lymphadenopathy persisting for more than 1 month, invasive diagnostic procedures are indicated to rule out a malignant cause. The aim should be to perform a histological analysis; excision of entire lymph nodes is exigent, especially for the work-up of lymphoma. In cases of malignant lymphoma, staging examinations should subsequently be conducted to assess the prognosis and formulate a treatment plan.

Abundant Expression of Spliced HDM2 in Hodgkin Lymphoma Cells does not Interfere with p14ARF and p53 Binding

Abstract Recently, comparative genomic hybridization (CGH)- and fluorescence in situ hybridization (FISH)-analyses of native Hodgkin and Reed-Sternberg (H&RS) cells extracted from Hodgkin lymphoma (HL) revealed a recurrent amplification of the HDM2 locus on chromosome 12. HDM2 is known to target, inactivate and to degrade p53. Wild type (wt) p53 protein is detected in high levels in HL. Simultaneously, stabilized wt p53 and spliced hdm2 transcripts have been observed in different tumors. Therefore, we examined the expression and structure of HDM2 in HL cell lines and possible effects on components of the p53 pathway. DNA integrity and induction potential of p53 was verified by DNA sequencing and detection of potential effector proteins (p21WAF/CIP, HDM2) using immunofluorescence, respectively. All HL cell lines show an overexpression of HDM2 protein. Furthermore, several different spliced hdm2 transcripts (mdm-sv) including five new variants lacking a functional p53 binding site were characterized. If expressed, corresponding proteins were shown to be not restricted to the nucleus. Co-localization of the potential binding partners HDM2/p14ARF and HDM2/p53 was found in HL cell lines. We suggest that HDM2-sv have no significant disturbing influence on the interaction of these proteins.

[Diagnostics and staging of non-Hodgkin's lymphomas].

ZusammenfassungNon-Hodgkin-Lymphome stellen eine klinisch und biologisch heterogene Gruppe von Erkrankungen dar. Neue Therapieansätze wie die humorale Immuntherapie und die Hochdosistherapie haben eine wesentliche Verbesserung der Heilungschancen für Lymphompatienten ermöglicht. Nur bei korrekter Diagnosestellung und exakter Ermittlung des initial vorliegenden Ausbreitungsstadiums der Erkrankung ist jedoch eine optimale Auswahl der bestehenden Therapieoptionen und somit die bestmögliche Behandlung des Lymphompatienten gewährleistet. Die klassischen klinischen, laborchemischen und bildgebenden Verfahren wie die neuen molekulargenetischen Diagnoseverfahren werden in dieser Übersicht dargestellt.AbstractNon-Hodgkin’s lymphomas represent a clinically and biologically heterogeneous group of diseases. Over the last few years, new treatment approaches such as humoral immunotherapy and high dose therapy with stem cell rescue have improved the chances for a cure in most patients with malignant lymphoma. However, only with the correct diagnosis and staging, including the evaluation of novel prognostic factors, are treating physicians able to choose the optimal treatment for their patients. This review focuses on conventional staging procedures and their role in the management of lymphoma patients, as well as on some new aspects of the molecular classification of lymphomas.

Retroperitoneal fibrosis as manifestation of chronic GVHD after allogeneic hematopoietic SCT.

Retroperitoneal fibrosis as manifestation of chronic GVHD after allogeneic hematopoietic SCT

Diagnostik und Stadieneinteilung bei Non-Hodgkin-Lymphomen

ZusammenfassungNon-Hodgkin-Lymphome stellen eine klinisch und biologisch heterogene Gruppe von Erkrankungen dar. Neue Therapieansätze wie die humorale Immuntherapie und die Hochdosistherapie haben eine wesentliche Verbesserung der Heilungschancen für Lymphompatienten ermöglicht. Nur bei korrekter Diagnosestellung und exakter Ermittlung des initial vorliegenden Ausbreitungsstadiums der Erkrankung ist jedoch eine optimale Auswahl der bestehenden Therapieoptionen und somit die bestmögliche Behandlung des Lymphompatienten gewährleistet. Die klassischen klinischen, laborchemischen und bildgebenden Verfahren wie die neuen molekulargenetischen Diagnoseverfahren werden in dieser Übersicht dargestellt.AbstractNon-Hodgkin’s lymphomas represent a clinically and biologically heterogeneous group of diseases. Over the last few years, new treatment approaches such as humoral immunotherapy and high dose therapy with stem cell rescue have improved the chances for a cure in most patients with malignant lymphoma. However, only with the correct diagnosis and staging, including the evaluation of novel prognostic factors, are treating physicians able to choose the optimal treatment for their patients. This review focuses on conventional staging procedures and their role in the management of lymphoma patients, as well as on some new aspects of the molecular classification of lymphomas.