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Neurofibromas rarely occur before the age of 7 in children. They are a rarity on the hand, especially if they are accompanied by sensory disturbances and impairment of the gripping function. We report on a 9-year-old girl with symptomatic neurofibroma of the third and fourth ray of the right palm.Neurofibrome treten im Kindesalter selten vor dem 7. Lebensjahr auf. An der Hand sind sie eine Rarität, insbesondere wenn diese mit Sensibilitätsstörungen und Beeinträchtigung der Greiffunktion einhergehen. Wir berichten über ein bei der Erstvorstellung 9-jähriges Mädchen mit symptomatischem Neurofibrom des dritten und vierten Strahls der rechten Hohlhand.

Ein 28-jahriger syrischer Fluchtling stellte sich zur Abklarung von Schmerzen im Bereich des rechten Knies und einer seit Monaten progredienten Verschlechterung des Allgemeinzustands vor. Es fanden sich eine ausgepragte Hyperkalzamie bei primarem Hyperparathyreoidismus sowie teilweise grose Osteolysen in nahezu allen Skelettabschnitten. Histologisch zeigten sich in diesen Osteolysen zahlreiche mehrkernige Riesenzellen vom osteoklastaren Typ. In der histopathologischen Aufarbeitung einer chirurgisch entfernten jugularen Raumforderung zeigte sich schlieslich der seltene Befund eines Nebenschilddrusenkarzinoms, das bei unserem Patienten mit einer molekulargenetisch nachgewiesenen Mutation im Gen HRPT2 assoziiert war.

Based on clinical and experimental data, oropharyngeal squamous cell carcinomas (OPSCC) associated with human papillomavirus (HPV) have been recognized as a distinct entity of head and neck cancers. However, outside of clinical trials, HPV status currently has no impact on treatment. The natural replication cycle of HPV takes place in epithelial cells, and is thus spatially separated from cytotoxic immune cells in the epidermis. Dendritic cells (Langerhans cells, LC), however, are frequent in this upper dermal layer. The ability of LC to process antigens, migrate, and, ultimately activate T cells is inhibited by the activity of the viral oncoproteins (E5-E7). Downregulation of functional human leukocyte antigen I (HLA-I) epithelial cell surface expression contributes to LC inhibition. However, due to their absence in upper skin layers, corresponding activation of natural killer (NK) cells via missing-self recognition is not relevant. Genome-wide analyses have revealed specific expression signatures for HPV-associated OPSCC that are distinct from HPV-negative cancers. Interestingly, aberrations in HLA-I genes were common in HPV-associated OPSCC. Our own findings indicate more frequent infiltration of HPV-associated OPSCC by CD56-positive (CD56

A 28-year-old Syrian refugee presented with right-sided knee pain and progressive deterioration of the general condition over the past months. Laboratory diagnostics revealed severe hypercalcemia due to primary hyperparathyroidism, and computed tomography (CT) scanning demonstrated disseminated osteolytic lesions throughout the skeleton. Histologically, these lesions were characterized by multinuclear giant cells (defining these lesions as so-called brown tumors). Finally, surgical removal of a jugular mass allowed the histopathologic diagnosis of a sporadic parathyroid carcinoma. In the patient, this condition was associated with a mutation in the HPRT2 gene locus.

Bei einer 75-jahrigen Patientin mit Pleuraerguss wurde die seltene Entitat eines adenoid-zystischen Karzinoms zunachst als Metastase im Magen entdeckt. Bei etwa 20% der Patienten mit diesem Karzinom werden Fernmetastasen diagnostiziert. Fur das initiale Staging haben sich in den letzten Jahren die Positronenemissionstomographie (PET) und die PET-Computertomographie (CT) etabliert. In der Halfte der Falle ist im Tumorgewebe die t(6;9)(q22–23;p23–24)-Translokation nachweisbar, die fur verschiedene Varianten von MYB-NFIB-Fusionstranskripten codiert. Die molekularpathologische Diagnostik erleichtert die korrekte Diagnosestellung und die Identifizierung des Primartumors.

We study transport properties of graphene with anisotropically distributed on-site impurities (adatoms) that are randomly placed on every third line drawn along carbon bonds. We show that stripe states characterized by strongly suppressed back-scattering are formed in this model in the direction of the lines. The system reveals L\'evy-flight transport in stripe direction such that the corresponding conductivity increases as the square root of the system length. Thus, adding this type of disorder to clean graphene near the Dirac point strongly enhances the conductivity, which is in stark contrast with a fully random distribution of on-site impurities which leads to Anderson localization. The effect is demonstrated both by numerical simulations using the Kwant code and by an analytical theory based on the self-consistent $T$-matrix approximation., Comment: 11 pages, 6 figures

Eine 53-jahrige Patientin stellt sich mit Splenomegalie, unklaren Milzlasionen, Trizytopenie und Verdacht auf Aortitis vor. Sie gibt eine verminderte Leistungsfahigkeit und Muskelschmerzen an. Eine B-Symptomatik ist nicht feststellbar. Die Milzveranderungen sind nach Angabe der Patientin schon langer bekannt. Die Aortitis bestatigt sich laborchemisch und in der MR-Bildgebung. Bezuglich der Milzveranderungen konnen weder sonographisch noch MR-tomographisch konklusive oder gar pathognomonische Befunde erhoben werden. Bei Trizytopenie und diagnostischer Unklarheit wird eine Splenektomie durchgefuhrt und die histologische Diagnose eines multifokalen Littoralzellangioms (LCA) gestellt.

Das wachsende Potenzial molekularer Werkzeuge hat zu einem deutlich verbesserten Einblick in die molekulare Dimension pathologischer Prozesse und damit zu einem wachsenden Einfluss pathologischer Diagnosen auf die Therapiewahl gefuhrt. Durch das wachsende Verstandnis neoplastischer Erkrankungen wird daruber hinaus zunehmend festgestellt, dass bis dato als homogen interpretierte Tumorentitaten in Wahrheit in Untergruppen mit spezifischen molekularen Attributen, Wachstumseigenschaften und infolgedessen unterschiedlichen prognostischen Eigenschaften sowie therapeutischen Bedurfnissen einzuteilen sind. Diese Untergruppen unterscheiden sich oft in der Zusammensetzung des „tumor microenvironment“ (ME), das wesentlich an der Kontrolle zentraler Prozesse der Karzinogenese (z. B. Angiogenese, invasives Wachstum) beteiligt ist. Daher verspricht die Untersuchung des ME ein aussichtsreiches Forschungsgebiet fur Pathologen zu werden, und es besteht Hoffnung, dass ein groseres Verstandnis der Interaktion zwischen neoplastischen Zellen und der Zellen des ME zu verbesserten diagnostischen Werkzeugen und neuen therapeutischen Ansatzen fur die Behandlung von Krebspatienten fuhren wird.

Um das Uberleben bei fortgeschrittenen Rhabdomyosarkomen (RMS) zu verbessern, versuchen wir, Bedingungen fur den adoptiven Transfer chimarer T-Zellen zu verbessern, die eine Spezifitat fur den fetalen Acetylcholinrezeptor, ein RMS-spezifisches Oberflachenmolekul, haben. Zur Optimierung der Rezeptorzytotoxizitat wurde dem ursprunglich vorhandenen chimaren Rezeptor, bestehend aus einem humanen Anti-fAChR-Antikorper, einer Fc-Hinge-Region und einer humanen CD3ζ-Kette, eine CD28-Domane zugefugt. Periphere Blutlymphozyten wurden mittels retroviraler Transduktion modifiziert und die Expression des chimaren Rezeptors mittels Durchflusszytometrie verifiziert. Das zytotoxische Potenzial der modifizierten T-Zellen gegenuber RMS-Zellen wurde uber MTT-Zytotoxizitatstests bestimmt. Die Expression kostimulatorischer Molekule und antiapoptotischer Faktoren wurde durchflusszytometrisch bzw. mithilfe quantitativer PCR untersucht. Die geringen Expressionslevel kostimulatorischer Molekule auf RMS-Zellen fuhrten zu der Uberlegung, einen chimaren Antigenrezeptor (CAR) mit einer CD28-CD3ζ-Signaldomane zu generieren. Die erfolgreiche Modifikation der T-Zellen mit der „zweiten Generation“ des AChR-spezifischen CAR zeigte trotz guter Expressionsraten geringe Lyseraten gegenuber RMS, im Vergleich zu CD20-positiven Lymphom- oder CEA-exprimierenden Adenokarzinomzelllinien mit CD20- bzw. CEA-spezifischem CAR. Die verminderten Lyseraten der RMS-Zellen durch einen fAChR-spezifischen CAR lassen eine Resistenz der RMS-Zellen gegenuber der T-Zell-Antwort vermuten. Die Inhibierung antiapoptotischer Stoffwechselwege konnte die Sensitivitat dieser Zellen gegenuber konventioneller und auch gegenuber T-Zell-basierten Therapien verbessern.

Objective: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF. Methods: Nested and non-nested real-time PCR were used to detect cell-specific and EBV-specific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells. Results: No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV. Conclusions: Application of real-time PCR to multiple sclerosis brain and single B-lymphocytes in CSF did not reveal any evidence of active Epstein-Barr virus infection.

Das hamophagozytische Syndrom (Makrophagenaktivierungssyndrom) beschreibt den klinischen, histologischen und biologischen Symptomenkomplex einer von T-Lymphozyten bzw. naturlichen Killerzellen ausgelosten Makrophagenstimulation mit nachfolgender Hamophagozytose, die sich in verschiedenen Organen, insbesondere im Knochenmark und der Milz manifestieren kann. Zu den wesentlichen klinischen Symptomen zahlen Zytopenie, multiple Organdysfunktionen, antibiotikaresistentes Fieber, Hepatosplenomegalie und Hautausschlage. Neben seltenen erblich bedingten Anomalien des Immunsystems (primares hamophagozytisches Syndrom) sind die haufigsten Ursachen virale, bakterielle und parasitare Infektionen, lymphoproliferative Erkrankungen, maligne Neoplasien und Autoimmunerkrankungen. Therapeutisch kommen Immunsuppressiva, Zytostatika, Plasmapherese sowie die intravenose Gabe von Immunglobulinen und Anti-TNF-α-Antikorpern zur Anwendung, wobei das Erkennen initialer Veranderungen fur den Therapieerfolg entscheidend ist. Hier konnte Ferritin als fruher sensitiver Serummarker identifiziert werden. Wesentliche histologische Merkmale sind die Vermehrung von Makrophagen und Retikulumzellen, deren Zytoplasma Kerntrummer und Erythrozytenfragmente enthalt, sowie in der Milz die Rarefizierung/Zerstorung der weisen Pulpa mit vollstandigem Fehlen der Lymphfollikel und Vermehrung von Lymphozyten, Plasmazellen und Plasmazellvorstufen in den Pulpastrangen.

Epithelial neuroendocrine tumors of the upper respiratory tract are rare and are classified as typical and atypical carcinoid versus small cell neuroendocrine carcinoma. Furthermore, a giant cell variant of neuroendocrine carcinoma is suggested corresponding to the bronchopulmonary system as well as a recently described subtype of oropharyngeal small cell neuroendocrine carcinoma associated with human papillomavirus. Many arguments relying on clinical as well as on molecular findings indicate that the distinction between carcinoid and poorly differentiated neuroendocrine carcinoma does not only reflect different degrees of differentiation of otherwise related tumors but indicates the existence of substantially different types of neoplasms.

Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.

A possible approach to objectively classify complex patterns in tumor tissue is a mathematical and statistical investigation of the distribution of cell nuclei as a geometric representation of cancer cells by fractal dimensions. Both the existence and changes in the fractal structure of tumor tissue have important consequences for the objective system of tumor grading. In addition, the complexity of growth in different carcinomas or their intercellular interactions can be compared to each other.We present a theoretical introduction into fractal geometry as well as in the computer algorithms based upon the Rényi family of fractal dimensions. Finally, a geometric model of prostate cancer is introduced and the relationship between geometric patterns of prostate tumor and the fractal dimensions of the Rényi family are explained.

Significant intra- and interobserver variability ranging between 40 and 80% is observed in tumor grading of prostate carcinoma. By combining geometric and statistical methods, an objective system of grading can be designed.The distributions of cell nuclei in two-dimensional patterns of prostate cancer classified subjectively as Gleason score 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, and 5+5 were analyzed with algorithms measuring the global fractal dimensions of the Rényi family and with the algorithm for the local connected fractal dimension (LCFD).The dimensions for global fractal capacity, information, and correlation (standard deviation) were 1.470 (045), 1.528 (046), and 1.582 (099) for homogenous Gleason grade 3 (n = 16), 1.642 (034), 1.678 (041), and 1.673 (084) for homogenous Gleason grade 4 (n=18), and 1.797 (042), 1.791 (026), and 1.854 (031) for homogenous Gleason grade 5 (n=12), respectively. The LCFD algorithm can be used to distinguish both qualitatively and quantitatively between mixed and heterogeneous patterns, such as Gleason score 3+4=7a (intermediate risk cancer) and Gleason score 4+3=7b (high-risk cancer). Sensitivity of the method is 89.3%, and specificity 84.3%.The method of fractal geometry enables both an objective and quantitative grading of prostate cancer.

We explore the longitudinal conductivity of graphene at the Dirac point in a strong magnetic field with two types of short-range scatterers: adatoms that mix the valleys and "scalar" impurities that do not mix them. A scattering theory for the Dirac equation is employed to express the conductance of a graphene sample as a function of impurity coordinates; an averaging over impurity positions is then performed numerically. The conductivity $\sigma$ is equal to the ballistic value $4e^2/\pi h$ for each disorder realization provided the number of flux quanta considerably exceeds the number of impurities. For weaker fields, the conductivity in the presence of scalar impurities scales to the quantum-Hall critical point with $\sigma \simeq 4 \times 0.4 e^2/h$ at half filling or to zero away from half filling due to the onset of Anderson localization. For adatoms, the localization behavior is obtained also at half filling due to splitting of the critical energy by intervalley scattering. Our results reveal a complex scaling flow governed by fixed points of different symmetry classes: remarkably, all key manifestations of Anderson localization and criticality in two dimensions are observed numerically in a single setup., Comment: 17 pages, 4 figures

A 75-year-old woman was found to have left-sided pleural effusion and endoscopy revealed the rare entity of adenoid cystic carcinoma metastases in the gastric mucosa. Approximately 20% of patients with this carcinoma suffer from distant metastases. For the initial staging detection of adenoid cystic carcinoma metastasis with positron emission tomography (PET) or PET computed tomography (CT) is recommended. The recurrent t(6;9)(q22-23;p23-24) translocation that results in a fusion of the two transcription factor genes MYB and NFIB is detectable in half of the cases. As in our case molecular pathology can confirm the correct diagnosis and identification of the localization of the primary tumor.

The frozen section procedure for immediate intraoperative pathological diagnosis represents a pivotal method in tumor diagnosis. In laryngeal tumors the most frequent indication for the use of this method is the documentation of the residual tumor status, while intraoperative consultation with the purpose of primary tumor diagnosis is less common. The specimen management employed in each case should be chosen depending on the clinical question: while the collection of a maximum amount of tissue is advisable for the determination of the residual tumor status, sparing a portion of the remaining tissue for possible future examinations is advisable in the case of primary tumor diagnosis. Moreover, intraoperative frozen section diagnosis with no immediate consequences should be avoided.

A 53-year-old female patient presented with splenomegaly, uncertain lesions of the spleen, pancytopenia and suspected aortitis. Reduced strength and muscular pain but no B symptoms were also present. Alterations of the spleen had been known for a long time. Blood examination, laboratory tests and magnetic resonance imaging (MRI) confirmed an aortitis. Concerning the splenic changes neither ultrasound nor MRI could provide conclusive or even pathognomonic findings. Because of an existing pancytopenia and diagnostic obscurity, the patient underwent splenectomy. The histological diagnosis was finally concluded as multifocal littoral cell angioma.

Eine 67-jahrige Patientin stellte sich mit belastungsabhangiger Angina pectoris vor. Eine dilatative Kardiomyopathie war bekannt. 5 Jahre zuvor war invasiv eine koronare Herzerkrankung ausgeschlossen worden. Die invasive Koronarangiografie des linken Koronararteriensystems zeigt einen Befund.

To improve survival of patients with advanced rhabdomyosarcomas (RMS), we aimed to adoptively transfer T-cells with redirected specificity for the fetal acetylcholine receptor (AChR), an RMS-specific cell surface antigen.A "second generation" chimeric antigen receptor (CAR) with a combined CD28-CD3ζ signaling domain was derived from our previously described chimeric antigen receptor composed of an extracellular human anti-fAChR antibody fragment, an Fc hinge region, and the intracellular T-cell receptor zeta chain. Lymphocytes from the peripheral blood were modified by retroviral transduction and monitored by FACS analysis. Cytotoxicity of modified T-cells towards RMS cells was recorded by MTT-based viability tests; expression of co-stimulatory molecules and anti-apoptotic genes was studied by FACS and qRT-PCR analysis.Co-stimulatory molecules were expressed in low levels on RMS cells giving the rationale to generate a CD28-CD3ζ signalling CAR (chimeric antigen receptor) for redirecting T-cells. T-cells were successfully engineered with the "second generation" AChR-specific chimeric antigen receptor. Despite of high CAR expression engineered T-cells showed low killing efficiency towards RMS compared to redirected killing of CD20+ lymphoma or CEA-expressing adenocarcinoma cell lines when redirected by CD20- and/or CEA-specific CAR.Data suggest that RMS cells exhibit resistance to a T-cell attack redirected by a fAChR-specific CAR. Inhibition of anti-apoptotic pathways in those cells may improve sensitivity to conventional as well as T-cell-based therapeutics.

Motivated by recent proposals on strain-engineering of graphene electronic circuits we calculate conductivity, shot-noise and the density of states in periodically deformed graphene. We provide the solution to the Dirac-Kronig-Penney model, which describes the phase-coherent transport in clean monolayer samples with an one-dimensional modulation of the strain and the electrostatic potentials. We compare the exact results to a qualitative band-structure analysis. We find that periodic strains induce large pseudo-gaps and suppress charge transport in the direction of strain modulation. The strain-induced minima in the gate-voltage dependence of the conductivity characterize the quality of graphene superstructures. The effect is especially strong if the variation of inter-atomic distance exceeds the value a^2/l, where a is the lattice spacing of free graphene and l is the period of the superlattice. A similar effect induced by a periodic electrostatic potential is weakened due to Klein tunnelling., Comment: 11 pages, 8 figures

Rosai-Dorfman disease belongs to the group of childhood histiocytoses and was initially described as sinus histiocytosis with massive lymphadenopathy. Its rare purely extranodal manifestation is primarily found in the head and neck region. An atypical primary manifestation in an elderly patient with multifocal extranodal disease is described, and this pathological entity is reviewed. Specific difficulties concerning differential diagnostic aspects as well as individually appropriate treatment strategies are discussed.

Carcinoma of unknown primary (CUP) is an intriguing clinical finding defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical workup. CUP is a relatively common clinical entity, accounting for approximately 3-5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. The mechanisms responsible for early metastasis and lack of a detectable primary tumor are largely unknown. Although remarkable tools have been developed for immunohistological classification of CUP on the basis of the likely tissue of origin, data on molecular pathogenesis and biology of this disorder are rare. A wide variety of chromosomal aberrations are seen in CUP, with aberrations of chromosomes 1, 6, 7, and 11 having been most frequently described. 66-75% of CUP express epidermal growth factor receptor while overexpression of Her2/neu seems to be rare. In contrast to most other tumor entities p53 mutations have been found only in a minority of CUP tumors. Recently, several independent studies have demonstrated proof of principle for the use of gene expression microarrays in identifying a primary site for CUP. Therefore, gene expression and also genomic profiling tools represent promising analytical approaches to assist with the management of CUP patients.

In Europe and the USA, the incidence of primary nasal natural killer (NK)/T-cell lymphoma is rare. The skin is one of the predilection sites for dissemination. Cutaneous dissemination is a poor prognostic sign and is consistently fatal. We describe the case of a 17-year-old white German girl with a primary nasal NK/T-cell lymphoma and cutaneous dissemination. She presented with multiple maculopapular patches involving the trunk and thighs, and a 4-week history of headache, fever and fatigue. Biopsies of the skin and the nasal mucosa were taken. Pathological examination of both specimens revealed a NK/T-cell lymphoma. Epstein-Barr virus RNA was detected in the lymphoma cells by in situ hybridization. Unfortunately, the patient died of disease within 1 week.

Chromosomal abnormalities like translocations and their corresponding gene fusions were first suggested to be causal factors in the development of cancer by Boveri in 1914. At present more than 350 gene fusions involving 337 different genes have been identified and in particular in malignant hematological diseases and sarcomas an increasing number of chromosomal aberrations are being recognized as important diagnostic and prognostic parameters. By contrast this type of gene rearrangement has been until recently only rarely described in the common carcinomas. However, with new powerful techniques, that enable the detection of cytogenetically cryptic rearrangement, this number is likely to increase substantially and carcinomas characterized by fusions oncogenes indicate that the pathogenetic mechaisms involved in epithelial carcinogenesis may be similar to those known to operate in hematological and soft-tissue malignancies.

Hemophagocytic syndrome (macrophage activation syndrome) is a group of disorders characterized by clinical, histological and biological symptoms of T-lymphocytes/NK cell-driven macrophage stimulation with subsequent hemophagocytosis which can be observed in various organs, particularly in the bone marrow and spleen. The main clinical symptoms include cytopenia, multiple organ dysfunction, fever unresponsive to antibiotics, hepatosplenomegaly and rash. Besides rare inherited immune system anomalies (primary hemophagocytic syndrome), the most prevalent etiologies of hemophagocytic syndrome are infections (viral, bacterial and parasitic), cancers, lymphoproliferative disorders and systemic diseases. Hemophagocytic syndrome is treated with immunosuppressives, cytostatic drugs, plasmapheresis and intravenous immunoglobulins/anti-TNF antibodies and due to the multiorgan involvement and the associated high mortality, recognition of early serum changes, such as very high levels of ferritin is mandatory. The most relevant histological changes are the increase of histiocytes showing evidence of phagocytosis of erythroid cells, platelets and granulocytes as well as in the spleen a rarefaction of the white pulpa with lack of lymph follicles and abundant lymphocytes, plasma cells and plasma cell precursors in the pulpa cords.

Rhabdomyosarcomas (RMSs) are the most frequent malignant soft tissue tumors of childhood. Since even aggressive multimodality treatments including autologous stem cell rescue have failed to improve the20 % overall survival rate of children with metastatic RMS, novel treatment approaches are urgently needed. Looking for potential targets for immunotherapies, we identified the gamma subunit of the fetal acetylcholine receptor (fAChR) as a specific and overexpressed membrane antigen in RMS. Additionally we established a duplex RT-PCR with simultaneous amplification of alpha and gamma subunit message of the fAChR and the quantification of both transcripts resulting in alpha/gammaAChR ratio1 was 100% sensitive in alveolar and embryonal rhabdomyosarcoma. Since the fAChR was the first extracellular tumor marker that can distinguish rhabdomyosarcomas from nonrhabdomyomatous tumors and from normal muscle and therefore implies, that the fAChR may be a target for immunotherapeutic strategies, we synthesized a scFv antibody fragment directed against the fAChR and enigineered both a Pseudomonas exotoxin A based immunotoxin as well as a chimeric T cell receptor composed of the antigen-binding domain of the scFv fragment joined to the signaling domain of the T cell receptor zeta chain. The interaction of fAChzeta-transduced T cells with several RMS cell lines but not with fAChR-negative controls induced strong T cell activation, characterized by secretion of high amounts of interferon-gamma. Moreover after co-incubations with RMS cell lines fAChRzeta-transduced T cells as well fAChR specific immunotoxin induced specific receptor-concentration dependent tumor cell lysis. Therefore, fAChRzeta-transduced T cells and the fAChR specific immunotoxin respectively are promising new tools for the immunotherapy of rhabdomyosarcomas and may provide an effective complementary approach to eradicate residual or metastatic RMS cells in patients, since 1. RMS-direceted chemotherapies increase the expression of fAChR on residual RMS cells in vivo and 2. the fully human fAChR autoantibody fragment with low immunizing potential allows prolonged/permanent application of fAChRzeta-transduced T cells/immunotoxin.

Anamnese und klinischer Befund: Eine 77-jahrige Patientin wurde mit starkem Juckreiz, generalisiertem papulosem Exanthem und Hyponatriamie aufgenommen. Untersuchungen und Diagnose: Als Ursache der Hyponatriamie konnte ein SIADH (Syndrom der inadaquaten ADH-Sekretion; Schwartz-Bartter-Syndrom) diagnostiziert werden. Die Biopsie eines Weichteiltumors der linken Skapula zeigte ein T-Zell-Lymphom (Typ NOS) mit knochernem Befall in den bildgebenden Untersuchungen einschlieslich PET-CT. Therapie und Verlauf: Die zytostatische Chemotherapie bewirkte schon nach dem 1. Zyklus eine unmittelbare Verbesserung des Hautbefundes und des Allgemeinbefindens. Das SIADH war mittels des spezifischen Vasopressin-2-Rezeptorantagonisten Tolvaptan zu kontrollieren. Folgerungen: Sowohl das SIADH als auch das papulose Exanthem sind als paraneoplastische Syndrome im Rahmen der Erstmanifestation des T-Zell-Lymphoms anzusehen.

The moleculargenetic detection of specific genetic abnormalities within malignant hematopoietic disorders is an important diagnostic tool with relevance for the differential diagnosis, therapy and prognosis.According to a modified and optimized RT-PCR based technique native bone marrow aspirates and peripheral blood samples of 183 patients were investigated for the presence of specific genetic abnormalities. The histological diagnosis of all CMLs t(9;22) and variants of AMLs M3 t(15;17) and t(11;17) were moleculargenetically confirmed. Additionally one t(5;12) positive chronic myelomonozytic leukemia, one t(8;21) positive AML M1, one t(9;22) positive B-ALL and in each case one t(6;9) and one t(3;21) positive myelodysplastic syndrome were detected. The hereby described method is a simple, specific and reliable technique for the rapid moleculargenetic detection of specific genetic abnormalities within malignant hematopoietic disorders with implication for the diagnosis/differential diagnosis, prognosis and therapy.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. We describe here for the first time a patient with a huge GIST of the abdominal wall without any relation to the gastrointestinal tract, omentum, or mesentery. With regard to the size of 24 cm and a low mitotic index, this GIST is considered an intermediate risk for metastasis. Radical surgical resection was performed with negative pathologic resection margins. The classic immunohistochemical phenotype of the tumor described facilitates the differential diagnosis to exclude abdominal desmoid tumor and solitary fibrous tumor (SFT). In the case of metastasis, therapeutic nihilism no longer seems justified with the availability of imatinib, a tyrosine kinase inhibitor, which shows encouraging results in the therapy of metastatic GIST.

Myogenin and the fetal type acetylcholine receptor (AChR) subunits are specific immunohistochemical markers for the diagnosis of rhabdomyosarcomas. In spite of light microscopy and immunohistochemistry, the diagnosis of doubtful cases and small biopsies of rhabdomyosarcomas remains a challenge. Therefore, a PCR-based highly sensitive approach, would be a valuable diagnostic adjunct and should be free from the risk of contamination of the tumor sample with normal tissue. We studied the transcription of myogenin and fetal type AChR in rhabdomyosarcomas, other childhood and adult tumors and normal tissues. In all embryonal and alveolar rahbdomyosarcomas transcripts of both myogenin and fetal type AChR could be detected. The detection of myogenin mRNA however was not specific for rhabdomyosarcomas but occurred in normal muscle and the majority of other normal tissues and childhood tumors. In contrast the transcription of fetal type AChR, which is defined by an alpha subunit AChR/gamma subunit AChR ratio1 was encountered only in rhabdomyosarcomas and denervated muscle. Therefore we suggest, that mRNA of the fetal type AChR but not myogenin is a highly specific and sensitive target for the PCR-based diagnosis of rhabdomyosarcomas.

The oncoprotein STP-C-488 induces salivary gland and thymic epithelial tumours when expressed as a transgene in mice (MURPHY et al. 1994). Given the enigmatic tumorigenesis of corresponding tumours in humans, we now investigated genomic DNA and RNA from 11 thymomas, 5 pleomorphic adenomas and control autopsy material (n = 8) for the occurrence of the STP-C-488 sequences by Southern-blotting, Northern-blotting and PCR.All tumor samples and control tissues were negative for the STP-C-488 in Southern-blot and Northern-blot-hybridization. PCR analyses did not reveal amplification products of the length expected for STP-C-488. However, a PCR fragment of a different size was found in 50% of the thymomas and pleomorphic adenomas, but in only one of 8 controls. The sequence of this PCR product revealed local homologies with various herpesviruses.The oncoprotein STP-C-488 is not involved in the tumorigenesis of human thymomas and salivary gland tumours. Whether the novel sequences amplified preferentially from these tumours play a role in pathogenesis needs further investigation.

To investigate the role of the acetylcholine receptor (AchR) in the pathogenesis of paraneoplastic Myasthenia gravis (MG), we screened a cDNA library of a MG-associated thymoma with a DNA oligonucleotide coding for aa 371-378, i.e. for part of the very immunogenic cytoplasmatic epitope (VICE-alpha, aa 373-380) of the human AChR alpha-subunit. We isolated two cDNA clones. Analysis of these clones has identified an open reading frame of 1371 bp, coding for the AChR alpha-subunit. No point mutation, insertion or deletion could be detected. Since the thymoma did not contain thymic myoid cells, which normally express AChR, the origin of the AChR transcripts must be the tumor cells itself. These findings confirm former results, where AChR alpha-subunit sequences from MG-thymomas were amplified by PCR.

Costimulatory stromal receptors were identified in thymuses and myasthenia gravis (MG)-associated thymic epithelial tumors (TETs) by immunohistochemistry. ICAM-1 occurred in areas with medullary or cortical differentiation of TETs and thymuses. B7 and LFA-3, absent in the normal cortex, were hyperexpressed in cortical type TETs. VCAM-1, confined to endothelium and dendritic cells in cortex and medulla, was focally expressed by epithelial cells of a medullary thymoma. We suggest that aberrantly expressed costimulatory molecules may contribute to the pathogenesis of paraneoplastic MG by an intratumorous activation of mature T cells.

Two findings in thymic epithelial tumors are correlated with the occurrence of myasthenia gravis(MG): (1) the expression of an acetylcholine receptor (AChR)-like-epitope in the neoplastic epithelium, and (2) the preservation of thymus-like features in the neoplasms, indicated by the presence of immature thymocytes. On this background it has been proposed that paraneoplastic MG may start with an intratumorous abnormal T cell selection due to aberrantly expressed AChR-epitopes (self-peptides). As appropriate thymocyte-stroma-interactions are prerequisites for thymocyte development in the thymus (and probably in MG-associated thymic tumors, too), we analyzed the expression of CD28/B7(BB1), CD2/:LFA3, LFA-1/ICAM-1 and VLA-4/VCAM-1 in human thymus and thymomas by immunohistochemistry. In normal thymuses and thymitis the stromal molecules were expressed at higher levels in the medulla than in the cortex. This was particularly true for B7(BB1) that was undetectable by immunoperoxidase techniques in the cortex. In contrast, cortical-type thymic epithelial tumors (cortical thymoma and well differentiated thymic carcinoma), known to exhibit the highest association with myasthenia, expressed the stromal molecules at almost medullary levels. The findings may be a clue to a functional difference between neoplastic and normal cortical epithelial cells: while we find the former to have the capacity to present soluble antigen to antigen-specific CD4+ T cells in vitro, normal cortical epithelium failed to do so. This altered microenvironment in thymomas might contribute to the autoimmunization by stimulating mature recirculating AChR-specific T cells.