Lymphom der Prostata - Diagnose auf den "zweiten Stich"

Zusammenfassung: Hintergrund:: Maligne Lymphome der Prostata sind eine klinische Rarität. In der Literatur werden insgesamt etwa 165 Fälle beschrieben, in denen ein primäres Lymphom oder eine sekundäre Infiltration der Prostata durch ein Lymphom vorlag. Fallbeschreibung:: Berichtet wird der Fall eines 59-jährigen Patienten mit einer unscharf begrenzten Raumforderung im Bereich der Prostata bei normalem prostataspezifischem Antigen (PSA), einer Wirbelkörperfraktur und bilateralen Nebennierenvergrößerungen. Eine zweizeitige Prostatastanzbiopsie erbrachte die Diagnose eines diffus-großzelligen B-Zell-Non-Hodgkin-Lymphoms. Weitere Staginguntersuchungen ergaben Anhaltspunkte für das Vorliegen eines epiduralen Befalls. Es wurde eine Polychemotherapie inklusive intrathekaler Applikation initiiert, unter der sich die Lymphommanifestationen bei einem ersten Zwischenstaging nach vier Zyklen deutlich zurückgebildet hatten. Nach weiteren zwei Zyklen R-CHOP zeigte ein CT zwar noch ein kleines Weichteilplus in der Prostataloge, im anschließenden PET-CT war jedoch kein vitales Lymphomgewebe mehr nachweisbar (komplette Remission). Schlussfolgerung:: Bei einer Raumforderung im Bereich der Prostata muss neben einem Prostatakarzinom als weitaus häufigste Tumorentität auch an ein solitäres Lymphom oder eine Infiltration der Prostata bei generalisiertem Lymphom gedacht werden, insbesondere bei einem normalen PS

Gene expression profiling reveals consistent differences between clinical samples of human leukaemias and their model cell lines

Microarray gene expression profiles of fresh clinical samples of chronic myeloid leukaemia in chronic phase, acute promyelocytic leukaemia and acute monocytic leukaemia were compared with profiles from cell lines representing the corresponding types of leukaemia (K562, NB4, HL60). In a hierarchical clustering analysis, all clinical samples clustered separately from the cell lines, regardless of leukaemic subtype. Gene ontology analysis showed that cell lines chiefly overexpressed genes related to macromolecular metabolism, whereas in clinical samples genes related to the immune response were abundantly expressed. These findings must be taken into consideration when conclusions from cell line-based studies are extrapolated to patients

First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors.

PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies

Anticorps ou fragments dérivés conçus pour l'usage thérapeutique

In the era of certain therapeutic antibodies coming of age, there is a medical need to generate new treatment modalities, engineered antibodies or derived fragments that might offer a new option. A classical antibody is a Y-shaped protein composed of two structurally independent parts, the variable region (V-region), and the constant region, (Fc). The V-region is responsible for targeting a specific antibody to an antigen and is different for every type of antibody. The Fc region does not interact with antigens, but rather interacts with components of the immune system through a variety of receptors on immune and other cells. These interactions allow antibodies to regulate the immune response and levels of cell-killing ability, or cytotoxicity, as well as their persistence in circulation and tissues. Fc regions are the same and interchangeable from antibody to antibody. Engineering of the Fc has been demonstrated to improve the serum half-life of antibodies in preclinical and clinical studies and potentially can improve tissue distribution.Camelids, more specifically llamas, produce highly diverse panels of antibodies with a high human homology, or similarity, in their V-regions. The use of their conventional antibodies allows to access and explore a broad selection of targets, including novel and complex targets, while minimizing the time associated with generating and optimizing antibody candidates using more traditional methods. We have applied several technologies to create antibodies with optimized V-regions and an enhanced Fc region for the chosen target.The aim of this thesis is to confirm the hypothesis that therapeutic antibodies issued from research on camelids, equipped with various Fc engineering technologies may offer a new potential option for clinical setting. Two examples will be analysed to confirm the hypothesis.The first example is Efgartigimod, the engineered human Fc fragment that functions as an antagonist of FcRn that was developed for the treatment of patients with myasthenia gravis, immune thrombocytopenia and pemphigus vulgaris, all of which are rare and severe autoimmune diseases associated with high levels of circulating pathogenic IgG antibodies for which a severe, yet unmet medical need exists. By introducing a series of mutations in the CH2 and CH3 regions that increase the affinity for FcRn at the low pH of the endosome and the neutral pH of the circulation Efgartigimod is designed to block the recycling of IgG antibodies, which results in their rapid clearance.The second example is cusatuzumab, the SIMPLE antibody against CD70, which is Fc engineered (afucosylated) resulting in increased antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Cusatuzumab was developed for cancer indications, initially for cutaneous T-cell lymphoma (TCL) and acute myeloid leukaemia (AML) as well as high-risk myeloid dysplastic syndrome (MDS). TCL and AML are rare and aggressive haematological cancers for which significant also unmet medical need exists. MDS, a rare bone marrow disorder, is often a precursor to AML. Cusatuzumab is an antibody designed to potently block the CD70/CD27 interaction and kill CD70-positive cells via its potent antibody effector functions.Several clinical trials were performed and analysed to confirm the hypothesis. Results will be discussed and compared with the available literature.Afin de pouvoir développer des approches thérapeutiques innovantes vers de nouvelles cibles, un besoin médical pour générer de nouveaux types d'anticorps existe. Ces protéines en forme de Y sont composées de deux parties structurellement indépendantes, une région variable (région V) et une région constante (région Fc). La région V est responsable du ciblage d'un anticorps spécifique contre un antigène et est différente pour chaque type d'anticorps. La région Fc n'interagit pas avec les antigènes, mais interagit plutôt avec les composantes du système immunitaire par l'intermédiaire d'une variété de récepteurs sur les cellules immunitaires entre autres. Ces interactions permettent aux anticorps de réguler la réponse immunitaire et la capacité de tuer les cellules, ou la cytotoxicité, ainsi que leur persistance dans la circulation et les tissus. Les régions Fc sont identiques au sein d’une même espèce. Les camélidés, plus précisément les lamas, produisent des panels d'anticorps très divers présentant une homologie ou une similarité élevée avec les anticorps humain dans leurs régions V. Leur utilisation permet d'accéder et d'explorer une large sélection de cibles, y compris des cibles nouvelles et complexes, tout en minimisant les longs délais associés à la génération d'anticorps candidats à l'aide de méthodes plus traditionnelles. Nous avons appliqué plusieurs technologies pour créer des anticorps avec des régions V optimisées et une région Fc améliorée pour la cible choisie.L'objectif de cette thèse est de confirmer l'hypothèse selon laquelle les anticorps thérapeutiques issu de la recherche sur les camélidés, équipés de diverses technologies d'ingénierie modifiant la région Fc des anticorps, améliorent les performances thérapeutiques. Deux exemples seront analysés pour confirmer l'hypothèseLe premier exemple est l’efgartigimod, le un fragment artificiel de Fc humain qui fonctionne comme un antagoniste de FcRn qui a été développé pour le traitement des patients atteints de myasthénie grave, de thrombocytopénie immunitaire et de pemphigus vulgaris. Ces maladies auto-immunes rares et graves sont associées à des niveaux élevés d'IgG pathogènes circulants. Efgartigimod est conçu pour bloquer le recyclage des anticorps IgG, ce qui entraîne leur élimination de la circulation.Le deuxième exemple est cusatuzumab, l'anticorps SIMPLE contre le CD70. Cet anticorps afucosylé, obtenu par génie cellulaire, a une plus grande activité de cytotoxicité à médiation cellulaire dépendante des anticorps (ADCC) et de phagocytose cellulaire dépendante des anticorps (ADCP). Il a été mis au point pour les indications de cancer, d'abord pour le lymphome cutané à lymphocytes t (LTC) et la leucémie myéloïde aiguë (LMA), ainsi que pour le syndrome dysplasique myéloïde (SDM) à risque élevé. Le LTC et la LMA sont des cancers hématologiques rares et agressifs pour lesquels il existe d'importants besoins médicaux non satisfaits. Le SDM, une maladie rare de la moelle osseuse, est souvent un précurseur de la LMA. Cusatuzumab est conçu pour bloquer l'interaction CD70/CD27 et tuer les cellules positives au CD70 par le biais de ses puissantes fonctions effectrices d'anticorps.Plusieurs essais cliniques ont été menés pour tester l'hypothèse. Les résultats seront discutés et comparés avec la littérature disponibl

Holiday souvenirs from the Mediterranean: three instructive cases of visceral leishmaniasis

With expanding travel activities, visceral leishmaniasis increasingly occurs in non-endemic areas and affects immunocompetent individuals with no other risk factor than holidays at the Mediterranean coast. We report 3 instructive Swiss cases of visceral leishmaniasis presenting with fever of unknown origin and pancytopenia and review current diagnostic and therapeutic concepts

[Malignant lymphoma of the prostate--diagnosis on the second biopsy]

BACKGROUND: Malignant lymphoma of the prostate is rare. In the literature, about 165 cases with either a primary lymphoma of the prostate or secondary infiltration of the prostate by a lymphoma are described. CASE REPORT: The case of a 59-year-old patient with an irregular tumor in the prostatic region, but normal prostate-specific antigen (PSA), a fracture in the vertebral column and a bilateral enlargement of the suprarenal glands is presented. Repetitive prostate biopsy revealed the diagnosis of a diffuse large B cell lymphoma. Further staging examinations gave hints to an epidural infiltration. A polychemotherapy including intrathecal drug applications was initiated. Staging after four therapeutic cycles already showed good partial remission of all lymphoma manifestations. After two further therapeutic cycles, a CT scan showed a small rest of prostatic bulk, but PET-CT did not detect vital lymphatic tissue (complete remission). CONCLUSION: In cases of irregular prostatic enlargements, carcinoma has to be considered as the most frequent diagnosis. Nevertheless, also a solitary lymphoma or infiltration of the prostate by a systemic lymphoma has to be taken into account, especially if the PSA value is in the normal range

Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization : a prospective multicenter phase II trial (protocol SAKK 34/02)

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (< or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients