Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma

16siAnaplastic large-cell lymphomas (ALCLs) are a group of clinically and biologically heterogeneous diseases including the ALK+ and ALK+ systemic forms. Whereas ALK+ ALCLs are molecularly characterized and can be readily diagnosed, specific immunophenotypic or genetic features to define ALK- ALCL are missing, and their distinction from other T-cell non-Hodgkin lymphomas (T-NHLs) remains controversial. In the present study, we undertook a transcriptional profiling meta-analysis of 309 cases, including ALCL and other primary T-NHL samples. Pathway discovery and prediction analyses defined a minimum set of genes capable of recognizing ALK- ALCL. Application of quantitative RT-PCR in independent datasets from cryopreserved and formalin-fixed paraffin-embedded samples validated a 3-gene model (TNFRSF8, BATF3, and TMOD1) able to successfully separate ALK- ALCL from peripheral T-cell lymphoma not otherwise specified, with overall accuracy near 97%. In conclusion, our data justify the possibility of translating quantitative RT-PCR protocols to routine clinical settings as a new approach to objectively dissect T-NHL and to select more appropriate therapeutic protocols. © 2012 by The American Society of Hematology.openopenAgnelli L.; Mereu E.; Pellegrino E.; Limongi T.; Kwee I.; Bergaggio E.; Ponzoni M.; Zamo A.; Iqbal J.; Piccaluga P.P.; Neri A.; Chan W.C.; Pileri S.; Bertoni F.; Inghirami G.; Piva R.Agnelli, L.; Mereu, E.; Pellegrino, E.; Limongi, T.; Kwee, I.; Bergaggio, E.; Ponzoni, M.; Zamo, A.; Iqbal, J.; Piccaluga, P. P.; Neri, A.; Chan, W. C.; Pileri, S.; Bertoni, F.; Inghirami, G.; Piva, R

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors

The structure and function of Alzheimer's gamma secretase enzyme complex

The production and accumulation of the beta amyloid protein (Aβ) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer’s disease (AD). A multi-subunit enzyme complex, referred to as gamma (γ) secretase, plays a pivotal role in the generation of Aβ from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Aβ levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of γ-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the γ-secretase enzyme and the effects of inhibiting its activity

Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas

Choosing And Implementing The Correct Whole Slide Imaging System

Introduction/ Background The whole slide imaging (WSI) market has developed enormously in the recent years. This evolution has made the selection and the implementation of digital pathology more complicated. Based on a validation process, we developed recommendations that need to be taken into account when implementing whole slide imaging. In addition to selecting the right hardware, one should also focus on laboratory organization, integration, training and handling. Aims The aim is to integrate WSI as efficiently as possible in a standardized process. This should lead to a user friendly workflow for pathologists and must ensure the quality of the diagnosis. Methods We organized on-site demonstrations to test several available WSI systems with a fixed set of histology slides. We evaluated scanning quality, measured the scanning time, the amount of data produced and made a simulation of a routine workflow. We developed a to-be workflow beginning with the scanning process until the final diagnosis of the pathologist. The workflow focused on the integration of the system into the laboratory information system. We standardized the technical laboratory processes to increase the quality of the slides and the efficiency of WSI. The standardization included good labeling, adequate quality, standardized location and correct number of sections on the slide. We introduced a continuous workflow to reduce batch size and to decrease the turn-around-time. The pathologists were only allowed to work with WSI after training in order to manipulate the images as efficiently as possible. Finally we validated the system according to CAP guidelines for WSI for diagnostic purpose in pathology. Results It is very important to determine what the purpose of WSI implementation in the lab is. The different systems show large variations between them and not every set up will fit in the specific workflow of each lab. The workflow simulation gave us an idea of the scanning turn-around-time and made it possible to estimate the amount of scanners that would be necessary in daily routine. Another focus point is the total integration of WSI to find a synergy between the hardware, workflow and the way the system can be integrated into the IT infrastructure of the lab. Beside the bidirectional communication with the laboratory information system, data storage organization and its influence on the lab’s productivity is also very important. Organizing the laboratory with a standardized continuous workflow will reduce the amount of data, increase speed and lower the amount of rescans. To prevent that WSI is used inefficiently, it is crucial to train the pathologists before they start using it. A lack of training will lead to a dislike of WSI due to poor knowledge of the available applications. The pathologists are indicating that it’s crucial to have the correct hardware to manipulate the image in order to ensure diagnostic speed and to lower the threshold towards WSI. We may conclude that choosing and implementing the correct WSI solution needs a systematic approach to succeed on the long term. Defining and optimizing the workflow before implementing whole slide imaging is crucial. Hardware, workflow and IT infrastructure should match to ensure productivity. Training of the pathologists is decisive in order to ensure efficient use.

Een 53-jarige vrouw met ernstige nierinsufficiëntie

A 53-year-old patient with acute kidney injury A 53-year-old patient was admitted with acute kidney injury and hypercalcemia. Further investigation with PET-CT revealed a strong FDG-uptake in the spleen and minor uptake in some mediastinal lymph nodes. EBUS-FNA of a mediastinal lymph node was unrevealing. Other examinations could not differentiate reliably between lymphoma and sarcoidosis. A diagnostic splenectomy was necessary to make a definitive diagnosis.status: publishe