The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

The analysis of the actor-spectator relationship on the basis of Juliusz Chrząstowski's roles.

Celem niniejszej pracy jest opisanie możliwości warsztatowych Juliusza Chrząstowskiego, aktora Starego Teatru oraz próba scharakteryzowania relacji zachodzących na linii aktor – widz. W pracy staram się zdefiniować, co leży u podstaw tej relacji. Próbuję również uchwycić, jak zmienia się sposób postrzegania widza przez aktora w zależności od spektaklu. Praca składa się z trzech głównych rozdziałów. Każdy rozdział dotyczy problemu rozpatrywanego w oparciu o jedną kreację Juliusza Chrząstowskiego, dzięki temu sprawdzam, w jaki sposób aktor dialoguje z widzem i na czym polega jego podejście do publiczności wynikające z założeń roli. Pierwszy rozdział jest zrealizowany w oparciu o analizę roli Chrząstowskiego w "Odprawie posłów greckich" w reżyserii Michała Zadary. Badam tutaj, w jakim stopniu za energię zwrotną, docierającą do aktora z widowni, odpowiedzialni są poszczególni widzowie. Drugi rozdział pracy w całości dotyczy roli widza w kształtowaniu siły oddziaływania spektaklu oraz postrzegania publiczności jako zbiorowości. Zajmuję się w nim zagadnieniem charakteryzowania publiczności przez zespół aktorski. Weryfikuję, czy zdefiniowanie publiczności wpływa na dialog między sceną a widownią, a co za tym idzie - na siłę oddziaływania spektaklu. Zagadnienia te realizuję na podstawie "Trylogii" w ujęciu Jana Klaty.Trzeci rozdział pracy skupia się na temacie obserwacji widza przez aktora. Bazą do analizy jest spektakl Iwana Wyrypajewa "Iluzje". W zakończeniu definiuję czym dla aktora jest publiczność oraz wysuwam wniosek, że podstawą kontaktu aktora i widza jest krążąca między nimi energia.The purpose of this paper is to describe the features of Julius Chrząstowski's acting and the attempt to characterize the relationships on the line actor-spectator. In this paper, I am trying to define what is the basis of relations between the actor and the spectator. I am also capturing the change in the perception of the viewer by the actor, which depends on each performance. The work consists of three main sections. Each chapter deals with the problem, which is based on one of Julius Chrząstowski's roles, so that I am able to check how actor interacts with the viewer and what is his attitude to the audience under the assumptions of the role.The first chapter is based on an analysis of the role of Chrząstowski in the "Odprawa posłów greckich", directed by Michał Zadara . The second chapter of the work entirety applies to the viewer's role in shaping the impact of the performance and the perception of the audience as a community. I also deal with the issue of the characterization of the audience given by the cast. I am veryfing how the audience affects the dialogue between stage and audience. These issues are based on the" Trilogy" by Jan Klata. The third chapter of the paper focuses on the theme of observation audience by an actor. Starting point for the analysis is the spectacle of Ivan Wyrypajew "Illusions". At the end of the work I am defining what audience means for the actor. The concluding remark is that the actor-spectator relationship is based on the energy which circulates between them during the performance

Patients with Primary Central Nervous System Lymphoma Not Eligible for Clinical Trials: Prognostic Factors, Treatment and Outcome

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1-141) in non-study patients and 51 months (1-105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) < 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0-21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0-45)/21 months (95% CI 18-25) in 27 non-study/526 study patients (p = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation

The Diagnosis and Treatment of Primary CNS Lymphoma

Background: Primary central nervous system lymphoma is a diffuse large B-cell lymphoma with exclusive manifestation in the central nervous system (CNS), leptomeninges, and eyes. Its incidence is 0.5 per 100 000 persons per year. Currently, no evidence-based standard of care exists. Methods: This review is based on pertinent publications (2000-2017) retrieved by a selective search in PubMed. Results: The clinical and neuroradiological presentation of primary CNS lymphoma is often nonspecific, and histopathological confirmation is obligatory. The disease, if left untreated, leads to death within weeks or months. If the patient's general condition permits, treatment should consist of a high-dose chemotherapy based on methotrexate (HD-MTX) combined with rituximab and other cytostatic drugs that penetrate the blood-brain barrier. Long-term survival can be achieved in patients under age 70 by adding non-myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HD-AST) to the induction therapy. Clinical trials comparing the efficacy and toxicity of these two treatment strategies are currently underway. Consolidation whole-brain radiotherapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment. Some 30% of patients are refractory to primary treatment, and at least 50% relapse. In patients who are still in good general condition, relapse can be managed with HD-AST. Re-exposure to conventional HD-MTX-based polychemotherapy is another option, if the initial response was durable. The 5-year survival rate of all treated patients is 31%, according to registry data. Conclusion: Current recommendations for the treatment of primary CNS lymphoma are based on only a small number of prospective clinical trials. Patients with this disease should be treated by interdisciplinary teams in experienced centers, and preferably as part of a controlled trial