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Cancers
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Primary CNS Lymphomas: Diagnosis and Treatment
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Primary CNS Lymphomas: Diagnosis and Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 39561

Special Issue Editor

Prof. Dr. Uwe Schlegel

E-Mail Website
Guest Editor
Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany
Interests: brain tumors; systemic tumor therapy; treatment toxicity; cognitive dysfunction due to brain tumor treatment

Special Issue Information

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma confined to the CNS, including the brain, spine, the meninges, and eyes. The B-cell receptor pathway, with its downstream effector NFĸB, is affected by frequent mutations, mainly in MYD88 and CD79B. Advanced imaging and non-invasive diagnostic analyses of cerebrospinal fluid (CSF) may aid in discriminating PCNSL from other brain lesions. Yet, histopathologic diagnosis of tumor tissue gained by (stereotactic) biopsy still is standard. High-dose systemic methotrexate (HDMTX) is the backbone of successful therapy, often applied in combination with cytarabine (araC), rituximab, and other agents. Induction therapy is followed by consolidation with high-dose chemotherapy followed by autologous stem cell transplantation (HDASCT), by intensified conventional chemotherapy and/or by (dose-reduced) whole-brain radiotherapy (WBRT). While the majority of patients initially respond, more than half will relapse or show primary progression. Thus, novel agents such as e.g., the Bruton tyrosine kinase inhibitor ibrutinib, immunomodulatory drugs such as lenalidomide or checkpoint inhibitors are investigated within clinical trials.

This Special Issue highlights recent findings on the molecular pathogenesis of PCNSL, novel developments of molecular-based non-invasive diagnostics, the backbone of current therapy in clinical practice, the therapeutic potential of novel agents and CAR-T cells, and last but not least, factors influencing Quality of Life in long-term survivors.

Prof. Dr. Uwe Schlegel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Primary central nervous system lymphoma (PCNSL)
  • Diffuse large B cell lymphoma (DLBCL)
  • B-cell receptor pathway
  • Advanced Imaging
  • Stereotactic biopsy
  • Non-invasive diagnostic measures
  • Systemic therapy
  • Novel agents

Published Papers (11 papers)

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Research

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10 pages, 1520 KiB  
Article
Patients with Primary Central Nervous System Lymphoma Not Eligible for Clinical Trials: Prognostic Factors, Treatment and Outcome
by Sabine Seidel, Michelle Margold, Thomas Kowalski, Alexander Baraniskin, Roland Schroers, Agnieszka Korfel, Eckhard Thiel, Michael Weller, Peter Martus and Uwe Schlegel
Cancers 2021, 13(12), 2934; https://doi.org/10.3390/cancers13122934 - 11 Jun 2021
Cited by 5 | Viewed by 2287
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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18 pages, 4374 KiB  
Article
What Is on Your Mind? Impaired Social Cognition in Primary Central Nervous System Lymphoma Patients Despite Ongoing Complete Remission
by Milena Pertz, Thomas Kowalski, Patrizia Thoma and Uwe Schlegel
Cancers 2021, 13(5), 943; https://doi.org/10.3390/cancers13050943 - 24 Feb 2021
Cited by 5 | Viewed by 2357
Abstract
Within the past decades, long-term survival was achieved in a substantial fraction of primary central nervous system lymphoma (PCNSL) patients, expanding the focus of research to their quality of life (QoL). Social relationships crucially contribute to well-being in the context of adversity. Therefore, [...] Read more.
Within the past decades, long-term survival was achieved in a substantial fraction of primary central nervous system lymphoma (PCNSL) patients, expanding the focus of research to their quality of life (QoL). Social relationships crucially contribute to well-being in the context of adversity. Therefore, abilities that facilitate social interactions essentially determine QoL. The present study specifically targeted those sociocognitive abilities. Forty-three PCNSL patients with ongoing complete remission to therapy for at least one year and 43 healthy controls matched for age, gender and education were examined with standardized self-report and behavioral measures of social cognition. An impaired ability to comprehend others’ feelings was found in patients for both positive and negative mental states. Patients had difficulties in identifying the awkward element in challenging social situations, whereas the degree of discomfort experienced in those situations was comparable between groups. Both the production of optimal solutions for social situations and the mere recognition of these among less optimal strategies were impaired in patients. Clinicians should be aware of possible sociocognitive impairment and ought to address this in additional supportive interventions. Impaired sociocognitive abilities may entail social conflicts at a time when patients rely on social support. This, in turn, could detrimentally affect QoL. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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Review

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15 pages, 319 KiB  
Review
Diagnosis and Treatment Using Autologous Stem-Cell Transplantation in Primary Central Nervous System Lymphoma: A Systematic Review
by Sara Steffanoni, Teresa Calimeri, Sarah Marktel, Rosamaria Nitti, Marco Foppoli and Andrés J. M. Ferreri
Cancers 2023, 15(2), 526; https://doi.org/10.3390/cancers15020526 - 15 Jan 2023
Cited by 2 | Viewed by 2773
Abstract
Background: Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are [...] Read more.
Background: Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT. Methods: We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed. Results: Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients. Conclusion: ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
20 pages, 2867 KiB  
Review
Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System
by Manuel Montesinos-Rongen, Anna Brunn, Monica Sanchez-Ruiz, Ralf Küppers, Reiner Siebert and Martina Deckert
Cancers 2021, 13(24), 6334; https://doi.org/10.3390/cancers13246334 - 17 Dec 2021
Cited by 10 | Viewed by 3255
Abstract
Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages [...] Read more.
Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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23 pages, 79399 KiB  
Review
Vitreoretinal Lymphoma
by Bianka Sobolewska, Soon-Phaik Chee, Fatma Zaguia, Debra Anne Goldstein, Justine R. Smith, Falko Fend, Manabu Mochizuki and Manfred Zierhut
Cancers 2021, 13(16), 3921; https://doi.org/10.3390/cancers13163921 - 4 Aug 2021
Cited by 23 | Viewed by 6275
Abstract
Vitreoretinal lymphoma (VRL) is a rare variant of primary central nervous system lymphoma (PCNSL), mostly of diffuse large B cell lymphoma, which affects the retina and/or the vitreous with or without optic nerve involvement. The disease course is aggressive. Up to 90% of [...] Read more.
Vitreoretinal lymphoma (VRL) is a rare variant of primary central nervous system lymphoma (PCNSL), mostly of diffuse large B cell lymphoma, which affects the retina and/or the vitreous with or without optic nerve involvement. The disease course is aggressive. Up to 90% of the patients develop central nervous system lymphoma within one year. The diagnosis of VRL is challenging due to nonspecific chronic and relapsing uveitis and is made by anterior chamber tab or vitreous aspirate biopsy. There is no established treatment protocol for VRL patients with bilateral involvement without CNS involvement. There are suggestions to use only intravitreal chemotherapy with methotrexate and/or rituximab. Alternatively, systemic high-dose MTX treatment or external beam radiotherapy is used. Further studies are needed to prove and confirm the prophylactic systemic therapy in preventing CNS involvement in limited VRL. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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18 pages, 908 KiB  
Review
Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives
by Andrea Morales-Martinez, Fernando Lozano-Sanchez, Alberto Duran-Peña, Khe Hoang-Xuan and Caroline Houillier
Cancers 2021, 13(14), 3479; https://doi.org/10.3390/cancers13143479 - 12 Jul 2021
Cited by 9 | Viewed by 3928
Abstract
The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity [...] Read more.
The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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13 pages, 507 KiB  
Review
Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma
by Hans-Georg Wirsching, Michael Weller, Stefan Balabanov and Patrick Roth
Cancers 2021, 13(12), 3073; https://doi.org/10.3390/cancers13123073 - 20 Jun 2021
Cited by 16 | Viewed by 3558
Abstract
This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The [...] Read more.
This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The mechanisms of action, results of completed clinical studies, ongoing clinical trials, and future perspectives are summarized. Among the most promising clinical developments in the field of CNS lymphomas is ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which relays activation of nuclear factor kappa B upon integration of constitutive B cell receptor and Toll-like receptor signals. Down-stream of nuclear factor kappa B, the thalidomide analogs lenalidomide and pomalidomide exert immunomodulatory functions and are currently explored against CNS lymphomas. Finally, immune checkpoint inhibitors, such as drugs targeting the PD-1 pathway, may become novel therapeutic options to unleash anti-tumor immunity in patients with primary CNS lymphoma. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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10 pages, 228 KiB  
Review
Liquid Biopsy and Other Non-Invasive Diagnostic Measures in PCNSL
by Alexander Baraniskin and Roland Schroers
Cancers 2021, 13(11), 2665; https://doi.org/10.3390/cancers13112665 - 28 May 2021
Cited by 23 | Viewed by 3602
Abstract
Primary central nervous system lymphoma is a rare but highly aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis. The diagnosis of PCNSL requires a high level of suspicion as clinical presentation varies depending on the involved CNS areas. Neurological [...] Read more.
Primary central nervous system lymphoma is a rare but highly aggressive form of non-Hodgkin lymphoma that remains confined to the CNS neuroaxis. The diagnosis of PCNSL requires a high level of suspicion as clinical presentation varies depending on the involved CNS areas. Neurological symptoms and MRI findings may mimic gliomas, demyelinating lesions, or infectious and granulomatous diseases. Almost all PCNSL patients undergo invasive surgical procedures for definite diagnosis. Stereotactic biopsy is still the gold standard in achieving a diagnostic accuracy of 73–97%. Both the potential procedural morbidity and mortality, as well as the time to definite histopathologic diagnosis resulting in delays of treatment initiation, have to be considered. On the contrary, minimally invasive procedures, such as MRI, CSF cytology, and flow cytometry, still have limited value due to inferior specificity and sensitivity. Hence, novel diagnostic approaches, including mutation analyses (MYD88) in circulating tumor DNA (ctDNA) and the determination of microRNAs (miR-21, miR-19b, and miR-92) as well as cytokine levels (IL10 and IL6) in blood, cerebrospinal fluid (CSF), and vitreous fluid (VRF), move into the focus of investigation to facilitate the diagnosis of PCNSL. In this review, we outline the most promising approaches that are currently under clinical consideration. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
11 pages, 225 KiB  
Review
Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma?
by Clemens Seidel, Christine Viehweger and Rolf-Dieter Kortmann
Cancers 2021, 13(11), 2580; https://doi.org/10.3390/cancers13112580 - 25 May 2021
Cited by 5 | Viewed by 2075
Abstract
Background: Primary CNS Lymphoma is a rare and severe but potentially curable disease. In the last thirty years treatment has changed significantly. Survival times increased due to high-dose methotrexate-based chemotherapy. With intensive regimens involving autologous stem cell transplantation (ASCT), 4-year survival rates of [...] Read more.
Background: Primary CNS Lymphoma is a rare and severe but potentially curable disease. In the last thirty years treatment has changed significantly. Survival times increased due to high-dose methotrexate-based chemotherapy. With intensive regimens involving autologous stem cell transplantation (ASCT), 4-year survival rates of more than 80% can be reached. However, this treatment regimen is not feasible in all patients, and is associated with some mortality. Methods: In this review, current evidence regarding the efficacy and toxicity of radiotherapy in PCNSL shall be summarized and discussed mainly based on data of controlled trials. Results: Being the first feasible treatment whole brain radiotherapy (WBRT) was initially used alone, and later as a consolidating treatment after high-dose methotrexate-based chemotherapy. More recently, concerns regarding activity and neurotoxicity of standard dose WBRT limited its use. On the contrary, latest evidence of some phase II trials suggests efficacy of consolidating WBRT is comparable to ASCT. After complete remission reduced dose WBRT appears as a feasible concept with decreased neurotoxicity. Evidence for use of local stereotactic radiotherapy is very limited. Conclusion: Radiotherapy has a role in the treatment of PCNSL patients not suitable to ASCT, e.g., as consolidating reduced dose WBRT after complete response. Local stereotactic radiotherapy for residual disease should be examined in future trials. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
15 pages, 524 KiB  
Review
CAR T-Cells for CNS Lymphoma: Driving into New Terrain?
by Philipp Karschnia, Jens Blobner, Nico Teske, Florian Schöberl, Esther Fitzinger, Martin Dreyling, Joerg-Christian Tonn, Niklas Thon, Marion Subklewe and Louisa von Baumgarten
Cancers 2021, 13(10), 2503; https://doi.org/10.3390/cancers13102503 - 20 May 2021
Cited by 13 | Viewed by 4694
Abstract
Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have [...] Read more.
Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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10 pages, 566 KiB  
Review
The Role of Rituximab in the Treatment of Primary Central Nervous System Lymphoma
by Ruben Van Dijck, Jeanette K. Doorduijn and Jacoline E.C. Bromberg
Cancers 2021, 13(8), 1920; https://doi.org/10.3390/cancers13081920 - 16 Apr 2021
Cited by 7 | Viewed by 3156
Abstract
Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma limited to the central nervous system. It has a poor prognosis. Consensus has been reached on the treatment of newly diagnosed patients with high-dose methotrexate-based chemotherapy, but whether the addition of [...] Read more.
Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma limited to the central nervous system. It has a poor prognosis. Consensus has been reached on the treatment of newly diagnosed patients with high-dose methotrexate-based chemotherapy, but whether the addition of the monoclonal anti-CD20 antibody rituximab improves survival, as it does in systemic B-cell non-Hodgkin lymphoma, remains disputed. In this review, we reflect on the available evidence of the use of rituximab in PCNSL. Whether rituximab has any beneficial effect remains uncertain. Full article
(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)
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