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ESMO Open Aug 2021Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of... (Review)
Review
Primary diffuse large B-cell (DLBCL) lymphoma of the central nervous system (CNS) (PCNSL) is a new lymphoma entity, recognized by the 2017 WHO classification of hematopoietic and lymphoid tumors. Unlike systemic DLBCL, the use of anthracycline-based chemotherapy combinations is associated with disappointing outcomes, due to low CNS bioavailability of related drugs. Therefore, international researchers investigated alternative strategies, mostly including drugs able to cross the blood-brain-barrier at low or high doses, with a progressive improvement in survival. Some effective chemotherapy combinations of high-dose methotrexate (HD-MTX) with alkylating agents and rituximab with or without cytarabine have been tested in international randomized trials and represent the induction treatment in everyday practice, with some variations among different geographical areas. In patients aged 70 years or younger, MATRix (HD-MTX/cytarabine/thiotepa/rituximab) chemotherapy followed by consolidative high-dose chemotherapy plus autologous stem cell transplantation or whole-brain irradiation has been associated with a significant improvement in overall survival. Other treatment options, such as non-myeloablative high-dose chemotherapy, oral drug maintenance, and some targeted drugs like ibrutinib or lenalidomide, are being tested in high-level international trials. These steps toward further effective treatments are motivated by an incessant search for less neurotoxic options. Thanks to international cooperation, we can affirm that PCNSL is a potentially curable tumor, especially in young patients. However, several questions remain unanswered: the optimal treatment for elderly patients as well as the management of intraocular and meningeal disease require further scientific efforts. Beside treatments, advances on molecular and radiological diagnostic tools will increase our knowledge of this disease, allowing the possibility to anticipate diagnosis and to better categorize patients' responses. This article analyzes the available literature in this setting and provides evidence-based recommendations for the management of PCNSL patients.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Transplantation, Autologous
PubMed: 34271311
DOI: 10.1016/j.esmoop.2021.100213 -
Annals of Oncology : Official Journal... Feb 2023Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to...
BACKGROUND
Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.
PATIENTS AND METHODS
To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data.
RESULTS
Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue.
CONCLUSIONS
The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.
Topics: Humans; Phosphatidylinositol 3-Kinases; Lymphoma, Large B-Cell, Diffuse; Mutation; Polycomb Repressive Complex 2; Central Nervous System; Central Nervous System Neoplasms
PubMed: 36402300
DOI: 10.1016/j.annonc.2022.11.002 -
Current Oncology (Toronto, Ont.) Jun 2023The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer... (Review)
Review
The present review aimed to establish an understanding of the pathophysiology of leptomeningeal disease as it relates to late-stage development among different cancer types. For our purposes, the focused metastatic malignancies include breast cancer, lung cancer, melanoma, primary central nervous system tumors, and hematologic cancers (lymphoma, leukemia, and multiple myeloma). Of note, our discussion was limited to cancer-specific leptomeningeal metastases secondary to the aforementioned primary cancers. LMD mechanisms secondary to non-cancerous pathologies, such as infection or inflammation of the leptomeningeal layer, were excluded from our scope of review. Furthermore, we intended to characterize general leptomeningeal disease, including the specific anatomical infiltration process/area, CSF dissemination, manifesting clinical symptoms in patients afflicted with the disease, detection mechanisms, imaging modalities, and treatment therapies (both preclinical and clinical). Of these parameters, leptomeningeal disease across different primary cancers shares several features. Pathophysiology regarding the development of CNS involvement within the mentioned cancer subtypes is similar in nature and progression of disease. Consequently, detection of leptomeningeal disease, regardless of cancer type, employs several of the same techniques. Cerebrospinal fluid analysis in combination with varied imaging (CT, MRI, and PET-CT) has been noted in the current literature as the gold standard in the diagnosis of leptomeningeal metastasis. Treatment options for the disease are both varied and currently in development, given the rarity of these cases. Our review details the differences in leptomeningeal disease as they pertain through the lens of several different cancer subtypes in an effort to highlight the current state of targeted therapy, the potential shortcomings in treatment, and the direction of preclinical and clinical treatments in the future. As there is a lack of comprehensive reviews that seek to characterize leptomeningeal metastasis from various solid and hematologic cancers altogether, the authors intended to highlight not only the overlapping mechanisms but also the distinct patterning of disease detection and progression as a means to uniquely treat each metastasis type. The scarcity of LMD cases poses a barrier to more robust evaluations of this pathology. However, as treatments for primary cancers have improved over time, so has the incidence of LMD. The increase in diagnosed cases only represents a small fraction of LMD-afflicted patients. More often than not, LMD is determined upon autopsy. The motivation behind this review stems from the increased capacity to study LMD in spite of scarcity or poor patient prognosis. In vitro analysis of leptomeningeal cancer cells has allowed researchers to approach this disease at the level of cancer subtypes and markers. We ultimately hope to facilitate the clinical translation of LMD research through our discourse.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Meningeal Carcinomatosis; Breast Neoplasms; Magnetic Resonance Imaging; Hematologic Neoplasms
PubMed: 37366925
DOI: 10.3390/curroncol30060442 -
British Journal of Haematology Jun 2022Central nervous system (CNS) lymphomas are rare malignancies characterised by lymphoid infiltration into the brain, spinal cord, cranial nerves, meninges and/or eyes in... (Review)
Review
Central nervous system (CNS) lymphomas are rare malignancies characterised by lymphoid infiltration into the brain, spinal cord, cranial nerves, meninges and/or eyes in the presence or absence of previous or concurrent systemic disease. Most CNS lymphomas are of the diffuse large B-cell lymphoma (DLBCL) subtype for which treatment strategies, particularly the use of high-dose methotrexate-based protocols and consolidation with autologous stem cell transplantation, are well established. Other histopathological subtypes of CNS lymphoma are comparatively less common with published data on these rare lymphomas dominated by smaller case series and retrospective reports. Consequently, there exists little clinical consensus on the optimal methods to diagnose and manage these clinically and biologically heterogeneous CNS lymphomas. In this review article, we focus on rarer CNS lymphomas, summarising the available clinical data on incidence, context, diagnostic features, reported management strategies, and clinical outcomes.
Topics: Central Nervous System Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Meninges; Retrospective Studies; Transplantation, Autologous
PubMed: 35292959
DOI: 10.1111/bjh.18128 -
Medicine Dec 2022Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and isolated meningeal PCNSL, without evidence of parenchymal involvement, is... (Review)
Review
RATIONALE
Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and isolated meningeal PCNSL, without evidence of parenchymal involvement, is even less common, occurring in only 10% to 15% of cases.
PATIENT CONCERNS
A 65-years-old female presented to our hospital with progressive lower extremity motor dysfunction and blurred vision. The initial neurological examination revealed decreased muscle strength in both lower extremities and sensory dysfunction of lower extremities, saddle area, and buttocks. Brain magnetic resonance imaging showed no abnormalities. Lumbar enhanced magnetic resonance imaging showed T11 to L3 horizontal meningeal enhancement. Cerebrospinal fluid (CSF) cytology revealed lymphoma cells. Immunohistochemistry and flow cytometry of the CSF were performed as auxiliary methods to establish the diagnosis of lymphoma.
DIAGNOSES
The patient was diagnosed primary meningeal central nervous system lymphoma.
INTERVENTIONS
During hospitalization, the patient was treated with 2 courses of high-dose intrathecal methotrexate and rituximab combined with intrathecal chemotherapy and supportive treatment.
OUTCOMES
After 2 years of follow-up, the patient was able to walk and take care of herself.
LESSONS
Cases of PCNSL involving only the meninges are rare. Multimodal analysis of the CSF comprises an important component of the diagnostic work-up for patients with primary meningeal central nervous system lymphoma.
Topics: Humans; Female; Aged; Central Nervous System Neoplasms; Lymphoma; Meninges; Rituximab; Brain
PubMed: 36596043
DOI: 10.1097/MD.0000000000032567 -
Hippokratia Jan 2014Functional hyposplenism is a condition accompanying many diseases such as sickle cell disease, celiac disease, alcoholic liver disease, hepatic cirrhosis, lymphomas and...
Functional hyposplenism is a condition accompanying many diseases such as sickle cell disease, celiac disease, alcoholic liver disease, hepatic cirrhosis, lymphomas and autoimmune disorders. It is characterised mostly by defective immune responses against infectious agents, especially encapsulated organisms, since the spleen is thought to play an important role in the production and maturation of B-memory lymphocytes and other substances like opsonins, both of which are considered crucial elements of the immune system for fighting infections. It is also associated with thrombocytosis, which might lead to thromboembolic events. Functional hyposplenism is diagnosed by the presence of Howell-Jolly bodies and pitted erythrocytes in the peripheral blood smear, and by nuclear imaging modalities such as spleen scintigraphy with the use of Technetium-99m and/or spleen scintigraphy with the use of heat-damaged Technetium-99m labeled erythrocytes. Severe infections accompanying functional hyposplenism can lead to the overwhelming post infection syndrome, which can often be fatal. Identifying patients with functional hyposplenism is important because simple measures such as vaccination against common infective microorganisms (e.g. Streptococcus pneumonia, Neisseria meningitides and Haemophilous influenzae) and antibiotic therapy when needed are considered beneficial in diminishing the frequency and gravity of the infections accompanying the syndrome.
PubMed: 25125944
DOI: No ID Found -
Chinese Clinical Oncology Jun 2015Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated... (Review)
Review
Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options.
Topics: Animals; Combined Modality Therapy; Humans; Meningeal Carcinomatosis; Meningitis; Neuroimaging; Patient Selection; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 26112812
DOI: 10.3978/j.issn.2304-3865.2015.05.02 -
Cancer May 2023Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction.... (Review)
Review
Management of brain tumors has been challenging given the limited therapeutic options and disabling morbidities associated with central nervous system (CNS) dysfunction. This review focuses on recent developments in the field, with an emphasis on clinical management. The growing clinical trials landscape reflects advanced insights into cancer immunology and genomics and the need to address molecular and clinical heterogeneity. Recent phase 3 trials investigating anti-PD-1 immunotherapies, particularly nivolumab, have failed to demonstrate improved survival in glioblastoma, underscoring the need to better understand the complexity of CNS immunologic surveillance. Conversely, targeted therapies have accounted for several US Food and Drug Administration approvals extended to brain tumors, particularly therapies directed to BRAF V600E mutations and TRAK fusions, underscoring a need to routinely screen patients for these rare molecular abnormalities. In primary CNS lymphoma, attention has turned to long-term outcomes of consolidation therapies, and recent studies have highlighted the excellent disease control afforded by high-dose chemotherapy and stem cell transplantation. Meningiomas remain a focus of investigations, with preliminary promising results observed with octreotide combined with mTOR inhibition, and immunotherapy with single-agent pembrolizumab. Finally, proton radiotherapy has emerged as a novel alternative for leptomeningeal metastases from solid tumors, which can now be treated more safely with craniospinal irradiation and monitored by the enumeration of circulating tumor cells in the cerebrospinal fluid as a biomarker. Taken together, these incremental advances have improved outcomes in select brain tumor patient populations, whereas ongoing clinical trials hold the promise of meaningful advances and breakthroughs for larger proportions of patients with brain tumors.
Topics: Humans; Brain Neoplasms; Glioblastoma; Meningioma; Meningeal Neoplasms
PubMed: 36825454
DOI: 10.1002/cncr.34711 -
European Journal of Case Reports in... 2022Uveo-meningeal syndromes are any disorder characterized by the involvement of the uvea and the meninges. They can have multiple causes, including infectious, autoimmune...
UNLABELLED
Uveo-meningeal syndromes are any disorder characterized by the involvement of the uvea and the meninges. They can have multiple causes, including infectious, autoimmune and malignant diseases. We report the case of a patient with a 10-year-old diagnosis of myelodysplastic syndrome that had been stable. He presented with new onset uveitis, ataxia, diplopia and fluctuating consciousness level, without any obvious cause revealed by brain imaging or blood chemistries. An extensive aetiological search showed no obvious cause. Initially, the patient improved spontaneously and was discharged. However, 2 months later, he deteriorated once again, this time with disperse adenomegalies that were not present previously. The bone marrow biopsy showed a high number of blasts, which affirmed the progression of the previously known myelodysplastic syndrome. The lymph nodes were not biopsied due to very low life expectancy, making the procedure futile. A presumptive diagnosis of uveo-meningitis caused by paraneoplastic syndrome was made. The patient died a few months later.
LEARNING POINTS
Uveo-meningeal syndrome (UMS) is a rare entity usually of infectious or inflammatory aetiology.UMS may be caused by some neoplastic disorders, mainly lymphoma and metastasis of solid tumours; myelodysplastic syndrome (MDS) has not been previously implicated.Diagnosis should include lumbar puncture and a thorough search for the aetiology; treatment is directed towards the aetiology.
PubMed: 36415835
DOI: 10.12890/2022_003633 -
Cancer Control : Journal of the Moffitt... Jan 2017Leukemic and lymphomatous meningitis is a major presentation of primary or secondary central nervous system (CNS) involvement by aggressive lymphomas or acute leukemia. (Review)
Review
BACKGROUND
Leukemic and lymphomatous meningitis is a major presentation of primary or secondary central nervous system (CNS) involvement by aggressive lymphomas or acute leukemia.
METHODS
The medical literature and ongoing clinical trials were reviewed on the clinical presentation, diagnosis, prognosis, prevention, and treatment of leukemic and lymphomatous meningitis.
RESULTS
Treatment for secondary leukemic and lymphomatous meningitis remains unsatisfactory, and efforts should be made to prevent and treat subclinical disease. Intrathecal and systemic chemotherapy remain the main therapeutic approaches for this disease. Outcomes have improved in patients with primary CNS lymphoma and meningeal involvement.
CONCLUSIONS
Appropriate selection of patients at high risk for leukemic and lymphomatous meningitis is important so that preventive strategies can decrease the incidence of this complication of leukemia and lymphoma. Use of chemotherapy agents that cross the blood-brain barrier and the adoption of high-dose chemotherapy with autologous hematopoietic stem cell transplantation have increased the proportion of patients whose primary disease is cured.
Topics: Disease Management; Humans; Leukemia; Lymphoma; Meningitis; Prognosis
PubMed: 28178710
DOI: 10.1177/107327481702400105