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1.
Eur J Cancer ; 202: 114004, 2024 May.
Article in English | MEDLINE | ID: mdl-38493668

ABSTRACT

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.


Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Aged , Glioblastoma/therapy , Glioblastoma/drug therapy , Temozolomide/therapeutic use , Dacarbazine/therapeutic use , Antineoplastic Agents, Alkylating/therapeutic use , Retrospective Studies , Brain Neoplasms/therapy , Brain Neoplasms/drug therapy , Prognosis
2.
Rev Neurol (Paris) ; 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38042665

ABSTRACT

BACKGROUND: Primary central nervous system lymphoma (PCNSL) accounts for less than 5% of primary brain tumors. Epileptic seizures are a common manifestation of brain tumors; however, literature on the prevalence, characteristics, and oncological implications of seizures in patients with PCNSL is limited, and the management of antiepileptic drugs (AEDs) is unclear. This review aimed to summarize the existing knowledge on seizures in PCNSL, their potential association with surgery, oncological treatment, survival rates, and management of AEDs. METHODS: A systematic review was performed according to the PRISMA recommendations and included articles published between 1953 and 2023 describing seizures in patients with PCNSL. RESULTS: The search identified 282 studies, of which 21 were included. Up to 33% of patients with PCNSL developed seizures, mostly at the initial presentation. Little information was found on changes in seizure incidence through the course of the disease, and no details were found on seizure frequency, the percentage of treatment-resistant patients, or the evolution of seizures at remission. Younger age, cortical location, and immunodeficiency have been identified as potential risk factors for seizures, but evidence is very limited. The growing use of vigorous treatments including intensive chemotherapy with autologous stem cell transplantation and immunotherapy with CAR-T cells is associated with a higher incidence of seizures. The association between seizure development and patient mortality in PCNSL remains unknown. There are no data on AED prophylaxis or the use of specific AEDs in PCNSL. CONCLUSIONS: Further studies are needed to investigate seizures in larger cohorts of PCNSL, to clarify their prevalence, better characterize them, identify risk factors, analyze survival rates, and make recommendations on AED management. We recommend following general practice guidelines for seizures symptomatic of brain tumors and not to prescribe AED prophylaxis in PCNSL.

3.
Rev Neurol (Paris) ; 179(5): 481-489, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37045615

ABSTRACT

This review focuses on the recent progress in the management of primary central nervous system lymphoma (PCNSL). Multiomic analyses allowed to better understand the tumorigenesis of PCNSL and to establish a molecular classification with prognostic value that will optimize patient management and guide future targeted approaches. Cooperative clinical trials have demonstrated the feasibility and efficacy, in selected fit patients, of high-dose chemotherapy with autologous stem cell transplantation as post-induction consolidation, that will progressively replace whole brain radiotherapy associated with a much higher risk of delayed neurotoxicity. Several novel treatments have shown efficacy and overall good tolerance in PCNSL patients, such as Bruton's tyrosine kinase (BTK) inhibitors, imids, immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR-T). This opens promising therapeutic perspectives to improve the current standard treatment, especially for elderly and unfit patients who represent a growing population.


Subject(s)
Central Nervous System Neoplasms , Hematopoietic Stem Cell Transplantation , Lymphoma , Humans , Aged , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/drug therapy , Transplantation, Autologous , Combined Modality Therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma/therapy , Lymphoma/drug therapy
4.
Ann Hematol ; 102(5): 1159-1169, 2023 May.
Article in English | MEDLINE | ID: mdl-36991231

ABSTRACT

Primary central nervous system lymphomas (PCNSLs) classically remain confined within the CNS throughout their evolution for unknown reasons. Our objective was to analyse the rare extracerebral relapses of PCNSL in a nationwide population-based study. We retrospectively selected PCNSL patients who experienced extracerebral relapse during their follow-up from the French LOC database. Of the 1968 PCNSL included in the database from 2011, 30 (1.5%, median age 71 years, median KPS 70) presented an extracerebral relapse, either pure (n = 20) or mixed (both extracerebral and in the CNS) (n = 10), with a histological confirmation in 20 cases. The median delay between initial diagnosis and systemic relapse was 15.5 months [2-121 months]. We found visceral (n = 23, 77%), including testis in 5 (28%) men and breast in 3 (27%) women, lymph node (n = 12, 40%), and peripheral nervous system (PNS) (n = 7, 23%) involvement. Twenty-seven patients were treated with chemotherapy, either with only systemic targets (n = 7) or mixed systemic and CNS targets (n = 20), 4 were consolidated by HCT-ASCT. After systemic relapse, the median progression-free survival and overall survival (OS) were 7 and 12 months, respectively. KPS > 70 and pure systemic relapses were significantly associated with higher OS. Extracerebral PCNSL relapses are rare, mainly extranodal, and frequently involve the testis, breast, and PNS. The prognosis was worse in mixed relapses. Early relapses raise the question of misdiagnosed occult extracerebral lymphoma at diagnostic workup that should systematically include a PET-CT. Paired tumour analysis at diagnosis/relapse would provide a better understanding of the underlying molecular mechanisms.


Subject(s)
Central Nervous System Neoplasms , Lymphoma , Male , Humans , Female , Aged , Retrospective Studies , Positron Emission Tomography Computed Tomography , Neoplasm Recurrence, Local/drug therapy , Lymphoma/diagnosis , Lymphoma/epidemiology , Lymphoma/therapy , Prognosis , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols
5.
Ann Oncol ; 34(2): 186-199, 2023 02.
Article in English | MEDLINE | ID: mdl-36402300

ABSTRACT

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.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Humans , Phosphatidylinositol 3-Kinases/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Mutation , Polycomb Repressive Complex 2/genetics , Central Nervous System/pathology , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology
6.
Rev Neurol (Paris) ; 179(4): 361-367, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36302709

ABSTRACT

The role of Human pegivirus (HPgV) in patients with encephalitis has been recently questioned. We present cases of 4 patients with similar clinical, biological, and radiological characteristics, including a past history of transplantation with long-term immunosuppression and a progressive course of severe and predominantly myelitis, associated in 3 cases with optic neuropathy causing blindness. Extensive workup was negative but analysis of the CSF by use of pan-microorganism DNA- and RNA-based shotgun metagenomics was positive for HPgV. This case series further supports the hypothesis of HPgV CNS infection and highlights the utility of metagenomic next-generation sequencing of CSF in immunocompromised patients.


Subject(s)
Encephalitis , Myelitis , Optic Neuritis , Humans , Pegivirus , Myelitis/diagnosis , Myelitis/etiology , Immunocompromised Host
7.
Rev Neurol (Paris) ; 179(3): 141-149, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36336490

ABSTRACT

PCNSL is a non-Hodgkin lymphoma (NHL) affecting brain, spinal cord, eyes and leptomeninges. In the past two decades, its prognosis significantly improved due to therapeutic advances but it remains a highly aggressive tumor and early diagnosis is necessary for optimal management. Diagnosis relies on the identification of lymphoma cells in brain tissue obtained by stereotactic biopsy. Alternatively, lymphoma cells may be found in CSF through lumbar puncture (LP) or by a vitrectomy. For several reasons, the diagnosis of PCNSL may be challenging. Misleading radiological presentations are frequent. Dramatic response to steroids may bias histological analysis and deep brain location or frail health status can contraindicate brain biopsy. In the follow-up of patients who have been previously treated, differential diagnosis between tumor relapse and post-treatment may be also difficult. Therefore, the development of complementary reliable diagnostic tools is needed. This review will summarize several diagnostic or prognostic CSF biomarkers which have been proposed in PCNSL, their interests and limits.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, Non-Hodgkin , Humans , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/pathology , Neoplasm Recurrence, Local , Biomarkers , Prognosis
10.
Eur J Cancer ; 117: 121-130, 2019 08.
Article in English | MEDLINE | ID: mdl-31279304

ABSTRACT

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%). RESULTS: Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway. CONCLUSION: Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment. CLINICAL TRIAL NUMBER: NCT02542514.


Subject(s)
Central Nervous System Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Lymphoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Retinal Neoplasms/drug therapy , Salvage Therapy , Adenine/analogs & derivatives , Aged , Aged, 80 and over , Central Nervous System Neoplasms/pathology , Female , Follow-Up Studies , Humans , Lymphoma/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Piperidines , Prognosis , Prospective Studies , Retinal Neoplasms/pathology , Survival Rate
11.
Ann Oncol ; 30(4): 621-628, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30698644

ABSTRACT

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL. PATIENTS AND METHODS: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%). RESULTS: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03). CONCLUSIONS: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. CLINICAL TRIALS NUMBER: NCT01956695.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Central Nervous System Neoplasms/drug therapy , Intraocular Lymphoma/drug therapy , Lenalidomide/administration & dosage , Lymphoma, Large B-Cell, Diffuse/drug therapy , Rituximab/administration & dosage , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/mortality , Drug Administration Schedule , Female , Follow-Up Studies , France/epidemiology , Humans , Intention to Treat Analysis , Intraocular Lymphoma/mortality , Lenalidomide/adverse effects , Lymphoma, Large B-Cell, Diffuse/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Progression-Free Survival , Proof of Concept Study , Prospective Studies , Remission Induction/methods , Rituximab/adverse effects
12.
Ann Hematol ; 98(4): 915-922, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30535802

ABSTRACT

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5-82.5) and median Karnofsky performance status (KPS) was 60 (range, 40-80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2-6.2), and median overall survival was 8.2 months (95%CI: 0.6-15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Central Nervous System Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Lymphoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Rituximab/administration & dosage , Age Factors , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/mortality , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Disease-Free Survival , Female , Humans , Lymphoma/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Retrospective Studies , Survival Rate
13.
Bone Marrow Transplant ; 52(8): 1113-1119, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28436974

ABSTRACT

In this retrospective multicentre study, we investigated the outcomes of elderly primary central nervous system lymphoma (PCNSL) patients (⩾65 years) who underwent high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) at 11 centres between 2003 and 2016. End points included remission, progression-free survival (PFS), overall survival (OS) and treatment-related mortality. We identified 52 patients (median age 68.5 years, median Karnofsky Performance Status before HDT-ASCT 80%) who all underwent thiotepa-based HDT-ASCT. Fifteen patients (28.8%) received HDT-ASCT as first-line treatment and 37 (71.2%) received it as second or subsequent line. Remission status before HDT-ASCT was: CR 34.6%, PR 51.9%, stable disease 3.8% and progressive disease 9.6%. Following completion of HDT-ASCT, 36 patients (69.2%) achieved CR (21.2% first-line setting and 48.1% second or subsequent line setting) and 9 (17.3%) PR (5.8% first-line setting and 11.5% second or subsequent line setting). With a median follow-up of 22 months after HDT-ASCT, median PFS and OS were reached after 51.1 and 122.3 months, respectively. The 2-year PFS and OS rates were 62.0% and 70.8%, respectively. We observed two HDT-ASCT-associated deaths (3.8%). In selected elderly PCNSL patients, HDT-ASCT, using thiotepa-based conditioning regimes, is feasible and effective. Further prospective and comparative studies are warranted to further evaluate the role of HDT-ASCT in elderly PCNSL patients.


Subject(s)
Central Nervous System Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Thiotepa/administration & dosage , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/administration & dosage , Central Nervous System Neoplasms/mortality , Combined Modality Therapy , Disease-Free Survival , Europe , Hematopoietic Stem Cell Transplantation/mortality , Humans , Remission Induction , Retrospective Studies , Survival Analysis , Transplantation Conditioning/methods , Transplantation Conditioning/mortality , Transplantation, Autologous
15.
J Neurooncol ; 115(2): 261-5, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23955572

ABSTRACT

The aim of the present study was to evaluate the impact of first-line radiotherapy on low-grade gliomas (LGGs) growth kinetics. The mean tumor diameter (MTD) of 39 LGGs was retrospectively measured on serial magnetic resonance images before (n = 16) and after radiotherapy onset (n = 39). After radiotherapy, a decrease of the MTD was observed in 37 patients. Median duration of the MTD decrease was 1.9 years (range 0-8.1 years). According to RANO criteria, the rates of partial and minor responses were 15 and 28 % at the first evaluation after radiotherapy and 36 and 34 % at the time of maximal MTD decrease. The presence of a 1p19q codeletion and the absence of p53 expression were associated with longer durations of MTD decrease (5.3 vs 1 years, p = 0.02 and 2.4 vs 1.8 years, p = 0.05, respectively) while no association was observed between IDH1-R132H expression and duration of MTD decrease. In most patients, MTD decrease after radiotherapy occurred in two phases: an initial phase of rapid MTD decrease followed by a second phase of slower MTD decrease. Patients with a high rate of MTD decrease during the initial phase (>7 mm/year) had both a shorter duration of response (1.9 vs 5.3 years, p = 0.003) and a shorter overall survival (5.5 vs 11.6 years, p = 0.0004). LGGs commonly display a prolonged and ongoing volume decrease after radiotherapy. However, patients who respond rapidly should be carefully monitored because they are at a higher risk of rapid progression.


Subject(s)
Brain Neoplasms/radiotherapy , Glioma/radiotherapy , Adolescent , Adult , Aged , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Disease Progression , Female , Follow-Up Studies , Glioma/mortality , Glioma/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Grading , Retrospective Studies , Survival Rate , Time Factors , Treatment Outcome , Young Adult
16.
Rev Neurol (Paris) ; 167(10): 721-8, 2011 Oct.
Article in French | MEDLINE | ID: mdl-21906768

ABSTRACT

Primary CNS lymphoma is the malignant brain tumor whose prognosis has improved the most the two past decades. The majority of the patients achieve a complete remission with treatment and a substantial minority may hope to be cured. The treatment includes high-dose methotrexate polychemotherapy combined or not with whole brain radiotherapy (WBRT). Elderly patients who are exposed to a high risk of treatment induced neurotoxicity need a specific management avoiding or defering WBRT. In young patients, the main questions concerning the treatment are the role of consolidation WBRT and intensive chemotherapy with peripheral blood stem cell rescue in the initial treatment of PCNSL. As recently shown, national and international collaborative efforts make now possible randomized trials for this rare disease, which would contribute to better define the treatment strategy. New insights in PCNSL tumorigenesis would help to better understand the heterogeneity of outcome and to develop efficient targeted therapies.


Subject(s)
Central Nervous System Neoplasms/therapy , Lymphoma/therapy , Adult , Aged , Aging/physiology , Antimetabolites, Antineoplastic/therapeutic use , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/physiopathology , Combined Modality Therapy , Humans , Lymphoma/diagnosis , Lymphoma/physiopathology , Methotrexate/therapeutic use , Prognosis
17.
Neurology ; 75(17): 1560-6, 2010 Oct 26.
Article in English | MEDLINE | ID: mdl-20975057

ABSTRACT

OBJECTIVES: Recent studies have shown that IDH1 and IDH2 mutations occur frequently in gliomas, including low-grade gliomas. However, their impact on the prognosis and chemosensitivity of low-grade gliomas remains unclear. METHODS: Search for IDH1 and IDH2 mutations, loss of heterozygosity on chromosomes 1p and 19q, MGMT promoter methylation, and p53 expression was performed in a series of 271 low-grade gliomas and correlated with overall survival. A subgroup of 84 patients treated up-front with temozolomide was individualized. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, and then correlated with molecular alterations. RESULTS: IDH (IDH1 or IDH2) mutations were found in 132/189 patients (70%). IDH mutation and 1p-19q codeletion were associated with prolonged overall survival in univariate (p = 0.002 and p = 0.0001) and multivariate analysis (p = 0.003 and p = 0.004). 1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01) were correlated with a higher rate of response to temozolomide. Further analysis of the course of the disease prior to any treatment except for surgery (untreated subgroup) showed that 1p-19q codeletion was associated with prolonged progression-free survival in univariate analysis, whereas IDH mutation was not. CONCLUSION: IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in low-grade gliomas, independently of 1p-19q codeletion, whereas its impact on the course of untreated tumors seems to be limited.


Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms , Dacarbazine/analogs & derivatives , Glioma , Isocitrate Dehydrogenase/genetics , Mutation/genetics , Pharmacogenetics , Adolescent , Adult , Aged , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/mortality , Chi-Square Distribution , DNA Methylation/drug effects , DNA Methylation/genetics , DNA Modification Methylases/genetics , DNA Mutational Analysis , DNA Repair Enzymes/genetics , Dacarbazine/therapeutic use , Disease-Free Survival , Female , Glioma/drug therapy , Glioma/genetics , Glioma/mortality , Humans , Loss of Heterozygosity/genetics , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Statistics as Topic , Temozolomide , Tumor Suppressor Proteins/genetics , Young Adult
18.
Neurology ; 73(24): 2093-8, 2009 Dec 15.
Article in English | MEDLINE | ID: mdl-19907009

ABSTRACT

BACKGROUND: Low-grade gliomas (LGG) are thought to be very rare in elderly patients (>60 years) and have not been thoroughly studied. METHODS: A series of 62 elderly (>or=60 years of age) LGG patients were identified in a department database collecting information on pathologically identified adult supratentorial LGG. The clinical, radiologic, pathologic, and therapeutic data of these patients were analyzed and compared to those of 704 younger LGG patients (<60 years). RESULTS: Comparisons between older and younger groups showed that elderly patients more often presented with a clinical deficit (p < 0.0001), a lower Karnofsky performance status (p = 0.0002), a larger tumor on MRI (p = 0.03), and a lower rate of tumor resection (p < 0.0001). Chemotherapy was more often used as first line treatment (p = 0.001). Among the patients who died of progressive disease, 55% of the elderly patients had not received radiotherapy compared to 11% in the younger group (p < 0.0001). Survival was shorter in older patients (p < 0.0001), with a 5-year survival rate of 40%. An astrocytic phenotype (p = 0.0097), increasing age (p = 0.0049), and a tumor crossing the midline (p = 0.028) were negative prognostic factors in the older group. CONCLUSION: We found that 8% of low-grade gliomas (LGG) occur in older patients (>or=60 years of age). The clinical-radiologic picture of LGG in the elderly population differs from younger patients. Although long-term survival occurs, the course is generally more severe because elderly patients accumulate negative prognostic factors and because they are probably undertreated.


Subject(s)
Glioma/physiopathology , Glioma/therapy , Supratentorial Neoplasms/physiopathology , Supratentorial Neoplasms/therapy , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Disease-Free Survival , Drug Therapy/statistics & numerical data , Female , Glioma/diagnosis , Glioma/epidemiology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neurosurgical Procedures/statistics & numerical data , Prognosis , Radiotherapy/statistics & numerical data , Severity of Illness Index , Supratentorial Neoplasms/diagnosis , Supratentorial Neoplasms/epidemiology , Survival Rate , Young Adult
19.
Rev Neurol (Paris) ; 160(11): 1075-7, 2004 Nov.
Article in French | MEDLINE | ID: mdl-15602350

ABSTRACT

INTRODUCTION: Neuromyotonia is a late and rare complication of radiation therapy, consisting of involuntary sustained muscle contractions with a delay in relaxation. OBSERVATION: We report the case of a 68-year-old man who developed neuromyotonia of the masseter muscle 6 years after irradiation for tonsil carcinoma. CONCLUSION: This observation underlines the importance of a correct diagnosis that can lead to an efficient treatment by carbamazepine.


Subject(s)
Isaacs Syndrome/etiology , Masseter Muscle , Radiation Injuries/etiology , Aged , Humans , Male
20.
J Natl Cancer Inst ; 88(16): 1136-45, 1996 Aug 21.
Article in English | MEDLINE | ID: mdl-8757193

ABSTRACT

BACKGROUND: The development of immunotoxins has been hampered by difficulties, particularly in solid tumors, of finding appropriate target antigens and of linking sufficiently potent toxins. PURPOSE: We evaluated the tissue specificity of an immunotoxin, N901-blocked ricin (N901-bR), and assessed its potential for eliminating neural cell adhesion molecule (NCAM)-positive tumor cells in conditions appropriate for in vitro purging, prior to autologous stem cell transplantation, and its potential for myelosuppression. N901-bR consists of a monoclonal antibody (MAb), N901, directed against CD56, an antigen of the family of NCAMs, covalently linked to blocked ricin as the cytotoxic effector moiety. METHODS: The tissue specificity of the N901 MAb and the N901-bR immunotoxin was tested against a wide array of human tumor tissues and normal human tissues by immunohistochemical staining. The cytotoxic activity of N901-bR was tested against both small-cell lung cancer (SCLC) cells and neuroblastoma cells, either alone or among normal bone marrow mononuclear cells, and the efficacy of this treatment to specifically eliminate these cells was evaluated in a limiting dilution assay. In addition, normal bone marrow mononuclear cells were incubated with N901-bR, and the toxic effects of the immunotoxin on normal hematopoietic progenitors was evaluated. RESULTS: N901 and N901-bR exhibited specificity for several neoplasms of neuroectodermal origin, including SCLC and neuroblastoma. Staining of normal tissues was essentially limited to various neuroendocrine cells, cardiac muscle cells, and cells in peripheral nerve tissue. We observed a time- and dose-dependent elimination of tumor cells in vitro, with three logs (i.e., > 99.9%) of malignant cells being killed following only 5 hours of exposure to 10 nM N901-bR. Unconjugated N901 MAb specifically blocked the elimination of NCAM-positive cells by N901-bR, whereas neither an isotype-matched control MAb nor galactose (the ligand of native ricin) had any effect on the activity of the immunotoxin, confirming the specificity of its cytotoxic activity. Importantly, N901-bR used under optimal conditions for in vitro tumor cell depletion was not toxic to hematopoietic precursors. CONCLUSIONS: N901-bR has the properties required to target CD56, an antigen present not only on cells from a large number of cancers of neuroendocrine origin, but also on some important normal tissues. In addition, treatment with this immunotoxin results in the highly effective and specific elimination of neuroblastoma and SCLC cells and does not affect normal hematopoietic progenitors. IMPLICATIONS: N901-bR may have clinical utility for purging of neuroblastoma cells and SCLC cells before autologous stem cell transplantation. Further toxicology studies are warranted to assess the potential of N901-bR for in vivo administration.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Carcinoma, Small Cell/immunology , Immunotoxins/therapeutic use , Lung Neoplasms/immunology , Neural Cell Adhesion Molecules/immunology , Neuroblastoma/drug therapy , Ricin/analogs & derivatives , Bone Marrow Purging/methods , Dose-Response Relationship, Drug , Hematopoietic Stem Cells , Humans , Immunoconjugates , Immunohistochemistry , Immunophenotyping , Organ Specificity , Ricin/therapeutic use , Time Factors
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