Molecular and clinical diversity in primary central nervous system lymphoma.

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.

Systemic relapses of primary CNS lymphomas (PCNSL): a LOC network study.

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.

Long-term survival in patients with recurrent glioblastoma treated with bevacizumab: a multicentric retrospective study.

PURPOSE: Recurrence of glioblastoma (GB) occurs in most patients after standard concomitant temozolomide-based radiochemotherapy (CTRC). Bevacizumab (BV), an anti-VEGF antibody, has an effect on progression-free survival (PFS) but not on overall survival (OS). However, a small part of the patients experience a survival, longer than expected. This retrospective study aims to characterize long responder (LR) patients treated with BV for a first or second GBM recurrence. METHODS: Medical records from patients (814) who received BV for a first or second recurrence of primary glioblastoma between September 2010 and September 2015, and initially treated by CTRC were analyzed. Patients, who had at least a stable disease according to RANO criteria at 12 months from the start of BV, were included. Patients who had, a secondary GB, or received BV in neoadjuvant or adjuvant setting were excluded. RESULTS: We focused on 65 LR patients without progression 12 months after the first injection of BV (8%). Median PFS was 21.7 months [95% CI (19.3; 27.2)] and median OS was 31.1 months [95% CI (24.3; 37.5)] from the start of BV. No prognostic factor was associated with OS in multivariate analysis. Karnofsky performance status, neurological status and corticosteroid dose were stable at 12 months. CONCLUSIONS: Our results highlight that among patients receiving bevacizumab in first or second recurrence, one patient out of twelve could be classified as LR. A median OS of 31.1 months from the start of BV could be expected in this subpopulation. These findings reinforce the potential benefit of the use of BV in the situation of recurrence. 256 words.

Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEF†.

BACKGROUND: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB. PATIENTS AND METHODS: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm. RESULTS: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm. CONCLUSIONS: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB. CLINICAL TRIAL REGISTRATION: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).

Impact of fractionated stereotactic radiotherapy on activity of daily living and performance status in progressive/recurrent glioblastoma: a retrospective study.

BACKGROUND: The prognosis of recurrent glioblastoma (GBM) is poor, with limited options of palliative localized or systemic treatments. Survival can be improved by a second localized treatment; however, it is not currently possible to identify which patients would benefit from this approach. This study aims to evaluate which factors lead to a lower Karnofsky performance status (KPS) score after fractionated stereotactic RT (fSRT). METHODS: We retrospectively collected data from patients treated with fSRT for recurrent GBM at the Institut de Cancérologie de Lorraine between October 2010 and November 2017 and analyzed which factors were associated with a lower KPS score. RESULTS: 59 patients received a dose of 25 Gy in 5 sessions spread over 5-7 days (80% isodose). The median time from the end of primary radiotherapy to the initiation of fSRT was 10.7 months. The median follow-up after fSRT initiation was 8.8 months. The incidence of KPS and ADL impairment in all patients were 51.9% and 37.8% respectively with an adverse impact of PTV size on KPS (HR = 1.57 [95% CI 1.19-2.08], p = 0.028). Only two patients showed early grade 3 toxicity and none showed grade 4 or late toxicity. The median overall survival time, median overall survival time after fSRT, median progression-free survival and institutionalization-free survival times were 25.8, 8.8, 3.9 and 7.7 months, respectively. Initial surgery was associated with better progression-free survival (Hazard ratio (HR) = 0.48 [95% CI 0.27-0.86], p = 0.013). CONCLUSIONS: A larger PTV should predicts lower KPS in the treatment of recurrent GBM using fSRT.

Supportive care in neurooncology.

The quality of life of patients treated for brain tumor is, in all cases, deeply altered by the tumor and the treatments. Optimizing the symptomatic management is a key objective for all care givers. We present in this paper a very pragmatic focus concerning the management of intracranial hypertension (and/or neurological deficits), venous thromboembolism, confusion, epilepsy and symptoms more directly associated with the end of life.

[Medulloblastomas: review]. / Les médulloblastomes: revue générale.

INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.

[Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. / Bevacizumab/irinotecan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d'une étude multicentrique de l'Anocef.

RATIONALE: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. OBJECTIVE: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. METHODS: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. RESULTS: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1). CONCLUSION: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

Descriptive epidemiology of 13,038 newly diagnosed and histologically confirmed meningiomas in France: 2006-2010.

PURPOSE: This work describes the clinical epidemiology and pathology for patients undergoing surgery for newly diagnosed meningiomas in France between 2006 and 2010. METHODS: The methodology is based on a multidisciplinary national network previously established by the French Brain Tumor DataBase (FBTDB) (in French: Recensement national histologique des tumeurs primitives du système nerveux central [RnhTPSNC]), and the active participation of the scientific societies involved in neuro-oncology in France. RESULTS: From 2006 to 2010, 13,038 incident cases of meningioma with histological validation were identified and analyzed (9769 women, 3269 men, resection 98.2%, cryopreservation 20.5%). For each histological subtype of meningioma (meningothelial, fibrous, transitional, psammomatous, angiomatous, rare variety, microcystic, secretory, lymphoplasmacyte-rich, clear-cell, chordoid, rhabdoid, metaplastic, atypical, papillary, anaplastic and not otherwise specified), number of cases, sex, median age, cryopreservation and surgery were reported. Among the various histological subtypes, atypical meningioma (grade II) slightly, but significantly, increased after 2007. Headache, sensory-motor impairments and seizures were the most frequent clinical symptoms. Time between the first clinical symptom and surgery ranged from 0 to 314 months, and was <3 months in 37% of cases. At the time of surgery, 9% of patients were asymptomatic. DISCUSSION/CONCLUSION: Given the number of meningiomas not histologically-validated, we can estimate that the gross incidence rate for meningiomas operated in France is about 4.2 per 100,000 person/year. To our knowledge, this work is the most important study evaluating the different subtypes of meningiomas and it validates the relevance of histological databases for central nervous system tumors.

[Hypofractionated stereotactic radiotherapy for brain metastasis: Benefit of additional whole brain radiotherapy?] / Radiothérapie stéréotaxique hypofractionnée des métastases cérébrales : bénéfice de l'irradiation encéphalique totale ?

PURPOSE: To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife®, according to the association or not with an additional whole brain irradiation. PATIENTS AND METHODS: Institutional retrospective study of 102 patients treated for one to three brain metastasis: 76 with exclusive hypofractionated stereotactic radiotherapy and 26 with hypofractionated stereotactic radiotherapy and whole brain irradiation. Objectives were assessed and compared between these two groups according to the Kaplan-Meier method and Cox model. RESULTS: Median follow-up was 18.8 months. There were no difference between exclusive hypofractionated stereotactic radiotherapy and hypofractionated stereotactic radiotherapy with whole brain irradiation for overall survival (respective median 21.5 and 20.1 months), risk of neurological death (respectively 9.2% and 15.4% at one year). At one year: the risk of cerebral progressive disease was greater in the group receiving exclusive hypofractionated stereotactic radiotherapy (respectively 43.4% vs. 26.2%, P=0.043), the risk of local recurrence was 25% versus 17.6% (P=0.28) and the development of new brain metastasis was 23.7% versus 11.5% (P=0.27). After salvage treatments, crude local control was similar in the two groups, respectively 78.6% and 73.5%. Whole brain irradiation has been avoided for 72.4% of patients in the group receving exclusive hypofractionated stereotactic radiotherapy. CONCLUSION: Whole brain irradiation improves local control of brain metastatic disease in addition to hypofractionated stereotactic radiotherapy. Sparing whole brain irradiation for salvage treatments only does not affect overall survival or risk of neurological death in selected patients with favourable prognosis.

[Cerebral gliomas: imaging diagnosis and follow-up]. / Imagerie cérébrale des gliomes: diagnostic et suivi conventionnels.

The management of gliomas evolves towards more aggressive strategies with a combination of surgery, radiotherapy and chemotherapy. Follow-up imaging based on morphological MRI, with simple and reproducible protocols, may be associated with functional MRI and spectroscopy. Baseline postsurgical MRI must be performed within the first three days. Follow-up examinations should be done 2 months after radiotherapy and during chemotherapy, usually after each cycle of two or three treatments. Continued follow-up after therapy is recommended to assess response and detect recurrences or therapeutic complications.

Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

PURPOSE: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma. PATIENTS AND METHODS: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years. RESULTS: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively. CONCLUSION: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.

Comparison of intravenous and intra-arterial urokinase thrombolysis for acute ischaemic stroke.

Intravenous fibrinolysis (IVF) with rt-PA (alteplase) provides significant benefits in acute ischaemic stroke when it is given within the first three hours following stroke onset. Intra-arterial fibrinolysis (IAF) with pro-urokinase in PROACT II study provides quite the same benefit in the first 6 hours. IVF and IAF have never been compared. To compare the efficacy and safety of IVF and IAF with urokinase given within the first 6 hours of acute ischaemic stroke. Patients fulfilling the selection criteria were randomly assigned to receive urokinase 900,000 units via intravenous or intra-arterial routes. This randomised monocentre study was done between December 1995 and August 1997. The primary outcome was defined as the number of patients with a modified Rankin score of 2 or less. Secondary outcomes included mortality, frequency of symptomatic intracranial haemorrhage (SIH), neurological and functional scores. Fourteen patients were given IVF and 13 IAF. The study was terminated by the National Health Authorities when 27 patients had been included because of the mortality rate. Seven patients (26%) died, 4 in the IV group (oedematous infarct in 3 and recurrence in 1), 3 in the IA group (SIH in 2, and oedematous infarct in 1). Patients given IVF were treated significantly earlier (4:16 h vs 5:24 h; p=.007). Although IA patients showed greater and earlier improvement there was no significant difference in primary and secondary outcomes. Because of premature termination, the trial was too small to provide any reliable and conclusive results. Intra-arterial fibrinolysis began significantly later than IV fibrinolysis but it gave non-significantly better results in this prematurely terminated study.

[Supportive care, cognition and quality of life in brain metastases]. / Soins de support, cognition, qualité de vie et métastases cérébrales.

Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.

Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study.

Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event.

Astrocytomas and choroid plexus tumors in two families with identical p53 germline mutations.

Germline p53 mutations carry an increased risk of development of breast cancer, soft tissue and osteosarcomas, brain tumors, leukemia and adrenocortical carcinomas. Cerebral neoplasms are usually of astrocytic lineage and occur in 40% of affected families. This report presents clinical, neuropathological and molecular genetic data from 2 families in France with an identical p53 germline mutation in codon 248 (CGG->TGG; Arg->Trp) and a clustering of CNS tumors. The youngest patient in each family developed a malignant choroid plexus tumor while several young adults of both kindred succumbed to low-grade astrocytoma, anaplastic astrocytoma or glioblastoma. The only non-neural neoplasm was an adrenocortical carcinoma in a boy aged 4 years who developed an anaplastic choroid plexus papilloma 2 years later. Of 2 previously reported inherited choroid plexus tumors, 1 occurred in a family which also carried a germline mutation in codon 248. It remains to be shown whether this unusual pattern of CNS tumors is due to an organ-specific effect of this particular p53 mutation or whether it reflects the genetic background of the affected families.

Radiation therapy for malignant astrocytomas in adults.

High grade (or malignant) astrocytomas remain a formidable therapeutic challenge. The main prognostic factors are patient age, patient performance status, tumor grade, the extent of surgical resection and the presence of fits. These factors could help to identify different groups of patients and should be an advantage in deciding on treatment strategies. Modern imaging techniques provide a more precise idea of tumor volume. The study of tumor recurrence shows that they occur in the immediate vicinity of the primary site. Surgery aside, radiotherapy remains the most important treatment modality. Currently, its standards concerning optimal dose and target volume appear to be accepted overall. There is no doubt that a dose-response relation exists; however, doses exceeding 60 Gy increase morbidity. Therefore 60 Gy is the dose most often cited in the literature. Furthermore, as whole brain irradiation does not decrease the risk of recurrence, a focal irradiation including a defined mean volume is generally used today. Radiosensitizers and heavy particles have not fulfilled their initial promise. Brachytherapy remains an interesting alternative for a limited number of patients. Nevertheless, it seems to increase recurrence at a distance from the primary site and to lead to severe focal lesions. Interstitial thermoradiotherapy may minimize local doses and thus help avoid serious local necrosis. Amongst the other therapeutic alternatives, intravenous chemotherapy using nitrosoureas provides a certain but modest benefit. Other administration modalities are currently undergoing evaluation. These include intra-arterial chemotherapy or high dose chemotherapy with auto-bone marrow transplantation. The interest of this latter is concerned mainly with anaplastic astrocytomas. Finally, among the future alternatives, gene therapy appears to hold the most promise. Intensive therapies, combined modality treatments, with the recent help of biological innovations, should be proposed to favorable groups of patients.

[Thrombosis of deep cerebral veins in form adults: clinical features and diagnostic approach]. / Les thromboses veineuses profondes de l'encéphale de l'adulte: aspects cliniques et approche diagnostique.

Thrombosis of deep cerebral veins is a rare condition, and is associated with a poor prognosis. We report four new cases observed between 1994 and 1997. All four cases were women, aged less than 45 years. Initial symptoms associated alteration of consciousness, change in mental status, progressive headache and vomiting. We observed also uni or bilateral signs of long tract injury. In three cases, diagnosis initially suspected by CT scan was confirmed with encephalic MRI. For the last patient, conventional angiography was needed. Thrombosis affected straight sinus, vein of Galien and internal cerebral veins in all patients. Basilar veins were also affected in one patient, without dural sinuses extension. Lateral sinus was involved in two others cases, and superior sagittal in the last patient. Etiology remains undetermined in one patient, associated with post-partum, use of oral contraceptive pill, and familial protein S deficiency, one case each. Outcome was favorable in all four cases with anticoagulation therapy. Precocity of diagnosis is determinant and MRI is usefull in this issue. These observations show that evolution of deep veins thrombosis can be favorable, without needing fibrinolytic therapy.

[Multifocal progressive leukoencephalitis in a patient given fludarabine for chronic lymphoid leukemia]. / Leucoencéphalopathie multifocale progressive après traitement par fludarabine dans une leucémie lymphoïde chronique.

A 74-year- man was hospitalized for subacute aphasia and right hemiparesis. He had had chronic lymphoid leukemia for 11 years and had been treated 5 months earlier with 3 courses of fludarabine. Magnetic resonance imaging showed lesions of the temporo-occipital white matter compatible with progressive multifocal leukoencephalitis (PML). The presence of JC virus was demonstrated first by in situ hybridation after a brain biopsy and second with polymerase chain reaction on CSF. The diagnosis of PML was confirmed. The causality of fludarabine treatment is discussed.

[Ocular involvement during primary central nervous system lymphoma]. / L'atteinte oculaire au cours des lymphomes primitifs du système nerveux central.

PURPOSE: The aim of our study was to assess and to characterize the ocular involvement in patients with primary central nervous system lymphoma. POPULATION AND METHODS: We conducted a prospective study between August 1995 and December 1998 on a cohort of consecutive patients affected by primary central nervous system lymphoma and who underwent a systematic ophthalmological examination before treatment. RESULTS: The study population comprised 24 patients (mean age, 57 years; 16 women and 8 men). Among these patients, 6 had ocular involvement (2 patients with ocular signs revealing the cerebral process, 2 evidenced at the time of the initial ocular examination, and 1 as the disease evolved). Ocular involvement was vitritis in all cases, anterior uveitis in 1 patient, obliterant vasculitis in 1 patient and yellowish subretinal lesions in 1 patient. In 1 case, a vitrectomy led to adequate diagnosis of the disease. CONCLUSION: Our study shows a 25% incidence of ocular involvement in patients with primary central nervous system lymphoma, with posterior uveitis as the most common manifestation. Because of the relatively high incidence of ocular involvement, a systematic ophthalmological examination of this subset of patients should be mandatory.