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.

CSF biomarkers in primary CNS lymphoma.

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.

(R)-GEMOX chemotherapy for unfit patients with refractory or recurrent primary central nervous system lymphoma: a LOC study.

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.

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.

Myelin oligodendrocyte glycoprotein antibodies in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disease of the central nervous system characterized, in particular, by disabling episodes of optic neuritis and longitudinal extensive transverse myelitis. Its main pathogenic characteristic is the presence of anti-aquaporin-4 antibodies (AQP4-Abs) in the serum of affected patients. However, a proportion of patients with the typical NMOSD phenotype are, in fact, negative (seronegative) for AQP4-Abs and, within this category of patients, a proportion of them instead express antibodies to myelin oligodendrocyte glycoprotein (MOG-Abs). The presence of MOG-Abs in the sera of seronegative NMOSD patients is more frequently associated with monophasic disease and moderate symptom severity, and also appears to predict a better outcome. The present report is a review of the clinical and immunological features of MOG-Ab-positive NMOSD.

Patterns of relapse in patients with high grade glioma receiving combined treatments including stereotactic re-irradiation for a first relapse.

PURPOSE: Bevacizumab and stereotactic treatment are efficient combined or alone in relapse glioma. However, patterns of relapse after this kind of salvage treatment have never been studied. The purpose of this unicentric retrospective analysis was to assess and understand the patterns of relapse of high grade glioma treated with stereotactic radiation, with or without bevacizumab. PATIENTS AND METHODS: Twenty patients with high grade glioma relapse received a stereotactic radiation; among them two patients received temozolomide and eight patients received bevacizumab; among the latter, four received also irinotecan. We matched the stereotactic radiation treatment planning scan with the images of the first treatment and of the second relapse in order to determine the patterns of failure and associate dosimetric profile. RESULTS: For the total population, median follow-up from the first diagnosis and relapse were 46.1 and 17.6 months, respectively. Among the 13 patients who relapsed, ten did not receive chemotherapy and three received it (P<0.05), two received temozolomide and one bevacizumab. Patients who received bevacizumab had no "out-of-field" recurrences. Among the 32 irradiated relapses, 15 were "in-field" recurrences; among them two were treated with bevacizumab and 13 were not (P<0.05). For the 32 lesions, a favourable prognostic factor of control was the association of a high-dose of irradiation and the use of bevacizumab. CONCLUSION: For patients with relapsed high grade glioma, local control was higher with combined bevacizumab and high-dose stereotactic radiation.

Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a common side effect of long-term medication with typical neuroleptics. TD presents itself by abnormal involuntary movements and may lead to a potentially disabling and chronic clinical course. A vast majority of patients suffering from schizophrenia are smokers. Smoking has been reported to induce the activity of the CYP1A2 enzyme, which is an established metabolic pathway within the disposition of antipsychotics. Recently, a C-->A genetic polymorphism in the first intron of the CYP1A2 gene was reported to influence CYP1A2 activity in smokers. Subsequently, a pharmacogenetic study in 85 U.S. patients with schizophrenia (44 smokers, 41 individuals with unknown smoking status) showed the C/C genotype to be associated with higher TD severity (measured by the Abnormal Involuntary Movement Scale, AIMS) than the A/C or A/A genotype. This finding prompted us to investigate whether this effect was also present in a larger German sample of 119 patients with schizophrenia (82 smokers, 37 individuals with unknown smoking status). However, we could not replicate the reported association. The median AIMS scores did not differ between individuals with the A/A, A/C, or C/C genotypes. In an additional analysis, we compared the genotypic and allelic distribution among individuals grouped according to the criteria established by Schooler and Kane [1982: Arch Gen Psychiatry 39:486-487] (persistent TD vs. absent TD). We did not observe a differential genotypic or allelic distribution between the two diagnostic groups. Thus, our results do not support the hypothesis that the C-->A polymorphism in the CYP1A2 gene is involved in the etiology of TD in the German population.

Cushing's syndrome in an 81-year-old patient treated with budesonide and amiodarone.

This is the first report of Cushing's syndrome under oral budesonide treatment. An 81-year-old man known for paroxysmal atrial fibrillation and chronic renal insufficiency, treated with 6 mg budesonide for collagenous colitis, developed Cushing's syndrome under co-administration of amiodarone. The Cushing's syndrome disappeared after discontinuation of the amiodarone treatment. Metabolism of the two medications by hepatic cytochrome P 450 3A may explain the development of Cushing's syndrome.

[SMART syndrome: case report of a rare complication after cerebral radiation therapy]. / SMART Syndrome : à propos d'un cas d'une complication rare après radiothérapie cérébrale et revue de la littérature.

The authors report a 71-year-old woman case who developed, 7 years after a cerebral radiation therapy for a parietooccipital glioblastoma, a stroke-like migraine attacks after radiotherapy syndrome (SMART syndrome), a rare complication characterized by reversible neurologic deficits with migraine described after cerebral irradiation. Transient gyriform reversible enhancement is found on MRI during crises. This case report allows discussing the clinical, iconographic presentation and the clinical outcome of this syndrome at the light of the literature publication.

Transcranial magnetic stimulation as a provocation for epileptic seizures in multiple sclerosis.

Epileptic seizures may be of a provoked origin in acute phases of multiple sclerosis (MS), while chronic epilepsy typically occurs in advanced stages of the disease. A case of seizure provocation during diagnostic transcranial magnetic stimulation (TMS) is described here with a corresponding central nervous system (CNS) lesion in cranial magnetic resonance imaging. A subsequent chronic epileptogenesis originating from the opposite cerebral hemisphere was observed without further TMS influence after several years. The case in its clinical rarity demonstrates that standard single pulse TMS may trigger epileptic seizures only under limited conditions. Single pulse TMS is still regarded a safe procedure in MS.

Diagnosis of multiple sclerosis: comparison of the Poser criteria and the new McDonald criteria.

OBJECTIVES: A confident and accurate diagnosis of multiple sclerosis (MS) is important, but a specific diagnostic test for the disease does not exist. The traditional diagnostic criteria of Poser et al. were published in 1983, and recently, McDonald et al. recommended new criteria for the diagnosis of MS. PATIENTS AND METHODS: In this study these two diagnostic schemes were compared by prospectively applying both of them to 76 patients with clinical features suggesting a new diagnosis of MS. RESULTS: Using the Poser criteria, 29 patients (38%) were classified as clinically definite and 35 patients (46%) as laboratory definite MS. According to the new McDonald criteria, MS was diagnosed in 39 (52%) patients, 37 patients (48%) had 'possible MS'. All patients with a clinically definite MS with the Poser criteria were also given the diagnosis of MS as recommended by McDonald et al. Of those 35 patients with laboratory definite MS according to Poser et al., four patients could be classified as having MS with the McDonald criteria, 89% of them had 'possible MS'. Conversely, 75% of the 39 patients, who fulfilled the new McDonald criteria for MS were assigned to the category of clinically definite MS according to the Poser criteria, and 83% of the patients with a 'possible MS' using the McDonald criteria, had a laboratory definite MS with the Poser criteria. CONCLUSION: MS according to the McDonald criteria was diagnosed more often than 'clinically definite MS' according to Poser et al., but combining the categories of clinically and laboratory definite MS, the diagnosis of MS could clearly be established more frequently using the Poser criteria.

[Clinical characteristics of patients with tardive dyskinesias]. / Klinische Charakteristika von Patienten mit tardiven Dyskinesien.

UNLABELLED: Although there is a great number of studies on the relationship between tardive dyskinesia and patient characteristics, too often their validity is impaired by the lack of operationalized criteria for the description of patients and signs. Reliable phenotyping is of utmost importance for linking clinical data with data from methods in neurobiology or molecular genetics. 241 patients with the DSM IV diagnosis "schizophrenia" or "schizoaffective disorder" were examined with the instruments SADS-L, OPCRIT, BPRS and PANSS. Motor phenomena were analyzed on 2 separate days within 3 months with the scales TDRS, AIMS, SAS, BAS. Tardive dyskinesia was diagnosed following the research criteria of Schooler and Kane. Lifetime medication with neuroleptics and anticholinergic drugs was assessed quantitatively. RESULTS: 97 out of 233 patients (= 41.6%) displayed persistent tardive dyskinesia. In univariate analysis, significant associations were found between tardive dyskinesia and the following independent variables (higher values means greater risk): Age (p = 0.0001), years from onset of the disorder (p = 0.001), total length of stay in hospital (p = 0.001), PANSS (single scales and sum score) (p = 0.0001), total amount of neuroleptics expressed as CPZ equivalents (p = 0.004). Logistic regression analysis showed that only the variables "age" and "negative symptoms" expressed as score on the PANSS negative subscale showed an association with tardive dyskinesia that could not be explained by covariation with other variables. The same results were found when, instead of the dichotomous variable "tardive dyskinesia yes/no" the associations with the TDRS score were analyzed. Future research should aim to approach the neurobiological correlates of "age" and "negative symptoms" in relationship to tardive dyskinesia.

Familial occurrence of tardive dyskinesia.

OBJECTIVE: Familial occurrence of tardive dyskinesia (TD) and schizophrenia has been hypothesized to confer risk to the development of TD. We investigated these hypotheses in a large patient sample applying standardized methods for phenotype characterization. METHOD: Two hundred and twenty-two patients with a diagnosis of schizophrenia or schizoaffective disorder were assessed for TD and for family history of schizophrenia or schizoaffective disorder. Thirty-nine patients had 40 affected first-degree family members, one patient having two first-degree relatives. Of these, 17 pairs and one triplet were personally examined. RESULTS: 1) There was a tendency for TD in the affected relatives to be associated with the TD status of the index-patient; this finding was unrelated to age and doses of neuroleptic medication. 2) No association between a family history of schizophrenia or schizoaffective disorder and TD was found. CONCLUSION: A family history of TD might represent a risk factor for TD, whereas a family history of schizophrenia does not.