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.

Epileptic seizures in patients with primary central nervous system lymphoma: A systematic review.

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.

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.

Recent advances in the diagnosis and the treatment of primary CNS lymphoma.

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.

Neurological side effects of radiation therapy.

Radiation therapy (RT) is one of the main treatments administered to patients with cancer. The development of technology has improved RT accuracy by allowing more precise delivery of high doses to the target volumes with reduced exposure of healthy tissue. Life expectancy has increased due to these therapeutic advancements and the patients' quality of life remains a major concern. The adverse events related to RT are quite various and most likely will impair essential neurological functions, e.g. cognitive status. This literature review aims to describe the physiopathological processes, the neurological symptoms as well as the local modifications observed in magnetic resonance imaging following RT. The specific therapeutic options and preventive actions will also be discussed.

MRI features of intra-axial histiocytic brain mass lesions.

AIM: To describe MRI features, including diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and perfusion-weighted imaging (PWI), of intra-axial tumour-like presentations of four different subtypes of histiocytosis. MATERIAL AND METHODS: The brain MRI findings of 23 patients with histologically proven histiocytosis were reviewed retrospectively (11 Langerhans cell histiocytosis [LCH], eight Erdheim-Chester disease [ECD], one overlap form LCH/ECD, two Rosai-Dorfman disease [RDD], and one haemophagocytic lymphohistiocytosis [HLH]) with single or multiple enhancing intraparenchymal brain lesions. RESULTS: Histiocytic brain mass lesions show some similar MRI features including Supra and/or infratentorial and/or paraventricular subcortical well-delineated masses, linear ependymal enhancement along the ventricles and brain stem lesions. Masses always present with mixed hyper- and hypointense signal on T2-weighted imaging (WI). Their enhancement is often homogeneous. Apparent diffusion coefficient (ADC) values are often normal or elevated. CONCLUSION: The presence of multiple periventricular and subcortical enhancing lesions with mixed signal intensity on T2WI and normal or high ADC values should lead radiologists to consider the diagnosis of histiocytic lesions and search for associated systemic lesions.

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†.

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.

(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.

Posterior reversible encephalopathy syndrome (PRES) and hypomagnesemia: A frequent association?

Posterior reversible encephalopathy syndrome (PRES) is a serious neurological condition encountered in various medical fields. Pathophysiological factor(s) common to PRES cases of apparently unrelated etiologies are yet to be found. Based on the hypothesis that hypomagnesemia might participate in the cascade leading to PRES, our study sought to verify whether hypomagnesemia is frequently associated with PRES regardless of etiology. From a retrospective study of a cohort of 57 patients presenting with PRES of different etiologies, presented here are the findings of 19 patients with available serum magnesium levels (SMLs) during PRES. In the acute phase of PRES, hypomagnesemia was present in all 19 patients in spite of differences in etiology (including immunosuppressive drugs, hypertensive encephalopathy, eclampsia, systemic lupus erythematosus, iatrogenic etiology and unknown). SMLs were within normal ranges prior to PRES and below normal ranges during the first 48h of PRES, with a significant decrease in SMLs during the acute phase. In this retrospective study, constant hypomagnesemia was observed during the acute phase of PRES regardless of its etiology. These results now require larger studies to assess the particular importance of acute hypomagnesemia in PRES and especially the possible need to treat PRES with magnesium sulfate.

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out. RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74). CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.

BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

Prognosis of glioblastoma patients improves significantly over time interrogating historical controls.

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.

Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

Ongoing and prolonged response in adult low-grade gliomas treated with radiotherapy.

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.

Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy.

BACKGROUND: This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). METHODS: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. RESULTS: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004). CONCLUSIONS: The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ.