Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Surface or full cementation of the tibial component in total knee arthroplasty: a matched-pair analysis of mid- to long-term results.

INTRODUCTION: Despite the clinical success of cemented TKA, aseptic loosening of the tibial component remains a potential long-term complication. Considering the constantly growing revision burden, there is a need for clarification regarding controversial views on primary fixation techniques. In this retrospective analysis, surface (SC) or full cementation (FC) of tibial components was compared in a matched-pair and long-term setting. METHODS: Matching pairs were identified in a patient series from 1989 to 1994. Hence, 25 primary TKA (SC) were compared to 42 TKA (FC). The study population included 34 patients with rheumatoid arthritis. Patients were matched in a 1:1.7 fashion according to age, gender and initial diagnosis. Outcome was assessed by multiple clinical parameters, detailed radiographic evaluation and survivorship analysis. RESULTS: Clinical follow-up (FU) was at 10.3 years (range 1.5-15.6) for the SC and 12 years (range 0.2-16.2) for the FC group. Survivorship at 10 years was 100 % for the surface cemented trays and 93.3 % (95 % CI 80.5-100) for the fully cemented implants considering aseptic loosening as endpoint (p = 0.3918). Improvement of the AKS Score was greater in the SC group (p = 0.044) and patients in this group were more satisfied (p = 0.013). For any other clinical parameter, no difference could be observed (p > 0.05). CONCLUSION: Results of this study showed no statistically significant difference regarding long-term survivorship for the two cementing techniques. This finding questions the claimed advantage of full cementation for tibial components. The presented data do not support the concern that surface cementation results in insufficient fixation in patients with rheumatoid arthritis.

[Primary CNS lymphoma. Progress in the diagnostics and therapy]. / Primäre ZNS-Lymphome : Fortschritte in der Diagnostik und Therapie.

BACKGROUND: Some important knowledge has recently been gained on primary central nervous system lymphomas (PCNSL) despite its rarity. GOAL: This article summarizes the most relevant progress in the diagnostics and therapy of PCNSL and discusses future directions. MATERIAL AND METHODS: Reference articles in the English language literature were studied with respect to future approaches in PCNSL. RESULTS: New diagnostic methods in cerebrospinal fluid have been developed to facilitate lymphoma diagnosis; however, their value still has to be validated. A better immunohistological and molecular characterization of PCNSL will probably result in identification of new therapeutic targets. The only phase III trial for PCNSL completed so far did not demonstrate a survival advantage with whole brain irradiation after high-dose methotrexate (HDMTX)-based chemotherapy as compared to chemotherapy alone. The optimal primary chemotherapy has not yet been established due to a lack of results from randomized trials. Non-comparative studies suggest a superiority of combined polychemotherapy over HDMTX monotherapy. Future therapeutic developments are directed towards consolidation of HDMTX-based induction chemotherapy with noncross-resistant conventional chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. An important goal of all therapies for PCNSL is to avoid delayed neurotoxicity. DISCUSSION: Further improvement of diagnostics and well-designed comparative studies, including new drugs when possible are still needed to define the optimal management of this still frequently prognostically unfavorable disease.

[Interdisciplinary neuro-oncology: part 1: diagnostics and operative therapy of primary brain tumors]. / Interdisziplinäre Neuroonkologie : Teil 1: Diagnostik und operative Therapie primärer Gehirntumoren.

By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function is increasingly feasible. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

[Interdisciplinary neuro-oncology: part 2: systemic therapy of primary brain tumors]. / Interdisziplinäre Neuroonkologie : Teil 2: Systemtherapie primärer Gehirntumoren.

By combining the expertise of clinical neuroscience, the aim of neuro-oncology is to optimize diagnostic planning and therapy of primary brain tumors in an interdisciplinary setting together with radio-oncology and medical oncology. High-end imaging frequently allows brain tumors to be diagnosed preoperatively with respect to tumor entity and even tumor malignancy grade. Moreover, neuroimaging is indispensable for guidance of biopsy resection and monitoring of therapy. Surgical resection of intracranial lesions with preservation of neurological function has become dramatically more extensive. Tools to achieve this goal are, for example neuronavigation, functional magnetic resonance imaging (fMRI), tractography, intraoperative cortical stimulation and precise intraoperative definition of tumor margins by virtue of various techniques. In addition to classical histopathological diagnosis and tumor classification, modern neuropathology is supplemented by molecular characterization of brain tumors in order to provide clinicians with prognostic and predictive (of therapy) markers, such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas. Although this is not yet individualized tumor therapy, the increasingly more detailed analysis of the molecular pathogenesis of an individual glioma will eventually lead to specific pharmacological blockade of disturbed intracellular pathways in individual patients. This article gives an overview of the state of the art of interdisciplinary neuro-oncology whereby part 1 deals with the diagnostics and surgical therapy of primary brain tumors and part 2 describes the medical therapy of primary brain tumors.

[Optimised rate of specific, revascularising therapies in acute stroke--what is the aim? Considerations from the experience of a tertiary centre]. / Optimierte rate spezifischer revaskularisierender therapien beim akuten ischämischen schlaganfall--was ist das ziel? Erwägungen anhand der erfahrungen eines tertiären versorgungszentrums.

BACKGROUND: Recanalisation favourably influences outcome in acute stroke. Improved endovascular approaches seem to have higher recanalisation rates than systemic thrombolysis. Substantial efforts have been undertaken to increase the proportion of patients to whom these therapies can be applied. It is still unclear what rates can be realised in a clinical setting. PATIENTS AND METHODS: This is a retrospective single-centre analysis of patients with acute ischaemic stroke and specific recanalisation therapy primarily admitted to our tertiary care centre from 1/2010 to 3/2012. RESULTS: 20 % of patients received systemic thrombolysis, 20 % of these additional endovascular strategies. Pathological multimodal CT patterns were more common in patients not fulfilling the inclusion criteria for thrombolysis. Short-term clinical outcomes were similar in on-label and off-label applications. CONCLUSION: Structured clinical pathways including multimodal CT imaging are useful in identifying patients likely to profit from revascularisation therapies. Based upon our data, some realistic aims concerning therapy rates in patients with ischaemic stroke treated in everyday practice may be formulated (20/20 in 2020).

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

Injuries and overuse syndromes in powerlifting.

Powerlifting is a discipline of competitive weightlifting. To date, no investigations have focused on pain encountered during routine training. The aim of the study was to identify such pain, assign it to particular exercises and assess the data regarding injuries as well as the influence of intrinsic and extrinsic factors. Data of 245 competitive and elite powerlifters was collected by questionnaire. Information regarding current workout routines and retrospective injury data was collected. Study subjects were selected from 97 incorporated powerlifting clubs. A percentage of 43.3% of powerlifters complained of problems during routine workouts. Injury rate was calculated as 0.3 injuries per lifter per year (1 000 h of training=1 injury). There was no evidence that intrinsic or extrinsic factors affected this rate. Most commonly injured body regions were the shoulder, lower back and the knee. The use of weight belts increased the injury rate of the lumbar spine. Rate of injury to the upper extremities was significantly increased based on age >40 years (shoulder/p=0.003, elbow/p=0.003, hand+wrist/p=0.024) and female gender (hand+wrist/p=0.045). The daily workout of a large proportion of powerlifters is affected by disorders which do not require an interruption of training. The injury rate is low compared to other sports.

[Squeaking as a cause for revision of a composite ceramic cup]. / Quietschen als Revisionsursache einer Kompositkeramikpfanne.

Squeaking in total hip arthroplasty (THA) has been observed only in hard-on-hard bearings, such as ceramic-on-ceramic or metal-on-metal. We report the case of a patient with a squeaking THA who had undergone multiple femoral head revisions combined with a composite ceramic cup (polyurethane, ceramic). Squeaking started 6 years postoperatively and acetabular revision was necessary to resolve the issue. Secondary deformation of the inlay resulted in clamping of the femoral head and increased friction. This should be considered when assessing and advising patients with squeaking THA when composite ceramic components are involved.

Cerclage handling for improved fracture treatment. A biomechanical study on the twisting procedure.

PURPOSE OF THE STUDY: Twisting is clinically the most frequently applied method for tightening and maintaining cerclage fixation. The twisting procedure is controversially discussed. Several factors during twisting affect the mechanical behaviour of the cerclage. This in vitro study investigated the influence of different parameters of the twisting procedure on the fixation strength of the cerclage in an experimental setup with centripetal force application. MATERIAL AND METHODS: Cortical half shells of the femoral shaft were mounted on a testing fixture. 1.0 mm, 1.25 mm and 1.5 mm stainless ste- el wire cerclages as well as a 1.0mm cable cerclage were applied to the bone. Pretension of the cerclage during the installation was measured during the locking procedure. Subsequently, cyclic testing was performed up to failure. RESULTS: Higher pretension could be achieved with increasing wire diameter. However, with larger wire diameter the drop of pre- tension due to the bending and cutting the twist also increased. The cable cerclage showed the highest pretension after locking. Cerclages twisted under traction revealed significantly higher initial cerclage tension. Plastically deformed twists offered higher cerclage pretension compared to twists which were deformed in the elastic region of the material. Cutting the wire within the twist caused the highest loss of cerclage tension (44% initial tension) whereas only 11 % was lost when cutting the wire ends separately. The bending direction of the twist significantly influenced the cerclage pretension. 45% pretension was lost in forward bending of the twist, 53% in perpendicular bending and 90% in backward bending. CONCLUSION: Several parameters affect the quality of a cerclage fixation. Adequate installation of cerclage wires could markedly improve the clinical outcome of cerclage.

Infection in fracture fixation: can we influence infection rates through implant design?

Musculoskeletal infection is one of the most common complications associated with surgical fixation of bones fractured during trauma. These infections usually involve bacterial colonisation and biofilm formation on the fracture fixation device itself, as well as infection of the surrounding tissues. Antibiotic prophylaxis, wound debridement and postsurgical care can reduce the incidence of, but do not prevent, these infections. Much research and development has been focussed on ways to further reduce the incidence of infection and in the following short review we describe our experiences investigating the contribution of the basic design of fracture fixation devices on the susceptibility to infection. It has been shown in animal studies that device size, shape, mode of action and material and topography play an interrelated role in the susceptibility to infection. Although direct extrapolation from animal studies to the clinical setting is difficult, close consideration of the design factors that can reduce the incidence of infection in animal models is expected to help minimise the incidence of infection associated with any clinically implemented fracture fixation device.

Clinical outcomes and quality of life 1 year after open microsurgical decompression or implantation of an interspinous stand-alone spacer.

BACKGROUND: Interspinous stand-alone implants are inserted without open decompression to treat symptomatic lumbar spinal stenosis (LSS). The insertion procedure is technically simple, low-risk, and quick. However, the question remains whether the resulting clinical outcomes compare with those of microsurgical decompression, the gold standard. MATERIAL AND METHODS: This prospective, comparative study included all patients (n=36) with neurogenic intermittent claudication (NIC) secondary to LSS with symptoms improving in forward flexion treated operatively with either interspinous stand-alone spacer insertion (Aperius (®); Medtronic, Tolochenaz, Switzerland) (group 1) or microsurgical bilateral operative decompression (group 2) between February 2007 and November 2008. Data (patient data, operative data, COMI, SF-36 PCS and MCS, ODI, and walking tolerance) were collected preoperatively as well as at 6 weeks, at 3, 6, and 9 months, and at one year follow-up (FU). All patients had complete FU over 1 year. RESULTS: Compared to preoperative measurements, surgery led to improvements of all parameters in the entire collective as well as both individual groups. There were no statistically relevant differences between the 2 groups over the entire course of FU. However, improvements in the ODI and SF-36 MCS were not significant in group 1, in contrast to those of group 2. Also, although in group 1 the improvements in leg pain (VAS leg) were still significant (p<0.05) at 6 months, this was no longer the case at 1 year FU. In group 1 at 1 year FU an increase in leg pain was observed, while in group 2, minimal improvements continued. Walking tolerance was significantly improved at all FU times compared to preoperatively, regardless of group (p<0.01). At no time there was a significant difference between the groups. In group 1, admission and operative times were shorter and blood loss decreased. The complication rate was 0% in group 1 and 20% in group 2, however reoperation was required by 27.3% of group 1 patients and 0% of group 2. CONCLUSION: Implantation of an interspinous stand-alone spacer yields clinical success comparable to open decompression, at least within the first year of FU. The 1-year conversion rate of 27.3% is, however, decidedly too high.

The present role of vertebroplasty and kyphoplasty in the treatment of fresh vertebral compression fractures.

Vertebroplasty (VP) and kyphoplasty (KP) are minimally invasive vertebral augmentation procedures for the treatment of fresh vertebral compression fractures (VCFs) associated with osteoporosis, trauma, malignant conditions, hemangiomas, and osteonecrosis. During these procedures, bone cement (e.g., polymethylmethacrylate) is percutaneously injected into the vertebral body. Systematic reviews of both procedures have shown significantly improved back pain and quality of life compared to conservative therapy. Direct comparison between VP and KP is not possible because of the lack of prospective randomized data comparing the two procedures. Both appear to improve patient functional status in most studies, although it is difficult to pool the available data because of differing measurement scales. With increasing popularity of both techniques, particularly over the past ten years, a rising number of publications have detailed potential complications secondary to cement extravasation, from compression of neural elements to venous embolism. Overall complication rates for both procedures are low. Systematic reviews have found significantly higher rates of cement leakage after VP (40%) versus KP (8%), with 3% of VP leaks being symptomatic. The evidence for increased risk of adjacent level fracture after these procedures compared to conservative treatment is inconclusive. When performed by a well-trained practitioner in appropriately selected patients, vertebroplasty and kyphoplasty are both safe and effective treatments for fresh vertebral compression fractures. Results from ongoing randomized controlled trials will provide further detailed information about both procedures in the future.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Cognitive decline in multiple sclerosis: impact of topographic lesion distribution on differential cognitive deficit patterns.

BACKGROUND: Multiple sclerosis (MS) is often accompanied by cognitive dysfunction. A negative correlation between cerebral lesion load and atrophy and cognitive performance has been pointed out almost consistently. Further, the distribution of lesions might be critical for the emergence of specific patterns of cognitive deficits. OBJECTIVE: The current study evaluated the significance of total lesion area (TLA) and central atrophy for the prediction of general cognitive dysfunction and tested for a correspondence between lesion topography and specific cognitive deficit patterns. METHODS: Thirty-seven patients with MS underwent neuropsychological assessment and magnetic resonance imaging. Lesion burden and central atrophy were quantified. Patients were classified into three groups by means of individual lesion topography (punctiform lesions/periventricular lesions/confluencing lesions in both periventricular and extra-periventricular regions). RESULTS: TLA was significantly related to 7 cognitive variables, whereas third ventricle width was significantly associated with 20 cognitive parameters. The three groups differed significantly in their performances on tasks concerning alertness, mental speed, and memory function. CONCLUSION: Third ventricle width as a straight-forward measure of central atrophy proved to be of substantial predictive value for cognitive dysfunction, whereas total lesion load played only a minor role. Periventricular located lesions were significantly related to decreased psychomotor speed, whereas equally distributed cerebral lesion load did not. These findings support the idea that periventricular lesions have a determinant impact on cognition in patients with MS.

DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development.

BACKGROUND: Diffuse lower WHO grade II and III gliomas (LGG) are slowly progressing brain tumors, many of which eventually transform into a more aggressive type. LGG is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the heterogeneity of the DNA methylome, its function in tumor biology, coupling with the transcriptome and tumor microenvironment and its possible impact for tumor development. METHODS: We here present novel DNA methylation data of an LGG-cohort collected in the German Glioma Network containing about 85% isocitrate dehydrogenase (IDH) mutated tumors and performed a combined bioinformatics analysis using patient-matched genome and transcriptome data. RESULTS: Stratification of LGG based on gene expression and DNA-methylation provided four consensus subtypes. We characterized them in terms of genetic alterations, functional context, cellular composition, tumor microenvironment and their possible impact for treatment resistance and prognosis. Glioma with astrocytoma-resembling phenotypes constitute the largest fraction of nearly 60%. They revealed largest diversity and were divided into four expression and three methylation groups which only partly match each other thus reflecting largely decoupled expression and methylation patterns. We identified a novel G-protein coupled receptor and a cancer-related 'keratinization' methylation signature in in addition to the glioma-CpG island methylator phenotype (G-CIMP) signature. These different signatures overlap and combine in various ways giving rise to diverse methylation and expression patterns that shape the glioma phenotypes. The decrease of global methylation in astrocytoma-like LGG associates with higher WHO grade, age at diagnosis and inferior prognosis. We found analogies between astrocytoma-like LGG with grade IV IDH-wild type tumors regarding possible worsening of treatment resistance along a proneural-to-mesenchymal axis. Using gene signature-based inference we elucidated the impact of cellular composition of the tumors including immune cell bystanders such as macrophages. CONCLUSIONS: Genomic, epigenomic and transcriptomic factors act in concert but partly also in a decoupled fashion what underpins the need for integrative, multidimensional stratification of LGG by combining these data on gene and cellular levels to delineate mechanisms of gene (de-)regulation and to enable better patient stratification and individualization of treatment.

Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate.

OBJECTIVE: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. MATERIAL AND METHODS: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. RESULTS: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. CONCLUSIONS: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.

Acute methotrexate-induced encephalopathy--causal relation to homozygous allelic state for MTR c.2756A>G (D919G)?

Methotrexate (MTX) is widely used in the treatment of hematological diseases. The typical side-effects of high-dose MTX chemotherapy on the CNS range from asymptomatic white matter changes to severe CNS demyelination. MTX neuro - toxicity has been described to be associated with homocysteine and folate levels as well as genetic variants affecting methionine metabolism. Here we describe a case of severe, acute MTX-induced encephalopathy in a patient who was found to be homozygous for the rare missense variant methionine synthase (MTR) c.2756A>G (D919G), which may have modified the effect of MTX on homocysteine metabolism. This finding encourages further studies to determine to what extent the individual conditions of folate and methionine metabolism influence the effects or side-effects of MTX treatment.