BACKGROUND:Primary CNS lymphoma is typically diagnosed by brain biopsy, a procedure with risks and diagnostic delay. Emerging cerebrospinal fluid (CSF) biomarkers, including the myeloid differentiation primary response 88 (MYD88) L265P mutation in CSF and several chemokines, might improve diagnostic accuracy, but evidence mostly comes from retrospective, non-consecutive cohorts. We aimed to validate the diagnostic utility of CSF biomarkers in patients with suspected primary CNS lymphoma. METHODS:Patients with suspected primary CNS lymphoma (aged ≥18 years) who underwent CSF analysis were enrolled in five hospitals in the Netherlands between March 1, 2021, and May 1, 2025. Analyses focused on MYD88 and chemokines with reported diagnostic value. A diagnostic panel was constructed with multivariable logistic regression and least absolute shrinkage and selection operator (LASSO) regression. We performed decision tree analysis to evaluate performance. FINDINGS:Of 255 patients (median age 61 years [IQR 52-72]; 171 [67%] males and 84 [33%] females), 50 (20%) were diagnosed with CNS lymphoma; 44 had primary CNS lymphoma and six were diagnosed with secondary CNS lymphoma. In univariable analyses, six of seven chemokines showed significant diagnostic value (area under the curve 0·67-0·96). MYD88 was detected in 28 (56%) of 50 patients with CNS lymphoma, with a sensitivity of 56·0% (95% CI 41·3-70·0) and specificity of 98·5% (198 of 201; 95% CI 95·7-99·7). In the multivariable logistic regression model, MYD88, interleukin-10 (IL-10), and C-X-C motif chemokine ligand 13 (CXCL13) remained independently associated with a CNS lymphoma diagnosis. Combining a positive MYD88 result with elevated IL-10 or CXCL13 (or both) yielded a sensitivity of 54·0% (27 of 50; 95% CI 39·3-68·2) with specificity of 100·0% (95% CI 98·2-100·0). A negative result for all three biomarkers provided a negative predictive value of 99·4% (162 of 163). INTERPRETATION:In this prospective, multicentre cohort of patients with suspected primary CNS lymphoma, we validated the high diagnostic value of MYD88, IL-10, and CXCL13. Results should be interpreted within the full clinical context and with caution, as the diagnostic algorithm and decision tree were derived within the same cohort. In selected clinical scenarios and with further validation of these results, combined CSF biomarker testing might support non-invasive diagnostic decision making and reduce reliance on brain biopsy. FUNDING:Stichting Annie van Koeverden.

Fatigue is a prevalent and debilitating symptom for patients with incurable cancer. Cognitive behavioral therapy (CBT) can significantly reduce cancer-related fatigue in this patient group. However, implementation of CBT into clinical care is difficult as the intervention is time-intensive, costly, and requires face-to-face consultations with a specialized CBT therapist. Since nurses already support patient with symptom management, including fatigue, internet supported CBT delivered by nurses could be a promising alternative for patients with incurable cancer. The primary aim of this study is to determine the non-inferiority of nurse-led web-based CBT in its effect on cancer-related fatigue, compared to CBT provided by CBT therapists. The study is a prospective, non-randomized study using historical cohorts as the benchmark for comparison. Severely fatigued patients with incurable cancer of a solid tumor receive a 12-week nurse-led web-based CBT intervention. Primary and secondary outcome measures are assessed at baseline, post-intervention (14 weeks), and follow-up (26 weeks). The primary outcome measure is fatigue severity assessed with the Checklist Individual Strength (CIS-subscale fatigue severity). Secondary outcomes include functional impairment, quality of life and fatigue assessed with EORTC-QLQ-C30, and health care costs. Primary and secondary outcomes of the TIRELESS study and the benchmark are compared to determine non-inferiority. Non-inferiority of fatigue reduction is concluded if the upper bound of the one-sided 95

Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell non-Hodgkin lymphoma confined to the central nervous system, without systemic involvement. The incidence has increased over the past 3 decades. The prognosis has improved in patients up to 70 years old, and this type of lymphoma can be potentially cured. The gold standard of diagnosing PCNSL is histological, usually on a brain biopsy specimen via a neurosurgical procedure. Recent developments in both imaging and laboratory analyses of the cerebrospinal fluid, can be helpful in narrowing the differential diagnosis, diagnosing PCNSL itself, and in follow-up after treatment. This narrative review gives an overview of the epidemiology, diagnosis, and treatment of PCNSL, with an emphasis on recent developments in diagnostic techniques and treatment.

Ependymomas are rare tumours of the central nervous system (CNS). This study reports real-world data regarding primary treatment and outcome for adult patients diagnosed in the Netherlands between 2014 and 2023. Diagnostic and treatment data on adult patients with a newly diagnosed ependymoma were obtained from the Dutch Brain Tumour Registry. Factors associated with incomplete resection and adjuvant radiotherapy (RT) were identified using logistic regression analyses, thereby accounting for variation between CNS regional tumour boards through mixed-effect modelling when relevant. In case of variation, case-mix adjusted ratios of tumour boards were evaluated in funnel plots. Prognostic factors for overall survival (OS) at 5 years were assessed with the Kaplan-Meier method and Cox proportional hazards regression models. Analyses were performed on multiple imputed datasets (m = 10) to account for missing data. Among 575 patients, 74 (12.9

BACKGROUND AND OBJECTIVES:The aim of this study was to evaluate the long-term results of seizure recurrence after antiseizure medication (ASM) withdrawal vs continuation in patients with diffuse glioma, grades 2 and 3. METHODS:A prospective multicenter observational study was conducted, and patients were recruited from January 2014 until May 2016 from 3 neuro-oncology outpatient clinics in the Netherlands. The main inclusion criteria were as follows: history of ≥1 seizure, for which ASM was started; clinically and radiologically stable disease for ≥12 months; and seizure freedom for ≥12 months from the date of last antitumor treatment or seizure freedom for ≥24 months from the last seizure if seizures occurred after the last antitumor treatment. The primary outcome was time to recurrent seizure. A competing risk model was used to estimate cumulative incidences of recurrent seizure for ASM groups (i.e., ASM withdrawal vs ASM continuation) with death as the competing event. The proportional hazard assumption was violated for the ASM group; therefore, 2 Cox models were constructed for different time intervals (<48 months and ≥48 months since study inclusion). RESULTS:A total of 71 patients were included (39 men [55%] and 58 older than 40 years [82%]); 46 patients with glioma (65%) were in the ASM withdrawal group and 25 (35%) in the ASM continuation group. The cumulative incidence of a recurrent seizure at 48 and 96 months was 48% (95% CI 33%-61%) and 66% (95% CI 48%-78%) for the ASM withdrawal group vs 28% (95% CI 12%-46%) and 52% (95% CI 31%-70%) for the ASM continuation group. The risk of a recurrent seizure differed in the 2 time intervals between the ASM continuation group (reference) and the ASM withdrawal group (cause-specific adjusted hazard ratio [aHR] 2.32 [95% CI 0.93-5.81], p = 0.071, during <48 months, and cause-specific aHR 0.73 [95% CI 0.21-2.49], p = 0.611, during ≥48 months since study inclusion). DISCUSSION:Risk of recurrent seizure when withdrawing ASM was not statistically significantly higher in patients continuing ASM. However, a clinically relevant higher percentage of patients had a recurrent seizure in the ASM withdrawal group compared with the ASM continuation group. The lack of a statistical difference may be explained by the small sample size. Larger studies are needed to confirm these findings. Our results suggest that ASM withdrawal should be initiated cautiously and only when necessary. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that withdrawal of ASM does not significantly increase the risk of recurrent seizures in patients with glioma with stable disease and no seizures for >1 year. Confidence intervals do not exclude a clinically important increased risk of seizures.

Pilocytic astrocytomas are circumscribed WHO grade I gliomas that predominantly affect children, although they also occur in adults. While maximal safe resection is standard treatment, until recently chemotherapy was often used in pediatrics with irresectable symptomatic tumors to delay radiotherapy. As evidence for this approach in adults is limited, we performed a multicenter retrospective cohort study on this subject. Adult patients (≥ 16 years) treated with chemotherapy between 2006 and 2020 across eight Dutch medical centers were included. Treatment response was centrally assessed using RAPNO criteria and survival outcomes were analyzed using the Kaplan–Meier method. Thirty-one patients with pilocytic astrocytoma were included (median age 27 years). Most patients had received prior treatments, including radiotherapy (n = 19) and/or surgery (n = 17), with a median interval of over five years from histopathological diagnosis to the start of chemotherapy. Temozolomide was most frequently used (64.5

The aim of this study was to evaluate the long-term results of seizure recurrence after antiseizure medication (ASM) withdrawal vs continuation in patients with diffuse glioma, grades 2 and 3. A prospective multicenter observational study was conducted, and patients were recruited from January 2014 until May 2016 from 3 neuro-oncology outpatient clinics in the Netherlands. The main inclusion criteria were as follows: history of ≥1 seizure, for which ASM was started; clinically and radiologically stable disease for ≥12 months; and seizure freedom for ≥12 months from the date of last antitumor treatment or seizure freedom for ≥24 months from the last seizure if seizures occurred after the last antitumor treatment. The primary outcome was time to recurrent seizure. A competing risk model was used to estimate cumulative incidences of recurrent seizure for ASM groups (i.e., ASM withdrawal vs ASM continuation) with death as the competing event. The proportional hazard assumption was violated for the ASM group; therefore, 2 Cox models were constructed for different time intervals (<48 months and ≥48 months since study inclusion). A total of 71 patients were included (39 men [55%] and 58 older than 40 years [82%]); 46 patients with glioma (65%) were in the ASM withdrawal group and 25 (35%) in the ASM continuation group. The cumulative incidence of a recurrent seizure at 48 and 96 months was 48% (95% CI 33%-61%) and 66% (95% CI 48%-78%) for the ASM withdrawal group vs 28% (95% CI 12%-46%) and 52% (95% CI 31%-70%) for the ASM continuation group. The risk of a recurrent seizure differed in the 2 time intervals between the ASM continuation group (reference) and the ASM withdrawal group (cause-specific adjusted hazard ratio [aHR] 2.32 [95% CI 0.93-5.81], p = 0.071, during <48 months, and cause-specific aHR 0.73 [95% CI 0.21-2.49], p = 0.611, during ≥48 months since study inclusion). Risk of recurrent seizure when withdrawing ASM was not statistically significantly higher in patients continuing ASM. However, a clinically relevant higher percentage of patients had a recurrent seizure in the ASM withdrawal group compared with the ASM continuation group. The lack of a statistical difference may be explained by the small sample size. Larger studies are needed to confirm these findings. Our results suggest that ASM withdrawal should be initiated cautiously and only when necessary. This study provides Class III evidence that withdrawal of ASM does not significantly increase the risk of recurrent seizures in patients with glioma with stable disease and no seizures for >1 year. Confidence intervals do not exclude a clinically important increased risk of seizures.

Abstract Objective A substantial part of central nervous system (CNS) disorders remains unexplained, despite various new and minimally invasive diagnostic techniques. Within this rapidly developing diagnostic field, the precise role of brain biopsy is unknown. We aimed to study the clinical impact and safety of brain biopsies in unexplained CNS disorders. Methods In this retrospective cohort study, we included all adult patients who were referred for a diagnostic work‐up to our academic center with neuro‐inflammatory, neuro‐oncological, and neuro‐infectious expertise and underwent a brain biopsy between January 2010 and December 2023. Typical cases of CNS neoplasms and infections were not analyzed. Brain biopsies were evaluated with respect to diagnostic and therapeutic impact and complication risk. Results Brain biopsy was performed in 587 patients. Ninety‐four patients with a CNS disorder of unknown cause, with 107 biopsies, were analyzed (44% female, median age 58 years). Postoperative diagnoses included brain tumors/lymphomas (37/94, 39%), inflammatory disorders (11/94, 12%), infections (8/94, 9%), autoimmune encephalitis (8/94, 9%), and primary angiitis of the CNS (4/94, 4%). Diagnostic yield of brain biopsy was 62%, increasing up to 72% after repeat biopsies, as 10 additional patients were diagnosed with a brain tumor. In 77% of patients, brain biopsy changed the treatment strategy. Symptomatic intracranial hemorrhage occurred in 4 of 107 brain biopsies (4%). Interpretation In a selected population of patients with unexplained CNS disorders, clinical impact of brain biopsies is high, while being relatively safe. A multidisciplinary team approach is fundamental in establishing optimal indication for brain biopsy and subsequent treatment decisions.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.

Given the rarity of primary central nervous system lymphoma (PCNSL), evaluations of different high-dose methotrexate-(HD-MTX)-based treatment regimens is sparse. This retrospective, multicenter study evaluates clinical characteristics and outcomes (progression-free, overall and disease-specific survival) after five HD-MTX-based polychemotherapeutic regimens and two consolidation therapies. 346 patients with histologically confirmed PCNSL, treated with ≥ 1 cycle HD-MTX-based strategies (≥3g/m2/cycle) were included. The regimens included MATRIX (HD-MTX, HD-AraC, thiotepa, and rituximab), (R)MBVP±HD-AraC (HD-MTX, teniposide/etoposide, carmustine, prednisolone, ± HD-AraC, ± rituximab), (R)MP (HD-MTX, procarbazine, ± rituximab), and a combination of HD-MTX and HD-AraC. The overall response rate after induction was 69 %, 28 % complete remission and progressive disease was observed in 100 (29 %) patients. 126 (36 %) patients received consolidation, including high-dose-BCNU-thiotepa with autologous stem cell transplantation (HD-BCNU-TT/ASCT, n = 59 (17 %)) or whole brain radiotherapy (WBRT, n = 67 (19 %)). Clinical characteristics associated with adverse mortality risk by multivariable prognostication contained age > 60 years (HR 1.61, p = 0.011), elevated LDH (HR 1.75, p = 0.004) and WHO status ≥ 2 (HR 1.56, p = 0.010). Independently, induction regimens containing HD-AraC demonstrated survival benefit compared to induction regimens without HD-AraC (HR 0.59, p = 0.002). Without preference for HD-BCNU-TT/ASCT or WBRT, a favorable effect of consolidation (HR 0.44 and HR 0.42, p < 0.001) was confirmed, also with consolidation as time-dependent variable. Competing risk analysis showed similar low incidence of lymphoma-unrelated deaths in consolidated and unconsolidated patients. This study confirms that age, elevated LDH and WHO status increase the mortality risk. HD-AraC containing treatment regimens and consolidation with HD-BCU-TT/ASCT or WBRT were associated with superior survival, including a favorable low incidence of lymphoma-unrelated deaths.

Background The utility of liquid biopsies is well documented in several extracranial and intracranial (brain/leptomeningeal metastases, gliomas) tumors.Methods The RANO (Response Assessment in Neuro-Oncology) group has set up a multidisciplinary Task Force to critically review the role of blood and cerebrospinal fluid (CSF)-liquid biopsy in CNS lymphomas, with a main focus on primary central nervous system lymphomas (PCNSL).Results Several clinical applications are suggested: diagnosis of PCNSL in critical settings (elderly or frail patients, deep locations, and steroid responsiveness), definition of minimal residual disease, early indication of tumor response or relapse following treatments, and prediction of outcome.Conclusions Thus far, no clinically validated circulating biomarkers for managing both primary and secondary CNS lymphomas exist. There is need of standardization of biofluid collection, choice of analytes, and type of technique to perform the molecular analysis. The various assays should be evaluated through well-organized central testing within clinical trials. For the podcast associated with this article, please visit 'https://soc-neuro-onc.libsyn.com/liquid-biopsy-in-cns-lymphoma'

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

Abstract BACKGROUND We previously reported on progression-free survival of our randomized phase 3 trial [Lancet Oncol. 2016;17:1521-1532]. Here we report results of long-term follow-up (FU) including overall survival (OS) and molecular subgroup analyses. METHODS 487 patients were randomized between 2005-2012 to either standard radiotherapy (RT, 50.4 Gy/ 28 fractions) or primary dose-dense temozolomide [TMZ] chemotherapy (75 mg/m² daily x 21/28 days, up to 12 cycles). Treatment at progression was at investigators discretion and commonly included cross-over to the alternative treatment modality. RESULTS At a median follow-up of 13 years, 68% of patients had died. Median age at inclusion was 45 years (range 18-75), 96% had a performance status of 0-1. There was no significant difference in PFS nor OS: PFS was 3.6 years (95% CI: 3.0-4.1) and 3.1 years (95% CI: 2.7-3.6), HR 1.12 (95% CI: 0.92-1.36); OS 6.6 years (95% CI: 5.8-7.5) and 8.0 years (95% CI: 6.9-9.1), HR 0.87 (95% CI: 0.69-1.09), for RT or TMZ, respectively. Subgroup analyses were performed for patients when available tissue allowed for molecular analyses (n=351/487,73%). In astrocytoma, IDHmt/1p/19q non-codeleted (n = 178), median OS with RT was 6.6 years (95% CI: 5.3-7.6) and with TMZ was 6.7 years (95% CI: 5.7-8.0); HR 0.98 (95% CI: 0.67-1.44). For oligodendroglioma, IDHmt/codeleted (n = 109) median OS with RT was 12.9 years (95% CI: 9.4 - NE) and with TMZ 14.9 years (95% CI: 10.1 - NE); HR 1.01 (95% CI: 0.56-1.81). For a heterogenous group of IDHwt tumors (n = 64), median OS with RT was 2.5 years (95% CI: 1.8-3.3) and with TMZ 4.7 years (95% CI: 2.2-7.2); HR 0.37 (95% CI: 0.18-0.77). CONCLUSIONS Primary treatment with RT or TMZ provided comparable PFS and OS. Choice of primary treatment can be tailored to individual tumor characteristics and patient preference.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.

The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma (NHL) manifesting in the brain, spinal cord, cerebrospinal fluid and/or eyes, in the absence of systemic manifestations. With an increasing incidence and a 30% 5-year overall survival if promptly treated, timely diagnosis and subsequent treatment is paramount. The typical MRI appearance for PCNSL is a solitary or multiple T2-hypointense, homogeneous gadolinium-enhancing lesion with restricted diffusion. Dexamethasone treatment might compromise and delay the diagnosis. Hallmark of treatment is induction with intravenous high-dose methotrexate consisting polychemotherapy followed by consolidation treatment. Consolidation treatment consists of either whole brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT). Given the (cognitive) side effects of WBRT, ASCT is increasingly being used as the first choice of treatment.

Journal Article Is there a future for maintenance temozolomide chemotherapy in PCNSL? Get access Jacoline E C Bromberg, Jacoline E C Bromberg Department of Neuro-Oncology, Erasmus MC University Medical Center Cancer Institute, Rotterdam, the Netherlands Corresponding Author: Jacoline E. C. Bromberg, MD, Department of Neuro-Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands (j.bromberg@erasmusmc.nl) Search for other works by this author on: Oxford Academic PubMed Google Scholar Jeanette K Doorduijn Jeanette K Doorduijn Department of Hematology, Erasmus MC University Medical Center Cancer Institute, Rotterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 4, April 2023, Pages 699–700, https://doi.org/10.1093/neuonc/noad015 Published: 19 January 2023 Article history Published: 19 January 2023 Corrected and typeset: 13 February 2023

Purpose Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. Methods Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. Results Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn’t statistically significant. Conclusion Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.