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Background Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a ‘low-grade appearance’ on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. Methods The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. Results Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. Conclusions The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Primary central nervous system lymphoma (PCNSL) is generally characterized by a poor prognosis and frequent relapsing disease. Consolidation therapy in the upfront setting usually consists of an autologous stem cell transplantation. We report the case of a 19-year-old Caucasian male who had previously undergone an allogeneic stem cell transplantation with complete engraftment for the treatment of juvenile myelomonocytic leukemia when he was 1 year old. He presented with two episodes of (donor-derived) PCNSL from allogeneic stem cells; however, after induction chemotherapy, he failed to harvest stem cells for the consolidation with autologous stem cell transplantation. He was consolidated successfully with a second allogeneic stem cell transplantation with another donor after conditioning with thiotepa, busulfan, and fludarabine.

This paper reviews 30 years of developments in the area of low-grade gliomas. This includes the changes in diagnostics with the incorporation of 1p/19q and IDH mutations in the diagnostic classifier, the improved surgical techniques, improved delivery of radiotherapy and chemotherapy. More recently, the better understanding of the altered cellular processes has lead to the development of novel drugs that may alter completely alter the management of patients early in the course of their disease.

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

• This Clinical Practice Guideline provides recommendations for managing leptomeningeal metastases from solid tumours. • The guideline covers clinical, imaging and cytological diagnosis, staging and risk assessment, treatment and follow-up. • A treatment and management algorithm is provided. • The author panel 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 Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. Methods Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150–200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. Results A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. Conclusions The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM. ClinicalTrials.gov NCT02617589

Background: Adolescents and young adults (AYAs, aged 18-39 years) with advanced cancer have an increased life expectancy due to improvements and refinements in cancer therapies, resulting in a growing group of AYAs living with an uncertain and/or poor cancer prognosis (UPCP). To date, no studies have examined the difficulties of health care professionals (HCPs) providing care to AYAs with a UPCP. This study aimed to understand the challenges in daily clinical practice experienced by HCPs from different disciplines who provide palliative as well as general care to AYAs with a UPCP. Methods: HCPs from a variety of backgrounds (e.g. clinical nurse specialists, medical oncologists, neurologists psychologists) were invited for a semi-structured interview. The interviews were transcribed verbatim and analysed using reflexive thematic analysis. Two AYA patients were actively involved as research partners to increase the relevance of the study design and to optimise interpretation of results. Results: Forty-nine HCPs were interviewed. Overall, we found that the threat of premature death within this young patient group increased emotional impact on HCPs and evoked a feeling of unfairness, which was an extra motivation for HCPs to provide the most optimal care possible. We generated four key themes: (i) emotional confrontation (e.g. feeling helplessness and experiencing a greater sense of empathy), (ii) questioning own professional attitude and skills, (iii) navigating uncertainty (e.g. discussing prognosis and end of life) and (iv) obstacles in the health care organisation (e.g. lack of knowledge and clarity about responsibilities). Conclusions: HCPs experienced unique emotional and practical challenges when providing care to AYAs with a UPCP. The results from this study highlight the need to develop an education module for HCPs treating AYAs with UPCP to increase their own well-being and optimise the delivery of person- and age-adjusted care.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients.MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included.RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment.CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

Survival in patients with IDH1/2 mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumour classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using one of two glioma-tailored NGS panels. The primary endpoint was overall survival measured from date of randomization. Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumours. Of these, 432 tumours were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazards model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.