Classification of tumors of the central nervous system currently requires tumor tissue analysis for histology and molecular markers, according to the 2021 WHO Classification of Tumors of the Central Nervous System. Cerebrospinal fluid (CSF)-based cell-free DNA (cfDNA) sequencing detects these defining molecular alterations and allows for accurate diagnosis and WHO-analogue tumor classification. We hereby report the case of a female patient with an IDH-mutant glioma, TERT promoter mutant, NEC, in whom IDH1 and TERT promoter mutations were identified in CSF after an initially non-informative tissue histology, then confirmed through tissue-based molecular analysis. The patient was initially treated with vorasidenib, an IDH inhibitor, which was then switched to a procarbazine-CCNU chemotherapy due to clinical worsening under initial therapy. CSF-based cfDNA sequencing is a promising tool for minimally invasive diagnosis of tumors of the CNS in situations in which tissue biopsy is challenging or non-informative.

Nitrosoureas are cytotoxic chemotherapeutic drugs that cause cell death by DNA damage. They are used to treat malignancies, including malignant glioblastomas, Hodgkin's and non-Hodgkin lymphomas, and pancreatic islet cell tumors. Three of the most commonly used nitrosourea compounds are carmustine (BCNU), lomustine (CCNU), and fotemustine. Nitrosoureas are lipophilic chemicals with antitumor and cytotoxic effects via alkylating and carbamoylating compounds; they are active in multiple cell cycle phases. Lomustine readily crosses the blood-brain barrier and is commonly used for recurrent glioblastoma multiforme; in some European countries, fotemustine is used instead of lomustine. Carmustine was the first nitrosourea developed for public use (United States Food and Drug Administration approval in 1977). The drug has been widely discontinued due to toxicity, intravenous (IV) administration, and low availability.. Nitrosoureas are used alongside other chemotherapeutic agents (such as procarbazine, lomustine, and vincristine, a first-line regimen for oligodendroglioma) or as stand-alone chemotherapy agents. Streptozocin has methylnitrosourea activity against pancreatic islet cell tumors. Nitrosoureas are associated with significant and severe adverse effects, including leukoencephalopathy, pulmonary toxicity, nephrotoxicity, hepatotoxicity, neurotoxicity, myelosuppression, secondary leukemias, nausea, vomiting, stomatitis, alopecia, anemia, anorexia, and phlebitis and burning at the injection site. Due to their severe side effect profiles, nitrosoureas are mostly used for tumor recurrence or refractory cases. Nitrosourea metabolites are primarily excreted through the kidneys. 

Primary and secondary central nervous system lymphomas (PCNSL and SCNSL, respectively) are aggressive non-Hodgkin lymphomas with high relapse risk. Methotrexate rarely achieves durable remission, necessitating combination therapy or consolidation. Although high-dose busulfan and thiotepa (BuTT) conditioning followed by autologous stem cell transplantation (ASCT) is a promising consolidation strategy, the optimal timing and real-world outcomes of ASCT remain unclear. We retrospectively analyzed 12 patients (eight with PCNSL and four with SCNSL) treated with BuTT/ASCT at a single center between 2019 and 2024. Nine patients underwent upfront ASCT shortly after achieving complete remission with rituximab, methotrexate, procarbazine, and vincristine and remained in remission at a median follow-up of 681 days (range, 147-1322 days). Three patients (two with PCNSL and one with SCNSL) who underwent salvage ASCT following multiple prior therapies experienced early relapse (51-125 days post-ASCT) and died of their disease. BuTT/ASCT is highly effective when administered promptly after remission, whereas salvage ASCT after multiple therapies is associated with poor outcomes. Timely clinical decision-making and upfront consolidation may be key to optimizing the therapeutic benefits of ASCT in CNSL, although further validation is warranted.

The in vitro genotoxicity testing battery comprising a bacterial gene mutation test (Ames test) and an in vitro micronucleus (MNvit) test is widely recommended by regulatory authorities since it detects the 3 key modes of genotoxic action (gene mutations, clastogenicity and aneuploidy). The recommendations that this battery is acceptable for regulatory use are based on its ability to effectively detect in vivo genotoxins and carcinogens. However, substances inducing gene mutations are a particular concern (representing stable genetic change and a key step in the carcinogenic process), and more in vivo gene mutation data have been published in recent years due to the wider use of transgenic rodent gene mutation (TGR) and Pig-a assays. It is appropriate to question whether the Ames + MNvit battery is efficient at detecting substances that induce gene mutations in vivo. A review of several compilations of genotoxicity studies revealed 26 substances that were reported positive in TGR and/or Pig-a but negative in the Ames test. A detailed analysis showed that 25 of these results were questionable for various reasons, and not robust examples of the failure of the 2-test in vitro battery. Only procarbazine was convincingly positive in vivo but predominantly negative in vitro, and this is mainly due to its complex metabolism which is probably not optimal with standard in vitro metabolic activation systems. The analysis shows no evidence that adding a mammalian cell gene mutation test to the in vitro battery would improve the detection of in vivo gene mutagens.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma, with diffuse large B cell lymphoma accounting for most cases. T cell variants are uncommon and associated with poor outcomes. We report a case of primary CNS T cell lymphoma with simultaneous brain and spinal cord involvement. A 37-year-old Japanese man presented with impaired consciousness, and brain magnetic resonance imaging revealed multiple contrast-enhancing parenchymal lesions. Histopathological examination of a brain biopsy specimen demonstrated medium- to large-sized atypical lymphoid cells, leading to a diagnosis of peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). Comprehensive systemic evaluation showed no extracranial disease; however, contrast-enhanced spinal magnetic resonance imaging revealed extensive lesions from the cervical spinal cord to the thoracic spinal cord. Next-generation sequencing analysis identified a mutation in SETD2, possibly contributing to the aggressive disease behavior. The patient received methotrexate, procarbazine, and vincristine as first-line therapy and achieved an initial radiological complete response. However, rapid disease relapse occurred with newly developed lesions in the pineal gland and cranial nerves, and the patient died shortly after initiation of consolidation therapy. This case highlights the aggressive clinical course of primary CNS T cell lymphoma with spinal cord involvement and underscores the importance of molecular genetic profiling in this rare entity.

Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is the most common subtype of autoimmune encephalitis, typically associated with ovarian teratomas, but also reported in men and children. We describe an exceptionally rare case of anti-NMDA receptor encephalitis following glioma resection. A 34-year-old man with no prior medical history presented with severe headache and generalized tonic-clonic seizure. Brain MRI suggested a tumor in the right insular region, and surgical resection confirmed a diffuse astrocytoma, WHO grade II. Postoperatively, the patient developed fever, seizures, confusion, and visual symptoms. Initial cerebrospinal fluid analysis suggested viral encephalitis, but repeated testing revealed marked pleocytosis and elevated protein. Autoimmune antibody panel confirmed anti-NMDA receptor antibody, while other antibodies and viral studies were negative. High-dose methylprednisolone and intravenous immunoglobulin therapy resulted in clinical improvement. The patient subsequently received adjuvant chemotherapy with procarbazine and lomustine for glioma, and no recurrence of encephalitis was observed during a 4-year follow-up. This case highlights the diagnostic challenge of distinguishing glioma-related neuropsychiatric symptoms from anti-NMDA receptor encephalitis, and raises the possibility that surgical manipulation may act as a trigger. Early recognition and appropriate immunotherapy remain essential for favorable outcomes. Further studies are needed to clarify the role of chemotherapy in long-term prognosis of tumor-associated anti-NMDA receptor encephalitis.

Advanced-stage classical Hodgkin lymphoma (cHL) has been traditionally treated with effective chemotherapy regimens, albeit some associated with substantial toxicity. The recently introduced brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD) regimen has proved more effective and less toxic than escalated BEACOPP (escBEACOPP: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). Our retrospective multicentre study assessed outcomes of this treatment in the real-world setting. It incorporated 100 advanced-stage cHL patients receiving BrECADD at 19 cancer centres between July 2023 and October 2025. The primary end-point was progression-free survival (PFS); secondary end-points included overall response rate (ORR), positron emission tomography (PET)-2 negativity, complete response (CR), overall survival (OS) and toxicity. The median age was 30 (18-65) years; 80% had stage IV disease; 85% had an International Prognostic Score ≥3. ORR and CR were 100% and 95%, respectively; 83% achieved PET-2 negativity, enabling therapy de-escalation from six to four cycles. At a median follow-up of 13.7 months, estimated 1-year PFS and OS were 96% and 100% respectively. Only 4% required radiotherapy. Grade ≥3 neutropenia (83%) and febrile neutropenia (55%) were common; yet, 95% of patients completed all planned cycles. Peripheral neuropathy occurred in 25%, mostly grade 1-2. In this real-world cohort, including high-risk patients, BrECADD demonstrated remarkable efficacy and tolerability, supporting its feasibility and potential to reduce chemotherapy and radiotherapy exposure, while maintaining high treatment efficacy.

The treatment efficacy, acute toxicity, and neurocognitive sequelae of older patients with primary central nervous system lymphoma (PCNSL) remain therapeutic challenges. The standard first-line therapy consisted of high-dose methotrexate and cytarabine (AraC) and led to a complete response (CR) in half of the patients. To improve the response rate, we proposed intensifying the standard rituximab, methotrexate, procarbazine, vincristine, and cytarabine (R-MPVA) regimen by sequentially adding etoposide (100 mg/m[2] D2) to R-MPV (R-MPV-E) and ifosfamide (1.5 g/m[2] Days 1-3) to R-AraC (R-AraC-I) for patients aged between 60 and 70 years. The primary objective of this retrospective study was to determine the CR rates after three and two planned cycles of R-MPV-E and R-AraC-I, respectively. Thirty-two consecutive patients received this regimen between 2013 and 2021 in Lyon University Hospitals. After the R-MPV-E and R-AraC-I sequences, 11 (34.4%) and 26 (81.3%) patients achieved CR or unconfirmed CR (CRu), respectively, with favorable safety profiles (19% and 38%, of ≥ Grade 3 hematological toxicity; 19% and 27%, of ≥ Grade 3 infection during the induction and consolidation, respectively). With a median follow-up of 42.4 months, the 3-year event-free survival (EFS) and overall survival (OS) rates were 40.2% and 63.2%, respectively. Historical comparisons with a subset of patients from the LOC network database revealed an improvement in CR rates of 81% after R-MPV-E/R-AraC-I versus 42.9% and 60.5% after MPVA and R-MPVA, respectively, mainly owing to the addition of ifosfamide to the R-AraC sequence. Similar results were observed in an independent retrospective cohort of 20 patients treated at Toulouse University-Hospital, with a 70% CR rate after R-MPV-E/R-AraC-I. In addition, 7/26 (27%) CR/CRu patients in the main cohort could then be referred for autograft consolidation. In conclusion, this study revealed that ifosfamide combined with R-AraC could increase the CR/CRu rate at the end of induction in 60-70-year-old PCNSL patients.

The Lugano Imaging Committee recently refined the Deauville score (DS), subdividing DS5 into DS5a (>2× liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography (PET) after 2 cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent German Hodgkin Study Group randomized phase 3 trials. The primary analysis cohort was HD18 postamendment standard arms (uniform treatment with 6 cycles of escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [eBEACOPP]); sensitivity cohorts were HD18 intention-to-treat and HD21 eBEACOPP and brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET-2. DS5a was infrequent (4%-6% across cohorts; 39/639, 67/1745, 33/568, and 29/560). In the primary cohort, DS5 was associated with inferior PFS vs DS1 to DS3 (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.25-7.23) and vs DS1 to DS4 (HR, 2.35; 95% CI, 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1 to DS4 (HR range, 2.57-5.47), whereas DS4 according to the new definition did not consistently separate from DS1 to DS3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. The HD18 and HD21 trials were registered at www.clinicaltrials.gov as NCT00515554 and NCT02661503, respectively.