• CNS penetration (brain-penetrant drugs): How well a drug crosses from the blood into the brain, where most cancer drugs are kept out by the blood-brain barrier.
• Cell of origin in practice: Hans against expression profiling, and what it changes: Large B-cell lymphoma is split into two types by which normal B cell it most resembles.
• Cell of origin (GCB vs ABC): Whether a large B-cell lymphoma resembles a germinal-centre B cell or an activated B cell; the activated type does worse and depends on different pathways.
• LymphGen and the genetic clusters of large B-cell lymphoma: Sequencing shows that large B-cell lymphoma is at least seven diseases, each defined by which faults occur together.
• Blood-brain barrier (BBB): The tight seal around brain blood vessels that keeps most drugs out, one of the two main reasons brain cancer is so hard to treat.
• CNS prophylaxis in aggressive B-cell lymphoma, and the evidence against it: Some people with aggressive lymphoma are given extra methotrexate, into the spine or into a vein, to stop the lymphoma reaching the brain.
• MYD88 L265P and CXCR4 mutations: One letter change in MYD88 (L265P) keeps a B-cell survival signal permanently on; it is found in more than nine in ten Waldenström's macroglobulinaemia, most primary CNS and testicular lymphomas and a poor-risk group of DLBCL, and it predicts that BTK inhibitors will work, while a second mutation in CXCR4 predicts that they will work more slowly.
• Intrathecal therapy (lumbar puncture, Ommaya reservoir): Giving drugs directly into the fluid around the brain and spinal cord, by needle in the lower back or through a small reservoir under the scalp, because most drugs cannot cross from the blood into that space.
• A clinical trial or standard treatment in lymphoma: Lymphoma has more trials open to it than almost any other cancer, and in several situations a trial is a reasonable choice beside standard treatment rather than a last resort.
• Stem cell transplant in lymphoma: what it is still for: An autologous transplant is very high-dose chemotherapy followed by the patient's own stored stem cells to rescue the bone marrow.

Newly diagnosed, fit (<65-70): Rituximab + high-dose methotrexate + cytarabine ± thiotepa (MATRix) ×4, then high-dose thiotepa-based chemotherapy with autologous transplant (IELSG32, IELSG43).

Newly diagnosed, older/unfit: High-dose methotrexate with temozolomide, procarbazine or rituximab (e.g. MT-R, R-MP), then maintenance (temozolomide, lenalidomide) or reduced-dose WBRT; ibrutinib-based induction in trials.

Biomarker results to ask for: MYD88 L265P and CD79B mutations (tissue and CSF ctDNA), CSF cytology and flow cytometry, IL-10 in CSF/vitreous, MSKCC and IELSG prognostic scores (age, performance status), Slit-lamp examination for ocular involvement.

Scans and tests linked to this cancer: Comprehensive genomic profiling, Histopathology & immunohistochemistry, Liquid biopsy (ctDNA), MRI, Multidisciplinary tumour boards.

Bring copies of scan reports, pathology and blood results, and a list of every medicine and supplement.

• Primary CNS lymphoma: why R-CHOP fails, and what is given instead: A diffuse large B-cell lymphoma confined to the brain, spinal cord, eyes or meninges. The drugs that cure it elsewhere do not reach it: cyclophosphamide, doxorubicin and vincristine cross the blood-brain barrier poorly, so R-CHOP produces responses in the body and not in the brain, and trials of it in this disease were abandoned decades ago. Surgery has no therapeutic role beyond biopsy, and debulking does not help. Corticosteroids shrink the tumour dramatically and dissolve the diagnostic material with it, so steroids are withheld until the biopsy is taken wherever the patient is stable enough to wait. Induction is built around high-dose methotrexate at 3 to 3.5 g per square metre or more, given with leucovorin rescue and urinary alkalinisation, every two to three weeks. MATRix adds cytarabine, thiotepa and rituximab: in the first randomisation of IELSG32 the complete remission rate was 49 per cent with MATRix against 23 per cent with methotrexate and cytarabine alone and 30 per cent with methotrexate, cytarabine and rituximab. Six per cent of patients died of toxicity, so it is for patients fit enough to take it. The contribution of rituximab itself is contested: HOVON 105 randomised it into a methotrexate-based regimen and did not show the benefit that IELSG32's arm B against arm A comparison suggested. (Methotrexate, Cytarabine, Thiotepa, Rituximab, CNS penetration (brain-penetrant drugs), The lymphoma regimen alphabet: R-CHOP, pola-R-CHP, DA-EPOCH-R, ABVD, BEACOPP and the rest, Intrathecal therapy (lumbar puncture, Ommaya reservoir), Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial)
• Consolidation after methotrexate-based induction: transplant against whole-brain radiotherapy: Induction alone relapses, so responders are consolidated. The two options are thiotepa-based high-dose chemotherapy with an autologous stem cell transplant, or whole-brain radiotherapy, and the choice is dominated by what each does to thinking. MATRix/IELSG43 randomised consolidation in the largest trial ever run in this disease: three-year progression-free survival was 78 per cent (95 per cent confidence interval 69 to 85) with transplant against 51 per cent (41 to 60) with non-myeloablative R-DeVIC consolidation, hazard ratio 0.43, with overall survival also improved; the cost was more toxicity, a mean of 14.6 against 9.3 adverse events per patient and five against two fatal serious adverse events. In the earlier IELSG32 trial, whole-brain radiotherapy and autologous transplant were similarly effective, and at seven years the difference was cognitive: patients who had whole-brain radiotherapy lost attention and executive function, while those who had transplant improved in those domains, in memory and in quality of life. Seven-year overall survival was 21, 37 and 56 per cent for the three induction arms, and 70 per cent for patients who received MATRix and went on to consolidation. So transplant is preferred for patients fit enough. Whole-brain radiotherapy is reserved for those who are not, usually at a reduced dose, and is increasingly deferred to relapse. (MATRix/IELSG43: high-dose chemotherapy and autologous stem cell transplant versus non-myeloablative consolidation in primary CNS lymphoma, Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial, Autologous stem cell transplant (high-dose therapy), Thiotepa, Carmustine, Busulfan, Stem cell transplant in lymphoma: what it is still for, Radiotherapy in lymphoma: involved-site fields, 24 Gy, 4 Gy and total skin electron therapy, Late effects and survivorship toxicity)
• Relapsed/refractory: Re-induction with methotrexate if durable first remission; ibrutinib, lenalidomide-rituximab, high-dose chemotherapy/ASCT if not done, WBRT; CD19 CAR-T and PD-1 inhibitors in trials or off-label. (Ibrutinib, Lenalidomide, Axicabtagene ciloleucel, Nivolumab)
• Primary CNS lymphoma in older or less fit patients, and at relapse: Age is not by itself a reason to withhold methotrexate: reduced-intensity methotrexate-based combinations, usually with rituximab and an alkylating agent such as procarbazine or temozolomide, are given to patients in their seventies and eighties with attention to renal function, and produce durable remissions in a minority. Whole-brain radiotherapy in older patients carries a high risk of progressive cognitive decline and is generally avoided as first consolidation. At relapse the options depend on the interval. Re-treatment with methotrexate is effective in patients who relapse late, and in the seven-year IELSG32 report it was the only salvage that clearly benefited anyone. Other options are high-dose cytarabine with thiotepa and transplant if not already given, whole-brain radiotherapy if not already given, ibrutinib, which crosses into the brain and has single-agent activity, lenalidomide with rituximab, temozolomide, and a clinical trial. Ocular involvement is treated with systemic therapy, often with intravitreal methotrexate or rituximab added. (Methotrexate, Rituximab, Procarbazine, Temozolomide, Ibrutinib, Lenalidomide, Cytarabine, Thiotepa, CNS penetration (brain-penetrant drugs), Stem cell transplant in lymphoma: what it is still for, Early integrated palliative care)

From the standard of care recorded for this cancer; which apply depends on your stage and biomarkers. Ask which the team recommends and why.