Background:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.Methods:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP ‘group 1' R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX ‘group 2' dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX ‘group 3'.Results:Overall, 217 patients were identified (49, 125 and 43 in groups 1–3, respectively). With median follow-up of 3.4 (range 0.2–18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1–3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5–33.1%), 6.9% (3.5–13.4%) and 2.3% (0.4–15.4%) in groups 1–3, respectively (P=0.009).Conclusions:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and are typically Epstein-Barr virus (EBV)-tissue positive. We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. 47 were EBV-tissue negative: 45 EBV(-) HIV(-) PCNSL, 2 EBV(-) HIV(+) PCNSL; and 44 were EBV-tissue positive: 23 EBV(+) HIV(+) PCNSL, 21 EBV(+) HIV(-) PCNSL. As with prior studies, EBV(-) HIV(-) PCNSL had frequent MYD88, CD79B and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin (COO) sub-type. In contrast, these mutations were absent in all EBV-tissue positive cases and ABC frequency was low. Furthermore, copy number loss in HLA-class I/II and antigen presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV(+) HIV(-) PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-tissue positive PCNSL in the immunosuppressed is immunobiologically distinct from EBV(-) HIV(-) PCNSL, and despite expressing an immunogenic virus retains the ability to present EBV-antigens. Results provide a framework for targeted treatment.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

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reatine supplements are commonly used by professional and amateur athletes to help enhance their sporting performance. 2 Creatine is typically sold in powder form to limit spontaneous hydrolysis to creatinine. Recently, creatine monohydrate suspended in water (Creatine Water AsthNon3000, Immuno-Biological Laboratories Co, Takasaki-Shi, Gunma, Japan) has become commercially available in Australia. The manufacturing process attempts to stabilise creatine in liquid for prolonged periods of time. Our patient's disproportionately elevated creatinine level compared with a urea level within reference range, lack of evidence for organic renal abnormality, and rapid normalisation of creatinine level once he stopped using the creatine supplement suggest that artefactual elevation of creatinine secondary to consumption of creatine water was responsible for the abnormal biochemical test results seen.We investigated this hypothesis further by analysing a previously unopened bottle of the creatine water product that the patient had been using. The product information stated that a 500 mL bottle contains water, sorbitol 5 g, creatine monohydrate 3 g and sodium 0.27 mg. We analysed the fluid on the hospital' s laboratory analyser (UniCel DxC-800 Synchron, Beckman-Coulter, Brea, Calif, USA) using the Jaffé method and obtained a creatinine concentration of 21 000 mol/L. To determine whether the drink actually contained creatinine or if this concentration was an artefact of the creatine present in the supplement, we then analysed it using high-performance liquid chromatography. This analysis showed a creatine concentration of 46.5 mmol/L, which was about the same as that stated on the product label, and a creatinine concentration of 20 000 mol/L, which was similar to that from the hospital' s laboratory analyser. Further testing also found that creatine itself caused minimal cross-reactivity; a separately produced creatine solution with a concentration of 55.6 mmol/L recorded a creatinine concentration of only 80 mol/L (Jaffé method). Clinical recordWe report the case of a 20-year-old man who suffered an artefactual elevation of creatinine after consuming a creatine water supplement. Before this event, the patient was regularly seen in our clinic to monitor progression of a secondary paroxysmal nocturnal haemoglobinuria clone complicating childhood aplastic anaemia, for which he was previously treated with immunosuppression. Aside from his asymptomatic, stable, moderate thrombocytopenia (platelet count, 50-60 10 9 /L), there had never been evidence of haemolysis or thrombosis. The patient took no regular prescription medications and had previously documented normal renal function (Table). Blood tests performed 1 day before the patient's admission to hospital showed a significantly elevated creatinine level of 196 μmol/L (reference range, 40-120 μmol/L), with an estimated glomerular filtration rate of 38 mL/min, calculated using the MDRD (modification of diet in renal disease) formula. 1 The patient reported no recent systemic illne...

The study shows that point-of-care INR testing devices should not be used in suspected snakebite cases in Australia to diagnose venom-induced consumption coagulopathy.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haemolytic disease with a propensity for causing thrombotic complications. Purpura fulminans (PF) has only rarely been described in association with PNH. 1,2 We report a case of PF in a patient with PNH; however, in contrast to previous cases, cessation of anticoagulation did not result in recurrent thrombotic complications.A 21-year-old male with PNH that developed during follow-up of immunosuppression refractory severe aplastic anaemia presented with a widespread purpuric rash. He had been unwell for several days prior to initial presentation with non-specific URTI symptoms, treated with oral amoxicillin. He had also been commenced escitalopram several weeks beforehand.His PNH was manifest by stable moderate thrombocytopenia (platelet count 50 ¥ 10 9 /L) but normal Hb and WCC/differential. On flow cytometry, his PNH clone affected 100% neutrophils, 70% monocytes but <5% RBC. The patient had never suffered haemolysis or prior thromboembolic disease, and as such had never been treated with eculizumab. There was no family history of blood or clotting disorders.At presentation, the patient exhibited a classic PF rash over his face, back and chest. Skin biopsies displayed classic PF features with prominent haemorrhage throughout the dermis and focal necrosis of the epidermis in association with widespread thrombi in dermal blood vessels. Repeat FBC was unchanged. Coagulation profile and thrombotic screen were normal with no evidence of DIC. Protein C levels were mildly reduced (0.62 U/mL; RR 0.7 to 1.3 via chromogenic activity assay); protein S levels, blood cultures, vasculitic screen and liver and renal function tests were all normal.The patient was treated with FFP, prednisone (1 mg/ kg/day), enoxeparin 1 mg/kg BD, platelet transfusions (to maintain platelet count >50 ¥ 10 9 /L), vitamin K and empirical Tazocin. Skin lesions rapidly improved, and no new lesions developed after the first 48 h. Once vasculitic screen results were available, prednisolone was weaned. Repeat protein C levels performed 7 days after presentation, after active PF manifestations had clinically resolved, were normal (0.91U/mL). Due to persistent thrombocytopenia, warfarin therapy was felt to be relatively contra-indicated, and given the possibility of either a viral or a drug trigger for the PF, enoxeparin was ceased 8 weeks after all skin lesions fully healed, 18 weeks post-initial presentation. After 12mths the patient remains well with no change in his PNH and no further thrombotic events including no recurrence of his PF. Given the lack of family history of clotting disorders and the normalisation of protein C levels after PF treatment, the mildly low protein C levels at PF presentation were felt secondary to an acquired deficiency in the setting of active PF.Only two cases of PF associated with PNH have been previously published. In both cases, infectious triggers (non-specific febrile illness and presumed meningococcal sepsis) preceded the onset of PF. 1,2 In one case, despite a...