Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.

Lack of adrenoleukodystrophy protein enhances oligodendrocyte disturbance and microglia activation in mice with combined Abcd1/Mag deficiency.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disease associated with the accumulation of very long-chain fatty acids. Mutations in the ABCD1 gene encoding ALD protein (ALDP) cause this clinically heterogeneous disorder, ranging from adrenocortical insufficiency and neurodegeneration to severe cerebral inflammation and demyelination. ALDP-deficient mice replicate metabolic dysfunctions and develop late-onset axonopathy but lack histological signs of cerebral inflammation and demyelination. To test the hypothesis that subtle destabilization of myelin may initiate inflammatory demyelination in Abcd1 deficiency, we generated mice with the combined metabolic defect of X-ALD and the mild myelin abnormalities of myelin-associated glycoprotein (MAG) deficiency. A behavioural phenotype, impaired motor performance and tremor, developed in middle-aged Mag null mice, independent of Abcd1 genotype. Routine histology revealed no signs of inflammation or demyelination in the CNS, but immunohistochemical analyses of spinal cord neuropathology revealed microglia activation and axonal degeneration in Mag and Abcd1/Mag double-knockout (ko) and, less severe and of later onset, in Abcd1 mutants. While combined Abcd1/Mag deficiency showed an additive effect on microglia activation, axonal degeneration, quantified by accumulation of amyloid precursor protein (APP) in axonal spheroids, was not accelerated. Interestingly, abnormal APP reactivity was enhanced within compact myelin of Abcd1/Mag double-ko mice compared to single mutants already at 13 months. These results suggest that ALDP deficiency enhances metabolic distress in oligodendrocytes that are compromised a priori by destabilised myelin. Furthermore, the age at which this occurs precedes by far the onset of axonal degeneration in Abcd1-deficient mice, implying that oligodendrocyte/myelin disturbances may precede axonopathy in X-ALD.