Intrathecal administration of methotrexate (IT-MTX) can lead to neurotoxicity. MTX-induced neurotoxicity occasionally manifests with a stroke-like presentation that is difficult to distinguish from genuine stroke. We retrospectively reviewed records of nine patients with leukemia or lymphoma and episodes of stroke-like presentation at our institute between 2010 and 2015 for whom magnetic resonance imaging (MRI) data were available. Coagulation test results were compared between the two diagnostic groups. Four patients were diagnosed with MTX-induced stroke-like neurotoxicity. The first neurological event occurred 10-13 days after the fourth or later IT-MTX treatment. All four patients had hemiparalysis, two exhibited disturbed consciousness and three presented with speech disorders. Fibrin/fibrinogen degradation products (FDP) and D-dimer values were within normal ranges. MRI revealed bilateral lesions with restricted diffusion in all four cases. Neurological symptoms fluctuated and resolved within 5 days, and IT-MTX was subsequently re-initiated in all four cases. One patient developed transient hemiparalysis after a subsequent IT-MTX treatment, but this did not recur thereafter. Bilateral lesions on MRI and normal coagulation are indicative of MTX-induced stroke-like neurotoxicity. Continuation of IT-MTX after these events is generally feasible, but adverse event risk should be carefully weighed against anti-tumor benefits.

The ruthenabicyclic complex RuCl[(R)‐daipena][(R)‐dm‐segphos] with potassium tert‐butoxide catalyzes the hydrogenation of 2‐alkylquinoxalines and a 3‐methyl‐2H‐1,4‐benzoxazine in toluene under 20–100 atm of hydrogen at 40 °C to afford S‐configured cyclic amino products in greater than 97% enantiomeric excess {DAIPENA=anion of DAIPEN at the 2‐position of an anisyl group, DAIPEN=1,1‐di(4‐anisyl)‐2‐isopropyl‐1,2‐ethylenediamine, DM‐SEGPHOS=(4,4′‐bi‐1,3‐benzodioxole)‐5,5′‐diylbis[di(3,5‐xylyl)phosphine]}. The high catalytic activity results in a turnover number as high as 9400. Hydrogenation of the benzoimine heterocycles with the RuCl[(R)‐daipena][(R)‐segphos]/potassium tert‐butoxide system yields the R‐configured products in high enantiomeric excess [SEGPHOS=(4,4′‐bi‐1,3‐benzodioxole)‐5,5′‐diylbis(diphenylphosphine)]. The mode of enantioselection is discussed based on transition state models involving six‐membered pericyclic structures.magnified image

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Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.