Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.

Pretreatment d-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia.

Mutations in isocitrate dehydrogenases (IDHs) 1 and 2 frequently occur in acute myeloid leukemia (AML) and result in the production of the oncometabolite d-2-hydroxyglutarate (D2HG). D2HG has been shown to promote leukemogenesis even in the absence of mutated IDH, but the prognostic significance of pretreatment serum D2HG levels in patients with IDH-mutated AML is unclear. We measured D2HG serum levels in 84 patients with IDH-mutated AML treated in the prospective, randomized multicenter AML2003 trial of the German Study Alliance Leukemia. Multivariate Cox regression showed D2HG levels to negatively impact on event-free survival (EFS) as a continuous variable in the entire IDH(mut) cohort (P=0.04), with no effect on overall survival (OS). In a subgroup analysis, the negative impact of D2HG on EFS was found to be restricted to patients with mutations in IDH1 (P=0.003), adjusted for age, leukocyte count, serum lactate dehydrogenase and European LeukemiaNet risk score. We thus conclude that pretreatment D2HG serum levels may yield prognostic information in patients with IDH1-mutated, but not in IDH2-mutated AML, possibly due to different subcellular localizations of IDH1 and IDH2.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Fibronectin concentrations in pleural and abdominal effusions in dogs and cats.

A commercial nephelometric test kit for human fibronectin (FN) was found suitable for the estimation of fibronectin concentration in body effusions of cats and dogs. The FN measurements were set in relation to the FN concentration of plasma pools in cats and dogs. A discrimination line of 31.5% completely separated malignant from cardiogenic pleural effusions in cats. For the diagnosis of a malignant pleural effusion, sensitivity was 100% and specificity was 57%. Pleuritis also resulted in high FN concentrations. The FN concentration in malignant pleural effusions in dogs differed significantly (P < .02) from that in cardiogenic effusions. There were no clinically useful differences in the FN concentration in peritoneal effusions in cats and dogs. The FN/albumin ratio was significantly higher (P < .02) in dogs with neoplastic abdominal effusion than in those with congestive heart failure.

[Infarction of the spinal cord in the posterior spinal arterial supply area as a result of intervertebral disc embolism (author's transl)]. / Bandscheibengewebsembolien in Spinalgefässen als Ursache von Myelomalazien vorwiegend in Spinalis-posterior-Versorgungsgebieten.

A female patient aged 49 developed an acute transverse lesion of the spinal cord from D11 downwards. Autopsy revealed spinal cord infarcts mainly in the dorsal parts corresponding to the posterior spinal arterial supply area, caused by multiple arterial and venous fibrocartilaginous emboli. This particular cause of spinal vascular syndrome has been reported previously only in 11 patients, all outside Austria. This case report serves to stress the poor clinical delineation of a distinct "posterior spinal syndrome". The source of the emboli is the intervertebral disc, mainly the nucleus pulposus. The spinal cord vessels are probably entered by the following route: extrusion of disc material into the venous bone marrow sinus (probably favoured by trauma or endocrine factors) yield basivertebral veins yield internal vertebral venous plexus; the spread is supported by blood stream changes caused by increased intraabdominal/intrathoracic pressure; there is also the possibility of direct penetration of disc material into the internal vertebral plexus, as demonstrated in dogs yield radicular veins yield meningeal and cord veins; sometimes entry occurs through arteriovenous shunts into cord arteries. The true incidence of this condition is unknown since cases are likely to be overlooked in the absence of extensive histopathological investigation.

[Infusion therapy with mif (melanocyte inhibiting factor) in Parkinson's disease (author's transl)]. / Infusionstherapie mit MIF (Melanocyte Inhibiting Factor) beim Parkinson-Syndrom

On the basis of reports in the literature and of our own clinical experience it appears that melanocyte inhibiting factor (MIF) is a very promising therapeutic agent in the management of Parkinson's disease. Besides theoretical considerations relating to biochemical and pathophysiological spheres, the question of the current dosage for clinical usage seems to be of the utmost importance. We are of the opinion that the currently-employed dosage of 400 mg daily is still too low. Hence, the present investigation will be continued with a view to establishing the optimum dosage for maximal therapeutic effect.