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Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Immuntherapeutische Behandlungsansätze für Gliome mit dem Ziel, einerseits gegen den Tumor gerichtete Immunantworten zu stärken und andererseits dem immunsuppressiven Tumormikromilieu entgegenzuwirken, werden seit Jahrzehnten in präklinischen und klinischen Studien untersucht, ohne dass es bisher eine zugelassene Immuntherapie für die Behandlung von primären Hirntumoren gibt. Dennoch erfährt die Neuroonkoimmunologie aktuell sowohl aufgrund neuer diagnostischer Möglichkeiten und zielgerichteter Therapieoptionen als auch aufgrund erfolgsversprechender Ergebnisse bei systemischen Tumoren ein gesteigertes Interesse. Dieser Artikel gibt einen Überblick über aktuelle Konzepte zur Immuntherapie bei Gliomen und fasst bisherige Studienergebnisse zusammen. Während erste klinische Erfahrungen zum Einsatz von Immuncheckpointinhibitoren bei Gliomen keine grundlegenden Sicherheitsbedenken ergaben, scheint auf Grundlage der bisherigen Studienergebnisse die Wirksamkeit zumindest einer Monotherapie in nicht selektierten Patientenpopulationen bei malignen Gliomen begrenzt zu sein. Klinische Ergebnisse zu Kombinationsbehandlungen, beispielsweise mit T‑Zell-basierten Therapieansätzen wie antigenspezifischen Vakzinierungen, stehen aus. Diese nutzen meist Peptidimpfstoffe, die gegen Tumorantigene gerichtet sind, um eine möglichst effektive und gleichzeitig spezifische Antitumorimmunantwort zu generieren. Neben Impfstoffen gegen individuell variable Antigene eignen sich insbesondere rekurrente Neoepitope wie eine in Glioblastomen vorkommenden Splicevariante des epidermalen Wachstumsfaktors (EGFRvIII) oder eine in diffusen Gliomen vorkommende Punktmutation im Gen der Isocitratdehydrogenase-1 (IDH1R132H) als Vakzinierungsziel. Immunotherapeutic approaches for treatment of malignant gliomas aim at inducing effective anti-tumor immune responses while counteracting the immunosuppressive tumor microenvironment. Despite extensive preclinical and clinical research during the last decades, there are currently no approved immunotherapeutic drugs for primary brain tumors; however, neuro-oncoimmunology is currently experiencing major interest due to new diagnostic and targeted therapy options as well as due to promising results in systemic tumors. This article provides an overview of current concepts for glioma immunotherapy and summarizes the results of available clinical trials. While first clinical experiences with the administration of immune checkpoint inhibitors for gliomas did not raise any safety concerns, the efficacy of immune checkpoint monotherapy for malignant gliomas appears to be limited in an unselected patient population. Clinical results on combination treatment, such as T cell-based therapy approaches with antigen-specific vaccinations are pending. This involves mostly peptide vaccines that are directed against tumor antigens in order to generate an effective and at the same time specific anti-tumor immune response. In addition to vaccines against individually variable antigens, recurrent neoepitopes are particularly suitable as a target of vaccination, such as a splice variant of the epidermal growth factor (EGFRvIII) occurring in glioblastomas and a point mutation occurring in diffuse gliomas in the gene of isocitrate dehydrogenase-1 (IDH1R132H).

The authors performed a comprehensive analysis of the functional outcome of 10 patients who had survived 5 years from a diagnosis of glioblastoma. Neurologic deficits were mild in most patients, but neuropsychological testing demonstrated cognitive deficits in all patients. Depression and anxiety were common. Although most patients thought that their social functioning and work ability were impaired, little reduction in overall quality of life was perceived.

We prove the central limit theorem for the density fluctuation field of a one-dimensional mechanical system (hard rods with equal masses and lengths and elastic collisions) in the hydrodynamic limit on the Euler time scale. The limiting process is deterministic and is governed by the linearized Euler equations of the model.

We present an invariance principle for antisymmetric functions of a reversible Markov process which immediately implies convergence to Brownian motion for a wide class of random motions in random environments. We apply it to establish convergence to Brownian motion (i) for a walker moving in the infinite cluster of the two-dimensional bond percolation model, (ii) for ad-dimensional walker moving in a symmetric random environment under very mild assumptions on the distribution of the environment, (iii) for a tagged particle in ad-dimensional symmetric lattice gas which allows interchanges, (iv) for a tagged particle in ad-dimensional system of interacting Brownian particles. Our formulation also leads naturally to bounds on the diffusion constant.

A simple example of a “nongradient” stochastic interacting particle system is analyzed. In this model, symmetric simple exclusion in one dimension in a periodic environment, the dynamical term in the Green-Kubo formula contributes to the bulk diffusion constant. The law of large numbers for the density field and the central limit theorem for the density fluctuation field are proven, and the Green-Kubo expression for the diffusion constant is computed exactly. The hydrodynamic equation for the model turns out to be linear.

The local equilibrium picture of the time evolution of a gas may have to be modified in the presence of shocks in order to admit statistical mixtures of pure states in the hydrodynamic description. An example drawn from a stochastic many-particle model (asymmetric zero-range model) is described.

Chromatographic studies and microbiological assays show that, after oral administration, cephaloglycin is partially converted in man to a biologically active metabolite desacetylcephaloglycin. The antibacterial activity of this metabolite compared to that of cephaloglycin is equivalent against gram-positive organisms but is lower against gram-negative bacilli. Successful therapy of urinary tract infections with cephaloglycin must be mainly attributed to the antibacterial activity of this metabolite. At the present time, it is not possible to assess what influence low amounts of unaltered cephaloglycin have on the outcome of therapy.

Compound 64716, 1-ethyl-4 (1H)-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid, is a new synthetic antibacterial agent. The antibacterial spectrum of this compound includes gram-negative bacteria that are most frequently isolated from urinary tract infections. Minimal inhibitory concentration values of 64716 for isolates of Escherichia coliand Proteussp. ranged from 2 to 4 and 2 to 8 µg/ml, respectively, and the compound was bactericidal at concentrations close to the minimal inhibitory concentration values. In vivo, doses required for successful therapy of experimental mouse infections were comparable to those for nalidixic acid. After oral administration of 40 mg/kg, peak concentrations of this compound in mouse blood reached 19.2 µg/ml. Within 30 min after doses of 20 mg/kg, bacteriologically active drug concentrations of 64716, nalidixic acid, and oxolinic acid in mouse urine were >1,000, 170, and <1.5 µg/ml, respectively. Resistant bacteria were not selected when bacteria were exposed to 500 µg/ml of 64716. Compound 64716 was less bound by human serum proteins than was nalidixic acid. Equivalent antibacterial activity along with superior pharmacological properties of 64716 when compared with nalidixic acid lead to the conclusion that this new compound is a promising antibacterial agent.

Boniece, W. S. (Lilly Research Laboratories, Indianapolis, Indiana), W. E. Wick, D. H. Holmes, and C. E. Redman. In vitro and in vivo laboratory evaluation of cephalothin, a new broad-spectrum antibiotic. J. Bacteriol. 84:1292–1296. 1962.—Cephalothin, a new cephalosporin antibiotic, is the sodium salt of 7-(thiophene-2-acetamido) cephalosporanic acid. The activity of this antibiotic against a variety of gram-positive and gram-negative bacteria is described, as determined by the tube-dilution and disc-plate methods. Correlations of the results of the therapy of experimental infections in mice with in vitro sensitivity to cephalothin are presented. The data from the gram-negative bacterial infection tests suggest the following relationship on a within strain basis: ed50= Cild50bi, where the subscript istands for the various strains.

Twenty-one patients with recurrent or progressive glioblastoma were enrolled in a prospective phase II trial to determine the safety and efficacy of a 1-week on/1-week off regimen of temozolomide administered at 150 mg/m2on days 1 to 7 and days 15 to 21 of 28-day treatment cycles. Two patients achieved a partial response (10), and 17 patients (81) had stable disease. The median progression-free survival was 5 months. The progression-free survival at 6 months was 48.

A series of 3-nitropyrazole compounds represent a new class of synthetic antibacterial agents. One member of this series, 1-(2-hydroxyethyl)-3-nitro-4-pyrazolecarboxamide, exhibited an antibacterial spectrum similar to that of nitrofurantoin. The inhibitory concentrations of this nitropyrazole were lower than those required for nitrofurantoin. Single oral doses of 20 mg/kg resulted in peak nitropyrazole concentrations of 5.8 and >1,000 µg/ml in mouse blood and urine, respectively. In dogs, 87% of a 10 mg/kg oral dose was recovered in urine during a 24-h period with a peak serum concentration of 13.6 µg/ml. This nitropyrazole was highly effective against experimental bacterial infections in mice. The low acute toxicity in mice, rats, or dogs and significant antibacterial activity lead to the conclusion that further evaluation of this compound is warranted.