On the use of ELF/VLF emissions triggered by HAARP to simulate PLHR and to study associated MLR events

A spectrogram of Power Line Harmonic Radiation (PLHR) consists of a set of lines with frequency spacing corresponding exactly to 50 or 60 Hz. It is distinct from a spectrogram of Magnetospheric Line Radiation (MLR) where the lines are not equidistant and drift in frequency. PLHR and MLR propagate in the ionosphere and the magnetosphere and are recorded by ground experiments and satellites. If the source of PLHR is evident, the origin of the MLR is still under debate and the purpose of this paper is to understand how MLR lines are formed. The ELF waves triggered by High-frequency Active Auroral Research Program (HAARP) in the ionosphere are used to simulate lines (pulses of different lengths and different frequencies). Several receivers are utilized to survey the propagation of these pulses. The resulting waves are simultaneously recorded by ground-based experiments close to HAARP in Alaska, and by the low-altitude satellite DEMETER either above HAARP or its magnetically conjugate point. Six cases are presented which show that 2-hop echoes (pulses going back and forth in the magnetosphere) are very often observed. The pulses emitted by HAARP return in the Northern hemisphere with a time delay. A detailed spectral analysis shows that sidebands can be triggered and create elements with superposed frequency lines which drift in frequency during the propagation. These elements acting like quasi-periodic emissions are subjected to equatorial amplification and can trigger hooks and falling tones. At the end all these known physical processes lead to the formation of the observed MLR by HAARP pulses. It is shown that there is a tendency for the MLR frequencies of occurrence to be around 2 kHz although the exciting waves have been emitted at lower and higher frequencies. Graphical Abstract

CTNI-27. SINGLE AGENT ACTIVITY OF ONC201 IN NON-MIDLINE H3 K27M-MUTANT DIFFUSE GLIOMAS

BACKGROUND H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti- cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. METHODS We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). RESULTS Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. CONCLUSIONS These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.

Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas.

e14037 Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.

The Time-dependent Problem of the Line Radiation Reflection

We consider the classical time-dependent problem of diffuse reflection of the line-radiation from a semi-infinite absorbing and scattering atmosphere. By the example of the simplest 1D problem it is shown how its solution is constructed in the general case, when both the photon lifetime in the absorbed state and the time of its travel between two consecutive acts of scattering are taken into account. The numerical values of the coefficients in the expansion of the reflection function in the Neumann series are given. The obtained solution is applied to the problem, in which the scattering in both the spectral line and in the continuous spectrum is taken into account.

BIOM-47. LONGITUDINAL MONITORING OF PLASMA H3K27M IN DIFFUSE MIDLINE GLIOMA PATIENTS TREATED WITH ONC201

Diffuse midline glioma, H3 K27M-mutant (DMG) is a 2016 WHO Grade IV glioma that has no established treatment beyond first-line radiation. ONC201 is an investigational small molecule that has been shown to be clinically active in recurrent DMG clinical trials. While biopsies of DMG are sometimes feasible, many patients defer secondary to complication risk. MR scans have many limitations in monitoring DMG progression, including distinguishing pseudoprogression and pseudoresponse and measuring diffuse lesions that often do not contrast enhance. Digital droplet PCR (ddPCR) is capable of sensitively detecting and quantifying the allelic frequency of circulating-tumor DNA (ctDNA) fragments against a backdrop of non-tumor DNA. Using sequence-specific probes for H3F3A (H3.3 K27M) and HIST1H3B (H3.1 K27M) ddPCR detects very low frequency variants and provides an assessment of mutational burden. A pilot cohort of 5 patients treated with ONC201 who had a range of outcomes were assessed with serial ctDNA analyses. Two patients with immediately progressive disease had a concordant H3 K27M ctDNA increase that precedes radiographic detection by 4 weeks. Two patients with >50% tumor regressions while on ONC201 had concordant H3 K27M ctDNA burden at the onset of response and subsequent radiographic progression was preceded by increases in ctDNA 8–16 weeks prior. One patient who had prolonged stable disease had decreased H3 K27M ctDNA burden over time. Upon radiographic progression, the addition of bevacizumab with ONC201 caused a radiographic pseudoresponse, however H3 K27M ctDNA remained stable. These pilot results suggest H3 K27M ctDNA may be a sensitive and accurate biomarker of disease burden. Longitudinal evaluation of H3 K27M ctDNA in a cohort of 34 recurrent contrast-enhancing H3 K27M-mutant glioma patients while on ONC201 will be reported. Primary tumor locations range across the thalamus, cerebellum, basal ganglia, temporal lobe, and midbrain; median age is 31 years old (range 20–70).