Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma

BackgroundDiffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis.MethodsWe conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma ({"type":"clinical-trial","attrs":{"text":"NCT03416530","term_id":"NCT03416530"}}NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI).ResultsChange in H3.3K27M VAF over time (“VAF delta”) correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF “spikes” (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression.ConclusionOur work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.     

Fracture of cutting balloon microsurgical blade inside coronary artery during angioplasty of tough restenotic lesion: a case report.

We report a rare complication due to fracture of the blade of a cutting balloon in the setting of a tough nondilatable restenotic lesion. This resulted in a mural hematoma as a result of dissection of coronary artery.     

Effects of local application of 5-HT and 8-OH-DPAT into the dorsal and median raphe nuclei on core temperature in the rat

The core temperature of male Wistar rats was measured after local application of 5-HT (10 µg) or 8-OH-DPAT (5 µg) into the dorsal (DR) or the median raphe (MR) nuclei. The core temperature was measured by a rectal thermistor probe, 20 and 60 min after the injection procedure started. The injected volume was 0.5 µl and injections were made by means of 31G needles, at a rate of 0.33 µl min^–1. The raphe nuclei were approached at 30° in order to avoid penetration of the cerebral aqueduct or to avoid the DR with injections aimed for the MR. The application of 5-HT or the 5-HT_1A agonist 8-OH-DPAT into the DR produced a marked decrease in core temperature, whereas injections into the MR had no effect. These results demonstrate an important role for the DR in temperature regulation in the rat. The fact that the 5-HT_1A agonist 8-OH-DPAT produced a decrease in core temperature, together with the observation that administration of the 5-HT₁ antagonist (–)pindolol antagonized the 5-HT as well as the 8-OH-DPAT-induced decrease, indicates the involvement of DR 5-HT_1A receptors in rat thermoregulation.     

Effects of 5-HT1A Receptor Agonists on Patterns of Rat Motor Activity in Relation to Effects on Forebrain Monoamine Synthesis

Abstract: The effects of the 5-HT_1A receptor agonists 8-OH-DPAT (0.15–2.5 μmol kg^?1 subcutaneously), flesinoxan (0.6–10.0 μmol kg^?1 subcutaneously) and buspirone (1.9–30.0 μmol kg^?1 subcutaneously) on spontaneous motor activity in male Sprague-Dawley rats was examined in a photocell-equipped open-field arena. Following motor activity observations, the cerebral aromatic L-amino acid decarboxylase inhibitor NSD-1015 (100 mg kg^?1 intraperitoneally) was administered and 30 min. later the animals were decapitated for subsequent analysis of the accumulated forebrain DOPA and 5-HTP levels, as an estimate of the rate of monoamine synthesis. 8-OH-DPAT and flesinoxan produced a similar and characteristic pattern of changes of the spontaneous motor activity in normal animals i.e. a moderate decrease in locomotor activity, a marked suppression of rearing and an increase in the relative amount of forward locomotion and of activity in the periphery of the open-field arena. This behavioural profile was closely related to a decrease in forebrain 5-HTP accumulation, indicating 5-HT receptor stimulation. In agreement with these observations buspirone also produced an increase in peripheral activity and a suppression of rearing. In contrast to effects by 8-OH-DPAT and flesinoxan, however, buspirone produced a further reduction of locomotor activity and reduced the forward locomotion. This difference in behavioural profile between buspirone and the other two compounds is probably explained by its DA receptor blocking properties, as indicated by an increased DOPA accumulation in the neostriatum. At least partially, 8-OH-DPAT, flesinoxan and buspirone, all antagonized reserpine-induced (5 mg kg^?1 subcutaneously – 16 hr) suppression of locomotor activity. This stimulation of locomotor activity in reserpine-treated rats is in all probability related to 5-HT_1A receptor stimulation since concomitant DA D₂ receptor blockade, in the case of buspirone, did not markedly affect this behavioural response.     

pRb2/p130 protein in relation to clinicopathological and biological variables in rectal cancers with a clinical trial of preoperative radiotherapy

Background  

pRb2/p130 plays a key role in cell proliferation and is a considerable progress about expression patterns of pRb2/p130 in number of malignancies. However, pRb2/p130 expression and its significance in rectal cancer remain unknown. The purpose of the present study was to investigate pRb2/p130 protein patterns and their correlations with clinicopathological and biological factors in rectal cancer patients with or without preoperative radiotherapy (RT).     

Water Development Projects and Marital Violence: Experiences From Rural Bangladesh

In this article, the authors present the main findings from a qualitative study of processes undergone by women who have left abusive male partners. Three overlapping leaving processes are described: Breaking Up, Becoming Free, and Understanding. Breaking Up covers action (i.e., the physical breakup), and the turning point by which it is preceded or with which it coincides is analyzed. Becoming Free covers emotion and involves release from the strong emotional bond to the batterer, a process that entails four stages. Understanding covers cognition, and is a process in which the woman perceives and interprets what she has been subjected to as violence and herself as a battered woman.     

Why does she leave? The leaving process(es) of battered women

In this article, the authors present the main findings from a qualitative study of processes undergone by women who have left abusive male partners. Three overlapping leaving processes are described: Breaking Up, Becoming Free, and Understanding. Breaking Up covers action (i.e., the physical breakup), and the turning point by which it is preceded or with which it coincides is analyzed. Becoming Free covers emotion and involves release from the strong emotional bond to the batterer, a process that entails four stages. Understanding covers cognition, and is a process in which the woman perceives and interprets what she has been subjected to as violence and herself as a battered woman.