DDIS-31. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.4

Clinically Significant Differences in Acute Pain Measured on Self-report Pain Scales in Children

OBJECTIVES: The objective was to determine the minimum and ideal clinically significant differences (MCSD, ICSD) of the Faces Pain Scale–Revised (FPS-R) and the Color Analog Scale (CAS) in children and to identify any differences in these estimates based on patient characteristics. METHODS: This was a prospective study of children aged 4 to 17 years with acute pain presenting to two urban pediatric emergency departments. Participants self-reported their pain severity using the FPS-R and CAS and qualitatively described their changes in pain. Changes in pain score reported using the FPS-R and CAS that were associated with “a little less” and “much less” pain (MCSD and ICSD, respectively) were identified using a receiver operating characteristic–based method and expressed as raw change score and percent reductions. Estimates of MCSD and ICSD were determined for each category of initial pain severity (mild, moderate, and severe) and patient characteristics (age, sex, and ethnicity). Post hoc exploratory analyses evaluated categories of race, primary language, and etiology of pain. RESULTS: A total of 314 children with acute pain were enrolled; mean (±SD) age was 9.8 (±3.8) years. The FPS-R raw change score and percent reduction MCSD estimates were 2/10 and 25%, with ICSD estimates of 3/10 and 60%. For the CAS, raw change score and percent reduction MCSD estimates were 1/10 and 15%, with ICSD estimates of 2.75/10 and 52%. For both scales, raw change score and percent reduction estimates of the MCSD remained unchanged in children with either moderate or severe pain. For both scales, estimates of ICSD were not stable across categories of initial pain severity. There was no difference in MCSD or ICSD based on age, sex, ethnicity, race, primary language, or etiology of pain. CONCLUSIONS: The MCSD estimates can be expressed as raw change score and percent reductions for the FPS-R and CAS. These estimates appear stable for children with moderate to severe pain, irrespective of age, sex, and ethnicity. Estimates of ICSD were not stable across different categories of initial pain severity, therefore limiting their potential generalizability