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INTRODUCTION Neurocognitive dysfunction can result from radiation therapy which is the mainstay of treatment for high-grade glioma, particularly glioblastoma. Preclinical observations found that BMX-001, a novel metalloporphyrin, acts as a radioprotectant for normal CNS cells yet as a radiosensitizer to cancer cells in human GBM xenograft experiments. In a phase 1 study evaluating the safety of BMX-001 in combination with concurrent radiation therapy and temozolomide, we further studied neurocognitive function before and after concurrent radiation therapy and temozolomide in newly diagnosed high-grade glioma patients. METHODS We performed a phase 1 study of BMX-001 combined with radiation therapy (6-week total of 59.4-60 Gy) and temozolomide (75 mg/m2/day for 42 days). We administered BMX-001 as a subcutaneous injection at a loading dose before radiation therapy and temozolomide and then subsequent doses twice weekly for eight weeks. A key secondary endpoint was the evaluation of neurocognition. We performed neurocognitive testing with the computerized program CNS Vital Signsâ. This battery consists of seven tests: verbal memory, visual memory, finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, and a continuous performance test. We defined neurocognitive impairment at baseline as a z-score ≥ 1.5 SDs below the normative mean. We described improvements or declines in neurocognition at 2 and 6 months from baseline. RESULTS Fifteen patients (age 19-80 years) enrolled and underwent neurocognitive testing before and after RT. All patients had WHO grade 4 glioblastoma. Most subjects had neurocognitive impairment ranging from 46.7-to 80% on specific neurocognitive tests. At two months (N=15) and six months (N=9), most testing demonstrated improved neurocognitive performance. CONCLUSIONS Neurocognitive function is maintained and can improve after concurrent radiation therapy and temozolomide in this high-grade glioma cohort treated with BMX-001 during concurrent radiation therapy and temozolomide.

TPS2069 Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.

ObjectiveHeart rate variability is useful in evaluating cardiac autonomic balance. We investigated cardiac autonomic modulation in patients with severe chronic obstructive pulmonary disease (COPD) during heavy and very heavy exercise at and above the critical power (CP).Materials and MethodsNine nonhypoxemic patients with COPD (mean forced expiratory volume in 1 second: 1.2±0.5L; forced expiratory volume in 1 second/forced vital capacity: 37.6±12%) completed an initial incremental exercise test on a cycle ergometer followed by four constant work rate tests to define their CP. In addition, patients underwent a test at their calculated CP for a target of 20 minutes. The CP test plus a test above CP of sufficient duration to allow heart rate variability analysis were studied further. In these tests, R-R interval data were analyzed for variability in the frequency domain before and during exercise.ResultsCompared with rest, the power of the normalized low-frequency component (nuLF) decreased (73.0±20.9 vs. 54.2±20.1; p=0.01) and the power of normalized high-frequency component (nuHF) increased (27.0±20.9 vs. 45.8±20.1; p=0.01) during exercise, resulting in a decrease in LF/HF (4.1±2.3 vs. 1.6±1.2; p=0.01) suggesting a relative increase in parasympathetic tone during exercise. When compared with exercise at CP, exercise above CP featured significantly higher values for the square root of the mean squared differences of the successive R-R intervals, the baseline width of the minimum square difference triangular interpolation of the highest peak of the histogram of all N-N intervals and the nuHF, as well as significantly lower values for the nuLF and LF/HF. During exercise above and at the CP, both LF and HF negatively correlated with the respiratory rate (r=−0.76 and r=−0.70, p

Inhomogeneous distributions of liquid water like those observed in real clouds generally reflect less solar radiation than idealized uniform distributions assumed in plane-parallel theory. Here the authors determine cloud reflectivity and the associated plane-parallel albedo bias from distributions of liquid water path derived from 28 days of microwave radiometer measurements obtained on Porto Santo Island in the Madeiras during June 1992 as part of the Atlantic Stratocumulus Transition Experiment (ASTEX). The distributions are determined for each hour of the day, both for composites of the full act of 28 days and for a subset of 8 days having a high fraction of relatively thick cloud. Both sets are compared with results obtained from California stratocumulus during FM [First ISCCP (International Satellite Cloud Climatology Project) Regional Experiment]. In FIRE the albedo bin was dominated by variability of the cloud optical depth, as measured by a fractal parameter, 0≤ f 0 ≤ 1, while the ASTEX ...