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Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.

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Introduction Turbulence in the Solar WindSolar wind is a supersonic and super Alfvénic plasma flow originating from the Sun. It is a continuously expanding plasma that is highly ionized and threaded with large scale magnetic fields (Bruno & Carbone, 2016). The thermodynamic adiabatic expansion law applied to proton temperatures in the solar wind would suggest that temperature declines with heliocentric distance as T r r ( )   43 . Instead, solar wind evolves in a highly non-trivial way as it expands from the Sun (e.g., Matteini et al., 2007). There exist numerous observations to imply that some heating mechanism must be at work within the solar wind to supply the energy required to slow down the decay (Pine et al., 2020). One potential explanation for this heating is turbulence. As the highly ionized and magnetized solar wind develops into a turbulent flow at large scales, it can act as a reservoir of energy.