Report of National Brain Tumor Society roundtable workshop on innovating brain tumor clinical trials: building on lessons learned from COVID-19 experience

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.     

SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been linked to the production of inflammatory cytokines/mediators/inflammation and death/apoptosis following cell stress. In these studies, a second-generation p38 MAPK inhibitor, SB 239063 (IC(50) = 44 nM), was found to exhibit improved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis factor production (IC(50) = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 microg/ml (i.e., begun 15 min poststroke and continuing over the initial 6-h p38 activation period) was used. Significant and dose-proportional brain penetration of SB 239063 was demonstrated during these infusion periods. In both moderate and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respectively. No effects of the drug were observed on cerebral perfusion, hemodynamics, or body temperature. Direct neuroprotective effects from oxygen and glucose deprivation were also demonstrated in organotypic cultures of rat brain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotection emphasizes the potential role of MAPK pathways in ischemic stroke and also suggests that p38 inhibition warrants further study, including protection in other models of nervous system injury and neurodegeneration.     

Accessory cell damage and loss of overall white cell viability inhibit lymphocyte responses after ultraviolet-B irradiation but without evidence of in vitro suppression

The effect of different doses of ultraviolet B irradiation (UVR) on the proliferative responses of Balb/c spleen cells has been tested. In 72-hour cultures, there was dose-dependent suppression of proliferation in response to phytohemagglutinin (PHA). Cell viability after UVR was found to be reduced in a dose- and time-dependent manner. Proliferation increased by greater than 100 percent after low-dose (20 J/m2) UVR when either normal or gamma-irradiated peritoneal cells were added to the cultures, but not at higher doses. Delaying UVR until 24 hours after stimulation of cultures with PHA did not substantially increase [3H]-thymidine uptake. Stimulation of mixtures of UV-irradiated and control cells or incorporation of medium conditioned with UV-irradiated cells provided no evidence of suppression of proliferation. The accessory cell population is an important target for UVR, but cells are physically damaged to the extent that, at higher doses, the response to PHA stimulation cannot be restored.     

Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia

Mitogen-activated protein kinases (MAPKs) are involved in many cellular processes. The stress-activated MAPK, p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Here, we demonstrate focal ischemic stroke-induced p38 enzyme activation (i.e., phosphorylation) in the brain. The second generation p38 MAPK inhibitor SB 239063 was identified to exhibit increased kinase selectivity and improved cellular and in vivo activity profiles, and thus was selected for evaluation in two rat models of permanent focal ischemic stroke. SB 239063 was administered orally pre- and post-stroke and intravenously post-stroke. Plasma concentration levels were achieved in excess of those that effectively inhibit p38 activity. In both moderate and severe stroke, SB 239063 reduced infarct size by 28-41%, and neurological deficits by 25-35%. In addition, neuroprotective plasma concentrations of SB 239063 that reduced p38 activity following stroke also reduced the stroke-induced expression of IL-1beta and TNFalpha (i.e., cytokines known to contribute to stroke-induced brain injury). SB 239063 also provided direct protection of cultured brain tissue to in vitro ischemia. This robust SB 239063-induced neuroprotection emphasizes a significant opportunity for targeting MAPK pathways in ischemic stroke injury, and also suggests that p38 inhibition be evaluated for protective effects in other experimental models of nervous system injury and neurodegeneration.     

Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain

Background Pain is the most common discomfort experienced by children with cancer and occurs in almost 89% of patients in an advanced stage of the disease. It is most often not adequately treated because of inexperience and unfounded fears of analgesic treatment. In adults, patient controlled analgesia (PCA) is widely administered, while in children with moderate to severe cancer pain its use is still under evaluation for safety and efficacy. Goals of work To evaluate the efficacy and safety of fentanyl administered by PCA in children with cancer pain. Materials and methods Eighteen children (range 6 to 15 years) with moderate to severe pain were enrolled and treated with fentanyl by PCA plus background infusion (BI) (BI of 1 μg/kg/h with booster doses of 1 μg/kg by intravenous route). To evaluate efficacy and safety of the analgesic treatment, different subjective and objective parameters were monitored at 4-h intervals. In addition, patients’ satisfaction was assessed by a questionnaire at the end of the treatment. Main results All children experienced a good degree of analgesia and did not require any other analgesic drug during the treatment. Both subjective and objective parameters improved after starting pain-relieving treatment and no major side effects occurred. The questionnaire administered to the children showed a high grade of satisfaction. Conclusions PCA plus BI with fentanyl administered by intravenous route is a safe and efficacious method for analgesia in children with moderate to severe cancer pain. Our policy of fentanyl-treatment did not show any major side effects.     

Domperidone: a peripherally acting dopamine2-receptor antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of domperidone in the treatment of gastrointestinal motility disorders and emesis. DATA SOURCES: MEDLINE and Excerpta Medica online databases were searched to identify published reports. STUDY SELECTION: Domperidone has been marketed worldwide outside the US since 1978, and extensive clinical data for this drug are available. This review focuses on the clinical experience from controlled studies of domperidone in the treatment of motility disorders, particularly diabetic gastroparesis. Also, case reports are used in summarizing safety. The control comparator groups included placebo or other prokinetic drugs (metoclopramide and cisapride). Controlled clinical trials of domperidone's efficacy and safety as an antiemetic are also briefly examined. Although a variety of domperidone dosage forms have been marketed, data generated from trials using the 10-mg tablet are highlighted because this is the only dosage form available in Canada and is under investigation in the US. DATA EXTRACTION: Because symptoms do not correlate with objective measures of gastrointestinal motility and they are the primary reason that patients with motility disorders seek treatment, the primary outcome extracted from the clinical studies was symptomatic response to treatment. Safety and efficacy between domperidone and placebo, metoclopramide, or cisapride were compared. DATA SYNTHESIS: Domperidone, a peripheral dopamine2-receptor antagonist, regulates the motility of gastric and small intestinal smooth muscle and has been shown to have some effects on the motor function of the esophagus. It also has antiemetic activity as a result of blockade of dopamine receptors in the chemoreceptor trigger zone. In controlled clinical trials, domperidone provided better relief of symptoms (anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, distension) than placebo in patients with symptoms of diabetic gastropathy; symptomatic improvement was similar with domperidone and metoclopramide or cisapride. Domperidone also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because very little domperidone crosses the blood-brain barrier, reports of central nervous system adverse effects, such as dystonic reactions, are rare. CONCLUSIONS: Domperidone is a unique gastrokinetic and antiemetic drug. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide. In the management of diabetic gastropathy, domperidone's antiemetic activity distinguishes it from cisapride.     

The angiotensin type 1 receptor antagonist, eprosartan, attenuates the progression of renal disease in spontaneously hypertensive stroke-prone rats with accelerated hypertension

The effects of the angiotensin type 1 (AT(1)) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 +/- 9 versus 284 +/- 8 mm Hg), renal expression of transforming growth factor-beta mRNA (1.5 +/- 0.2 versus 5.4 +/- 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 +/- 1.4 versus 31.4 +/- 10.7), fibronectin (2.2 +/- 0.6 versus 8.2 +/- 2.2), collagen I-alpha 1 (5.6 +/- 2.0 versus 23.8 +/- 7.3), and collagen III (2.7 +/- 0.9 versus 7.6 +/- 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 +/- 0.1 versus 1.9 +/- 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 +/- 2 versus 127 +/- 13 mg/day) and histological evidence of active renal damage (5 +/- 2 versus 195 +/- 6) and renal fibrosis (5.9 +/- 0.7 versus 16.4 +/- 1.9) in vehicle- versus eprosartan-treated rats, respectively. Our results demonstrated that AT(1) receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-beta1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.     

Plasma chitotriosidase in health and pathology

Chitotriosidase (Chit), a member of the mammalian chitinase family, structurally homologous to chitinases from other species, is synthesized and secreted by specifically activated macrophages. After discovery of a striking increase of plasma Chit activity in serum from Gaucher's disease type I patients, an increasing number of inherited and acquired conditions sharing macrophage activation have been associated with increased Chit activity. In addition to lipid storage disorders, where Chit activity has longer been used as a marker of disease activity and therapeutic response, elevation of plasma Chit may occur in hematological disorders with storage of erythrocyte membrane breakdown products as thalassemia and different systemic infectious diseases sustained by fungi and other pathogens. Recently, increased Chit activity was demonstrated in CNS from patients with different neurological disorders. After a wide range of unwanted stimuli such as those occurring in stroke, multiple sclerosis, and Alzheimer's disease, resident cells like microglia and a few other cell types promptly activate a complex immune cascade which then might be monitored also by measuring Chit activity. The increased activity of Chit, wherever it is documented, represents one ancestral response of innate immunity which may have a wide range of clinical applications.     

beta-hexosaminidase, alpha-D-mannosidase, and beta-mannosidase expression in serum from patients with carbohydrate-deficient glycoprotein syndrome type I

The activity of beta-hexosaminidase, determined with 4-methylumbelliferyl-beta-N-acetylglucopyranoside substrate, and of beta-D-mannosidase was significantly higher in the serum of patients with carbohydrate-deficient glycoprotein (CDG) syndrome type IA (phosphomannomutase deficiency) than in controls. No significant differences were observed in the activity of beta-hexosaminidase, determined using 4-methylumbelliferyl-beta-N-acetylglucopyranoside-6-sulphate as substrate, and the activity of alpha-D-mannosidase. Using DEAE-cellulose chromatography, a greater amount of hexosaminidase B than hexosaminidase A was detected in CDG serum. In CDG serum, hexosaminidase A was eluted in a more basic position in the salt gradient. An isoenzyme of alpha-D-mannosidase and beta-D-mannosidase was identified in control and CDG sera. alpha-D-Mannosidase isoenzyme was eluted in a slightly more basic position in CDG serum than in control serum, whereas beta-D-mannosidase isoenzyme was eluted in the same position.