The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors.

BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%. CONCLUSIONS: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448786.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Intra-arterial Bevacizumab for Posterior Fossa Hemangioblastoma.

Hemangioblastoma (HB) is a rare, highly vascularized, and benign central nervous system (CNS) tumor. This vascularity is due to a high degree of signaling by vascular endothelial growth factor (VEGF). Consequently, anti-VEGF agents, such as bevacizumab, have been postulated and shown in a few cases to be effective in treating these tumors when surgical therapy is not feasible. Additionally, selective intra-arterial (IA) administration of bevacizumab has shown promise in treating other cancers such as glioblastoma (GBM). Here, we present the case of a 60-year-old female with a symptomatic posterior fossa HB where embolization and surgery were not feasible due to tumor location. She underwent selective IA treatment with bevacizumab, which led to tumor stability and symptomatic improvement. Bevacizumab has been used intravenously (IV) as a treatment for HB, however, its efficacy has not been well-established. This case demonstrates the potential viability of selective bevacizumab in HB, as demonstrated by symptomatic improvement and decreased tumor size on MRI. Further research is needed to demonstrate the specific efficacy of IA bevacizumab for CNS HB when surgery or other treatment modalities are not viable options.

Dyspnea With Unilateral Pulmonary Ground Glass Opacities and Cavitary Lesions.

CASE PRESENTATION: A 62-year-old man presented with a 3-month history of shortness of breath and a dry cough. He had a medical history of hypertension (without use of angiotensin-converting enzyme inhibitors), hyperlipidemia, depression, and 10-pack-years of cigarette smoking several decades ago. He was a limousine driver and denied any history of occupational high-risk exposures. The patient denied significant weight gain or weight loss, night sweats, fevers, hemoptysis, chest pain, or palpitations. He had a normal physical examination. Pulmonary function studies with a hemoglobin level of 12.9 gm/dL revealed normal spirometry, normal lung volumes, and moderately low diffusion capacity (56% of predicted). A 6-minute walk test showed mild desaturation (97% to 92% after 432 m). Stress echo revealed ejection fraction of 60% with no regional wall motion abnormalities, no evidence of impaired diastolic filling, estimated peak pulmonary artery pressure 35 to 40 mm Hg, and no valvular abnormalities with desaturation to 87% during the test. Extensive rheumatologic, infectious disease, and hypercoagulability workup were unremarkable. BAL was negative for malignancy, infection, or eosinophilic lung disease.