Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody,in patients with recurrent glioblastoma

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66?% were male, and 66?% were aged ≥65 years. PFS-6 was 15.4?% [90?% confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1?%) patients had stable disease as best response. Median PFS was 1.4 months (90?% CI 1.4, 1.8); median OS was 9.7 months (90?% CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16?%), nausea (13?%), and fatigue (13?%). Twelve (21?%) patients reported grade ≥3 AEs, with hydrocephalus (n?=?3), dysphagia (n?=?2), and convulsion (n?=?2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n?=?1 each). Seven patients (13?%) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.     

Radical scavenging and antioxidant activities of isocoumarins and a phthalide from the endophytic fungus Colletotrichum sp

Five known isocoumarins, monocerin (1), derivative 2, and fusarentin derivatives 3-5, and a new phthalide (6) were isolated from the endophytic fungus Colletotrichum sp. 2 selectively exhibited cytotoxic activity toward the HepG2 cell line. Compounds 2 and 4 scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals (IC(50) values of 23.4 and 16.4 μM, respectively) and inhibited superoxide anion radical formation (IC(50) values of 52.6 and 4.3 μM, respectively). The C-7 hydroxyl group in 2 and 4 might be important for radical scavenging activities. Isocoumarins 1-3 and phthalide 6 showed potent antioxidant activity.     

Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m²/day and escalated by 25 mg/m²/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m²/day in the −EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. −EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m²/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.     

Colpocephaly: a case report

Colpocephaly is an abnormal enlargement of the occipital horn of the lateral ventricle, also described as persistence of the fetal configuration of the lateral ventricles. Since it was first described, colpocephaly has been found in association with several abnormalities of the brain. Various etiologies have been postulated, including intrauterine/perinatal injuries, genetic disorders, and an error of morphogenesis. We report a new case of colpocephaly associated with absence of the corpus callosum and review the literature.     

A phase I/II trial and pharmacokinetic study of ixabepilone in adult patients with recurrent high-grade gliomas

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m², in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m² for patients not taking EIAEDs and 9.6 mg/m² for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0–8.6) months and 6-month PFS rate was 4% (95% CI, 0–22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m²) than those not (24 ± 9.2 l/h/m²). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.     

How Long Does a Cough Last? Comparing Patients’ Expectations With Data From a Systematic Review of the Literature

PURPOSE

We hypothesized that antibiotic overuse for acute cough illness (ACI) is in part due to a mismatch between patients’ expectations and the natural history of ACI.

METHODS

We performed a population-based random digit dialing survey of 493 adults in Georgia to determine their expectations regarding the duration of ACI. We also performed a systematic review of observational studies and the placebo or untreated control groups of randomized controlled trials to determine the duration of ACI from the published medical literature. We included studies of otherwise healthy adults with undifferentiated ACI, no clear bacterial cause, data on at least 1 cough outcome, and at least 1 week of follow-up.

RESULTS

The mean duration of cough in the published literature was 17.8 days. Survey respondents reported a median duration of 5 to 7 days and a mean duration of 7.2 to 9.3 days depending on the specific scenario. Patients expecting a longer duration of illness were more likely to be white, female, and have self-reported asthma or chronic lung disease. Independent predictors of the belief that antibiotics are always helpful included nonwhite race (OR = 1.82, 95% CI, 1.14–2.92), some college education or less (OR = 2.08, 95% CI, 1.26–3.45), and previous antibiotics for ACI (OR = 2.20, 95% CI, 1.34–3.55).

CONCLUSIONS

There is a mismatch between patients’ expectations regarding the duration of ACI and the actual duration based on the best available evidence. Efforts to reduce inappropriate antibiotic use should target this discrepancy.     

Menstrual problems and side effects associated with long-term TCu 380A IUD use in perimenopausal women

The study assessing menstrual problems and side effects associated with long-term TCu 380A intrauterine device (IUD) use in perimenopausal women is reported. Fifty perimenopausal TCu 380A IUD acceptors who had IUD inserted after age 40 and used IUD at least 36 months were recruited. The mean age of acceptors at time of insertion was 44.2 years with an average parity of two live births. The mean body weight at insertion was 62.13 kg. Most of the bleeding patterns were regular cycles. Intermenstrual bleeding and pelvic pain were the side effects most often reported. No pregnancies, pelvic inflammatory disease, or IUD expulsions occurred during the follow-up period. This study suggests that the use of TCu 380A IUD in perimenopausal women is safe and effective.