A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the brain tumor investigational consortium (BTIC)

Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieve high brain concentration relative to plasma in animals. Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 1-month progression-free survival (PFS-1) for bevacizumab refractory (Group 2) and 6-month progression-free survival (PFS-6) for bevacizumab naïve patients (Group 1). Verubulin was administered at 3.3 mg/m² as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle. The planned sample size was 34 subjects per cohort. 56 patients (37 men, 19 women) were enrolled, 31 in Group 1 and 25 in Group 2. The PFS-6 for Group 1 was 14 % and the PFS-1 for Group 2 was 20 %. Median survival from onset of treatment was 9.5 months in Group 1 and 3.4 months in Group 2. Best overall response was partial response (n = 3; 10 % in Group 1; n = 1; 4.2 % in Group 2) and stable disease (n = 7; 23 % in Group 1; n = 5; 21 % in Group 2). In Group 1, 38.7 % of patients experienced a serious adverse event; however only 3.2 % were potentially attributable to study drug. In Group 2, 44 % of patients experienced a serious adverse event although none were attributable to study drug. Accrual was terminated early for futility. Single agent verubulin, in this dose and schedule, is well tolerated, associated with moderate but tolerable toxicity but has limited activity in either bevacizumab naïve or refractory recurrent GBM.     

Novel mutation of Endothelin-B receptor gene in Waardenburg–Hirschsprung disease

Homozygous mutations of EDNRB in human have been reported to result in Waardenburg–Hirschsprung disease (WS4), while mutated heterozygotes manifested isolated Hirschsprung disease in lower penetrance. We investigated a case of WS4 together with all members of her nuclear family for the alteration of the EDNRB gene by using PCR–SSCP and direct sequencing technique. The index patient, who was born to a family with no history of Hirschsprung disease, presented total colonic aganglionosis with small bowel extension, sensorineural hearing loss and generalized cutaneous pigmentary defects. Interestingly, both irides were normally black. The study detected a homozygous missense mutation at codon 196 in exon 2 (Ser196Asn), which has not been reported. Both parents and four in six siblings harbored heterozygous mutation without any clinical manifestation. Our findings were consistent with previous observations that full spectrum of WS4 occurred to the mutate homozygotes. Moreover, the non-penetrance of heterozygotes in our pedigree, which differs from other reports, demonstrates the high pleiotropic effect of EDNRB mutations in human.     

Surgery in management of snake envenomation in children

Background  

Snakebite is common in children especially in the developing countries. This study was undertaken to determine the role of surgery in the treatment of venomous snake bite in pediatric patients.     

Four-vessel umbilical cord associated with multiple congenital anomalies: a case report and literature review

A case is described of a neonate with a four-vessel umbilical cord containing two arteries and two veins. This was due to a rare persistence of the caudal portion of the right umbilical vein. The infant had multiple congenital anomalies including a complete atrioventricular canal, an interrupted inferior vena cava, a double superior vena cava, a left ventricular hypoplasia, dextrocardia, situs ambiguous, and malrotation of the small bowel. The birth of an infant with a four-vessel cord mandates comprehensive work-up for associated anomalies. The literature is reviewed.     

Antibacterial substances from Albizia myriophylla wood against cariogenic Streptococcus mutans

Albizia myriophylla has been used for long by Thai traditional healers as an important ingredient herb in Thai herbal formulas for caries. In this study, three flavonoids lupinifolin (6), 8-methoxy-7,3′,4′-trihydroxyflavone (7), and 7,8,3′,4′-tetrahydroxyflavone (8), a triterpenoid lupeol (3) as well as four sterols β-sitosterone (1), stigmasta-5,22-dien-3-one (2), β-sitosterol (4), and stigmasterol (5) were isolated from A. myriophylla wood. The antibacterial activity of these compounds against Streptococcus mutans ATCC 25175 was performed using broth microdilution method. All compounds exhibited antibacterial activity against S. mutans with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) ranging from 1–256 and 2–256 μg/ml, respectively. Among the isolated compounds, lupinifolin (6) was found to be the most potent with MIC and MBC of 1 and 2 μg/ml, respectively. Lupinifolin (6) also showed a strong activity against ten clinical isolates of S. mutans with MIC and MBC ranging from 0.25–2 and 0.5–8 μg/ml, respectively. These results reported the bioactive ingredients of A. myriophylla which support its ethnomedical claims as well. Lupinifolin (6) may have a potential to be a natural anticariogenic agent.     

Simple,Efficient, and Cost-Effective Multiplex Genotyping with Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry of Hemoglobin Beta Gene Mutations

A number of common mutations in the hemoglobin β (HBB) gene cause β-thalassemia, a monogenic disease with high prevalence in certain ethnic groups. As there are 30 HBB variants that cover more than 99.5% of HBB mutant alleles in the Thai population, an efficient and cost-effective screening method is required. Three panels of multiplex primer extensions, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were developed. The first panel simultaneously detected 21 of the most common HBB mutations, while the second panel screened nine additional mutations, plus seven of the first panel for confirmation; the third panel was used to confirm three HBB mutations, yielding a 9-Da mass difference that could not be clearly distinguished by the previous two panels. The protocol was both standardized using 40 samples of known genotypes and subsequently validated in 162 blind samples with 27 different genotypes (including a normal control), comprising heterozygous, compound heterozygous, and homozygous β-thalassemia. Results were in complete agreement with those from the genotyping results, conducted using three different methods overall. The method developed here permitted the detection of mutations missed using a single genotyping procedure. The procedure should serve as the method of choice for HBB genotyping due to its accuracy, sensitivity, and cost-effectiveness, and can be applied to studies of other gene variants that are potential disease biomarkers.To date, 739 point mutations in the hemoglobin, β (HBB) gene causing β-thalassemia (MIM# 141900) have been reported in HbVar: A Database of Human Hemoglobin Variants and Thalassemias (http://globin.cse.psu.edu/globin/hbvar/menu.html, accessed March 2009), but each ethnic group has a limited number of common mutations and a considerable number of rarer mutations.¹ The c.79G>A (also known as CD26G>A or Hb E) is the most frequent HBB variant in Southeast Asia including Thailand.² “Thai” generally refers to speakers of Thai (Tai) languages. The ethnic groups of Thailand comprise Thais (constituting 85% of the population) and Hill Peoples living primarily in the north, as well as other groups including the Chinese and minorities in the south.³ In the Thai population, approximately 40 HBB mutations have been identified,⁴ of which 30 variants account for more than 99.5% of all mutant HBB alleles