An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.     

Evaluation of a head-mounted display (HMD) in the performance of a simulated laparoscopic task

BACKGROUND: Head-mounted display (HM) units are used in various industries, but they have been tried only recently in surgery. In this study, we evaluated whether a commercially available HMD would improve or impede a laparoscopic task-in this case, suturing. METHODS: Six participants performed a total of 120 laparoscopic suture knots in an experimental model. The Olympus FMD011 model with a two-dimensional image was used. The order of each task with or without the head display unit was random. The time to complete each knot was recorded, and the results were analyzed. RESULTS: The display unit prolonged the suturing times of the subjects by 10% (p < 0.04). CONCLUSIONS: In this experimental model, the HMD we utilized did not appear to improve laparoscopic suturing. More developments, such as improved depth perception and better resolution, may increase its usefulness for laparoscopic tasks.     

Culture effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on cryopreserved human adipose‐derived stromal/stem cell proliferation and adipogenesis

Previous studies have demonstrated that EGF and bFGF maintain the stem cell properties of proliferating human adipose‐derived stromal/stem cells (hASCs) in vitro. While the expansion and cryogenic preservation of isolated hASCs are routine, these manipulations can impact their proliferative and differentiation potential. This study examined cryogenically preserved hASCs (n = 4 donors), with respect to these functions, after culture with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) at varying concentrations (0–10 ng/ml). Relative to the control, cells supplemented with EGF and bFGF significantly increased proliferation by up to three‐fold over 7–8 days. Furthermore, cryopreserved hASCs expanded in the presence of EGF and bFGF displayed increased oil red O staining following adipogenic induction. This was accompanied by significantly increased levels of several adipogenesis‐related mRNAs: aP2, C/EBPα, lipoprotein lipase (LPL), PPARγ and PPARγ co‐activator‐1 (PGC1). Adipocytes derived from EGF‐ and bFGF‐cultured hASCs exhibited more robust functionality based on insulin‐stimulated glucose uptake and atrial natriuretic peptide (ANP)‐stimulated lipolysis. These findings indicate that bFGF and EGF can be used as culture supplements to optimize the proliferative capacity of cryopreserved human ASCs and their adipogenic differentiation potential. Copyright © 2009 John Wiley & Sons, Ltd.     

Frequent concomitant epigenetic silencing of the stress‐responsive tumor suppressor gene CADM1, and its interacting partner DAL‐1 in nasal NK/T‐cell lymphoma

Nasal NK/T‐cell lymphoma (NL) is a rare but clinically important entity of lymphoma. Its preferential incidence in Orientals but not Caucasians suggests possible genetic predisposition. 11q deletion is common in NL, indicating certain tumor suppressor genes (TSGs) at this locus involved in its pathogenesis. We investigated the expression and methylation of an 11q23.2 TSG, CADM1 (or TSLC1), and its partner DAL‐1 (or EPB41L3) in NL. Methylation and silencing of CADM1 were detected in 2 NL and 4 of 8 (50%) of non‐Hodgkin lymphoma (NHL) cell lines, but not in normal NK cells and normal PBMC. Absence of CADM1 protein was also detected in NL cell lines. 5‐aza‐2′‐deoxycytidine (Aza) demethylation or genetic knockout of both DNMT1 and 3B genes restored CADM1 and DAL‐1 expression. CADM1 methylation was further detected in 36 of 45 (80%) of NL tumors. Concomitantly, DAL‐1 was epigenetically inactivated in NL cell lines and virtually all the tumors with methylated CADM1. A significant correlation between the methylation of both genes was found (p < 0.0001). Homozygous deletion of CADM1 was detected in only 3 of 18 (17%) of tumors. The stress‐response of CADM1 was abolished when its promoter becomes methylated. Our results demonstrate a frequent, predominant epigenetic silencing of CADM1 and DAL‐1 in NL, which likely play a synergic role in NL pathogenesis. © 2008 Wiley‐Liss, Inc.     

Anterior ischemic optic neuropathy associated with Vogt–Koyanagi–Harada disease

Background

Optic disc swelling is a common finding associated with Vogt–Koyanagi–Harada disease (VKH); however, visual field loss from optic disc involvement is uncommon. This reports report presents recent findings regarding unusual patients with visual field defects from optic disc involvement, thus suggesting the presence of anterior ischemic optic neuropathy (AION) in the acute phase of VKH.

Methods

Observational case series. A consecutive series of 52 patients with VKH (6 complete VKH, 46 incomplete VKH) was reviewed. Fifteen patients in this series had optic disc swelling, and six of them developed irreversible visual field defects in the acute phase of VKH. The clinical features of these six patients were analyzed.

Results

The patients with associated visual field loss were four males and two females between 54 to 79 years of age. They had bilateral panuveitis associated with meningismus. All of the patients had bilateral optic disc swelling and fluorescein angiography showed both a filling delay and late leakage of the optic disc. Visual field examinations revealed various degrees of visual field defects in 11 eyes. They were treated with high-dose corticosteroid therapy, and several weeks later, both the uveal inflammation and optic disc swelling disappeared. The visual fields showed some improvement as the retinal detachments and disc swelling resolved, but the visual field defects remained in ten eyes. The small and localized visual field defects were asymptomatic. Subsequently, optic disc pallor developed in nine eyes and retinal nerve fiber layer thickness, measured by optical coherence tomography, was decreased in six eyes. The fundus gradually showed various degrees of hypopigmentation, but did not show any chorioretinal atrophy causing visual field loss. Four patients had risk factors for AION, including diabetes mellitus or a relatively small optic nerve head.

Conclusions

In this consecutive series of patients with VKH, 15 out of 52 patients were found to have disc swelling, and six patients, who were mostly elderly, had associated visual field loss, which is probably due to AION associated with VKH.     

Predicting breast cancer risk: implications of a “weak” family history

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk ≥1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40–56, with family histories placing them below the “moderate” level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that “low penetrance” alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them. All the authors are from the Scottish Cancer Family Clinical Centres.     

Detection of the p53 response in zebrafish embryos using new monoclonal antibodies

The zebrafish has many advantages as a vertebrate model organism and has been extensively used in the studies of development. Its potential as a model in which to study tumour suppressor and oncogene function is now being realized. Whilst in situ hybridization of mRNA has been well developed in this species to study gene expression, antibody probes are in short supply. We have, therefore, generated a panel of anti-zebrafish p53 monoclonal antibodies and used these to study the p53 response in zebrafish embryos. By immunohistochemistry, we show that the exposure of zebrafish embryos to p53-activating agents such as R-roscovitine and gamma-irradiation results in the accumulation of p53 protein in the gut epithelium, liver and pancreas. A combination of R-roscovitine and gamma-irradiation results in massive p53 induction, not only in the pharyngeal arches, gut region and liver but also in brain tissues. Induction of apoptosis and expression of p53 response genes are seen in regions that correspond to sites of p53 protein accumulation. In contrast, although zebrafish tp53(M214K) mutant embryos showed a similar accumulation of p53 protein, a complete lack of a downstream p53-dependent response was observed. In this system the p53 gene is identified as a p53-responsive gene itself. Our results demonstrate that zebrafish p53 protein can readily be induced in embryos and detected using these new antibody tools, which will increase the usefulness of zebrafish as a model in compound-based screening for novel drugs in cancer research.     

Familial nasopharyngeal carcinoma in a cohort of 200 patients

OBJECTIVES: To describe the characteristics of familial nasopharyngeal carcinoma (NPC) in a high-risk population and to determine the role of screening first-degree relations. DESIGN: An analysis on a cohort of 200 patients newly diagnosed as having NPC. SETTING: A tertiary-level institution. PATIENTS: The patients were divided into 2 groups. Patients in group 1 had a first-degree relative with NPC, and those in group 2 did not. For patients in group 1, the relationship and the time interval between affected relatives were noted. The clinical and pathological factors of the 2 groups were obtained and statistically analyzed. RESULTS: There were 15.5% of NPC patients who had an affected first-degree relative. Of the affected relatives, 71% were siblings and 29% were parents. The mean interval between affected siblings was 5.3 years, while that between an affected parent and a child was 24.5 years. No differences were noted in the clinical factors between familial and nonfamilial NPC patients. Most patients in both groups were diagnosed as having stage III or IV NPC. CONCLUSIONS: The rate of familial NPC in our study is 15.5%. Siblings are more commonly affected, and the interval between 2 affected siblings is relatively short. No distinct clinical pattern exists in familial NPC. We recommend that siblings of NPC patients be screened as soon as possible once the index case is diagnosed.