Optimizing drug development of anti-cancer drugs in children using modelling and simulation

Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population.     

Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo

Background and Purpose

Growing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known.

Experimental Approach

The effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed.

Key Results

Deferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels.

Conclusions and Implications

The clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.

Linked Article

This article is commented on by Keeler and Brookes, pp. 1313–1315 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12093     

Intraoperative US as an aid to intraoperative electron beam radiation therapy

Intraoperative electron-beam radiation therapy (IRT) is being used to treat certain abdominal malignancies. Accurate determination of tumor size, depth, and extent is necessary to select a treatment cone of appropriate size and appropriate electron beam energy for the treatment portal. Fourteen patients undergoing evaluation for this treatment were examined with intraoperative ultrasonography (IUS) to aid therapy planning. IUS study required little additional time and readily delineated tumor size, depth, and relationship to adjacent structures. In two patients, the US and operative findings provided information that precluded use of IRT. The traditional method of tumor evaluation by intraoperative palpation and inspection was consistently enhanced by the use of IUS findings. IUS is a valuable adjunct that improves the accuracy of therapy planning for IRT.     

Changing appearance of the normal uterus during the menstrual cycle: MR studies

The authors obtained sagittal magnetic resonance (MR) images twice a week from six healthy women during one full menstrual cycle to establish the changes depicted in the uterine layers. Parallel endocrine and ultrasound studies were used to establish the day of ovulation precisely. Consistent changes in the thickness and intensity of the endometrium and myometrium wer noted in all subjects during the menstrual cycle. Both myometrial thickness and endometrial area increased linearly during the follicular (preovulatory) phase of the cycle; the rate of increase dropped significantly during the luteal phase. Two myometrial layers were observed; the best contrast between the layers was demonstrated during the first half of the cycle.     

The Cambridge and Somerville Program for Alcoholism Rehabilitation - Impressions

The rising incidence of alcoholism in the United States compoundedby the lack of adequate treatment programmes led to the initiationof new schemes in the early 1970s. One of the first was the Cambridge and Somerville Program forAlcohol Rehabilitation (CASPAR), established as a pilot programmeto be replicated elsewhere if successful. Having undergone withdrawal,total abstinence is advocated with emphasis placed on communitybased follow-up in conjunction with Alcoholics Anonymous (AA).Education of school children in attitudes towards alcohol isan important aspect of the programme and seeks to reduce alcoholabuse in future generations. These impressions were formed during an elective study immediatelyfollowing graduation from medical school and reflect a personalinterest stimulated by the Cambridge and Somerville Program.     

Dietary isoflavones alter regulatory behaviors, metabolic hormones and neuroendocrine function in Long-Evans male rats

BACKGROUND: Phytoestrogens derived from soy foods (or isoflavones) have received prevalent usage due to their 'health benefits' of decreasing: a) age-related diseases, b) hormone-dependent cancers and c) postmenopausal symptoms. However, little is known about the influence of dietary phytoestrogens on regulatory behaviors, such as food and water intake, metabolic hormones and neuroendocrine parameters. This study examined important hormonal and metabolic health issues by testing the hypotheses that dietary soy-derived isoflavones influence: 1) body weight and adipose deposition, 2) food and water intake, 3) metabolic hormones (i.e., leptin, insulin, T3 and glucose levels), 4) brain neuropeptide Y (NPY) levels, 5) heat production [in brown adipose tissue (BAT) quantifying uncoupling protein (UCP-1) mRNA levels] and 6) core body temperature. METHODS: This was accomplished by conducting longitudinal studies where male Long-Evans rats were exposed (from conception to time of testing or tissue collection) to a diet rich in isoflavones (at 600 micrograms/gram of diet or 600 ppm) vs. a diet low in isoflavones (at approximately 10-15 micrograms/gram of diet or 10-15 ppm). Body, white adipose tissue and food intake were measured in grams and water intake in milliliters. The hormones (leptin, insulin, T3, glucose and NPY) were quantified by radioimmunoassays (RIA). BAT UCP-1 mRNA levels were quantified by PCR and polyacrylamide gel electrophoresis while core body temperatures were recorded by radio telemetry. The data were tested by analysis of variance (ANOVA) (or where appropriate by repeated measures). RESULTS: Body and adipose tissue weights were decreased in Phyto-600 vs. Phyto-free fed rats. Food and water intake was greater in Phyto-600 animals, that displayed higher hypothalamic (NPY) concentrations, but lower plasma leptin and insulin levels, vs. Phyto-free fed males. Higher thyroid levels (and a tendency for higher glucose levels) and increased uncoupling protein (UCP-1) mRNA levels in brown adipose tissue (BAT) were seen in Phyto-600 fed males. However, decreased core body temperature was recorded in these same animals compared to Phyto-free fed animals. CONCLUSIONS: This study demonstrates that consumption of a soy-based (isoflavone-rich) diet, significantly alters several parameters involved in maintaining body homeostatic balance, energy expenditure, feeding behavior, hormonal, metabolic and neuroendocrine function in male rats.     

Obstructive hyperinflation treated by use of self-expandable stent

A self-expandable metal stent was used in the management of a young woman who developed respiratory failure as a result of obstructive hyperinflation caused by a bronchogenic tumour.     

Percutaneous Real-Time Ultrasonic Guided Biopsy in the Diagnosis of Deep-Seated,Non-Palpable Intra-abdominal Masses (Initial Experience)

The accuracy of detecting and assessing the nature of deep seated non-palpable lesions by ultrasonically guided biopsy has not been well established. Although various authors have reported the accuracy of this technique in large mass lesions^1,2 the accuracy in non-palpable lesions has not been emphasized. A real-time sector scanner with a biopsy guide attached to a 3 MHz transducer was used for guiding 23 gauge fine needles into 24 patients with deep seated non-palpable masses, detected on ultrasound studies, with a view to diagnose or exclude malignancy, and to establish the exact nature of these lesions, either benign or malignant. Aspiration biopsy accurately diagnosed the lesions in 18 patients (75%). No complications occurred in any case.