'Be active, eat right', evaluation of an overweight prevention protocol among 5-year-old children: design of a cluster randomised controlled trial

Background  

The prevalence of overweight and obesity in children has at least doubled in the past 25 years with a major impact on health. In 2005 a prevention protocol was developed applicable within Youth Health Care. This study aims to assess the effects of this protocol on prevalence of overweight and health behaviour among children.     

Preclinical evaluation of a monoclonal antibody targeting the epidermal growth factor receptor as a radioimmunodiagnostic and radioimmunotherapeutic agent

Background and purpose:

The studies described here are the first to evaluate the in vitro and in vivo properties of ¹¹¹In-CHX-A″-panitumumab for radioimmunotherapy (α- and β^--emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography).

Experimental approach:

Twenty-seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX-A″-DTPA (diethylenetriamine-pentaacetic acid) and radiolabelled with ¹¹¹In. Immunoreactivity of the CHX-A″-DTPA-panitumumab and ¹¹¹In-CHX-A″-DTPA-panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by γ-scintigraphy.

Key results:

For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX-A″-DTPA. Radiolabelling of the immunoconjugate with ¹¹¹In was efficient with a specific activity of 19.5 ± 8.9 mCi·mg⁻¹ obtained. Immunoreactivity and specificity of binding of the ¹¹¹In-panitumumab was shown with A431 cells. Tumour targeting by ¹¹¹In-panitumumab was demonstrated in athymic mice bearing A431, HT-29, LS-174T, SHAW or SKOV-3 s.c. xenografts with little uptake observed in normal tissues. The ¹¹¹In-panitumumab was also evaluated in non-tumour-bearing mice. Pharmacokinetic studies compared the plasma retention time of the ¹¹¹In-panitumumab in both non-tumour-bearing and A431 tumour-bearing mice. Tumour targeting was also visualized by γ-scintigraphy.

Conclusions and implications:

Panitumumab can be efficiently radiolabelled with ¹¹¹In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.     

Genetic factors in non‐syndromic congenital heart malformations

Wessels MW, Willems PJ. Genetic factors in non‐syndromic congenital heart malformations. The genetic defect in most patients with non‐syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM. We review here the monogenic disease genes with high‐penetrance mutations, susceptibility genes with reduced‐penetrance mutations, and somatic mutations implicated in non‐syndromic CHM.     

Conjugated linoleic acid and the control of cancer and obesity

The effects of conjugated linoleic acid (CLA) in animals are reviewed. In most of the CLA preparations that have been investigated to date for biological activity, two CLA isomers are present in about equal concentrations: cis-9,trans-11 CLA, and trans-10,cis-12 CLA. The occurrence of these isomers in foods and their production by rumen microorganisms are discussed. Potential mechanisms of action as regards the effects of CLA on cancer and body composition are reviewed, including recent evidence that body composition changes are produced by the trans-10,cis-12 CLA isomer. Evidence is presented indicating that CLA may modulate cellular response to tumor necrosis factor-alpha (TNF- alpha). The mechanistic implications of this finding are considered.      

Atopy in parents of children dying with sudden infant death syndrome

36 parents of infants who had died suddenly did not differ in frequency of atopic symptoms, immediate skin tests, IgE, IgE antibody, immunoglobulin G, A, and M, or yeast opsonisation, from 36 matched controls, although atopy was common (about half had atopy in both groups.     

Value of cystography in urinary tract infections

Fifty-one children with a bacteriologically proven urinary tract infection had both an intravenous urogram (IVU) and a micturating cystogram. The IVU was normal in 35. Only 6 of these children showed reflux in the cystogram, affecting 7 of the 70 ureters at risk. Since reflux on its own does not cause renal damage, which occurs only with super-added infection, detection of reflux is not important providing the urine is kept sterile. We suggest that cystography be deferred providing the IVU is normal until recurrent infections occur while under hospital care, and, with this policy this unpleasant and sometimes hazardous investigation could be avoided in many children with a single urinary tract infection.     

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

Expanding the therapeutic repertoire of epidermal growth factor receptor blockade: radiosensitization

Expression of epidermal growth factor receptor (EGFR) has been associated with radioresistance in cancer. Moreover, tumour cell recovery after irradiation paradoxically occurs, in part, as a result of activation of EGFR signalling by such treatment. A recent article by Huang, Li, Armstrong and Harari provides strong rationale for considering the anti-EGFR agent ZD1839 ('Iressa') as a radiosensitizing strategy. With the use of several in vitro and xenograft models of human squamous cell head and neck carcinoma, ZD1939 was shown to markedly improve radiotherapeutic response, with superior tumour inhibition and delayed tumour regrowth. Mechanisms underlying this effect included anti-proliferative and pro-apoptotic activity, with significant perturbation of tumour angiogenesis.     

The multifaceted roles of nitric oxide in cancer

The roles of nitric oxide (NO) in numerous disease states have generated considerable discussion over the past several years. NO has been labeled as the causative agent in different pathophysiological mechanisms, yet appears to protect against various chemical species such as those generated under oxidative stress. Similarly, NO appears to exert a dichotomy of effects within the multistage model of cancer. Chronic inflammation can lead to the production of chemical intermediates, among them NO, which in turn can mediate damage to DNA. Yet, NO also appears to be critical for the tumoricidal activity of the immune system. Furthermore, NO can also have a multitude of effects on other aspects of tumor biology, including angiogenesis and metastasis. This report will discuss how the chemistry of NO may impact the initiation and progression stages of cancer.      

Treatment of respiratory failure in an infant with bronchopulmonary dysplasia infected with respiratory syncytial virus using inhaled nitric oxide and high frequency ventilation

A 2-month-old, former 28-week premature infant with brochopulmonary dysplasia infected with respiratory syncytial virus was treated with nitric oxide and high frequency oscillatory ventilation after conventional therapy failed. Nitric oxide and high frequency oscillatory ventilation rapidly improved oxygenation allowing recovery without the need for extracorporeal membrane oxygenation. This treatment regimen should be considered as an option in high-risk infants with respiratory syncytial virus infection who meet extracorporeal membrane oxygenation criteria.