Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Whole body protein synthesis and energy expenditure in very low birth weight infants.

The aim of the present work was to study whole body protein synthesis and breakdown, as well as energy metabolism, in very low birth weight premature infants (less than 1500 g) during their rapid growth phase. Ten very low birth weight infants were studied during their first and second months of life. They received a mean energy intake of 114 kcal/kg X day and 3 g protein/kg X day as breast milk or milk formula. The average weight gain was 15 g/kg X day. The apparent energy digestibility was 88%, i.e. 99 kcal/kg X day. Their resting postprandial energy expenditure was 58 kcal/kg X day, indicating that 41 kcal/kg X day was retained. The apparent protein digestibility was 89%, i.e. 2.65 g/kg X day. Their rate of protein oxidation was 0.88 g/kg X day so that protein retention was 1.76 g/kg X day. There was a linear relationship between N retention and N intake (r = 0.78, p less than 0.001). The slope of the regression line indicates a net efficiency of N utilization of 67%. Estimates of body composition from the energy balance, coupled with N balance method, showed that 25% of the gain was fat and 75% was lean tissue. Whole body protein synthesis and breakdown were determined using repeated oral administration of 15N glycine for 60-72 h, and 15N enrichment in urinary urea was measured. Protein synthesis averaged 11.2 g/kg X day and protein breakdown 9.4 g/kg X day. Muscular protein breakdown, as estimated by 3-methylhistidine excretion, contributed to 12% of the total protein breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of oral glucose in children born small for gestational age : evidence for an impaired whole body glucose oxidation

Résumé Les études épidémiologiques indiquent que la restriction intra-utérine confère un risque accru de développement de diabète de type 2 au cours de la vie. Certaines études ont documenté la présence d'une résistance à l'insuline chez les jeunes adultes ou les adolescents nés petits pour l'âge gestationnel. Comme la plupart des études ont impliqués des individus post-pubères et comme la puberté influence de manière marquée le métabolisme énergétique, nous avons évalué le devenir du glucose administré oralement dans un groupe incluant essentiellement des enfants pré-pubères ou en début de puberté avec restriction intra-utérine, et chez des enfants matchés pour l'âge et pour le poids. Tous les enfants ont eu une évaluation de leur composition corporelle par mesure des plis cutanés. Ils ont ensuite été étudiés dans des conditions standardisées et ont reçu 4 charges consécutives orales de glucose à raison de 180 mg/kg de poids corporel jusqu'à atteindre un état d'équilibre relatif. La dépense énergétique et l'oxydation des substrats ont été évaluées durant la quatrième heure par calorimétrie indirecte. Comparativement avec les enfants matchés pour l'âge et le poids, les enfants nés petits pour l'âge gestationnel avaient une plus petite stature. Leur dépense énergétique n'était pas significativement abaissée, mais leur oxydation du glucose était plus basse. Ces résultats indiquent que des altérations métaboliques sont présentes précocement chez les enfants nés petits pour l'âge gestationnel, et qu'elles sont possiblement reliées à des altérations de la composition corporelle. Abstract: Epidemiological studies indicate that intrauterine growth restriction confers an increased risk of developing type 2 diabetes mellitus in subsequent life. Several studies have further documented the presence of insulin resistance in young adults or adolescent children born small for gestational age. Since most studies addressed postpubertal individuals, and since puberty markedly affects energy metabolism, we evaluated the disposal of oral glucose in a group including mainly prepubertal and early pubertal children with intrauterine growth restriction and in healthy age- and weight-matched control children. All children had an evaluation of their body composition by skinfold thickness measurements. They were then studied in standardized conditions and received 4 consecutive hourly loads of 180 mg glucose/kg body weight to reach a near steady state. Energy expenditure and substrate oxidation were evaluated during the fourth hour by indirect calorimetry. Compared to both age- and weight-matched children, children born small for gestational age had lower stature. Their energy expenditure was not significantly decreased, but they had lower glucose oxidation rates. These results indicate that metabolic alterations are present early in children born small for gestational age, and are possibly related to alterations of body composition.

Urgences vitales au cabinet médical: implications pour la formation et l'equipement du médecin de premier recours [Life-threatening emergencies at the office: implications for medical education and equipment of the primary care physician].

Every medical practitioner is confronted on a daily basis with emergencies. Among these, life-threatening emergencies can have disastrous consequences in term of morbidity and mortality; 22 cardiac arrests and 10 deaths were reported among the 1,650 Swiss practices during a 5 year period. The occurrence of life-threatening emergencies at the office necessitates, according to the type and place of the practice, the skills of the practitioner and the organization of his practice, the implementation of procedures, equipments (for example room equipped with a defibrillator, respiratory nebulizer, splints, emergency drugs) and specific continuous education programs that should be encouraged and made available to the whole medical corporation.

Whole genome sequencing as a means to assess pathogenic mutations in medical genetics and cancer.

The past decade has seen the emergence of next-generation sequencing (NGS) technologies, which have revolutionized the field of human molecular genetics. With NGS, significant portions of the human genome can now be assessed by direct sequence analysis, highlighting normal and pathological variants of our DNA. Recent advances have also allowed the sequencing of complete genomes, by a method referred to as whole genome sequencing (WGS). In this work, we review the use of WGS in medical genetics, with specific emphasis on the benefits and the disadvantages of this technique for detecting genomic alterations leading to Mendelian human diseases and to cancer.

Using life strategies to explore the vulnerability of ecosystem services to invasion by alien plants

Invasive plants can have different effects of ecosystem functioning and on the provision of ecosystem services, from strongly deleterious impacts to positive effects. The nature and intensity of such effects will depend on the service and ecosystem being considered, but also on features of life strategies of invaders that influence their invasiveness as well as their influence of key processes of receiving ecosystems. To address the combined effect of these various factors we developed a robust and efficient methodological framework that allows to identify areas of possible conflict between ecosystem services and alien invasive plants, considering interactions between landscape invasibility and species invasiveness. Our framework combines the statistical robustness of multi-model inference, efficient techniques to map ecosystem services, and life strategies as a functional link between invasion, functional changes and potential provision of services by invaded ecosystems. The framework was applied to a test region in Portugal, for which we could successfully predict the current patterns of plant invasion, of ecosystem service provision, and finally of probable conflict (expressing concern for negative impacts, and value for positive impacts on services) between alien species richness (total and per plant life strategy) and the potential provision of selected services. Potential conflicts were identified for all combinations of plant strategy and ecosystem service, with an emphasis for those concerning conflicts with carbon sequestration, water regulation and wood production. Lower levels of conflict were obtained between invasive plant strategies and the habitat for biodiversity supporting service. The added value of the proposed framework in the context of landscape management and planning is discussed in perspective of anticipation of conflicts, mitigation of negative impacts, and potentiation of positive effects of plant invasions on ecosystems and their services.

Validation of the IMPACT-III quality of life questionnaire in Swiss children with inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) frequently manifests during childhood and adolescence. For providing and understanding a comprehensive picture of a patients' health status, health-related quality of life (HRQoL) instruments are an essential complement to clinical symptoms and functional limitations. Currently, the IMPACT-III questionnaire is one of the most frequently used disease-specific HRQoL instrument among patients with IBD. However, there is a lack of studies examining the validation and reliability of this instrument. METHODS: 146 paediatric IBD patients from the multicenter Swiss IBD paediatric cohort study database were included in the study. Medical and laboratory data were extracted from the hospital records. HRQoL data were assessed by means of standardized questionnaires filled out by the patients in a face-to-face interview. RESULTS: The original six IMPACT-III domain scales could not be replicated in the current sample. A principal component analysis with the extraction of four factor scores revealed the most robust solution. The four factors indicated good internal reliability (Cronbach's alpha=.64-.86), good concurrent validity measured by correlations with the generic KIDSCREEN-27 scales and excellent discriminant validity for the dimension of physical functioning measured by HRQoL differences for active and inactive severity groups (p<.001, d=1.04). CONCLUSIONS: This study with Swiss children with IBD indicates good validity and reliability for the IMPACT-III questionnaire. However, our findings suggest a slightly different factor structure than originally proposed. The IMPACT-III questionnaire can be recommended for its use in clinical practice. The factor structure should be further examined in other samples.

Ventricular arrhythmia in coronary artery disease: limits of a risk stratification strategy based on the ejection fraction alone and impact of infarct localization.

AIMS: Estimates of the left ventricular ejection fraction (LVEF) in patients with life-threatening ventricular arrhythmias related to coronary artery disease (CAD) have rarely been reported despite it has become the basis for determining patient's eligibility for prophylactic defibrillator. We aimed to determine the extent and distribution of reduced LVEF in patients with sustained ventricular tachycardia or ventricular fibrillation. METHODS AND RESULTS: 252 patients admitted for ventricular arrhythmia related to CAD were included: 149 had acute myocardial infarction (MI) (Group I, 59%), 54 had significant chronic obstructive CAD suggestive of an ischaemic arrhythmic trigger (Group II, 21%) and 49 patients had an old MI without residual ischaemia (Group III, 19%). 34% of the patients with scar-related arrhythmias had an LVEF > or =40%. Based on pre-event LVEF evaluation, it can be estimated that less than one quarter of the whole study population had a known chronic MI with severely reduced LVEF. In Group III, the proportion of inferior MI was significantly higher than anterior MI (81 vs. 19%; absolute difference, -62; 95% confidence interval, -45 to -79; P < or = 0.0001), though median LVEF was higher in inferior MI (0.37 +/- 10 vs. 0.29 +/- 10; P = 0.0499). CONCLUSION: Patients included in defibrillator trials represent only a minority of the patients at risk of sudden cardiac death. By applying the current risk stratification strategy based on LVEF, more than one third of the patients with old MI would not have qualified for a prophylactic defibrillator. Our study also suggests that inferior scars may be more prone to ventricular arrhythmia compared to anterior scars.

Effect of carbohydrate overfeeding on whole body macronutrient metabolism and expression of lipogenic enzymes in adipose tissue of lean and overweight humans

OBJECTIVE: Lipids stored in adipose tissue can originate from dietary lipids or from de novo lipogenesis (DNL) from carbohydrates. Whether DNL is abnormal in adipose tissue of overweight individuals remains unknown. The present study was undertaken to assess the effect of carbohydrate overfeeding on glucose-induced whole body DNL and adipose tissue lipogenic gene expression in lean and overweight humans. DESIGN: Prospective, cross-over study. SUBJECTS AND METHODS: A total of 11 lean (five male, six female, mean BMI 21.0+/-0.5 kg/m(2)) and eight overweight (four males, four females, mean BMI 30.1+/-0.6 kg/m(2)) volunteers were studied on two occasions. On one occasion, they received an isoenergetic diet containing 50% carbohydrate for 4 days prior to testing; on the other, they received a hyperenergetic diet (175% energy requirements) containing 71% carbohydrates. After each period of 4 days of controlled diet, they were studied over 6 h after having received 3.25 g glucose/kg fat free mass. Whole body glucose oxidation and net DNL were monitored by means of indirect calorimetry. An adipose tissue biopsy was obtained at the end of this 6-h period and the levels of SREBP-1c, acetyl CoA carboxylase, and fatty acid synthase mRNA were measured by real-time PCR. RESULTS: After isocaloric feeding, whole body net DNL amounted to 35+/-9 mg/kg fat free mass/5 h in lean subjects and to 49+/-3 mg/kg fat free mass/5 h in overweight subjects over the 5 h following glucose ingestion. These figures increased (P<0.001) to 156+/-21 mg/kg fat free mass/5 h in lean and 64+/-11 mg/kg fat free mass/5 h (P<0.05 vs lean) in overweight subjects after carbohydrate overfeeding. Whole body DNL after overfeeding was lower (P<0.001) and glycogen synthesis was higher (P<0.001) in overweight than in normal subjects. Adipose tissue SREBP-1c mRNA increased by 25% in overweight and by 43% in lean subjects (P<0.05) after carbohydrate overfeeding, whereas fatty acid synthase mRNA increased by 66 and 84% (P<0.05). CONCLUSION: Whole body net DNL is not increased during carbohydrate overfeeding in overweight individuals. Stimulation of adipose lipogenic enzymes is also not higher in overweight subjects. Carbohydrate overfeeding does not stimulate whole body net DNL nor expression of lipogenic enzymes in adipose tissue to a larger extent in overweight than lean subjects.

Life partnerships in childhood cancer survivors, their siblings, and the general population.

BACKGROUND: Life partnerships other than marriage are rarely studied in childhood cancer survivors (CCS). We aimed (1) to describe life partnership and marriage in CCS and compare them to life partnerships in siblings and the general population; and (2) to identify socio-demographic and cancer-related factors associated with life partnership and marriage. METHODS: As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to all CCS (aged 20-40 years) registered in the Swiss Childhood Cancer Registry (SCCR), aged <16 years at diagnosis, who had survived ≥ 5 years. The proportion with life partner or married was compared between CSS and siblings and participants in the Swiss Health Survey (SHS). Multivariable logistic regression was used to identify factors associated with life partnership or marriage. RESULTS: We included 1,096 CCS of the SCCSS, 500 siblings and 5,593 participants of the SHS. Fewer CCS (47%) than siblings (61%, P < 0.001) had life partners, and fewer CCS were married (16%) than among the SHS population (26%, P > 0.001). Older (OR = 1.14, P < 0.001) and female CCS (OR = 1.85, <0.001) were more likely to have life partners. CCS who had undergone radiotherapy, bone marrow transplants (global P Treatment = 0.018) or who had a CNS diagnosis (global P Diagnosis < 0.001) were less likely to have life partners. CONCLUSION: CCS are less likely to have life partners than their peers. Most CCS with a life partner were not married. Future research should focus on the effect of these disparities on the quality of life of CCS.

Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.

Neonatal diabetes mellitus can be transient or permanent. The severe form of permanent neonatal diabetes mellitus can be associated with pancreas agenesis. Normal pancreas development is controlled by a cascade of transcription factors, where insulin promoter factor 1 (IPF1) plays a crucial role. Here, we describe two novel mutations in the IPF1 gene leading to pancreas agenesis. Direct sequence analysis of exons 1 and 2 of the IPF1 gene revealed two point mutations within the homeobox in exon 2. Genetic analysis of the parents showed that each mutation was inherited from one parent. Mutations localized in helices 1 and 2, respectively, of the homeodomain, decreased the protein half-life significantly, leading to intracellular IPF1 levels of 36% and 27% of wild-type levels. Both mutant forms of IPF1 were normally translocated to the nucleus, and their DNA binding activity on different known target promoters was similar to that of the wild-type protein. However, transcriptional activity of both mutant IPF1 proteins, alone or in combination with HNF3 beta/Foxa2, Pbx1, or the heterodimer E47-beta 2 was reduced, findings accounted for by decreased IPF1 steady state levels and not by impaired protein-protein interactions. We conclude that the IPF1 level is critical for human pancreas formation.