Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies.

Effect of testosterone on immunocompetence, parasite load, and metabolism in the common wall lizard (Podarcis muralis)

Testosterone can benefit individual fitness by increasing ornament colour, aggressiveness, and sperm quality, but it can also impose both metabolic and immunological costs. However, evidence that testosterone causes immuno suppression in freely living populations is scant. We studied the effects of testosterone on one component of the immune system (i.e., the cell-mediated response to phytohaemagglutinin), parasite load, and metabolic rate in the common wall lizard, Podarcis muralis (Laurenti, 1768). For analyses of immunocompetence and parasitism, male lizards were implanted at the end of the breeding season with either empty or testosterone implants and were returned to their site of capture for 5-6 weeks before recapture. For analyses of the effects of testosterone on metabolic rate, male lizards were captured and implanted before hibernation and were held in the laboratory for 1 week prior to calorimetry. Experimental treatment with testosterone decreased the cell-mediated response to the T-cell mitogen phytohemagglutinin and increased mean metabolic rate. No effects of testosterone on the number of ectoparasites, hemoparasites, and resting metabolic rate could be detected. These results are discussed in the framework of the immunocompetence handicap hypothesis and the immuno-redistribution process hypothesis. [Authors]

Effects of alpha-phosphoglucomutase deficiency on cell wall properties and fitness in Streptococcus gordonii.

Streptococcus gordonii alpha-phosphoglucomutase, which converts glucose 6-phosphate to glucose 1-phosphate, is encoded by pgm. The pgm transcript is monocistronic and is initiated from a sigma(A)-like promoter. Mutants with a gene disruption in pgm exhibited an altered cell wall muropeptide pattern and a lower teichoic acid content, and had reduced fitness both in vitro and in vivo. In vitro, the reduced fitness included reduced growth, reduced viability in the stationary phase and increased autolytic activity. In vivo, the pgm-deficient strain had a lower virulence in a rat model of experimental endocarditis.

Update on skin cancer incidence and mortality in Europe

The epidemiology of skin cancer shows interplay between host susceptibility, (ultraviolet) environment, socioeconomical conditions and behavioural patterns. Its etiology is not yet fully elucidated and reveals intriguing questions. Fair-skinned populations have experienced over the last 60 years a rapid increase in the incidence of melanoma which is unparalleled by any other cancer, although signs of levelling off and stabilization in incidence have recently been observed in some countries. Despite many primary prevention and early detection campaigns over the last decades in Europe, decreases in melanoma mortality are modest and limited to a few countries. Further, reduction in the incidence of thick melanomas has not yet been evidenced. In this presentation, drivers for the incidence and mortality trends of skin cancer, with a strong focus on melanoma, its most lethal form, will be discussed.

Measures of health and disease in Africa: are current methods giving us useful information about trends in cardiovascular diseases?

An enormous burst of interest in the public health burden from chronic disease in Africa has emerged as a consequence of efforts to estimate global population health. Detailed estimates are now published for Africa as a whole and each country on the continent. These data have formed the basis for warnings about sharp increases in cardiovascular disease (CVD) in the coming decades. In this essay we briefly examine the trajectory of social development on the continent and its consequences for the epidemiology of CVD and potential control strategies. Since full vital registration has only been implemented in segments of South Africa and the island nations of Seychelles and Mauritius - formally part of WHO-AFRO - mortality data are extremely limited. Numerous sample surveys have been conducted but they often lack standardization or objective measures of health status. Trend data are even less informative. However, using the best quality data available, age-standardized trends in CVD are downward, and in the case of stroke, sharply so. While acknowledging that the extremely limited available data cannot be used as the basis for inference to the continent, we raise the concern that general estimates based on imputation to fill in the missing mortality tables may be even more misleading. No immediate remedies to this problem can be identified, however bilateral collaborative efforts to strength local educational institutions and governmental agencies rank as the highest priority for near term development.

Effect of elective antibiotic therapy on resting energy expenditure and inflammation in cystic fibrosis.

Cystic fibrosis (CF) patients often present with malnutrition which may partly be due to increased resting energy expenditure (REE) secondary to inflammation. Both REE and tumour necrosis factor-alpha (TNF-alpha), as other markers of inflammation, are elevated during respiratory exacerbations and decrease after antibiotic treatment. However, the effect of antibiotic therapy on REE and inflammation in patients without respiratory exacerbation is not known. The aim of our study was to determine the effect of such an elective antibiotic therapy on REE, TNF-alpha, and other serum markers of inflammation. Twelve CF patients 5F/7M, age 15.9 +/- 6.1 years, weight for height ratio 89 +/- 8% without clinically obvious exacerbation and treated by intravenous antibiotics were studied. Both before (D0) and after (D14) treatment, pulmonary function tests were performed. REE was measured by indirect calorimetry and blood taken to measure inflammation parameters. Body weight increased by 1.1 kg from D0 to D14 (P < 0.001), composed of 0.3 kg fat mass and 0.8 kg fat-free mass (FFM). The forced expiratory volume at 1 s increased from 43 +/- 15% of predicted at D0 to 51 +/- 15% of predicted at D14 (P < 0.01). Mean REE was 41.1 +/- 7.6 kcal/kg FFM per day at D0 and did not change significantly at D14 (40.6 +/- 8.5 kcal/kg FFM per day). Serum markers of inflammation decreased from D0 to D14: C-reactive protein 17 +/- 17 mg/l to 4 +/- 7 mg/l (P < 0.05), elastase 62 +/- 29 microg/l to 45 +/- 18 microg/l (P < 0.02), orosomucoid acid 1.25 +/- 0.11 g/l to 0.80 +/- 0.15 g/l (P < 0.001), and TNF-alpha 37 +/- 14 pg/ml to 29 +/- 6 pg/ml (P = 0.05). Individual values showed a correlation between changes in REE and in TNF-alpha (P < 0.02). The contribution of inflammation to energy expenditure is possible but appears to be minimal in cystic fibrosis patients treated by antibiotics on a regular basis in the absence of clinically obvious exacerbation.

Mutual trust and cooperation in the evolutionary hawks-doves game

Using a new dynamical network model of society in which pairwise interactions are weighted according to mutual satisfaction, we show that cooperation is the norm in the hawks-doves game when individuals are allowed to break ties with undesirable neighbors and to make new acquaintances in their extended neighborhood. Moreover, cooperation is robust with respect to rather strong strategy perturbations. We also discuss the empirical structure of the emerging networks, and the reasons that allow cooperators to thrive in the population. Given the metaphorical importance of this game for social interaction, this is an encouraging positive result as standard theory for large mixing populations prescribes that a certain fraction of defectors must always exist at equilibrium.

Long-term results of a multicenter SAKK trial on high-dose ifosfamide and doxorubicin in advanced or metastatic gynecologic sarcomas.

BACKGROUND: Dose intensive chemotherapy has not been tested prospectively for the treatment of gynecologic sarcomas. We investigated the antitumor activity and toxicity of high-dose ifosfamide and doxorubicin, in the context of a multidisciplinary strategy for the treatment of advanced and metastatic, not pretreated, gynecologic sarcomas. PATIENTS AND METHODS: Thirty-nine patients were enrolled onto a phase I-II multicenter trial of ifosfamide, 10 g/m2 as a continuous infusion over 5 days, plus doxorubicin intravenously, 25 mg/m2/day for 3 days with Mesna and granulocyte-colony-stimulating factor every 21 days. Salvage therapy was allowed after chemotherapy. RESULTS: Among the 37 evaluable patients, the tumor was locally advanced (n = 11), with concomitant distant metastases (n = 5) or with distant metastases only (n = 21). After a median of three (range 1-7) chemotherapy cycles, six patients experienced a complete response and 12 a partial response for an overall response rate of 49% (95% CI 32% to 66%). The response rate was higher in poorly differentiated tumors (62%) compared with moderately well differentiated ones (18%), but was not different according to histology subtypes. Eleven patients had salvage therapy, either immediately following chemotherapy (n = 7) or at time of progression (n = 4). With a median follow-up time of 5 years, the median overall survival was 30.5 months. Hematological toxicity was as expected neutropenia, thrombopenia and anemia > or = grade 3 at 50%, 34% and 33% of cycles respectively. No toxic death occurred. CONCLUSIONS: High-dose ifosfamide plus doxorubicin is an active regimen for all subtypes of gynecological sarcomas. Its toxicity was manageable in a multicentric setting. The prolonged survival might be due to the multidisciplinary strategy that was possible in one-third of the patients.

Bridging the Gap: establishing the necessary infrastructure and knowledge for teaching and research in neuroscience in Africa.

Advances in neuroscience research over the last few decades have increased our understanding of how individual neurons acquire their specific properties and assemble into complex circuits, and how these circuits are affected in disease. One of the important motives driving neuroscience research is the development of new scientific techniques and interdisciplinary cooperation. Compared to developed countries, many countries on the African continent are confronted with poor facilities, lack of funding or career development programs for neuroscientists, all of which deter young scientists from taking up neuroscience as a career choice. This article highlights some steps that are being taken to promote neuroscience education and research in Africa.

Toward a Statistically Robust Assessment of Social and Solidarity Economy Actors. Conceptual Development and Empirical Validation

Many definitions and debates exist about the core characteristics of social and solidarity economy (SSE) and its actors. Among others, legal forms, profit, geographical scope, and size as criteria for identifying SSE actors often reveal dissents among SSE scholars. Instead of using a dichotomous, either-in-or-out definition of SSE actors, this paper presents an assessment tool that takes into account multiple dimensions to offer a more comprehensive and nuanced view of the field. We first define the core dimensions of the assessment tool by synthesizing the multiple indicators found in the literature. We then empirically test these dimensions and their interrelatedness and seek to identify potential clusters of actors. Finally we discuss the practical implications of our model.