Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors

Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm−2, respectively, P<0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1α expression. Poorly differentiated carcinomas were associated with nuclear HIF-1α and membranous CA9 expression. Low MVD (P=0.0001) and membranous CA9 expression (P=0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours

Impact of Liberalisation on Environmental, Social and Economic Value Dimensions of Selected Airline Companies and their Coping Strategies : An Archival Research Based on Qualitative Secondary Data in Form of Relevant Publications and Other Sources

The liberalization of the aviation industry has ushered in significant changes in economic, environmental, and social dimensions, impacting selected airline companies worldwide. This study aimed to investigate the implications of liberalization on the economic, environmental, and social value of selected airline companies and explore their coping strategies. The liberalization of the aviation sector, marked by deregulation and market opening, has transformed the industry landscape, leading to increased competition and market access. This shift has prompted airline companies to reevaluate their business models and strategies to remain competitive in the liberalized environment. The study sought to identify positive and negative impacts across these dimensions and explore the coping strategies employed by airlines to mitigate adverse effects. A mono-methods approach was employed, ensured by secondary data based on archival research. Selected airline companies were assessed based on key performance indicators related to economic profitability, environmental sustainability, and social responsibility. Analysis of the economic dimension revealed both positive and negative impacts of liberalization, including increased market access and intensified competition. Environmental evaluations highlighted the challenges of carbon emissions and resource depletion, alongside efforts to adopt green technologies and sustainable practices. Social assessments identified job creation opportunities and cultural exchange benefits, counterbalanced by concerns of job insecurity and social inequality. Coping strategies varied across companies but commonly included diversification, strategic partnerships, and sustainability initiatives. The findings underscore the complex interplay between liberalization, economic, environmental, and social dimensions in the airline industry. While liberalization offers opportunities for market expansion, it also poses challenges that require proactive measures and adaptive strategies. The study emphasizes the importance of integrated sustainability approaches that address economic, environmental, and social concerns concurrently. Recommendations include fostering innovation, enhancing regulatory compliance, and promoting stakeholder engagement to ensure the long-term viability and resilience of airline companies in the liberalized market

Etude de la dysplasie biliaire au pourtour de cholangiocarcinomes extra-hépatiques opérés

LYON1-BU Santé (693882101) / SudocSudocFranceF

EVALUATION DE LA SENSIBILITE AU CHANGEMENT DES MESURES RADIOLOGIQUES, DU PINCEMENT MAXIMUM, DE L'EPAISSEUR MOYENNE ET DE LA SURFACE ARTICULAIRE, ASSISTEE PAR ORDINATEUR DANS LA COXARTHROSE

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

IRM de diffusion dans le bilan pré-thérapeutique de l'adénocarcinome pancréatique potentiellement résécable

LYON1-BU Santé (693882101) / SudocSudocFranceF

Forfait obstétrical et inégalités dans l'accès aux soins maternels en Mauritanie

International audienc

Removing user fees to improve access to caesarean delivery: a quasi-experimental evaluation in western Africa

International audienceIntroduction Mali and Benin introduced a user feeexemption policy focused on caesarean sections in 2005and 2009, respectively. The objective of this study is toassess the impact of this policy on service utilisation andneonatal outcomes. We focus specifically on whether thepolicy differentially impacts women by education level,zone of residence and wealth quintile of the household.Methods We use a difference-in-differences approachusing two other western African countries with no feeexemption policies as the comparison group (Cameroonand Nigeria). Data were extracted from Demographic andHealth Surveys over four periods between the early 1990sand the early 2000s. We assess the impact of the policy onthree outcomes: caesarean delivery, facility-based deliveryand neonatal mortality.Results We analyse 99 800 childbirths. The freecaesarean policy had a positive impact on caesareansection rates (adjusted OR=1.36 (95% CI 1.11 to 1.66;P≤0.01), particularly in non-educated women (adjustedOR=2.71; 95% CI 1.70 to 4.32; P≤0.001), those livingin rural areas (adjusted OR=2.02; 95% CI 1.48 to 2.76;P≤0.001) and women in the middle-class wealth index(adjusted OR=3.88; 95% CI 1.77 to 4.72; P≤0.001). Thepolicy contributes to the increase in the proportion offacility-based delivery (adjusted OR=1.68; 95% CI 1.48 to1.89; P≤0.001) and may also contribute to the decreaseof neonatal mortality (adjusted OR=0.70; 95% CI 0.58 to0.85; P≤0.001).Conclusion This study is the first to evaluate the impactof a user fee exemption policy focused on caesareansections on maternal and child health outcomes withrobust methods. It provides evidence that eliminating feesfor caesareans benefits both women and neonates in sub-Saharan countries

Do free caesarean section policies increase inequalities in Benin and Mali?

International audienceBackground: Benin and Mali introduced user fee exemption policies focused on caesarean sections (C-sections) in2005 and 2009, respectively. These policies had a positive impact on access to C-sections and facility based deliveriesamong all women, but the impact on socioeconomic inequality is still highly uncertain. The objective of this study wasto observe whether there was an increase or a decrease in urban/rural and socioeconomic inequalities in access toC-sections and facility based deliveries after the free C-section policy was introduced.Methods: We used data from three consecutive Demographic and Health Surveys (DHS): 2001, 2006 and 2011–2012 inBenin and 2001, 2006 and 2012–13 in Mali. We evaluated trends in inequality in terms of two outcomes: C-sections andfacility based deliveries. Adjusted odds ratios were used to estimate whether the distributions of C-sections and facilitybased deliveries favoured the least advantaged categories (rural, non-educated and poorest women) or the mostadvantaged categories (urban, educated and richest women). Concentration curves were used to observe the degreeof wealth-related inequality in access to C-sections and facility based deliveries.Results: We analysed 47,302 childbirths (23,266 in Benin and 24,036 in Mali). In Benin, we found no significantdifference in access to C-sections between urban and rural women or between educated and non-educated women.However, the richest women had greater access to C-sections than the poorest women. There was no significantchange in these inequalities in terms of access to C-sections and facility based deliveries after introduction of the freeC-section policy.In Mali, we found a reduction in education-related inequalities in access to C-sections after implementation of thepolicy (p-value = 0.043). Inequalities between urban and rural areas had already decreased prior to implementation ofthe policy, but wealth-related inequalities were still present.Conclusions: Urban/rural and socioeconomic inequalities in C-section access did not change substantially after thecountries implemented free C-section policies. User fee exemption is not enough. We recommend switching tomechanisms that combine both a universal approach and targeted action for vulnerable populations to address thisissue and ensure equal health care access for all individuals