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Hydrological ensemble forecasting performances are analysed over 5 basins up to 2000 km2 in the French Upper Rhone region. Streamflow forecasts are issued at an hourly time step from lumped ARX rainfall-runoff models forced by different precipitation forecasts. Ensemble meteorological forecasts from ECMWF and NCEP are considered, as well as analogue-based forecasts fed by their corresponding control forecast. Analogue forecasts are rearranged using an adaptation of the Schaake-Shuffle method in order to ensure the temporal coherence. A new evaluation approach is proposed, separating forecasting performances on peak amplitudes and peak timings for high flow events. Evaluation is conducted against both simulated and observed streamflow (so that relative meteorological and hydrological uncertainties can be assessed), by means of CRPS and rank histograms, over the 2007-2014 period. Results show a general agreement of the forecasting performances when averaged over the 5 basins. However, ensemble-based and analogue-based streamflow forecasts produce a different signature on peak events in terms of bias, spread and reliability. Strengths and weaknesses of both approaches are discussed as well as potential improvements, notably towards their merging.

This paper presents a thorough analysis of foraminiferal assemblages ranging in age from the Bedoulian-Gargasian transition to the middle Gargasian in the Cassis-La Bédoule area (SE France), the historical stratotype of the Lower Aptian substage. This region is particularly suitable for detailed studies of Aptian foraminifera owing to rapid and continuous sediment depositional rates and well-diversified microfaunas. The ranges of benthic forms appear to be fairly stable but some species (Praedorothia praeoxycona, Lenticulina cf. nodosa, Astacolus crepidularis, Globorotalites bartensteini) become extinct at the end of the Bedoulian and thus can be used to separate this substage from the Gargasian. The stratotypic area also offers an opportunity to follow the evolution of planktonic forms step by step at a crucial period of their history, when modalities of speciation and phylogenetic relationships appear to be particularly complex. The important morphologic variability of Aptian planktonic foraminifera does not help finding stable stratigraphic markers; nevertheless, we are able to propose a biozonation comprising five zones (Cabri, Luterbacheri, Ferreolensis, Barri, Algerianus) for the interval under consideration, usually subdivided into three zones. Our study of foraminiferal assemblages and species took into account the range of variability among populations and not just the characteristics of a single specimen, such as the holotype. As a result this paper provides new taxonomic precisions on certain planktonic species hitherto controversial or possibly of doubtful validity.

L'analyse approfondie des associations de Foraminifères depuis les termes du passage Bédoulien-Gargasien jusqu'au Gargasien moyen a été réalisée dans le secteur de Cassis-La Bédoule (SE France), stratotype historique du Bédoulien (Aptien inférieur), particulièrement favorable à ce niveau en raison de la continuité et de la dilatation de la série ainsi que de la diversification de la microfaune. L'éventail des formes benthiques se révèle assez stable mais quelques espèces (Praedorothia praeoxycona, Lenticulina cf. nodosa, Astacolus crepidularis, Globorotalites bartensteini) s'éteignent à la fin du Bédoulien et peuvent être utilisées pour différencier ce sous-étage par rapport au Gargasien. L'aire stratotypique offre aussi la possibilité de suivre pas à pas l'évolution des formes planctoniques à un moment crucial de leur histoire, lorsque les processus de spéciation et les liens phylogénétiques s'avèrent particulièrement complexes. La grande variabilité morphologique des formes planctoniques durant l'Aptien ne facilite pas le choix de marqueurs stratigraphiques stables; il est cependant possible de proposer une biozonation comportant cinq zones (à Cabri, Luterbacheri, Ferreolensis, Barri, Algerianus) pour l'intervalle considéré, habituellement subdivisé en trois zones. L'étude populationnelle, et non pas seulement typologique, des associations nous a enfin permis d'apporter quelques précisions taxinomiques nouvelles, en particulier sur certaines formes planctoniques d'acception controversée ou même de validité douteuse.

In the middle of the last century Gargasian strata overlying the historical stratotypic beds of the lower substage of the Aptian (Bedoulian) were still well exposed in a number of quarries that extended in a NNE-SSW trending belt from the village of Roquefort-la Bédoule to the vicinity of the Cassis railway station (...)

Dans le stratotype historique du sous-étage inférieur de l'Aptien (Bédoulien), les couches gargasiennes sus-jacentes affleuraient encore largement au milieu du siècle dernier, au niveau de nombreuses carrières s'étendant selon une bande orientée NNE-SSW, depuis le village de Roquefort-La Bédoule jusqu'aux environs de la station de chemin de fer de Cassis (...)

Background: Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate., Methods: Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts., Results: GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival., Conclusion: This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC., (© 2023. The Author(s).)

Introduction: Venous sampling for blood gas analysis has been suggested as an alternative to arterial sampling in order to reduce pain. The main objective was to compare pain induced by venous and arterial sampling and to assess whether the type of sampling would affect clinical management or not., Methods: We performed an open-label randomised multicentre prospective study in four French EDs during a 4-week period. Non-hypoxaemic adults, whose medical management required blood gas analysis, were randomly allocated using a computer-generated randomisation list stratified by centres with an allocation ratio of 1:1 using random blocks to one of the two arms: venous or arterial sampling. The primary outcome was the maximal pain during sampling, using the visual analogue scale. Secondary outcomes pertained to ease of sampling as rated by the nurse drawing the blood, and physician satisfaction regarding usefulness of biochemical data., Results: 113 patients were included: 55 in the arterial and 58 in the venous sampling group. The mean maximal pain was 40.5 mm±24.9 mm and 22.6 mm±20.2 mm in the arterial group and the venous group, respectively, accounting for a mean difference of 17.9 mm (95% CI 9.6 to 26.3) (p<0.0001). Ease of blood sampling was greater in the venous group as compared with the arterial group (p=0.02). The usefulness of the results, evaluated by the prescriber, did not significantly differ (p=0.25)., Conclusions: Venous blood gas is less painful for patients than ABG in non-hypoxaemic patients. Venous blood gas should replace ABG in this setting., Trial Registration Number: NCT03784664., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high transforming growth factor beta-induced (TGFBI) expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates focal adhesion kinase signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic extracellular matrix interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies., (© 2019 UICC.)

Objectives: A lung retransplant has been shown to be a valid option in selected patients with chronic lung allograft dysfunction (CLAD). However, a subgroup of patients may require, in addition to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO) as a bridge to a retransplant. Overall and CLAD-free survival after ECMO-bridged retransplants are compared to first transplants with and without bridging ECMO and to retransplants without bridging ECMO., Methods: We reported a retrospective, single-institution experience based on a prospective data set of all patients undergoing lung transplants between January 2004 and December 2016 with a mean follow-up of 51 ± 41 months., Results: A total of 230 patients (96 men, 134 women, mean age 47.3 years) had lung transplants: 200 had first transplants without bridging ECMO; 13 had first transplants with bridging ECMO; 11 had retransplants without bridging ECMO; and 6 had retransplants with bridging ECMO. The 3- and 5-year survival rates were 81%/76%, 68%/68%, 69%/46% and 50%/25%, respectively. There was no significant difference in overall survival between those who had first transplants with and without bridging ECMO or retransplants without bridging ECMO. In contrast, patients undergoing ECMO-bridged retransplants had a significantly lower overall survival rate than those with a first transplant without bridging ECMO (P = 0.007). In addition, the post-transplant CLAD-free survival curves varied significantly among the 4 treatment groups (P = 0.041), paralleling overall survival., Conclusions: Patients requiring ECMO as a bridge to a retransplant had lower overall and CLAD-free survival rates compared to those who had a first transplant with and without bridging ECMO and a retransplant without bridging ECMO., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Colon adenocarcinoma is the third most commonly diagnosed cancer and the second deadliest one. Metabolic reprogramming, described as an emerging hallmark of malignant cells, includes the predominant use of glycolysis to produce energy. Recent studies demonstrated that mitochondrial electron transport chain inhibitor reduced colon cancer tumour growth. Accumulating evidence show that myoferlin, a member of the ferlin family, is highly expressed in several cancer types, where it acts as a tumour promoter and participates in the metabolic rewiring towards oxidative metabolism. In this study, we showed that myoferlin expression in colon cancer lesions is associated with low patient survival and is higher than in non-tumoural adjacent tissue. Human colon cancer cells silenced for myoferlin exhibit a reduced oxidative phosphorylation activity associated with mitochondrial fission leading, ROS accumulation, decreased cell growth, and increased apoptosis. We observed the triggering of a DNA damage response culminating to a cell cycle arrest in wild-type p53 cells. The use of a p53 null cell line or a compound able to restore p53 activity (Prima-1) reverted the effects induced by myoferlin silencing, confirming the involvement of p53. The recent identification of a compound interacting with a myoferlin C2 domain and bearing anticancer potency identifies, together with our demonstration, this protein as a suitable new therapeutic target in colon cancer.

Introduction: Extracorporeal membrane oxygenation (ECMO) is an efficient and innovative therapeutic tool for primary graft dysfunction (PGD). However, its effect on survival and long-term lung function is not well known. This study evaluated those parameters in patients with PGD requiring ECMO., Method: This single-center, retrospective study included patients who underwent LTx at our institute between January 2007 and December 2013. Patients and disease characteristics, survival, and pulmonary function tests were recorded., Results: A total of 309 patients underwent LTx during the study period and 211 were included. The patients were predominantly male (53.5%), the median age was 39 years, and the primary pathology was suppurative disease (53.1%). ECMO for PGD was mandatory in 24 (11.7%) cases. Mortality at 3 months in the ECMO group was 50% (N = 12). However, long-term survival after PGD did not correlate with ECMO. Forced expiratory volume and vital capacity were significantly reduced in patients with PGD requiring ECMO, especially those with idiopathic pulmonary fibrosis., Conclusion: Veno-arterial ECMO appears to be suitable for management of PGD after LTx. Patients with PGD requiring ECMO show increased initial mortality; however, long-term survival was comparable with that of other patients in the study. Lung function does not appear to be related to PGD requiring ECMO., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diabetes is one of the most frequent diseases throughout the world and its incidence is predicted to exponentially progress in the future. This metabolic disorder is associated with major complications such as neuropathy, retinopathy, atherosclerosis, and diabetic nephropathy, the severity of which correlates with hyperglycemia, suggesting that they are triggered by high glucose condition. Reducing sugars and reactive carbonyl species such as methylglyoxal (MGO) lead to glycation of proteins, lipids and DNA and the gradual accumulation of advanced glycation end products (AGEs) in cells and tissues. While AGEs are clearly implicated in the pathogenesis of diabetes complications, their potential involvement during malignant tumor development, progression and resistance to therapy is an emerging concept. Meta-analysis studies established that patients with diabetes are at higher risk of developing cancer and show a higher mortality rate than cancer patients free of diabetes. In this review, we highlight the potential connection between hyperglycemia-associated AGEs formation on the one hand and the recent evidence of pro-tumoral effects of MGO stress on the other hand. We also discuss the marked interest in anti-glycation compounds in view of their strategic use to treat diabetic complications but also to protect against augmented cancer risk in patients with diabetes., (Copyright © 2019. Published by Elsevier B.V.)

Background: Elevated aerobic glycolysis rate is a biochemical alteration associated with malignant transformation and cancer progression. This metabolic shift unavoidably generates methylglyoxal (MG), a potent inducer of dicarbonyl stress through the formation of advanced glycation end products (AGEs). We have previously shown that the silencing of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, generates endogenous dicarbonyl stress resulting in enhanced growth and metastasis in vivo. However, the molecular mechanisms through which MG stress promotes metastasis development remain to be unveiled., Methods: In this study, we used RNA sequencing analysis to investigate gene-expression profiling of GLO1-depleted breast cancer cells and we validated the regulated expression of selected genes of interest by RT-qPCR. Using in vitro and in vivo assays, we demonstrated the acquisition of a pro-metastatic phenotype related to dicarbonyl stress in MDA-MB-231, MDA-MB-468 and MCF7 breast cancer cellular models. Hyperactivation of MEK/ERK/SMAD1 pathway was evidenced using western blotting upon endogenous MG stress and exogenous MG treatment conditions. MEK and SMAD1 regulation of MG pro-metastatic signature genes in breast cancer cells was demonstrated by RT-qPCR., Results: High-throughput transcriptome profiling of GLO1-depleted breast cancer cells highlighted a pro-metastatic signature that establishes novel connections between MG dicarbonyl stress, extracellular matrix (ECM) remodeling by neoplastic cells and enhanced cell migration. Mechanistically, we showed that these metastasis-related processes are functionally linked to MEK/ERK/SMAD1 cascade activation in breast cancer cells. We showed that sustained MEK/ERK activation in GLO1-depleted cells notably occurred through the down-regulation of the expression of dual specificity phosphatases in MG-stressed breast cancer cells. The use of carnosine and aminoguanidine, two potent MG scavengers, reversed MG stress effects in in vitro and in vivo experimental settings., Conclusions: These results uncover for the first time the key role of MG dicarbonyl stress in the induction of ECM remodeling and the activation of migratory signaling pathways, both in favor of enhanced metastatic dissemination of breast cancer cells. Importantly, the efficient inhibition of mitogen-activated protein kinase (MAPK) signaling using MG scavengers further emphasizes the need to investigate their therapeutic potential across different malignancies.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18 F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.

Background: Liver and lungs are the two most frequent sites of metastatic spread of colorectal cancer (CRC). Complete resection of liver and/or lung metastases is the only chance of cure, and several studies have reported an improved survival after an aggressive treatment. Nevertheless, CRC liver metastases (CLM) have been recognized as a pejorative factor for patients undergoing pulmonary metastasectomy. We report our experience with patients successively operated on for CRC hepatic and pulmonary metastasis (CPM) and seek to identify prognostic factors., Methods: All consecutive patients who had resection of CPM and CLM between 2001 and 2014 were enrolled in the study. Clinicopathological and survival data were retrospectively analysed., Results: Forty-six patients underwent resections of both CLM and CPM. Hepatic resection preceded pulmonary resection in most cases (91.3%). The median intervals between the resection of the primary tumour and the hepatic recurrence and between hepatic and pulmonary recurrences were 12 months [0-72] and 21.5 months [1-84], respectively. The mortality rate following CPM resection was 4.3%. After a median follow-up of 41.5 months [0-126], 35 patients recurred of whom 14 (40%) and 11(31.4%) could benefit from repeated resection of recurrent CLM and CPM, respectively. The median and 5-year overall survivals (OS) were 53 months and 49%, respectively. No prognostic factor was identified., Conclusion: An aggressive management of CLM and CPM, including repeated resections, may provide a long-term survival comparable to survival of patients with unique metastasectomy. The absence of prognostic factor may reflect the highly selected pattern of the eligible patients.

Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [ 18 F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype.

Incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinomas (HNSCCs) has increased over the last few decades. The reaction of the host immune system to these tumors remains biologically complex. Here, we investigated CD68+ macrophage numbers, reporting the prognostic value in comparison to other risk factors. We also examined CD68+ macrophage infiltration during disease progression regarding the impact of HPV infection, and we studied the role of HPV16-E6/E7 oncoproteins in CD68+ macrophage recruitment. CD68+ macrophage numbers were evaluated in 10 cases of tumor-free peri-tumoral epithelia, 43 cases of low-grade dysplasia, 45 cases of high-grade dysplasia and 110 cases of carcinoma. Our in vivo model was developed in 80 C3H/HeN mice orthotopically injected with HPV16-E6, -E7 or -E6/E7-transfected SCC-VII cell lines. High CD68+ macrophage numbers in the intra-tumoral compartment were associated with shorter patient survival (recurrence-free survival: p = 0.001; overall survival: p = 0.01). Multivariate analyses reported that CD68+ macrophage infiltration and tumor stage were strong and independent prognostic factors of HNSCC. CD68+ macrophage numbers increased during HNSCC progression both in intra-epithelial ( p < 0.001) and stromal compartments ( p < 0.001). A higher density of CD68+ macrophages was observed in advanced stages ( p = 0.004). Patients with transcriptionally active HPV infections had higher CD68+ macrophage density than did HPV-negative patients ( p = 0.003). CD68+ macrophage infiltration was higher in HPV-E7+ and -E6/E7+ mouse tumors than in -E6+ tumors ( p = 0.029 and p < 0.001). In conclusion, the extent of CD68+ macrophage infiltration is a significant prognostic factor for HNSCC patients. The recruitment of macrophages increases during disease progression and is influenced by the HPV virus., Competing Interests: CONFLICTS OF INTEREST No conflicts of interest.

Background: Solitary pulmonary nodules (SPN) are frequently detected in cancer patients. These lesions are often considered as pulmonary metastases and increasingly treated by non-surgical techniques without histological confirmation. The aim of this study is to determine the histological nature of SPN resected by thoracoscopy and to identify risk factors of malignancy., Methods: Single-institution retrospective analysis of all consecutive patients with previously known malignancies who underwent thoracoscopic resection of SPN with unknown diagnosis between 2001 and 2014., Results: One hundred and forty cancer patients underwent thoracoscopic resection of a SPN. The resected SPN was benign in 34 patients (24.3%) and malignant in 106 patients. The latter were metastasis in 70 patients (50%) and a primary lung cancer in 36 patients (25.7%). Upon univariate analysis, malignancy was significantly associated with age >60 years, disease-free interval ≥24 months, SPN size >8 mm, upper lobe localization and SUV max  > 2.5 on PET-CT. Upon multivariate analysis, upper lobe localization and SUV max  > 2.5 were associated with malignancy. Smoking was significantly associated with SPN containing primary lung cancer., Conclusion: In this series, only 50% of SPN in patients with known malignant disease were pulmonary metastases and 25% had a newly diagnosed NSCLC. Smoking was associated with primary lung cancer but no other predictor was found to allow the distinction between pulmonary metastasis and lung cancer. These results endorse the need of histological confirmation of SPN in patients with previous malignancies to avoid diagnostic uncertainty and suboptimal treatments.

Objectives: Adrenal oligometastatic non-small-cell lung cancer is rare, and surgical management remains controversial., Methods: We performed a multicentre, retrospective study from January 2004 to December 2014. The main objective was to evaluate survival in patients who had undergone adrenalectomy after resection of primary lung cancer. Secondary objectives were to determine prognostic, survival and recurrence factors., Results: Fifty-nine patients were included. Forty-six patients (78%) were men. The median age was 58 years [39-75 years]. Twenty-six cases (44%) showed synchronous presentation, and 33 cases (56%) had a metachronous presentation. The median time to onset of metastasis was 18.3 months [6-105 months]. The 5-year overall survival rate was 59%; the median survival time was 77 months [0.6-123 months]. A recurrence was observed in 70% of the population. Mediastinal lymph node invasion (P = 0.035) is a detrimental prognostic factor of survival., Conclusions: After exhaustive staging, patients with adrenal oligometastatic non-small-cell lung cancer benefit from bifocal surgery., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth.

Objectives: Head and neck squamous cell carcinomas (HNSCC), one of the most frequent cancers in the world, are largely infiltrated by inflammatory immune cells. Our aim was to evaluate the number of Foxp3+ T cells in HNSCC, reporting its prognostic power in comparison to other risk factors., Material and Methods: Our clinical series was composed of 21 tumor-free peri-tumoral epithelia, 49 low grade dysplasia, 43 high grade dysplasia and 110 carcinoma samples including some cases with HPV infection. In vivo experiments were conducted on 80 C3H/HeN mice which were orthotopically injected with SCCVII CT, E7, E6 and E6/E7 cell lines., Results: Foxp3+ T cell infiltration increased with tumor progression from normal epithelia, dysplasia to carcinoma and the increase is more important in HPV+ patients than in negative ones. Animal experiments revealed that E7 oncoprotein expression was significantly associated with an increase in Foxp3+ T cell recruitment in tumor, a delay in tumor onset and improved animal survival. Univariate Cox regression analyses demonstrated that high Foxp3+ T cell number in stromal compartment is associated with longer patient recurrence-free and overall survivals. Foxp3+ T cell number improved the prognostic value of tumor stage. Multivariate analyses reported that stromal Foxp3+ T cell number is a strong prognostic factor independent of classical risk factors such as tobacco, alcohol, and HPV status., Conclusion: Foxp3+ T cell number is a significant prognostic factor for HNSCC, improving the tumor stage, and that viral E7 may play a role in the Foxp3+ T cell infiltration to the tumor., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cancer cells generally rely on aerobic glycolysis as a major source of energy. Methylglyoxal (MG), a dicarbonyl compound that is produced as a side product during glycolysis, is highly reactive and induces the formation of advanced glycation end-products that are implicated in several pathologies including cancer. All mammalian cells have an enzymatic defense against MG composed by glyoxalases GLO1 and GLO2 that converts MG to d-lactate. Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality. In this study, we used immunohistochemistry to examine the level of MG protein adducts, in a series of 102 CRC human tumors divided into four clinical stages. We consistently detected a high level of MG adducts and low GLO1 activity in high stage tumors compared to low stage ones suggesting a pro-tumor role for dicarbonyl stress. Accordingly, GLO1 depletion in CRC cells promoted tumor growth in vivo that was efficiently reversed using carnosine, a potent MG scavenger. Our study represents the first demonstration that MG adducts accumulation is a consistent feature of high stage CRC tumors. Our data point to MG production and detoxification levels as an important molecular link between exacerbated glycolytic activity and CRC progression., Competing Interests: The authors declare no conflict of interest.

Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of TGF-β in malignant development and progression requires a better understanding of the molecular mechanisms involved in its tumor suppressor to tumor promoter switch. One important aspect of TGF-β function is its interaction with proteins within the tumor microenvironment. Several stromal proteins have the natural ability to interact and modulate TGF-β function. Understanding the complex interplay between the TGF-β signaling network and these stromal proteins may provide greater insight into the development of novel therapeutic strategies that target the TGF-β axis. The present review highlights our present understanding of how stroma modulates TGF-β activity in human cancers., Competing Interests: Authors declare no conflict of interest.

Objectives: Head and neck squamous cell carcinomas (HNSCCs) exhibit great biological heterogeneity and relatively poor prognosis. Tobacco and alcohol consumption is involved in the cause of the majority of these cancers, but over the last several years, Human Papilloma Virus (HPV) infection has increased specifically in oropharyngeal cancers and become an additional risk factor. Here, we evaluated the number of Langerhans cells (LCs) in HNSCC and reporting its prognostic power in comparison to other risk factors., Materials and Methods: Our clinical series was composed of 25 tumor-free peritumoral epithelium, 64 low-grade dysplasia, 54 high-grade dysplasia and 125 carcinoma samples. HPV was detected by E6/E7 qPCR and p16 immunohistochemistry. CD1a-positive LCs were counted in intra-tumoral and stromal compartments as well as lymph nodes. MIP-3α was assessed in carcinomas using immunohistochemistry., Results: Univariate Cox regression analyses demonstrated that high LC number is associated with longer recurrence-free survival in both intra-tumoral and stromal compartments and longer overall survival in stromal compartment. Tobacco and alcohol habits, but not HPV status, are also correlated with poor prognoses in terms of recurrence. Multivariate analyses reported stromal LC number as a strong prognostic factor independent of tobacco, alcohol and HPV status. Moreover, LC number is higher in tumors and invaded lymph nodes than dysplastic lesions but it decreases in HPV-positive cancer patients. Further, LC number correlates with MIP-3α expression., Conclusion: These findings suggest that LC number is a significant and independent prognostic factor for HNSCC. LC infiltration is increased in cancer lesions but decrease with HPV infection., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We report the case of a 33-year-old woman who presented with increasing dyspnea secondary to a tumor arising from the carina. After desobstruction by bronchoscopy, the pathologic analysis revealed a glomic tumor. Carinal resection and reconstruction were performed with venoarterial extracorporeal membrane oxygenation support. The patient's postoperative course was uneventful, and the long-term result was excellent., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Tracheal necrosis is a rare life-threatening phenomenon that most often occurs after thyroid operations or prolonged intubation. Conservative treatment can be one choice in extensive tracheal necrosis. We report the case of a 59-year-old man, with tracheal necrosis that developed after pharyngolaryngectomy, that we treated conservatively using hyperbaric oxygen therapy and antibiotic therapy. The follow-up was assured by tracheobronchoscopy. A year after his discharge, the trachea was totally healed., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Residual upper pleural spaces after subtotal pulmonary resection continues to pose great challenge for the thoracic surgeon. Although not all residual spaces deserve surgical attention, only in special situation (empyema with or without bronchopleural fistula). It increases morbidity, mortality, hospital stays, and costs. Transposition of extrathoracic muscle flaps has been the cornerstone of treatment of this complication. Sometimes use of latissimus or serratus muscle might have been compromised by the incision for the original operation. In this situation the pectoralis major muscle flap (PMF) can be used successfully to reach and obliterate upper residual pleural space by anterior approach. The technique has never been specifically described before in the literature. We describe our technique for mobilization of PMF by anterior approach to obliterate residual upper space after major pulmonary resections.

Background: Postpneumonectomy empyema (PPE) is a serious complication. The treatment options are similar to the management of any abscess, with drainage, ideally open, often of critical importance. After infection control, many techniques for space obliteration have been described. This study summarizes a 10-year experience in the management of PPE in our center., Methods: From 2000 to 2010, 90 patients (83 men) with PPE were treated. Median follow-up was 5.3 years. Once the diagnosis of empyema was confirmed, chest drainage was performed through open window thoracostomy (OWT), with ensuing extramusculoperiosteal thoracoplasties if healthy tissue was present., Results: Pneumonectomy was performed in 72 patients with lung cancer. Mortality after PPE was 2.2%. OWT achieved infection control in 89 patients. Seven OWT spontaneously healed, and 24 were never closed. The remaining 59 patients with OWT underwent thoracoplasty. Mortality after thoracoplasty was 5%. Empyema recurred in 3 patients. Overall success rate of PPE control after pleural obliteration was 91.5%., Conclusions: Thoracoplasty is a reliable filling procedure. It has a significantly higher success rate and a lower mortality rate than the other techniques. We believe that this procedure has a part to play in the future management of PPE., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine the incidence and symptoms of postoperative ischemic bronchitis (POIB) after systematic lymph node dissection (LND) and evaluate the effect of hyperbaric oxygen therapy in patients with primary lung cancer., Methods: From January 2004 to December 2009, 1,071 patients underwent a standard resection for non-small cell lung cancer and radical systematic lymph node dissection. Fiberoptic bronchoscopy was performed systematically between days 7 and 12. We analyzed the clinical and biologic signs of POIB. Once the diagnosis established a treatment by hyperbaric oxygen, therapy was undertaken., Results: A POIB was observed in 34 patients (3.21%) (2 women and 32 men). Mean age was 59 ± 10 years (range, 25 to 79 years). A POIB occurred within 8 ± 3 days; after right pulmonary resection (n = 21; 62%) and after left resection (n = 13; 38%). A POIB appeared asymptomatically for 27 patients (80%), whereas only 7 patients (20%) presented with fever and hyperleukocytosis. Their localization were bronchial stumps (n = 21; 62%), homolateral bronchial tree (n = 11; 32%), or extension toward the contralateral bronchial tree (n = 2; 6%). The mean number of hyperbaric oxygen therapy sessions was 14 (1 to 48). A POIB worsening was observed in 6 patients (18%), requiring a surgical rescue therapy., Conclusions: The clinical presentation of POIB is poor and systematic fiberoptic bronchoscopy should be performed, especially in patients with a high risk of bronchopleural fistula. Hyperbaric oxygen therapy in the management of ischemic bronchitis may be a promising adjunctive treatment., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The natriuretic peptide receptor type C (NPR-C) binds all natriuretic peptides. It is thought to be involved in the clearance of natriuretic peptides and more recently has been defined as essential for the neuromodulatory effects of natriuretic peptides. Although the distribution of NPR-C mRNA has been reported in the rat forebrain, there are no data on the distribution of NPR-C in the brainstem. We report an immunofluorescence study on the distribution of NPR-C immunoreactivity in the rat brainstem, and its presence in cholinergic and catecholaminergic neurons. NPR-C immunoreactivity was detected in several regions, including the periaqueductal gray, oculomotor nucleus, red nucleus and trochlear nucleus of the midbrain; the pontine nucleus, dorsal tegmental nucleus, vestibular nucleus, locus coeruleus, trigeminal motor nucleus, nucleus of the trapezoid body, abducens nucleus and facial nucleus of the pons; and the dorsal motor nucleus of the vagus, hypoglossal nucleus, lateral reticular nucleus, nucleus ambiguus and inferior olivary nucleus of the medulla oblongata. Interestingly, NPR-C immunoreactivity was detected in the cholinergic neurons of the oculomotor nucleus, trochlear nucleus, dorsal tegmental nucleus, motor trigeminal nucleus, facial nucleus, dorsal motor nucleus of the vagus, nucleus ambiguus and hypoglossal nucleus. Furthermore, NPR-C immunoreactivity was detected in several catecholaminergic neuronal groups including the A6, A5, A1, C3 and C1 cell groups. These results are consistent with an important role for natriuretic peptides in neuroendocrine regulation and central cardiovascular integration. The extensive distribution of NPR-C in the brainstem supports the hypothesis that NPR-C is involved in the neuromodulatory effect of natriuretic peptides.

We previously showed that degenerating adult motor neurons of the murine mutant wobbler, a model of spinal muscular atrophy, express Transforming Growth Factor alpha (TGF alpha), a growth factor endowed with glio- and neurotrophic activities. Here, we evaluated whether TGF alpha expression is a general response of adult motor neurons to injury. Synthesis of its precursor (pro-TGF alpha) was investigated in another model of motoneuronal degeneration, the murine mutant muscle deficient, and in hypoglossal motor neurons following axonal crush and cut. In control conditions, motor neurons were devoid of pro-TGF alpha immunoreactivity. In the mutant lumbar spinal cord, pro-TGF alpha immunoreactive motor neurons appeared as soon as the disease developed and pro-TGF alpha expression persisted until the latest stages of degeneration. Motor neurons and astrocytes of the white matter weakly immunoreactive for the TGF alpha receptor were also present in both control and mutant lumbar spinal cords. Following hypoglossal nerve crush and cut, motoneuronal pro-TGF alpha expression was precocious and transient, visible at one day post-injury and lasting for only 3 days, during which time astrocyte-like cells immunoreactive for both TGF alpha and its receptor appeared within the injured nucleus. Enhanced TGF alpha mRNA levels following nerve crush showed that activation occurred at the transcriptional level. These results show that upregulation of TGF alpha is an early and common response of adult murine motor neurons to injury, regardless of its experimental or genetic origin.

Electrochemical methods such as voltammetry and chronoamperometry are very useful in the study of biodegradation processes. Voltammetry gives qualitative information on the behaviour of a biomaterial in an electrolytic medium. Accelerated ageing of a metallic biomaterial can be obtained using chronoamperometry. Quantitative information on elements released in a solution is also obtained.

Most metals used for orthopaedic and stomatology implants and prostheses belong to the families of titanium or nickel-based and cobalt-based superalloys designed for advanced technology industries (e.g. space, aeronautic and nuclear industries). Ideal materials should be as insoluble and biologically compatible as possible. In the present paper the corrosion behaviour of Ni-Cr and Co-Cr alloys in biological media is evaluated through potentiodynamic polarization tests. It is shown that these metals exhibit some minor release of the component elements and degradation products, which may induce cytotoxic and allergic effects. The corrosion resistance of these alloys can be strongly enhanced by hard ceramic coatings deposited by radio-frequency sputtering. The biocompatibility of coated and uncoated metals is compared from differentiated human cell cultures.