Metformin: a modulator of bevacizumab activity in cancer? A case report.

Recurrent type I endometrial cancer ((EC)) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced (EC) treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed (EC) G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong F-18-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findingsalbeit limited to a single casesuggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation

Etude d'un réseau à très faible teneur en matière organique biodégradable : le réseau de la ville de Nice

La Ville de Nice bénéficie de deux ressources en eau d'excellente qualité, la Vésubie et la nappe alluviale du Var, qui se caractérisent par leur très faible teneur en matière organique biodégradable. La Compagnie Générale des Eaux, gestionnaire de son alimentation en eau potable, applique depuis sa mise au point au début du siècle le procédé de désinfection par l'ozone et distribue une eau sans ajouter de chlore.Un diagnostic complet de la qualité microbiologique et sanitaire de ce réseau non chloré et sans Carbone Organique Dissous Biodégradable (CODB) a été entrepris.Le suivi de la qualité de l'eau dans le réseau a consisté en des campagnes de prélèvements à partir de plusieurs points d'observation répartis sur l'ensemble du réseau. Ce suivi a permis de confirmer la bonne qualité de l'eau distribuée et le maintien de cette qualité tout au long de son transport dans les canalisations. Le CODB est absent sur l'ensemble des points confirmant l'absence de relargage et de contamination pendant le transport.La récupération des dépôts présents dans les canalisations n'a pas révélé de colonisation du réseau par des micro-organismes supérieurs. La quantité de biofilm présente sur les parois des canalisations a été évaluée en suivant la colonisation de pastilles de matériau immergées dans les réservoirs.Ce diagnostic complet de l'état microbiologique et sanitaire du réseau de Nice montre que l'absence de chloration n'entraîne pas de dégradation de la qualité bactériologique de l'eau et que c'est essentiellement l'absence de matière organique biodégradable qui limite la croissance bactérienne et qui contribue au maintien de la qualité de l'eau dans le réseau de distribution.Within the more general scope of studies aiming at a better knowledge of the mechanisms responsible for biological biodegradation in water systems, it was interesting to learn the microbiological behaviour of a drinking water network supplied with water free of biodegradable organics. The case in point is the town of Nice which enjoys excellent quality water ressources, to the extent that the Compagnie Générale des Eaux, managers of the municipal water utility, were able to apply ozonation as a disinfectant when the technique first appeared at the beginning of the century, and supply chlorine free water.The Municipal Services of the Town of Nice, the Nice Health Laboratory and the Compagnie Générale des Eaux bave therefore combined forces to carry out a study on the development of water quality in the supply network in such an animal environment. The objective is to make a complete diagnosis of the microbiological and hygienic quality of a chlorine-free network which would confirm the excellent quality of the distributed water and serve as a reference within the scope of general research on the removal of biodegradable organics for the supply of non chlorinated water.The study consisted of monitoring three supply systems fed by three different water works :- the Super Rimiez plant treating water from the river Vésubie in the following stages : flocculation, primary clarification, sand filtration and virucidal ozonation;-the Jean Moreno plant : water pumped from the alluvion layers of the Var and ozonated;-the Prairies plant : pumping and temporary chlorination of the Var aquifer with chlorine dioxyde.In order to take seasonal variations info account, our study lasted for a whole year, with sampling campaigns every two weeks on 20 observation points along the network, and on the raw water treated in three production plants. The physico-chemical and microbiological characteristics of the water samples were analyzed.Samples were collected at a high flow rate from fire hydrants near the observation points. The sediments were gathered in a plankton net and analyzed to detect the presence of possible animalcules.The immersion of PVC coupons in two reservoirs, fed respectively with the two types of water, enabled the growth kinetics of fixed bacteria to be followed, and the quantifies of fixed biomass at steady state to be compared.It was possible, by monitoring the chloride content (on average 25 mg Cl¯/l in Var water compared with 5 mg Cl¯/l in Vésubie water), to identify the precise influence of the two water resources.Total bacteria measured by epilluorescence are not very high compared with networks in other large towns. It will be noted, however, that the figure is higher in the network supplied from the Vésubie than in those treating water from the Var aquifer. Bacterial regrowth in circulating water is minor, showing that the influence of bacteria released by the biofilm installed on the pipe walls is minimized. This biofilm is present just the same, as is shown by the results of colonization an the immersed coupons in reservoirs.The quantity of fixed bacteria at steady state is different according to the type of water but, in both cases, it was lower than the figure obtained with water loaded with biodegradable organics. The total plate count remains low on the whole, even at end sections of the network. The presence at fecal bacteria was only observed at a few points during some of the studies and the Nice network, on the whole, is of excellent quality judged by the very few fecal contamination indicators found.The presence of Aeromonas hydrophila was detected in very small quantities and at a few of the sampling points only.Analyses of Dissolved Organic Carbon (on average 0.3 mgC/l) and Biodegradable Dissolved Organic Carbon (less than 0.1 mgC/l, by the minimum detection threshold method) reveal a very low concentration in organics and a total absence of BDOC on all sampling points, thus confirming the good quality of the water supplied and the tact that these is very little bacteria) remise and contamination while the water is in transit.Examination of the sediments in water mains and at the bottom of reservoirs did not reveal the existence of higher forma of microorganisms.This complete diagnosis of the mirobiological and health condition of the Nice water system has brought confirmation of the good quality of the water supplied throughout its transit in the water mains. The lack of chlorination dues not cause a deterioration of the bacteriological quality of the water, the sustainable quality of which is essentially linked with the absence of BDOC which restricting the growth of bacteria.The importance of these findings on such a distinctive network as that of the Nice utility will enable this study to be used as reference for future research on the means of maintaining the quality of water in supply networks without using chlorine

SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc−/− MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc−/− MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc−/− than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc−/− MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc−/− MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway

Paramètres gouvernant la prolifération bactérienne dans les réseaux de distribution

L'étude a permis de suivre l'évolution des caractéristiques physico-chimiques et microbiologiques des eaux dans un réseau de distribution expérimental de taille industrielle, afin de comparer d'une part l'effet du chlore et de la monochloramine sur la biomasse présente dans le système à l'équilibre et d'autre part d'établir des relations quantitatives entre prolifération bactérienne, oxydant et matière organique biodégradable.Dès les premières heures de transit dans le réseau, une consommation des oxydants est constatée, avec toutefois une plus grande stabilité de la monochloramine (vitesse de consommation de 0,05 mgCl2 l-1h-1 et 0,02 mgCl2 l-1h-1 respectivement pour le chlore et la monochloramine).Même en présence d'un désinfectant résiduel, il est possible de noter une accumulation de bactéries-à ta surface des tuyaux de distribution (105 à 106 cellules. cm-2, dont environ 1 % est cultivable sur gélose) qui augmente avec la diminution de concentration du désinfectant résiduel. Les relations logarithmiques entre densité cellulaire (phase eau ou biofilm) et oxydant résiduel montrent d'une part que pour inactiver totalement les bactéries en suspension dans l'eau il convient de maintenir une chloration en continu avec un résiduel constant supérieur ou égal à 0,5 mgCl2 l-1 et, d'autre part que les chloramines sont au moins 2,5 fois moins efficaces que le chlore, même vis-à-vis des bactéries fixées.La présence de matière organique biodégradable dans les eaux explique la prolifération des bactéries dans le système de distribution. Ainsi une concentration additionnelle de 100 µg.l-1 de carbone organique dissous biodégradable (CODB) dans l'eau entrant dans le réseau de distribution occasionne en 24 heures et à 20°C une augmentation du nombre de bactéries fixées (+7,5.105 cellules.cm-2) ou en suspension (+ 4.104 cellules.ml-1) dans le réseau de distribution, à l'équilibre, déjà largement colonisé par des micro-organismes.Ainsi le contrôle de la fraction biodégradable de la matière organique apparaît toujours comme un objectif primordial.This study was carried out in order to evaluate the variations in the physicochemical characteristics of the water in an experimental distribution system.The primary objectives of the study were :- to compare the disinfectant efficiency of chlorine and monochloramine- to establish quantitative correlations among bacterial density, concentration of residual disinfectant, and concentration of biodegradable organic matter.The finished waters were obtained from a water treatment pilot plant characterized by : prechlorination (average treatment rate : 1.4 mgCl2 l-1 and residual alter sand filtration : 0.08 mgCl2 l-1), coagulation-flocculation-sedimentation (FeCl3 treatment rate : 30 to 60 mg l-1 adjusted to the raw water turbidity below 0.3 NTU), sand filtration (filtration rate : 6 h-1) and post-disinfection with chloramine (average treatment rate : 1.8 mgCl2 l-1) or chloramine (average treatment rate : 1.66 mgCl2 l-1). The concentrations of post-disinfectant used were chosen in order to maintain chlorine at 0.2 to 0.5 mgCl2 l-1 and monochloramine at 1 mgC2 l-1 after the first 24 hours residence time in the experimental distribution system.The experimental distribution system is composed of three parallel loops connected in series (31 m length, 100 mm diameter, cement lined cast iron, water velocity : 1m s-1). The configuration and operation of the system permitted a residence time of 24 hours in each loop (that is 72 hours for the whole system). Appropriate sample tap locations facilitated removal of bulk water samples. Special sampling parts also permitted sampling of cement coupons for determination of attached biofilm.The measured parameters were : residual oxidant (DPD method), DOC, BDOC (28 days of incubation at 28 °C with a bacterial inoculum), cell density in the bulk water phase (CFU ml-1) and in the biofilm (CFU cm-2) after 15 days of incubation at 20-22 °C. Total cells were enumerated using the epifluorescence direct count technique.For each experiment, all the sampling sequences were carried out on each of three days, after quasi steady-state was achieved in the system (4 to 6 weeks after starting each experiment). The data were analysed in order to characterize the treated and distributed waters; the results discussed here are based on the averages of the measured parameters tram the water samples and biofilm samples taken after the system achieved quasi steady-state.Characteristics of the treated watersThe treated waters were characterized by important variations at the DOC, BDOC and cell density. For example, the concentrations of DOC showed a seasonal variation ranging from 0.8 to 1.3 mg Cl-1 in winter to 1.6 to 2.6 mg Cl-1 in summer.The treated waters contained approximately the same concentrations of residual disinfectant, averaging 1.6 mgCl2 l-1 for chlorine and 1.5 mgCl2 l-1 for monochloramine.However, a significant difference cell density was found between the two post-disinfectants. Cell densities by the epifluorescence direct count technic were 1.6 x 103 ml-1 (0.3 % of CFU ml-1) with chlorine and 6.3 x 104 ml-1 (0.03 % of CFU ml-1) with monochloramine. The difference on cell density between the post-chlorination and the post-chloramination treatments has been observed systematically, and may be explained either as cellular lysis with chlorine or an interference when using epifluorescence counting for chlorinated waters.Characteristics of the distributed watersWhatever the season, depletion of oxidant (chlorine or monochloramine), and elimination of dissolved organic matter (DOC, BDOC) occured during the first hours of circulation of water in the distribution system. The net result was an increase in bacterial cell density.During the first hours of circulation of the waters in the distribution system, depletion of the disinfectant occured. Depletion was more rapid for chlorine (-0.05 mgCl2 l-1 h-1) titan for monochloramine (-0.02 mgCl2 l-1 h-1), winch is considered more stable titan chlorine.Even in the presence of a residual disinfectant in the distribution system, microorganisms are present in the water phase (104 to 106 cells ml-1 by epifluorescence direct count; 1 % CFU ml-1 after 15 days of incubation at 20-22 °C) and in the biofilm (105 to 106 cells cm-2 by epifluorescence direct count; 1 % CFU ml-1 after 15 days of incubation at 20-22 °C). The bacterial density increased white the disinfectant residual decreased. The apparent growth rate of the attached biomass (µfix) in loop 2 of the chlorinated distribution system (equivalent to 48 hours detention), was close to the µfix calculated for loop 2 of the chloraminated distribution system : the values were 0.0043 h-1 and 0.005 h-1 respectively.In addition, the change in the organic matter (expressed as DOC) occured in two steps :- a slight increase in DOC during the 24 first hours of residence time (loop 1), when increased residual disinfectant were present.- a bacterial consumption of DOC after 24 hours of residence time (loops 2 and 3), even in the presence of small concentrations of disinfectants.In loop 2 (48 hours residence time of the water in the system; chlorine : 0.01 mgCl2 l-1, chloramine : 0.3 mgCl2 l-1 h-1), the rates of DOC elimination averaged 13 mgCl2 l-1 h-1 and 0.42, mgCl2 l-1 h-1, respectively in the chlorinated and chloraminated distribution systems. This decrease in DOC concentrations was related to the increase in bacterial density.Relationships between cell density, oxidant and organic matterLinear relationships between the concentration of residual oxidant (chlorine or monochloramine) and the cell density in the water phase or in the biofilm show that :- whichever oxidant was used, the pipe loop sections without residual disinfectants were characterized by about 5 x 106 attached cells per cm2 (4 to 10% were able to grow on agar medium in 15 days at 20-22 °C) and by 4 x 105 planktonic cells per ml (1 % CFU ml-1);- consistently, in the sections of the system with a residual disinfectant, the bacteria (CFU and epilluorescence counting) in the water phase were more sensitive to the residual disinfectant (chlorine or monochloramine) than the bacteria attached to the pipe walls (biofilm).However, there was a difference in effectiveness between the two disinfectants; chlorine was more efficient in controlling planktonic bacteria and biofilm bacteria than was monochloramine.For example, to achieve complete inactivation of the planktonic bacteria (CFU ml-1) a constant chlorine residual of 0.5 mgCl2 l-1 was required throughout the whole distribution system, compared to 2.5 times more chloramine to achieve the same efficiency.Finally, with equivalent concentrations of residual disinfectant, the microbiological quality of the chlorinated distribution waters was better than that of the chloraminated distribution waters.From loop to loop, linear relationships between ∆DOC and cell density pointed out that the presence of biodegradable organic matter can explain the bacterial proliferation in the distribution system. For example, a concentration of BDOC as low as 0.1 mgC l-1 resulted in an increase in the cell density : an additional accumulation of 7.5 x 105 attached cells cm-2 and 4 x 104 planktonic cells ml-1 was observed in the experimental distribution system at quasi steady-state.Consequently, the control of the biodegradable organic carbon remains one of the prime objectives in order to achieve biologically stable distribution waters

Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer

OBJECTIVES: Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients aged 6565. As NSCLC is often diagnosed in patients aged 6570, real-world data about efficacy and safety of immunotherapy (IO) in elderly patients are essential. MATERIALS AND METHODS: We retrospectively collected data about all patients with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. The patients were stratified for age as follows: <70 year-old, 70-79 year-old, 6580 year-old. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model. RESULTS: We reviewed 290 cases, with a median age of 67 (range: 29-89). Patients aged<70, 70-79 and 6580 year-old were 180, 94 and 16, respectively. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (p 0.9470). Median Progression Free Survival (PFS) and Overall Survival (OS) did not differ according to age (p 0.2020 and 0.9144, respectively). Toxicity was comparable across subgroups (p 0.6493). The only variables influencing outcome were performance status (PS) (p\u2009<\u20090.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p\u2009<\u20090.0001 for both PFS and OS). CONCLUSION: Advanced age was not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerged even among the eldest pts. To our opinion, ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy

Clinical and molecular determinants of extrahepatic disease progression (ePD) in initially unresectable, liver-limited metastatic colorectal cancer (mCRC)

e15511Background: In the last years, availability of active upfront systemic regimens, development of surgical techniques and diffusion of locoregional treatments (LrTx) increased the therapeutic o..