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OBJECTIVES Volatile anaesthetics can provide significant protection against reperfusion injury in various experimental settings. The aim of this study was to assess the potential of sevoflurane treatment, the most commonly used volatile anaesthetic in modern anaesthesia, in rat lungs donated after circulatory death and reconditioned in an ex vivo lung perfusion (EVLP) system. METHODS Fifteen rats were sacrificed and divided into 3 groups. In the control and sevoflurane groups, the heart-lung blocks were exposed to 1 h of warm ischaemia and 2 h of cold ischaemia and were mounted on an EVLP circuit for 3 h, in the absence or in the presence of 2% sevoflurane. In the baseline group, heart-lung blocks were harvested immediately after euthanasia. Physiological data, lung nitro-oxidative stress, lactate dehydrogenase (LDH), expression of cytokines, oedema and histopathological findings were assessed during or post-EVLP. RESULTS The sevoflurane group showed significantly reduced LDH (8.82 ± 3.58 arbitrary unit vs 3.80 ± 3.02 arbitrary unit, P = 0.03), protein carbonyl (1.17 ± 0.44 nmol⋅mg−1 vs 0.55 ± 0.11 nmol⋅mg−1, P = 0.006), 3-nitrotyrosine (197.44 ± 18.47 pg⋅mg−1 vs 151.05 ± 23.54 pg⋅mg−1, P = 0.004), cytokine-induced neutrophil chemoattractant factor 1 (1.17 ± 0.32 ng⋅mg−1 vs 0.66 ± 0.28 ng⋅mg−1, P = 0.03) and tumour necrosis factor alpha (1.50 ± 0.59 vs 0.59 ± 0.38 ng⋅mg−1, P = 0.02) when compared with the control group. In addition, sevoflurane lungs gained significantly less weight (0.72 ± 0.09 g vs 0.72 ± 0.09 g, P = 0.044), had less perivascular oedema (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036), and improved static pulmonary compliance (+0.215 ml⋅cmH2O−1, P = 0.003) and peak airways pressure (-1.33 cmH2O, P = 0.04) but similar oxygenation capacity (+1.61 mmHg, P = 0.77) and pulmonary vascular resistances (+0.078 mmHg⋅min⋅ml−1, P = 0.15) when compared with the control group. CONCLUSIONS These findings suggest that the potential of sevoflurane in protecting t

OBJECTIVES Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors. METHODS First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model. RESULTS L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals. CONCLUSIONS L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression., info:eu-repo/semantics/published

Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.

BACKGROUND Neoadjuvant chemotherapy (CT) followed by radiotherapy (RT) and surgery showed a median survival of 28.7 months in resectable stage IIIB non-small-cell lung cancer (NSCLC) patients (pts). Here, we evaluate the impact of concomitant cetuximab to the same neoadjuvant chemo-radiotherapy (CRT) in selected patients (pts) with NSCLC, stage IIIB. METHODS Resectable stage IIIB NSCLC received three cycles of CT (cisplatin 100 mg/m and docetaxel 85 mg/m d1, q3w) followed by RT (44 Gy in 22 fractions) with concomitant cetuximab (250 mg/m, q1w) and subsequent surgery. The primary endpoint was 1-year progression-free survival (PFS). RESULTS Sixty-nine pts were included in the trial. Fifty-seven (83%) pts underwent surgery, with complete resection (R0) in 42 (74%) and postoperative 30 day mortality of 3.5%. Responses were: 57% after CT-cetuximab and 64% after CRT-cetuximab. One-year PFS was 50%. Median PFS was 12.0 months (95% CI: 9.0-15.6), median OS was 21.3 months, with a 2- and 3-yr survival of 41% and 30%, respectively. CONCLUSIONS This is one of the largest prospective phase 2 trial to investigate the role of induction CRT and surgery in resectable stage IIIB disease, and the first adding cetuximab to the neoadjuvant strategy. This trial treatment is feasible with promising response and OS rates, supporting an aggressive approach in selected pts.

Udgivelsesdato: 2009-Feb, Here we integrated multiphoton laser scanning microscopy and the registration of second harmonic generation images of collagen fibers to overcome difficulties in tracking stromal cell-matrix interactions for several days in live mice. We show that the matrix-modifying hormone relaxin increased tumor-associated fibroblast (TAF) interaction with collagen fibers by stimulating beta1-integrin activity, which is necessary for fiber remodeling by matrix metalloproteinases.

Udgivelsesdato: 2009-Feb, Here we integrated multiphoton laser scanning microscopy and the registration of second harmonic generation images of collagen fibers to overcome difficulties in tracking stromal cell-matrix interactions for several days in live mice. We show that the matrix-modifying hormone relaxin increased tumor-associated fibroblast (TAF) interaction with collagen fibers by stimulating beta1-integrin activity, which is necessary for fiber remodeling by matrix metalloproteinases.

OBJECTIVES The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions. METHODS Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne® 400μg/kg, fluence rate 200mW/cm2and fluence 60J/cm2) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody. RESULTS PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran. CONCLUSIONS Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesothelioma

OBJECTIVES Volatile anaesthetics can provide significant protection against reperfusion injury in various experimental settings. The aim of this study was to assess the potential of sevoflurane treatment, the most commonly used volatile anaesthetic in modern anaesthesia, in rat lungs donated after circulatory death and reconditioned in an ex vivo lung perfusion (EVLP) system. METHODS Fifteen rats were sacrificed and divided into 3 groups. In the control and sevoflurane groups, the heart-lung blocks were exposed to 1 h of warm ischaemia and 2 h of cold ischaemia and were mounted on an EVLP circuit for 3 h, in the absence or in the presence of 2% sevoflurane. In the baseline group, heart-lung blocks were harvested immediately after euthanasia. Physiological data, lung nitro-oxidative stress, lactate dehydrogenase (LDH), expression of cytokines, oedema and histopathological findings were assessed during or post-EVLP. RESULTS The sevoflurane group showed significantly reduced LDH (8.82 ± 3.58 arbitrary unit vs 3.80 ± 3.02 arbitrary unit, P = 0.03), protein carbonyl (1.17 ± 0.44 nmol⋅mg−1 vs 0.55 ± 0.11 nmol⋅mg−1, P = 0.006), 3-nitrotyrosine (197.44 ± 18.47 pg⋅mg−1 vs 151.05 ± 23.54 pg⋅mg−1, P = 0.004), cytokine-induced neutrophil chemoattractant factor 1 (1.17 ± 0.32 ng⋅mg−1 vs 0.66 ± 0.28 ng⋅mg−1, P = 0.03) and tumour necrosis factor alpha (1.50 ± 0.59 vs 0.59 ± 0.38 ng⋅mg−1, P = 0.02) when compared with the control group. In addition, sevoflurane lungs gained significantly less weight (0.72 ± 0.09 g vs 0.72 ± 0.09 g, P = 0.044), had less perivascular oedema (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036), and improved static pulmonary compliance (+0.215 ml⋅cmH2O−1, P = 0.003) and peak airways pressure (-1.33 cmH2O, P = 0.04) but similar oxygenation capacity (+1.61 mmHg, P = 0.77) and pulmonary vascular resistances (+0.078 mmHg⋅min⋅ml−1, P = 0.15) when compared with the control group. CONCLUSIONS These findings suggest that the potential of sevoflurane in protecting t