Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible

Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 mu g PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTXnano-GP-MS) instead of ethanolic PTX solution (PTXEtOH-GP-MS). PTX release from PTX-GP-MS was prolonged. PTXnano-GP-MS displayed a more controlled release compared to a biphasic release from PTX-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTXEtOH-GP-MS, D = 7.5 mg PTX/kg; PTXnano-GP-MS D= 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTXnano-GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTXnano-GP-MS caused drug-related toxicity in 27% of high-dosed PTXnano-GP-MS-treated mice. Dose simulations for PTXnano-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5-15 mg PTX/kg. Low-dosed PTXnano-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells

Correlation between homogeneous propane pyrolysis and pyrocarbon deposition

International audiencePyrocarbon deposition through propane pyrolysis is studied in a 1-D hot-wall CVD furnace. The gas-phase pyrolysis is modelled with a partially reduced kinetic mechanism leading to polycyclic aromatic compounds (PAHs). The C2-C4 and C3 reaction paths are in competition for benzene formation. There is also an independent C3-C5 path leading to naphthalene. The gas-phase concentrations are correlated with experimental data including in-situ FTIR spectra intensities, pyro- carbon deposition rates, and pyrocarbon nanotextures. Rough Laminar pyrocarbon deposition appears to be more related to PAHs than Smooth Laminar pyrocarbon

Kinetic modeling of gas-phase decomposition of propane : correlation with pyrocarbon deposition

International audienceA chemical kinetic model for gas-phase pyrolysis of propane has been set up, partially reduced, and validated against FTIR measurements in a tubular hot-wall reactor at P = 2 kPa, and T = 900 to 1400 K. It confirms the notion of "maturation" from propane to lighter hydrocarbons, the to aromatic compounds and PAHs. The gas-phase composition above the substrate has been correlated to pyrocarbon deposition rates and to the deposit nanostructure. It is confirmed that the growth of the rough laminar (RL) form would be related to heavier gaseous species than for the smooth laminar (SL) form

In vivo selection of the MDA-MB-231br/eGFP cancer cell line to obtain a clinically relevant rat model for triple negative breast cancer brain metastasis

Young triple negative breast cancer (TNBC) patients are at high risk for developing very aggressive brain metastases associated with a poor prognosis and a high mortality rate. Preclinical models that allow follow-up by magnetic resonance imaging (MRI) can contribute to the development of new therapeutic approaches for brain metastasis. To date, preclinical brain tumor research has almost exclusively relied on xenograft mouse models. Yet, rats are an ideal model for imaging of brain metastasis as their larger brain offers better relative spatial resolution compared to a mouse brain. For the development of a clinically relevant rat model for TNBC brain metastasis, the MDA-MB-231br/eGFP cancer cell line can be used. However, as a result of species-dependent extracranial features, the propensity of the MDA-MB-231br/eGFP cancer cell line to metastasize exclusively to the brain needs to be enhanced by in vivo selection. In this study, repeated sequential passages of metastatic cancer cells obtained from brain metastases in nude rats were performed. Brain metastasis formation was evaluated using preclinical MRI, while bone metastasis formation was assessed using high-resolution computed tomography (CT) and 2-deoxy-2-[F-18] fluoro-D-glucose ([F-18] FDG) positron emission tomography (PET) imaging. Our results demonstrated that the metastatic tumor burden in the rat brain (number and volume) significantly increased with increasing passage, while the metastatic tumor burden in the skeleton (i.e., number of metastasis-affected bones) significantly decreased with increasing passage. However, bone metastasis development was not reduced to a negligible amount. Consequently, despite in vivo selection, our rat model is not recommended for investigating brain metastasis as a single disease. Our findings highlight the importance of well-reasoned selection of both the preclinical model and the cancer cell line in order to obtain reliable and reproducible scientific results

Combining short-range dispersion simulations with fine-scale meteorological ensembles: probabilistic indicators and evaluation during a 85Kr field campaign

Numerical atmospheric dispersion models (ADMs) are used for predicting the health and environmental consequences of nuclear accidents in order to anticipate countermeasures necessary to protect the populations. However, these simulations suffer from significant uncertainties, arising in particular from input data: weather conditions and source term. Meteorological ensembles are already used operationally to characterize uncertainties in weather predictions. Combined with dispersion models, these ensembles produce different scenarios of radionuclide dispersion, called “members”, representative of the variety of possible forecasts. In this study, the fine-scale operational weather ensemble AROME-EPS (Applications of Research to Operations at Mesoscale-Ensemble Prediction System) from Météo-France is coupled with the Gaussian puff model pX developed by the IRSN (French Institute for Radiation Protection and Nuclear Safety). The source term data are provided at 10 min resolution by the Orano La Hague reprocessing plant (RP) that regularly discharges 85Kr during the spent nuclear fuel reprocessing process. In addition, a continuous measurement campaign of 85Kr air concentration was recently conducted by the Laboratory of Radioecology in Cherbourg (LRC) of the IRSN, within 20 km of the RP in the North-Cotentin peninsula, and is used for model evaluation. This paper presents a probabilistic approach to study the meteorological uncertainties in dispersion simulations at local and medium distances (2–20 km). First, the quality of AROME-EPS forecasts is confirmed by comparison with observations from both Météo-France and the IRSN. Then, the probabilistic performance of the atmospheric dispersion simulations was evaluated by comparison to the 85Kr measurements carried out during a period of 2 months, using two probabilistic scores: relative operating characteristic (ROC) curves and Peirce skill score (PSS). The sensitivity of dispersion results to the method used for the calculation of atmospheric stability and associated Gaussian dispersion standard deviations is also discussed. A desirable feature for a model used in emergency response is the ability to correctly predict exceedance of a given value (for instance, a dose guide level). When using an ensemble of simulations, the “decision threshold” is the number of members predicting an event above which this event should be considered probable. In the case of the 16-member dispersion ensemble used here, the optimal decision threshold was found to be 3 members, above which the ensemble better predicts the observed peaks than the deterministic simulation. These results highlight the added value of ensemble forecasts compared to a single deterministic one and their potential interest in the decision process during crisis situations.</p