Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES‐bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.     

Thermal sensitisation by lonidamine of human melanoma cells grown at low extracellular pH

Purpose: This study tested the ability of lonidamine (LND), a clinically applicable inhibitor of monocarboxylate transporters (MCT), to thermally sensitise human melanoma cells cultured at a tumour-like extracellular pH (pH_e) 6.7.

Materials and methods: Human melanoma DB-1 cells cultured at pH_e 6.7 and pH_e 7.3 were exposed to 150?µM LND for 3?h, beginning 1?h prior to heating at 42?°C (2?h). Intracellular pH (pH_i) was determined using 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and whole spectrum analysis. Levels of heat shock proteins (HSPs) were determined by immunoblot analysis. Cell survival was determined by colony formation.

Results: Treatment with LND at pH_e 6.7 reduced pH_i to 6.30?±?0.21, reduced thermal induction of HSPs, and sensitised cells growing at pH_e 6.7 to 42?°C. When LND was combined with an acute acidification from pH_e 6.7 to pH_e 6.5, pH_i was reduced to 6.09?±?0.26, and additional sensitisation was observed. LND had negligible effects on cells cultured at pH 7.3.

Conclusions: The results show that LND can reduce pH_i in human melanoma cells cultured at a tumour-like low pH_e so that the 42?°C induction of HSPs are abrogated and the cells are sensitised to thermal therapy. Cells cultured at a normal tissue-like pH_e 7.3 were not sensitised to 42?°C by LND. These findings support the strategy that human melanoma cells growing in an acidic environment can be sensitised to thermal therapy in vivo by exposure to an MCT inhibitor such as LND.     

Preparation of Nanoparticles by Solvent Displacement Using a Novel Recirculation System

Submicron colloidal suspensions of poly(ε-caprolactone) (PCL) were prepared by the solvent displacement method, using either the conventional form or a new recirculation device. In the latter case, a process that allows the recirculation of the aqueous phase into a device, providing a continuous flow, is proposed. The influence of the organic solution injection rate and polymer concentration on mean particle size and process yield were studied for both methods. The recirculation rate was also analyzed for the recirculation system. Nanoparticles (NPs) showed mean sizes that ranged from 156 to 381. The smallest particles were obtained when recirculation rate, injection rate and polymer concentration were maximized but at the expense of the yield. The only acceptable yields (83–96%) were obtained at the lowest PCL concentration (2.5% w/v). ANOVA tests (α = 0.05) showed that the variables implicated in the recirculation system significantly affected the mean particle size and the process yield. The entrapment efficiencies of NPs prepared by the conventional method were not significantly different (α = 0.05) from those obtained by the recirculation system.     

Carboplatin delays mammary cancer 4T1 growth in mice

Carboplatin is commonly used to treat a variety of tumors. We investigated the effects of carboplatin (100 mg/kg) in the development and metastatic dissemination of the 4T1 mice mammary carcinoma. Carboplatin was able to reduce tumor volume and the number of lung metastases in 50% compared to the control animals. Mitotic and apoptotic indices were also decreased by the treatment. Assessment of the vascularization of the tumors revealed a significant decrease in blood vessel formation by carboplatin. A decrease in nuclear positivity of CDC47 and cyclin D1 was observed in the group treated with carboplatin when compared to the control group. Positivity for p53 was observed in the control group (2/28; 5%) and the treated group (5/71; 4%). Carboplatin has been demonstrated to be an efficient regulator of 4T1MMT growth and dissemination. The action of this chemotherapeutic agent seems to be related to the induction of apoptosis and inhibition of angiogenesis and cell proliferation.     

Surgical treatment of pleural empyema in Coronavirus disease 19 patients: the Southern Switzerland experience

We report the first surgical series of patients developing pleural empyema after severe bilateral interstitial lung disease in confirmed severe acute respiratory syndrome coronavirus 2 infection. The empyema results in a complex medical challenge that requires combination of medical therapies, mechanical ventilation and surgery. The chest drainage approach was not successful to relieve the symptomatology and to drain the excess fluid. After multidisciplinary discussion, a surgical approach was recommended. Even though decortication and pleurectomy are high-risk procedures, they must be considered as an option for pleural effusion in Coronavirus disease-positive patients. This is a life-treating condition, which can worsen the coronavirus disease manifestation and should be treated immediately to improve patient’s status and chance of recovery.