Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+) T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy

Computational electromagnetic modeling is key in objective control of hyperthermia

\u3cp\u3eConfining treatment to the tumor to improve therapeutic outcome and reduce toxicity, is a hot issue in cancer research. Hyperthermia is recognized as a strong sensitizer for radiotherapy and chemotherapy enhancing tumor control without increasing toxicity. Today's electromagnetic hyperthermia systems heat large tissue volumes with limited ability to selectively heat the tumor. Fortunately, tremendous improvements in 3-dimensional electromagnetic & temperature modelling provide an exciting opportunity to design advanced multi-element electromagnetic applicator systems. Together with feedback control using MR non-invasive thermometry and smart E-field sensors, this paves the way for selective tumor heating and potentially prescription of a thermal dose.\u3c/p\u3

SAR thresholds for electromagnetic exposure using functional thermal dose limits

\u3cp\u3eBACKGROUND AND PURPOSE: To protect against any potential adverse effects to human health from localised exposure to radio frequency (100 kHz-3 GHz) electromagnetic fields (RF EMF), international health organisations have defined basic restrictions on specific absorption rate (SAR) in tissues. These exposure restrictions incorporate safety factors which are generally conservative so that exposures that exceed the basic restrictions are not necessarily harmful. The magnitude of safety margin for various exposure scenarios is unknown. This shortcoming becomes more critical for medical applications where the safety guidelines are required to be relaxed. The purpose of this study was to quantify the magnitude of the safety factor included in the current basic restrictions for various exposure scenarios under localised exposure to RF EMF.\u3c/p\u3e\u3cp\u3eMATERIALS AND METHODS: For each exposure scenario, we used the lowest thermal dose (TD) required to induce acute local tissue damage reported in literature, calculated the corresponding TD-functional SAR limits (SARTDFL) and related these limits to the existing basic restrictions, thereby estimating the respective safety factor.\u3c/p\u3e\u3cp\u3eRESULTS: The margin of safety factor in the current basic restrictions on 10 g peak spatial average SAR (psSAR10g) for muscle is large and can reach up to 31.2.\u3c/p\u3e\u3cp\u3eCONCLUSIONS: Our analysis provides clear instructions for calculation of SARTDFL and consequently quantification of the incorporated safety factor in the current basic restrictions. This research can form the basis for further discussion on establishing the guidelines dedicated to a specific exposure scenario, i.e. exposure-specific SAR limits, rather than the current generic guidelines.\u3c/p\u3

Murine head & neck applicator:hyperthermia prototype development

IntroductionCancer treatments remain a heavy load for the patient due to the many side effects. Mild hyperthermia, locally heating tissue to 42⁰ C, has proven to be a powerful treatment enhancer with no severe side effects. Recently, new potential applications of mild hyperthermia in cancer therapy were discovered. Converting these cell-culture based findings into clinical protocols requires pre-clinical investigation of the various strategies by clinical trials with small animals. For this goal, a site-specific head & neck hyperthermia applicator for murine models was developed. Hereto, we studied a design with an antenna array operating at 2.45 GHz embedded in a water bolus.Methodology A simulation-based approach was used to design the separate antennas operating at 2.45 GHz, and later on the antenna array. Simulation programs SEMCAD and CST are used, both of which use a Finite Difference Time Difference (FDTD) calculation methods. The design yields an air-water boundary between the antenna feed and antenna arms. To reduce detuning due to varying water levels, the connections between those elements (feed lines) were embedded within the PCB. A capacitive patch, also used for attachment of the connector, matched the antenna to 50 Ohm. Next, the antenna return loss (S11) was experimentally validated for various circumstances. Lastly, the single antenna and array performance was assessed by simulating first the power absorption distributions, and second the temperature distribution using Penne’s bioheat equation [1]. ResultsThe Simulation results as well as measurements show that the antenna is stable for variations in water levels. Simulation results of a grid of nine antennas show that controlled and focused application of heat can be delivered at target regions under the tongue, and that 14-25W suffices.ConclusionsBased on these promising results, we will now embark on experimental validation of the heating performance of a single antenna setup: firstly in tissue-equivalent gels and secondly in vivo

An MRI-compatible hyperthermia applicator for small animals

Introduction to design novel treatment combinations involving mild hyperthermia, pre-clinical trials are essential. These studies into treatment effectiveness require close monitoring of the temperature during testing . Invasive thermometry restricts testing of the link between hyperthermia and immune responses, so MRI-compatibility is a necessity. Next to that, the applicator must heat locally, and secondary hot spots especially in vulnerable regions like the spinal cord must be prevented. Lastly, the system must be non-invasive, for disturbances in the tissues studied interfere with the accuracy of the research.With these goals in mind, we designed and built an applicator based on a novel water-embedded antenna design. In this study, we report the mode of operation for the head&neck region, but it can also be used for other tissues up to about 2 cm deep.MethodsA simulation-based approach was used to design the antenna element, and the surrounding system including the load. Simulation programs SEMCAD and CST were used, both of which use a Finite Difference Time Difference (FDTD) calculation methods. SEMCAD was also used for Penne’s Bioheat equation temperature predictions. The single antenna and array performance were assessed by simulating the power absorption distributions, i.e. the Specific Absorption Rate (SAR), and the temperature distribution. The antenna was designed to achieve at least a -15 dB match to 50 Ω at 2.45 GHz. Furthermore, it was stabilized for various water temperatures and for disturbances in the air-water bolus boundary. The metal plates were designed to be thin enough to ensure MRI compatibility. The latter property was tested by inspecting MRI images for disturbances when the antenna plus related cables were scanned.ResultsAccording to our simulations, a single antenna operating at 5W power is able to heat tongue tissue to 42º C without creating hot spots in other areas. Next to that, experiments showed that the antenna stability required was achieved and a match of -19 dB was reached in all cases. Lastly, the MRI scan showed excellent compatibility in the area of interest.ConclusionsOur novel setup provides operation within the specifications defined. Based on these promising results, we will now elucidate on the experimental validation of the heating performance of the single antenna setup and develop a phased array for deep heating

An MRI-compatible hyperthermia applicator for small animals

Introduction to design novel treatment combinations involving mild hyperthermia, pre-clinical trials are essential. These studies into treatment effectiveness require close monitoring of the temperature during testing . Invasive thermometry restricts testing of the link between hyperthermia and immune responses, so MRI-compatibility is a necessity. Next to that, the applicator must heat locally, and secondary hot spots especially in vulnerable regions like the spinal cord must be prevented. Lastly, the system must be non-invasive, for disturbances in the tissues studied interfere with the accuracy of the research.With these goals in mind, we designed and built an applicator based on a novel water-embedded antenna design. In this study, we report the mode of operation for the head&neck region, but it can also be used for other tissues up to about 2 cm deep.MethodsA simulation-based approach was used to design the antenna element, and the surrounding system including the load. Simulation programs SEMCAD and CST were used, both of which use a Finite Difference Time Difference (FDTD) calculation methods. SEMCAD was also used for Penne’s Bioheat equation temperature predictions. The single antenna and array performance were assessed by simulating the power absorption distributions, i.e. the Specific Absorption Rate (SAR), and the temperature distribution. The antenna was designed to achieve at least a -15 dB match to 50 Ω at 2.45 GHz. Furthermore, it was stabilized for various water temperatures and for disturbances in the air-water bolus boundary. The metal plates were designed to be thin enough to ensure MRI compatibility. The latter property was tested by inspecting MRI images for disturbances when the antenna plus related cables were scanned.ResultsAccording to our simulations, a single antenna operating at 5W power is able to heat tongue tissue to 42º C without creating hot spots in other areas. Next to that, experiments showed that the antenna stability required was achieved and a match of -19 dB was reached in all cases. Lastly, the MRI scan showed excellent compatibility in the area of interest.ConclusionsOur novel setup provides operation within the specifications defined. Based on these promising results, we will now elucidate on the experimental validation of the heating performance of the single antenna setup and develop a phased array for deep heating

A hyperthermia system and a method for generating a focused three-dimensional rf field

The invention relates to a hyperthermia system (30) for treating a patient, comprising an RF power unit, one or more RF antenna's connected to the RF power unit for generating a focused three-dimensional RF field, a controller (37) for adjusting the RF power source and/or the one or more RF antenna's for steering the focused three-dimensional RF field; a sensor for sensing a parameter (34) representative of the focused three-dimensional RF field; a communication environment (36) for inputting data from the said sensor and/or additional information provided by the patient, said communication environment being capable of generating trigger signals to the controller for in use steering the focused three-dimensional RF filed in real time. The invention further relates to a method for generation a focused three- dimensional RF field