Tailored cancer therapy by magnetic nanoparticle hyperthermia: A virtual scenario simulation method.

BACKGROUND AND OBJECTIVE: Hyperthermia is a cancer treatment aiming to induce cell death by directly warming cancerous tissues above 40 °C. This technique can be applied both individually and together with other cancer therapies. The main challenge for researchers and medics is to heat only tumoral cells avoiding global or localized heating of sane tissues. The objective in this study is to provide a realistic virtual scenario to develop an optimized multi-site injection plan for tailored magnetic nanoparticle-mediated hyperthermia applications. METHODS: A three-dimensional model of a cat's back was tested in three different simulation scenarios, showing the impact of magnetic nanoparticles in each specific environment configuration. RESULTS: As a result of this study. This simulation method can, minimising the affection to healthy tissue. CONCLUSIONS: This virtual method will help real and personalized therapy planning and tailor the dose and distribution of magnetic nanoparticles for an enhanced hyperthermia cancer treatment.

Rapid SAR optimization for hyperthermic oncology: combining multi-goal optimization and time-multiplexed steering for hotspot suppression.

PURPOSE: Healthy tissue hotspots are a main limiting factor in administering deep hyperthermia cancer therapy. We propose an optimization scheme that uses time-multiplexed steering (TMPS) among minimally correlated (nearly) Pareto-optimal solutions to suppress hotspots without reducing tumor heating. Furthermore, tumor heating homogeneity is maximized, thus reducing toxicity and avoiding underexposed tumor regions, which in turn may reduce recurrence. MATERIALS AND METHODS: The novel optimization scheme combines random generation of steering parameters with local optimization to efficiently identify the set of (Pareto-) optimal solutions of conflicting optimization goals. To achieve simultaneous suppression of hotspots, multiple steering parameter configurations with minimally correlated hotspots are selected near the Pareto front and combined in TMPS. The performance of the novel scheme was compared with that of a multi-goal Genetic Algorithm for a range of simulated treatment configurations involving a modular applicator heating a generic tumor situated in the bladder, cervix, or pelvic bone. SAR cumulative histograms in tumor and healthy tissue, as well as hotspot volumes are used as metrics. RESULTS: Compared to the non-TMPS optimization, the proposed scheme was able to reduce the peak temperature in healthy tissue by 0.2 °C-1.0 °C (a thermal dose reduction by at least 26%) and, importantly, the hotspot volume above 42 °C in healthy tissue by 41%-86%. At the same time, tumor heating homogeneity was maintained or improved. CONCLUSIONS: The extremely rapid optimization (5 s for TMPS part, on a standard PC) permits closed-loop treatment reoptimization during treatment administration, and empowers physicians with a selection of optimal treatment scenarios reflecting different weighting of conflicting treatment goals.

Tumour-specific amplitude-modulated radiofrequency electromagnetic fields induce differentiation of hepatocellular carcinoma via targeting Cav3.2 T-type voltage-gated calcium channels and Ca2+ influx.

BACKGROUND: Administration of amplitude modulated 27·12 MHz radiofrequency electromagnetic fields (AM RF EMF) by means of a spoon-shaped applicator placed on the patient's tongue is a newly approved treatment for advanced hepatocellular carcinoma (HCC). The mechanism of action of tumour-specific AM RF EMF is largely unknown. METHODS: Whole body and organ-specific human dosimetry analyses were performed. Mice carrying human HCC xenografts were exposed to AM RF EMF using a small animal AM RF EMF exposure system replicating human dosimetry and exposure time. We performed histological analysis of tumours following exposure to AM RF EMF. Using an agnostic genomic approach, we characterized the mechanism of action of AM RF EMF. FINDINGS: Intrabuccal administration results in systemic delivery of athermal AM RF EMF from head to toe at levels lower than those generated by cell phones held close to the body. Tumour shrinkage results from differentiation of HCC cells into quiescent cells with spindle morphology. AM RF EMF targeted antiproliferative effects and cancer stem cell inhibiting effects are mediated by Ca2+ influx through Cav3·2 T-type voltage-gated calcium channels (CACNA1H) resulting in increased intracellular calcium concentration within HCC cells only. INTERPRETATION: Intrabuccally-administered AM RF EMF is a systemic therapy that selectively block the growth of HCC cells. AM RF EMF pronounced inhibitory effects on cancer stem cells may explain the exceptionally long responses observed in several patients with advanced HCC. FUND: Research reported in this publication was supported by the National Cancer Institute's Cancer Centre Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Centre (BP) and by funds from the Charles L. Spurr Professorship Fund (BP). DWG is supported by R01 AA016852 and P50 AA026117.

Novel ETV6-RUNX1 Mouse Model to Study the Role of ELF-MF in Childhood B-Acute Lymphoblastic Leukemia: a Pilot Study.

Exposure to extremely low-frequency magnetic fields (ELF-MFs) has been classified by the International Agency for Research on Cancer (IARC) as "possibly carcinogenic to humans," based on limited scientific evidence concerning childhood leukemia. This assessment emphasized the lack of appropriate animal models recapitulating the natural history of this disease. Childhood B-cell acute lymphoblastic leukemia (B-ALL) is the result of complex interactions between genetic susceptibility and exposure to exogenous agents. The most common chromosomal alteration is the ETV6-RUNX1 fusion gene, which confers a low risk of developing the malignancy by originating a preleukemic clone requiring secondary hits for full-blown disease to appear. To develop potential prophylactic interventions, we need to identify the environmental triggers of the second hit. Recently, we generated a B-ALL mouse model of the human ETV6-RUNX1+ preleukemic state. Here, we present the results from the ARIMMORA pilot study, obtained by exposing 34 Sca1-ETV6-RUNX1 mice (vs. 27 unexposed) to a 50 Hz magnetic field of 1.5 mT with both fundamental and harmonic content, with an on/off cycle of 10 min/5 min, for 20 h/day, from conception until 3 months of age. Mice were monitored until 2 years of age and peripheral blood was periodically analyzed by flow cytometry. One of the exposed mice developed B-ALL while none of the non-exposed did. Although the results are statistically non-significant due to the limited number of mice used in this pilot experiment, overall, the results show that the newly developed Sca1-ETV6-RUNX1 mouse can be successfully used for ELF-MF exposure studies about the etiology of childhood B-ALL. Bioelectromagnetics. 2019;40:343-353. © 2019 Bioelectromagnetics Society.

Effect of cell phone radiofrequency radiation on body temperature in rodents: Pilot studies of the National Toxicology Program's reverberation chamber exposure system.

Radiofrequency radiation (RFR) causes heating, which can lead to detrimental biological effects. To characterize the effects of RFR exposure on body temperature in relation to animal size and pregnancy, a series of short-term toxicity studies was conducted in a unique RFR exposure system. Young and old B6C3F1 mice and young, old, and pregnant Harlan Sprague-Dawley rats were exposed to Global System for Mobile Communication (GSM) or Code Division Multiple Access (CDMA) RFR (rats = 900 MHz, mice = 1,900 MHz) at specific absorption rates (SARs) up to 12 W/kg for approximately 9 h a day for 5 days. In general, fewer and less severe increases in body temperature were observed in young than in older rats. SAR-dependent increases in subcutaneous body temperatures were observed at exposures ≥6 W/kg in both modulations. Exposures of ≥10 W/kg GSM or CDMA RFR induced excessive increases in body temperature, leading to mortality. There was also a significant increase in the number of resorptions in pregnant rats at 12 W/kg GSM RFR. In mice, only sporadic increases in body temperature were observed regardless of sex or age when exposed to GSM or CDMA RFR up to 12 W/kg. These results identified SARs at which measurable RFR-mediated thermal effects occur, and were used in the selection of exposures for subsequent toxicology and carcinogenicity studies. Bioelectromagnetics. 39:190-199, 2018. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.

Comparative dosimetry for children and rodents exposed to extremely low-frequency magnetic fields.

We describe a method to correlate E-fields induced by exposure to extremely low frequency magnetic fields in laboratory mice and rats during in vivo experiments to those induced in children. Four different approaches of mapping relative dose rates between humans and rodents are herein proposed and analyzed. Based on these mapping methods and volume averaging guidelines published by the International Commission on Non-Ionizing Radiation Protection (ICNRP) in 2010, maximum and median induced field values for whole body and for tissues of children and rodents were evaluated and compared. Median induced electric fields in children younger than 10 years old are in the range 5.9-8.5 V/m per T (±0.4 dB). Maximum induced electric fields, generally in the skin, are between 48 V/m and 228 V/m per T (±4 dB). To achieve induced electric fields of comparable magnitude in rodents, external magnetic field must be increased by a factor of 4.0 (±2.6 dB) for rats and 7.4 (±1.8 dB) for mice. Meanwhile, to achieve comparable magnetic field dose in rodents, ratio is close to one. These induced field dose rates for children and rodents can be used to quantifiably compare experimental data from in vivo studies with data on exposure of children from epidemiological studies, such as for leukemia. Bioelectromagnetics. 37:310-322, 2016. © 2016 Wiley Periodicals, Inc.

An HF exposure system for mice with improved efficiency.

An exposure system that addresses difficulties that arise for exposure of small animals at low frequencies with a high exposure level is presented. The system, intended to operate at 27 MHz, consists of two identical transverse electro-magnetic (TEM) cells for exposure and sham exposure of groups of 16 free-running mice housed in pairs within standard cages, capable of exposure over extended daily periods while being provided food and water. Inclusion of the exposure cell in a half-wavelength resonator has been developed as a new paradigm to enhance field strength for an increase of >50-fold in available specific absorption rate (SAR) levels compared to traditional TEM cell configurations. The system described allows both daily and weekly exposure schedules and supports blinded protocols with continuous wave (CW) and amplitude modulation (AM) signals with programmable modulation depths and frequencies. Electric field (E-field) homogeneity across the TEM cell along a vertical plane (orthogonal to the axis of the TEM line) was within 3.3%, and 3.1% along the horizontal plane. Accurate and comprehensive dosimetric assessments based on whole-body and organ-specific SAR essential for in vivo bioelectromagnetic experiments are presented, which takes into account various factors (e.g., mouse activities, close proximity, and field homogeneity). Average SAR levels are controllable in the range of 1 mW/kg to 2 W/kg, with expanded uncertainty (k = 2) of 1 dB and instantaneous variation (k = 1) of 4 dB.

Extremely low-frequency magnetic fields and risk of childhood leukemia: A risk assessment by the ARIMMORA consortium.

Exposure to extremely low-frequency magnetic fields (ELF-MF) was evaluated in an International Agency for Research on Cancer (IARC) Monographs as "possibly carcinogenic to humans" in 2001, based on increased childhood leukemia risk observed in epidemiological studies. We conducted a hazard assessment using available scientific evidence published before March 2015, with inclusion of new research findings from the Advanced Research on Interaction Mechanisms of electroMagnetic exposures with Organisms for Risk Assessment (ARIMMORA) project. The IARC Monograph evaluation scheme was applied to hazard identification. In ARIMMORA for the first time, a transgenic mouse model was used to mimic the most common childhood leukemia: new pathogenic mechanisms were indicated, but more data are needed to draw definitive conclusions. Although experiments in different animal strains showed exposure-related decreases of CD8+ T-cells, a role in carcinogenesis must be further established. No direct damage of DNA by exposure was observed. Overall in the literature, there is limited evidence of carcinogenicity in humans and inadequate evidence of carcinogenicity in experimental animals, with only weak supporting evidence from mechanistic studies. New exposure data from ARIMMORA confirmed that if the association is nevertheless causal, up to 2% of childhood leukemias in Europe, as previously estimated, may be attributable to ELF-MF. In summary, ARIMMORA concludes that the relationship between ELF-MF and childhood leukemia remains consistent with possible carcinogenicity in humans. While this scientific uncertainty is dissatisfactory for science and public health, new mechanistic insight from ARIMMORA experiments points to future research that could provide a step-change in future assessments. Bioelectromagnetics. 37:183-189, 2016. © 2016 Wiley Periodicals, Inc.