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Simple Summary: The treatment of pancreatic tumors is challenging because they are poorly vascularized and because this inhibits drug delivery. Using mild magnetic hyperthermia in combination with chemotherapy, we show that drug accessibility can be increased by the transient induction of new blood vessel growth in the tumors. By examining molecular and physiological factors in an orthotopic tumor model in mice, we show that the combination therapy results in local cellular stress, and that blood vessel growth is triggered by cell-to-cell communications within the treated tumors. This mechanism is quite different from the usually reported driver of tumor vessel formation—viz. hypoxia—and may therefore offer a means of modulating both the extent and the location of the tumor vasculature for therapeutic benefit. We anticipate that combined chemo- and thermo-therapy may in the future improve the efficacy and tolerability of pancreatic cancer therapies. There is a growing interest in exploring the therapeutically mediated modulation of tumor vascularization of pancreatic cancer, which is known for its poorly perfused tumor microenvironment limiting the delivery of therapeutic agents to the tumor site. Here, we assessed how magnetic hyperthermia in combination with chemotherapy selectively affects growth, the vascular compartment of tumors, and the presence of tumor cells expressing key regulators of angiogenesis. To that purpose, a orthotopic PANC-1 (fluorescent human pancreatic adenocarcinoma) mouse tumor model (Rj:Athym-Foxn1nu/nu) was used. Magnetic hyperthermia was applied alone or in combination with systemic chemotherapy (gemcitabine 50 mg per kg body weight, nab-pacitaxel 30 mg/kg body weight) on days 1 and 7 following magnetic nanoparticle application (dose: 1 mg per 100 mm3 of tumor). We used ultrasound imaging, immunohistochemistry, multi-spectral optoacoustic tomography (MSOT), and hematology to assess the biological parameters mentioned above. We found that magnetic hyperthermia in combination with gemcitabine/paclitaxel chemotherapy was able to impact tumor growth (decreased volumes and Ki67 expression) and to trigger neo-angiogenesis (increased small vessel diameter) as a result of the therapeutically mediated cell damages/stress in tumors. The applied stressors activated specific pro-angiogenic mechanisms, which differed from those seen in hypoxic conditions involving HIF-1α, since (a) treated tumors showed a significant decrease of cells expressing VEGF, CD31, HIF-1α, and neuropilin-1; and (b) the relative tumor blood volume and oxygen level remained unchanged. Neo-angiogenesis seems to be the result of the activation of cell stress pathways, like MAPK pathways (high number of pERK-expressing tumor cells). In the long term, the combination of magnetic hyperthermia and chemotherapy could potentially be applied to transiently modulate tumor angiogenesis and to improve drug accessibility during oncologic therapies of pancreatic cancer. [ABSTRACT FROM AUTHOR]

In this Perspective article, we explore the definition and use of clinical tolerability metrics associated with nonspecific eddy current heating in magnetic field hyperthermia (MFH). We revisit the origins of the "Brezovich criterion," Hof ≤ 485 MA m−1s−1, as it is applied to axial time-varying magnetic fields H (t) = Ho sin(2πft) and the human torso. We then consider alternative metrics, including the "maximal specific absorption rate" (SARmax) of eddy-current-induced power absorbed per unit mass of tissue. With reference to previously published clinical data and the results of two volunteer studies in our laboratory, we show that the SARmax metric is both suitable and reliable. We also show how it may be extracted from in silico finite element models to cope with confounding effects such as anatomical hot spots and non-axial-field geometries. We note a parallel with a standardized metric, the "local SAR" used in magnetic resonance imaging (MRI). We suggest that the limits established in clinical MRI (that the local SAR, averaged over 10 g of tissue and 6 min of treatment, should not exceed 20 mW g−1 in the torso or head, and 40 mW g−1 in the limbs) might be regarded as a good starting point for the design of MFH interventions. We conclude with the recommendation that the SARmax metric is adopted for future use in the development of clinically safe and tolerable MFH equipment. [ABSTRACT FROM AUTHOR]

We present a new oxybarometer for magnesiowustite-bearing systems, which is easily applied using widely available techniques. A scale relating the proportion of [Fe.sup.3+] [[Alpha] = [Fe.sup.3+]/([Fe.sup.3+] + [Fe.sup.2+)] to the position of the (220) reflection and total Fe (y) in magnesiowustites ([Mg.sub.1-y] [multiplied by] [Fe.sub.y]).sub.1-x]O has been derived from measured values in samples equilibrated at various oxygen fugacities: [Alpha] = 13.0047 - 39.4829f + 40.0540[f.sup.2] - 13.5701[f.sup.3]([+ or -]0.007 + 0.09[Alpha]), f = ([d.sub.220] - 1.4890)/(0.0510y + 0.0206[y.sup.2])([+ or -] 0.0001). Previously established partition coefficients can then be used to relate estimated [Fe.sup.3+] content to equilibrium oxygen fugacity ([f.sub.[O.sub.2]]) in the composition range 0 < y < 0.2. Equilibrium oxygen fugacities of log [f.sub.[O.sub.2]] [less than or equal to] - 1.7 can be estimated to [+ or -] 0.5 log units using just X-ray powder diffraction and electron microprobe analytical techniques.

High-frequency hysteresis measurements were performed on two different types of hydrosois of iron oxide particles: fully dispersed and highly clustered. The fully dispersed sol showed superparamagnetic behavior across the frequency range investigated, while the clustered sample exhibited significant hysteresis. The hysteretic losses were then directly related to magnetic hyperthermia measurements in a sinusoidal field of amplitude 10 mT at 140 kHz, where the clustered sample heated by up to 25[degrees]C in 1000 s while the dispersed sample at similar concentration showed no measurable heating. Index Terms--Frequency response, hysteresis, magnetic particles.