Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.     

Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats

The Flinders Sensitive Line (FSL) of rats has been selectively bred to have increased sensitivity to cholinergic agonists. However, these rats exhibit altered responsiveness to a number of noncholinergic agents, such as apomorphine, buspirone and ethanol. This study compared the FSL and control Flinders Resistant Line (FRL) rats in terms of their hyperthermic response to the phencyclidine (PCP) receptor agonist, MK-801 (0.2 mg/kg SC) and their MK-801 binding characteristics. We have found that FSL rats react with a delayed hyperthermia, having a significantly lower hyperthermia for the first 120 min of observation. Thereafter the response does not differ in FSL and FRL rats. Both groups had similar affinities and numbers of [3H]MK-801 binding sites in the hippocampus/cerebral cortex. Pretreatment with scopolamine (1 mg/kg SC) failed to affect MK-801-induced hyperthermia in either line of rats. These findings suggest that selective breeding of FSL rats attenuated the secondary mechanisms involved in the PCP receptor-mediated hyperthermic response. However, by itself cholinergic supersensitivity does not appear to be a major factor in the blunted responsiveness of FSL rats to MK-801.     

Influence of differences in tumor vascularity upon the effects of hyperthermia

Summary Utilizing two types of human renal carcinoma heterotransplanted in nude mice, we investigated the variations in hyperthermic effects (42.5°C for 30 min) caused by differences in tumor type with special reference to variations in tumor vascularity. In the hypovascular JRC1 strain, sporadic vascular dilation was observed throughout the tumors after heating. Destruction of tumor cells was observed mainly in the region of dilation. In the hypervascular JRC11 strain, homogenous vascular dilation was observed immediately after heating, mainly at the periphery of tumors. There was a decrease in the viability of cells in the center of the tumor. Therefore, the hypervascular tumors showed greater destruction mainly at the center where blood circulation was reduced. The range of necrosis was also greatly affected by the extent of vascular dilation caused by heating in hypovascular tumors.     

全身热疗法治疗晚期肝脏恶性肿瘤39例报告

目的 探讨全身热疗法（whole body hyperthermia，WBH）治疗肝脏恶性肿瘤的疗效及其对肝功能的影响。方法 采用WBH治疗肝脏恶性肿瘤患者39例，并对治疗前、后患者肝功能指标进行动态观察，分析该疗法对肝脏功能的影响，并通过分析治疗效果，初步评估该疗法的疗效。结果 ①WBH治疗不能手术切除的晚期肝脏恶性肿瘤患者的有效率为61．5％（24／39），60．0％（9／15）的患者AFP有不同程度下降，肿瘤疼痛缓解率达100％；存活期〉2年者占12．8％（5／39），〉1年者占59．0％（23／39），〉6个月者占76．9％（30／39）。②谷丙转氨酶于治疗后1～3d出现明显升高（P〈0．05），7d后下降并接近治疗前水平；谷草转氨酶于治疗后1d明显升高（P〈0．05），3～7d则下降并接近治疗前水平；白蛋白于治疗后1d出现下降（P〈0．05），但3d即已恢复；肝功能正常组总胆红素于治疗后第1～3d出现升高（P〈0．05），而肝功能异常组未观察到同样变化；转肽酶则无明显变化。结论 WBH能改善晚期肝脏恶性肿瘤患者的预后，提高生存质量，延长生存时间，但同时可造成患者肝功能一定程度的可逆性损害。     

凋亡诱导因子在实验性脑卒中后高温状态下的表达

目的探讨caspase非依赖途径在卒中后高温的神经元损伤环节中是否发挥重要作用。方法应用SD大鼠局灶性脑缺血模型,分别设立缺血后高温、缺血后正常温度和假手术组,每组8只。观察动物行为学评分、梗死体积和凋亡诱导因子(AIF)在海马的表达。利用PC12细胞培养缺氧及高温处理后,观察荧光双染AIF在细胞内的表达变化,及流式细胞仪技术检测细胞凋亡水平。结果缺血后高温组的行为学评分和梗死体积明显增加,AIF表达增高。PC12缺氧及高温培养后AIF从30min开始在胞核内表达,且随时间延长逐渐增多,细胞凋亡率随时间延长和温度增高而增加,且不被caspase广谱抑制剂所抑制。结论AIF在卒中后高温的过程中发生由胞浆到胞核的转移,caspase非依赖途径由此发挥重要作用。     

热疗联合化疗与单纯化疗治疗非小细胞肺癌的疗效比较

目的：探讨热疗联合化疗治疗非小细胞肺癌（non—small cell lung carcinoma，NSCLC）的疗效。方法：2003年9月～2006年11月我院对52例NSCLC进行微波热疗联合NP方案化疗联合治疗（热疗联合化疗组），3个周期后评价疗效；并与2006年1～11月16例NSCLC单纯化疗（单纯化疗组）进行对比。结果：热疗联合化疗组近期疗效明显好于单纯化疗组，热疗联合化疗组总有效率（RR）为65．4％（34／52），显著高于单纯化疗组总有效率37．5％（6／16）（Z=-2．419．P=0．016）；热疗联合化疗组结束后疼痛明显改善，单纯化疗组无镇痛作用，差异具有高度统计意义（Z=-6．486，P=0．000）；2组的不良反应主要表现为恶心、粒细胞减少、血小板降低和肝功能异常，差异无显著性（P〉0．05）。结论：热疗联合化疗治疗NSCLC疗效优于单纯化疗治疗NSCLC。     

激光多普勒技术测定组织血流及其在高温治癌研究中的意义

应用激光多普勒血流仪测量比较津白Ⅱ号小鼠三个部位皮肤的血流,观察HDZ对血流的影响,评价了HDZ的体内热增敏作用。结果发现,同一小鼠不同部位的血流是不同的,同一部位的连续6天结果无何区别。但同部位小鼠间的血流差别可达1倍以上。提示了预测放、化、热疗的疗效时,监测个体血流的前后变化有重要意义。2.5mg/kg以上的HDZ可以明显降低血流75％左右。HDZ与高温联合应用时对肿瘤显示了热增敏效应。     

Invited. Brain edema development after MRI-guided focused ultrasound treatment

The aim of this study was to investigate a potential technique for image-guided minimally invasive neurosurgical interventions. Focused ultrasound (FUS) delivers thermal energy without an invasive probe, penetrating the dura mater, entering through the cerebrospinal fluid (CSF) space, or harming intervening brain tissue. We applied continuous on-line monitoring by MRI to demonstrate the effect of the thermal intervention on the brain tissue. For this, seven rabbits had a part of their skull removed to create access for the FUS beam into the brain through an acoustic window of 11 mm in diameter. Dura was left intact and skin was sutured. One week later, the rabbits were sonicated for 3 seconds with 21 W acoustic power, and the FUS focus was visualized with a temperature-sensitive T1-weighted MRI pulse sequence. The tissue reaction was documented over 7 days with T2-weighted images of the brain. The initial area of the central low signal intensity in the axial plane was .4 ± .3 mm², and for the bright hyperintensity surrounding the lesion, it was 2.3 ± .6 mm² (n = 7). In the coronal plane, the corresponding values were .4 ± .1 mm² and 3.4 ± .9 mm² (n = 5). The developing brain edema culminated 48 hours later and thereafter diminished during the next 5 days. Histology revealed a central necrosis in the white matter surrounded by edematous tissue with inflammatory cells. In summary, the image-guided thermal ablation technique described here produced a relatively small lesion in the white matter at the targeted location. This was accomplished without opening the dura or the need for a stereotactical device. MRI allowed on-line monitoring of the lesion setting and the deposition of thermal energy and demonstrated the tissue damage after the thermal injury.     

Spontaneous arterial baroreflex control of the heart rate during head-down tilt in heat-stressed humans

The purpose of this study was to elucidate the effect of raised body temperature per se during acute heat stress on the spontaneous arterial baroreflex control of heart rate (f _c) in humans. To investigate whether unloading of cardiopulmonary baroreceptors during whole-body heating would alter the arterial baroreflex control of f _c, we controlled loading of the cardiopulmonary baroreceptors by head-down tilt (HDT) at angles of 5°, 10°, 15°, and 30° during heat stress produced by hot-water-perfused suits. The sensitivity of the arterial baroreceptor-cardiac reflex was calculated from the spontaneous changes in beat-to-beat arterial pressure and f _c. As an index of cardiopulmonary baroreceptor loading, the left atrial diameter (LAD) was measured by echocardiography. During whole-body heating, the LAD decreased with the rising body core temperature and increased with the HDT. The decreased LAD during heating almost recovered to the normothermic control level by 10° HDT. In the supine position, cardiac baroreflex sensitivity remained unchanged during heating. Arterial pressure, f _c and cardiac baroreflex sensitivity were not changed by HDT ranging from 5° to 30° during heating. These results suggest that cardiac baroreflex sensitivity remain unchanged during graded loading of the cardiopulmonary baroreceptors in heat-stressed humans. Also, we conclude that the sensitivity of the spontaneous arterial baroreflex controlling the f _c is not influenced by raised body temperature per se during acute heat stress. Electronic Publication     

Passive hyperthermia reduces voluntary activation and isometric force production

It has been suggested that a critically high body core temperature may impair central neuromuscular activation and cause fatigue. We investigated the effects of passive hyperthermia on maximal isometric force production (MVC) and voluntary activation (VA) to determine the relative roles of skin (T_sk) and body core temperature (T_c) on these factors. Twenty-two males [O_2max=64.2 (8.9) ml kg^–1 min^–1, body fat=8.2 (3.9)%] were seated in a knee-extension myograph, then passively heated from 37.4 to 39.4°C rectal temperature (T_re) and then cooled back to 37.4^oC using a liquid conditioning garment. Voluntary strength and VA (interpolated twitch) were examined during an isometric 10-s MVC at 0.5°C intervals during both heating and cooling. Passive heating to a T_c of 39.4^oC reduced VA by 11 (11)% and MVC by 13 (18)% (P<0.05), but rapid skin cooling, with a concomitant reduction in cardiovascular strain [percentage heart rate reserve decreased from 64 (11)% to 29 (11)%] and psychophysical strain did not restore either of these measures to baseline. Only when cooling lowered T_c back to normal did VA and MVC return to baseline (P<0.05). We conclude that an elevated T_c reduces VA during isometric MVC, and neither T_sk nor cardiovascular or psychophysical strain modulates this response. Results are given as mean (SD) unless otherwise stated.