A new experimental trial using repeated heating every 24 hours for local hyperthermic therapy with bleomycinin vivo

This report presents the effect of repeated heating every 24 hrs using bleomycin (BLM) which, although seemingly contrary to the usual agreement that hyperthermia should be carried out with a long interval due to thermotolerance, holds many possibilities. FM3A cells on the foot pad of C3H mouse were immersed in a heated water bath at 43 and 44°C for 30 min. The effect of repeated heating was appreciated by an improved growth curve and 50 day survival compared to mice which received heating twice with a 96-hr interval. Repeated heating every 24 hrs 5 times with BLM suppressed tumor growth significantly as compared to heating twice with a 96-hr interval without BLM. The longest survival time was obtained by the repeated heating with BLM among all protocols. There is therefore a good possibility that more effective results could be obtained clinically by repeated heating over a short period.     

加温合并药物治疗Lewis肺癌的实验研究

本实验以荷 Lewis 肺癌的 NIH 小鼠为模型,以肿瘤平均直径倍增时间(MDDT)为终点,进行加温合并抗癌药物的研究。结果表明:①43℃加温25分钟,对 Lewis 肺癌有明显的治疗效果(P<0.05);②喜树碱16mg/kg合并加温25分钟,对 Lewis 肺癌的抑制作用随加热温度升高而加强,在43℃时出现相加作用(P<0.001);③斑蝥素0.45mg/kg,高三尖杉酯碱1.2mg/kg 或消瘤芥0.75mg/kg 合并加温25分钟,对Lewis 肺癌的抑制作用随加热温度升高而增强,其中斑蝥素和消瘤芥在43℃时出现协同作用(P<0.001);①去甲斑蝥酸钠3mg/kg 对 Lewis 肺癌无治疗作用,但合并43℃加温25分钟时有协同作用;⑤鸦胆子油口服乳液8ml/kg,间隔27小时合并43℃加温25分钟,对 Lewis 肺癌的治疗有相加作用,并明显延长了荷瘤动物的生存时间。     

人大肠癌细胞体外常温及温热环境中药物敏感性试验

用ＭＴＴ比色法对２０例大肠癌患者术后标本在常温及温热环境中进行体外药物敏感性试验，结果显示，某些药物在温热环境中，对癌细胞的杀伤作用有显著提高，此项试验为临床温热化疗法提供了理论依据。     

Demonstration of synergistic effects of hyperthermia and photodynamic therapy using the chick chorioallantoic membrane model.

The chick chorioallantoic membrane (CAM) model was used to study vascular effects of photodynamic therapy (PDT) and hyperthermia (HPT) and the synergism of these modalities. The CAM is a convenient medium for monitoring the modifications of the vasculature. It is possible to view the CAM and to examine structural changes of individual blood vessels in real time. Moreover, the CAM is a closed system which lends itself to mathematical modeling of the temporal and spatial temperature profile and in which HPT can be performed quantitatively and to a selected depth, using different lasers. A porphyrin-type photosensitizer solution was applied to areas of the CAM, defined by teflon O-rings placed on the surface. Uptake dynamics of the sensitizer into the CAM was determined by analyzing its fluorescence in vivo. The CAM area was irradiated with a dual-wavelength laser system composed of a dye laser at 644 nm (to induce PDT) and a CO2 laser at 10.6 microns (to bring about HPT). Damage to the CAM vasculature, due to combined PDT+HPT, was compared to the outcome of the separate modalities, and a synergistic effect of about 40% was observed.     

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。     

Effect of temperature variation (22˚C- 44˚C) on halothane and caffeine contracture testing in normal humans

Background: Malignant hyperthermia (MH) susceptibility is diagnosed using halothane-caffeine contracture testing of a muscle sample maintained at 37˚C. However, there has not been a systematic study that examines the effect of different temperatures on the response of normal muscle to halothane and caffeine. We hypothesized that altering bath temperature would modify the contracture responses.
Methods: We obtained muscle samples from 20 patients undergoing surgical procedures of the lower extremities. The samples were dissected into 245 bundles and the bundles were exposed to halothane 3% or incremental caffeine, according to the North American MH group protocol. Several bundles from each patient were simultaneously studied at four different temperatures (22˚C, 30˚C, 37˚C and 44˚C). Each bundle was studied at only one temperature, the muscle samples of 3 patients were simultaneously studied at all four temperatures for halothane and caffeine.
Results: Maximum contracture to caffeine (32 mM) was highest at 37˚C; however, at lower caffeine concentrations (2–4 mM), there was no consistent effect of temperature on contracture response. Likewise, temperature did not alter contracture responses to halothane. The extremes of temperature (22˚C and 44˚C) were associated with lack of twitch in response to electrical stimulation. For the bundles exposed to halothane at 22"C, the absence of a twitch was associated with the presence of a contracture, although these were never above the diagnostic threshold.
Conclusions: We conclude that temperature has little effect on responses of normal muscle to halothane and caffeine.     

In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low-risk subjects

Background: Determination of sensitivity and specificity of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility using the European MH Group (EMHG) protocol has been performed in some laboratories but only on a small sample from the combined EMHG. Thus, the purpose of the present study was to determine combined EMHG sensitivity and specificity of the test. Methods: Results of IVCT of patients with previous fulminant MH and normal, low-risk subjects (controls) were collected from 22 centresof the EMHG. IVCT was performed according to the EMHG protocol. Patients were included inthe study if the clinical crisis had a score of at least 50 points with the Clinical Grading Scale. Low-risk subjects were included provided they did not belong to a family with known MH susceptibility, they had not developed any signs of MH at previous anaesthetics, and they did not suffer from any neuromuscular disease. For inclusion of both MH patientsand low-risk subjects, at least 1 muscle bundle in the IVCT should have twitches of 10 mN(1 g) or more. For evaluation of individual tests, only muscle bundles with twitch heights of 10 mN (1 g) or more were used. Results: A total of 1502 probands had undergone IVCT because of a previous anaesthesia with symptoms and signs suggestive of MH. Of these, 119 had clinical scores of 50 and above. From these 119 MH-suspected patients and from 202 low-risk subjects, IVCT data were collected. Subsequently, 14 MH-suspected patients were excluded from further analysis for thefollowing reasons: In 3 patients, the suspected MH episode could be fully explained by diseases other than MH; in 11 MHS patients, IVCT was incomplete (n=l), data were lost (n=3), or none of the muscle bundles fulfilled twitch criteria (n=7). Of the remaining 105 MH-suspected patients, 89 were MHS, 10 MHEh, 5 MHEc, and one MHN. Thus, we observed a diagnostic sensitivity of the IVCT of 99.0% if the MHE group is considered susceptible(95% confidence interval 94.8–100.0%). Of the 202 low-risk subjects, 3 were MHS, 5 MHEh, 5 MHEc, and 189 MHN. This gives a specificity of the IVCT of 93.6% (95% confidence interval 89.2–96.5%). Conclusion: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.     

Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma

Interleukin–2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 × 10⁵ IU ip tid) on days 3–7; plus WBHT(41°C for 30 min) on days 3, 5, and 7; or WBHT only on days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10–14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature. © 1993 Wiley-Liss, Inc.     

Age, fiber type composition and in vitro contracture responses in human malignant hyperthermia

Muscle fiber typing and in vitro contracture tests were performed in 59 patients investigated for susceptibility to malignant hyperthermia (MH). Eighteen patients were found to be susceptible to MH. There was no difference in age or fiber type distribution between MH susceptible and non-susceptible patients. No correlation was found between age and fiber type distribution. Separate analyses for each diagnostic group revealed no relationship between age or fiber type distribution and response to halothane or caffeine. When all caffeine results were pooled, however, there was a significant effect of age on the caffeine specific concentration (the concentration eliciting a contracture of 1 g), but not on the caffeine threshold concentration (the minimal concentration eliciting an increase in tension). It is concluded that age and fiber type distribution have no influence on MH diagnosis, if the protocol of the European MH Group for evaluation of susceptibility to MH is followed.     

Fever and feeding in the rat: Actions of intrahypothalamic interleukin-6 compared to macrophage inflammatory protein-1β (MIP-1β)

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1β, induce an intense fever in the rat when they are injected directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (T_b) of MIP-1β with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T_b continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 μl of pyrogen-free artificial CSF, recombinant murine MIP-1β, or recombinant human IL-6. MIP-1β in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in T_b of 2.4 ± 0.21°C reached by 3.7 ± 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T_b of 1.2 ± 0.25°C, 1.8 ± 0.15°C, and 2.1 ± 0.22°C and duration of 6.2 ± 1.28 hr, 6.7 ± 0.49 hr, and 6.8 ± 0.65 hr when given in doses of 25, 50, and 100 ng, respectively. These results show that MIP-1β and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-1β exerts its action in a much lower concentration. Thus, the de novo synthesis and subsequent action of the MIP-1 family of cytokines on neurons of the AH/POA in response to a pyrogen challenge apparently play a functional role in the pathogenesis of fever. Further, the endogenous activity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute phase response to a bacterial challenge. Copyright © 1994 Wiley-Liss, Inc.