Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH(3)

Hyperthermia has been shown to be a potential purging modality in autologous stem cell transplantation settings owing to its selective toxicity towards leukaemic cells. We describe two approaches to further increase the therapeutic index of the hyperthermic purging modality by using normal murine bone marrow cells and a murine model for acute myeloid leukaemia. First, the tetrapeptide AcSDKP was used to protect the normal haematopoietic progenitor cells against hyperthermic damage. Pretreatment for 8 h at 37 degrees C with 1 x 10(-9) mol/l AcSDKP resulted in a decrease in hyperthermic sensitivity of only normal haematopoietic progenitor cells. This combined treatment protocol revealed a therapeutic index (ratio of surviving fractions of normal vs. leukaemic cells) of > 500, which was considered to be sufficient for purging. This was confirmed in vivo by the survival of lethally irradiated recipients transplanted with purged simulated remission bone marrow (1 x 10(6) normal bone marrow cells and 5 x 10(4) leukaemic cells). A further increase of the therapeutic index cells was achieved by the alkyl-lysophospholipid ET-18-OCH(3). An incubation for 4 h at 37 degrees C with 25 microg/ml in the presence of 5% fetal calf serum preferentially enhanced the cytotoxic effect towards the leukaemic stem cell. The combination of AcSDKP and ET-18-OCH(3) with hyperthermia resulted in a therapeutic index of > 5000. This enabled a reduction of the hyperthermic treatment and will further minimize the toxicity to normal haematopoietic stem cell subsets, while a therapeutic index far above the required value is achieved. This tripartite purging treatment therefore offers a safe and fast purging protocol for the elimination of residual leukaemic cells in autografts.     

磁热相变型超声造影剂治疗肝癌的初步研究

目的研究自制的新型磁热相变型纳米粒造影剂(PFH-HIONS)体内磁热性能、相变能力及磁加热治疗裸鼠肝癌移植瘤的效果。方法采用皮下注射细胞悬液的方法建立裸鼠肝癌移植瘤模型,选取建模成功的裸鼠60只,随机分为2组,每组30只。对照组瘤内注射0.3 ml生理盐水,实验组瘤内注射等量20 mg/ml的PFH-HIONS,将裸鼠注射前后分别用超声显影,再放入磁加热线圈加热,红外热成像仪观察加热的温度,之后用超声以造影模式观察瘤内相变显影情况,第二天每组处死10只裸鼠,立即用TTC染色观察肿瘤凝固性坏死情况,并将肿瘤切片做HE染色和免疫组化染色,剩余裸鼠继续喂养至2周后处死,测量肿瘤大小,比较肿瘤治疗效果。结果实验组磁加热后从15 s开始明显升温,至3 min后温度达到80℃;超声造影模式下,可见加热后瘤内明显呈强回声证实相变气泡的产生;对照组磁加热后温度没有明显上升,也未观察到肿瘤内增强显影;实验组肿瘤内可见明显的灰白色坏死,对照组肿瘤整体呈红色,无明显坏死,且实验组肿瘤内细胞增值率较低,凋亡率较高,肿瘤较小,与对照组比较,差异均有统计学意义。结论制备的PFH-HIONS具备良好的磁热效果,既能在温升作用下发生相变,增强超声显影,又能用作肝癌移植瘤的热疗。PFH-HIONS为超声分子影像学基础上的肿瘤诊治一体化提供了新的思路和平台,具有较好的应用前景。     

Characterization of PEG–iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery

Hyperthermia, the heating of tissue from 41 to 45?°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n?=?1000) methyl ether methacrylate and PEG (n?=?400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non-Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response.     

Hyperthermic Enhancement of Tumor Radiosensitization Strategies

Local hyperthermia of living tissue can cause significant increases in blood flow and oxygenation depending on time-temperature history. Increases in perfusion of the abnormal and insufficient vasculature found in solid tumors may increase tumor oxygenation, thereby increasing the radiation sensitivity of the tumor. We hypothesized that local heating of tumor would increase the oxygenation of the tumor tissue and allow other oxygenating agents to further modify tumor oxygenation and radiation response. In the present study the effect of moderate temperature hyperthermia (MTH) at 41.5–42.5°C for 30–60 min, 250 mg/kg nicotinamide, or carbogen breathing (95% O₂/5% CO₂) on the radiation sensitivity of FSaII murine fibrosarcomas or R3230 AC rat adenocarcinomas was studied. Individually, these treatments increased the tumor cell sensitivity to single dose 10–15 Gy X-irradiation by 1–5 fold on average, as measured by the in vivo/in vitro tumor excision assay. The combination of tumor MTH with nicotinamide or carbogen breathing increased the radiation sensitivity by 3–5 fold in FSaII tumors and 10–30 fold in R3230 tumors with varying levels of statistical significance. Finally, the triple combination of adjuvant MTH, nicotinamide and carbogen breathing increased the radiation-induced cell death in FSaII tumors to a similar extent as the dual combinations of MTH, nicotinamide or heat, carbogen breathing. However, in R3230 AC tumors the triple adjuvant combination significantly increased radiation-induced cell killing compared to all other dual adjuvant treatments (p < 0.04). To interrogate the mechanism by which heating alters tumor physiology, nitric oxide production in tumor and endothelial cells in culture and tumor tissue after heating was studied. Heating caused an increase in nitric oxide production over a 24 h period after treatment. Subsequently, inhibiting the enzymatic production of NO with L-NAME was found to increase heat-induced growth delay of FSaII tumors. The cause and effect of increased nitric oxide production and the response of the tumor vasculature to heat are discussed in the context of the tumor radiosensitization achieved by heating, carbogen breathing and nicotinamide.     

The Anti-Tumor Effect of Interleukin-12 is Enhanced by Mild (Fever-Range) Thermal Therapy

The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-γ, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, N^G-monomethyl-l-arginine (l-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies.     

Effect of transient scrotal hyperthermia on sperm parameters,seminal plasma biochemical markers,and oxidative stress in men

In this experimental prospective study, we aimed to analyze the effect of transient scrotal hyperthermia on the male reproductive organs, from the perspective of sperm parameters, semen plasma biochemical markers, and oxidative stress, to evaluate whether different frequencies of heat exposure cause different degrees of damage to spermatogenesis. Two groups of volunteers (10 per group) received testicular warming in a 43°C water bath 10 times, for 30 min each time: group 1: 10 consecutive days; group 2: once every 3 days. Sperm parameters, epididymis and accessory sex gland function, semen plasma oxidative stress and serum sex hormones were tested before treatment and in the 16-week recovery period after treatment. At last, we found an obvious reversible decrease in sperm concentration (P = 0.005 for Group 1 and P= 0.008 for Group 2 when the minimums were compared with baseline levels, the same below), motility (P = 0.009 and 0.021, respectively), the hypoosmotic swelling test score (P = 0.007 and 0.008, respectively), total acrosin activity (P = 0.018 and 0.009, respectively), and an increase in the seminal plasma malondialdehyde concentration (P = 0.005 and 0.017, respectively). The decrease of sperm concentration was greater for Group 2 than for Group 1 (P = 0.031). We concluded that transient scrotal hyperthermia seriously, but reversibly, negatively affected the spermatogenesis, oxidative stress may be involved in this process. In addition, intermittent heat exposure more seriously suppresses the spermatogenesis compared to consecutive heat exposure. This may be indicative for clinical infertility etiology analysis and the design of contraceptive methods based on heat stress.     

Anesthetic considerations in myofibrillar myopathy

Myofibrillar myopathy (MFM) is a relatively newly recognized genetic disease that leads to progressive muscle deterioration. MFM has a varied phenotypic presentation and impacts cardiac, skeletal, and smooth muscles. Affected individuals are at increased risk of respiratory failure, significant cardiac conduction abnormalities, cardiomyopathy, and sudden cardiac death. In addition, significant skeletal muscle involvement is common, which may lead to contractures, respiratory insufficiency, and airway compromise as the disease progresses. This study is the first report of anesthetic management of a patient with MFM. We report multiple anesthetic encounters of a child with genetically confirmed BAG3‐myopathy, a subtype of MFM with severe childhood disease onset. A review of the anesthetic implications of the disease is provided, with specific exploration of possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to other anesthetic agents.     

深部热疗联合化疗在晚期小细胞肺癌中的疗效观察

目的探讨深部热疗结合化疗在晚期小细胞肺癌中的临床效果。方法将80例晚期小细胞肺癌患者随机平均分成治疗组和对照组,每组各40例。2组患者均采用依托泊苷联合顺铂常规化疗治疗,治疗组患者在化疗同时给予肺部原发病灶深部热疗;比较6周期后两组患者的缓解率、无进展生存期、体能变化及不良反应。结果治疗组患者的缓解率为85.0%,对照组患者的缓解率为67.5%,治疗组缓解率显著高于对照组(P<0.05);治疗组的无进展生存期明显高于对照组(P<0.05);治疗组KPS评分较化疗前明显增加(P<0.05),对照组KPS评分较化疗前比较差异无统计学意义;2组患者的恶心、呕吐、及骨髓抑制程度明显低于对照组,但均无统计学意义(P>0.05)。结论晚期小细胞肺癌患者在化疗的同时联合深部热疗可显著提高患者的化疗疗效,延长患者生存时间,减轻患者化疗的不良反应,提高患者生存质量。