Clinical Application Of Hyperthermia Research Articles

Hyperthermia as a Potential Cornerstone of Effective Multimodality Treatment with Radiotherapy, Cisplatin and PARP Inhibitor in IDH1-Mutated Cancer Cells.

Mutations in the isocitrate dehydrogenase 1 (IDH1MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1MUT are causal in the development and progression of these types of cancer due to neomorphic production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Intracellular accumulation of D-2HG has been implicated in suppressing homologous recombination and renders IDH1MUT cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi). Hyperthermia increases the efficacy of DNA-damaging therapies such as radiotherapy and platinum-based chemotherapy, mainly by inhibition of DNA repair. In the current study, we investigated the additional effects of hyperthermia (42 °C for 1 h) in the treatment of IDH1MUT HCT116 colon cancer cells and hyperthermia1080 chondrosarcoma cancer cells in combination with radiation, cisplatin and/or a PARPi on clonogenic cell survival, cell cycle distribution and the induction and repair of DNA double-strand breaks. We found that hyperthermia in combination with radiation or cisplatin induces an increase in double-strand breaks and cell death, up to 10-fold in IDH1MUT cancer cells compared to IDH1 wild-type cells. This vulnerability was abolished by the IDH1MUT inhibitor AGI-5198 and was further increased by the PARPi. In conclusion, our study shows that IDH1MUT cancer cells are sensitized to hyperthermia in combination with irradiation or cisplatin and a PARPi. Therefore, hyperthermia may be an efficacious sensitizer to cytotoxic therapies in tumors where the clinical application of hyperthermia is feasible, such as IDH1MUT chondrosarcoma of the extremities.

Hyperthermia: Clinical Applications and Theoretical Models

Nanotechnology applications, which aid radiotherapy and chemotherapy, have revolutionized diagnosis, treatment planning, imaging, and medical machinery. The ability of nanoparticles to kill or freeze cancer cells by raising heat locally is a prominent application of nanoparticles. This paper will review the research on clinical applications of hyperthermia using nanoparticles stimulated by an alternating magnetic field and electromagnetic waves such as microwave and laser, as well as the foundation of the theoretical model used in bio-thermal applications.

Size-dependent electromagnetic properties and the related simulations of Fe3O4 nanoparticles made by microwave-assisted thermal decomposition

A great deal of effort has demonstrated magnetite nanoparticles (Fe3O4 NPs) are important subject applied in tumor hyperthermia due to their excellent magneto-thermal effect. Our previous study had ultrafast prepared 6nm Fe3O4 NPs via microwave approach and found that these small size NPs are responsible for microwave energy conversion to accelerate NPs formation. Hence, we suppose that investigating the size-dependent behavior of Fe3O4 NPs should be beneficial for developing their electromagnetic energy conversion application for hyperthermia. In this study, Fe3O4 NPs with four sizes (i.e. 4nm, 20nm, 50nm and 200nm) were prepared by a rapid microwave synthetic strategy. The specific absorption rate (SAR) value and reflection loss (RL) value of samples were investigated by measuring the time-dependent temperature curves in alternating magnetic field (AMF, 390 and 780kHz, 12A) and via vector network analyzer (VNA) range from 2 to 18GHz, respectively. Results indicated that using magnetic induction hyperthermia frequency Fe3O4 NPs with single domain size of 20nm possess maximum, whereas the RL value increases with the size at microwave frequency. More importantly, the frequency of maximum RL value was matched with the clinical microwave hyperthermia. We subsequently introduce the micromagnetic (OOMMF) simulation to help understanding the issue due to the fundamental importance of size effect for magnetic NPs in energy conversion. Simulation results suggested that coupling interaction and magnetic dipole-dipole interaction between magnetic NPs and electromagnetic field would be seen as synergistic effect to impact absorption behavior, and we believe that this work can provide a valuable reference for size selection of magnetic nanoparticles in clinical application of hyperthermia.

Clinical Application of Hyperthermia to Soft Tissue Sarcoma; Result of Single Institution

Clinical Application of Hyperthermia to Soft Tissue Sarcoma; Result of Single Institution

Effect of magnetic nanoparticle heating on cortical neuron viability

Purpose: Superparamagnetic iron oxide nanoparticles are currently approved for use as an adjunctive treatment to glioblastoma multiforme radiotherapy. Radio frequency stimulation of the nanoparticles generates localised hyperthermia, which sensitises the tumour to the effects of radiotherapy. Clinical trials reported thus far are promising, with an increase in patient survival rate; however, what are left unaddressed are the implications of this technology on the surrounding healthy tissue.Methods and materials: Aminosilane-coated iron oxide nanoparticles suspended in culture medium were applied to chick embryonic cortical neuron cultures. Cultures were heated to 37 °C or 45 °C by an induction coil system for 2 h. The latter regime emulates the therapeutic conditions of the adjunctive therapy. Cellular viability and neurite retraction was quantified 24 h after exposure to the hyperthermic events.Results: The hyperthermic load inflicted little damage to the neuron cultures, as determined by calcein-AM, propidium iodide, and alamarBlue® assays. Fluorescence imaging was used to assess the extent of neurite retraction which was found to be negligible.Conclusions: Retention of chick, embryonic cortical neuron viability was confirmed under the thermal conditions produced by radiofrequency stimulation of iron oxide nanoparticles. While these results are not directly applicable to clinical applications of hyperthermia, the thermotolerance of chick embryonic cortical neurons is promising and calls for further studies employing human cultures of neurons and glial cells.

Hyperthermia on skin immune system and its application in the treatment of human papillomavirus-infected skin diseases

Hyperthermia is a condition characterized by increased body temperature as a consequence of failed thermoregulation. Hyperthermia occurs when a body produces or absorbs more heat than it dissipates. Hyperthermia also elicits various effects on the physiology of living cells. For instance, fever-range temperature (39°C to 40°C) can modulate the activities of immune cells, including antigen-presenting cells, Tcells, and natural killer cells. Heat shock temperature (41°C to 43°C) can increase the immunogenicity of tumor cells. Cytotoxic temperature (> 43°C) can create an antigen source to induce an anti-tumor immune response. The immunomodulatory effect of hyperthermia has promoted an interest in hyperthermia-aided immunotherapy, particularly against tumors. Hyperthermia has also been used to treat deep fungal, bacterial, and viral skin infections. We conducted a series of open or controlled trials to treat skin human papillomavirus infection by inducing local hyperthermia. More than half of the patients were significantly cured compared with those in the control trial. A series of challenging clinical cases, such as large lesions in pregnant patients or patients with diabetes mellitus, were also successfully and safely managed using the proposed method. However, further studies should be conducted to clarify the underlying mechanisms and promote the clinical applications of hyperthermia.

Mechanisms and clinical application of hyperthermia for tumors

Hyperthermia has selective destruction to tumor cells,and effects on their material and en-ergy metabolism, nucleic acid and protein synthesis,apoptosis, cell cycle,and so on. Meanwhile,hyperthermia can reduce the local blood supply of tumors,inhibit the tumor growth,up-regulate immune function and increasethe sensitivity of radiotherapy and chemotherapy,which play an important role in the treatment for tumor. At present,the whole body hyperthermia,regional hyperthermia and other methods have been widely applied in the clinical oncotherapy of digestive system,nervous system,reproductive system and other parts of body. Key words: Hyperthermia; Chemotherapy; Radiotherapy; Neoplasms

Combination of chemotherapy and mild hyperthermia enhances the anti-tumor effects of cisplatin and adriamycin in human bladder cancer T24 cells in vitro

Although the combined effects of hyperthermia and chemotherapy for cancer therapy have been theoretically established, combination therapy with hyperthermia is not widely used clinically, since the application of hyperthermia is complex and maintaining a tumor temperature of 43°C or above is very difficult. Thus, in the present study, the combined effects of chemotherapy and mild hyperthermia, which is easier to apply than hyperthermia, were examined using a human bladder cancer cell line, T24. T24 cells were incubated at 37-47°C for 0-5 h, and the survival rate of cells was measured using the MTT method. Cisplatin and adriamycin, which are indicated for human bladder cancer, were used as anti-tumor drugs. In the combination experiment, T24 cells were treated with cisplatin (20 and 200 µg/ml) or adriamycin (4 and 40 µg/ml) at 41°C for 0-5 h and at 37°C for 7-12 h. After a total incubation of 12 h, cell survival was measured by the MTT method. i) T24 cells, like cells in general, survived mild hyperthermia at 41°C, but were killed at over 43°C. ii) Although a low concentration (20 µg/ml) of cisplatin or of mild hyperthermia at 41°C did not affect the survival rate of T24 cells, this combination therapy decreased the survival rate of T24 cells with increasing incubation times at 41°C. The anti-tumor effect of the combination of 20 µg/ml cisplatin and 41°C for 5 h was the same as that of 10 times the concentration (200 µg/ml) of cisplatin. iii) Adriamycin showed the same effects as cisplatin. The anti-tumor effect of the combination of 4 µg/ml adriamycin and 41°C for 5 h was identical to the anti-tumor effect of a 10-fold higher concentration (40 µg/ml) of adriamycin. Based on these results, combination with mild hyperthermia may enable a reduction in the dose of anti-tumor drugs. It was suggested that the side effects of chemotherapy could be reduced clinically by combining the drugs with mild hyperthermia. Mild hyperthermia might be a useful and practical heating method which could lead to the increased clinical applications of hyperthermia. We previously reported the preliminary results of M-VAC chemotherapy (methotrexate, vinblastine, doxorubicin and cisplatin) combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium. This basic research strongly supports the clinical beneficial results of chemotherapy combined with mild hyperthermia.

Combining anti-tumor drugs with mild hyperthermia increases the cytotoxic effects of drugs on human leukemia cells in vitro

Although the benefits of using a combination of hyperthermia and chemotherapy or radiotherapy in the treatment of cancer have been theoretically established, the use of such combination therapy is not widespread at the clinical level, as the application of hyperthermia is complex and maintaining a tumor temperature of 43°C or higher is exceedingly difficult. Consequently, in the present study, the effects of chemotherapy combined with mild hyperthermia at 41°C (which is easier to apply than standard hyperthermia) were examined in the NALM-6 leukemia cell line. The results were as follows: i) NALM-6 leukemia cells, like most cells, survived mild hyperthermia at 41°C, but were killed at temperatures over 43°C. ii) Low concentrations of adriamycin (0.1 µg/ml) or mild hyperthermia applied separately did not have a visible effect on the survival rate of NALM-6 cells, whereas combined treatment with these therapies decreased the survival rate of NALM-6 cells in a time-dependent manner. The anti-tumor effect after 5 h of the combination of 0.1 µg/ml adriamycin and mild hyperthermia was the same as that observed with a 10-fold higher concentration (1 µg/ml) of adriamycin alone. iii) Another anti-tumor drug, vincristine, exhibited the same behavior as adriamycin. The anti-tumor effect after 1 h of the combination of 5x10-11 M vincristine and mild hyperthermia was the same as that observed with a 10-fold higher concentration (5x10-10 M) of vincristine alone. The results indicate that it may be possible to reduce the required concentrations of anti-tumor drugs by using them in combination with mild hyperthermia. In this way, the side effects of chemotherapy may be reduced in clinical settings. Mild hyperthermia is a useful and practical heating method, and could result in the increasing clinical application of hyperthermia in the treatment of cancer.

Hyperthermia on immune regulation: A temperature’s story

Over the last decade the linkage between hyperthermia, heat shock proteins and fever with the body’s immune system has been well investigated. The immunomodulatory function of hyperthermia has been found to be quite sensitively regulated by temperature, as different levels of heating can bring different modulatory effect on different sensitive targets. Understanding these intrinsic mechanisms could bring new inspirations on the design of clinical trials combining local tumor hyperthermia with immunotherapy in cancer patients. This review will attempt to tell the story about the effect of temperature on immune regulation, with special emphasis on the clinical application of hyperthermia and the feasibility of combining it with immunotherapy in the clinic.

The Past and Present Status of Clinical Hyperthermia in Japan: a Survey in 2004 using a Questionnaire

Clinical research in hyperthermic oncology began in 1978, when the research group chaired by Prof. T. Sugahara, supported by a grant from the Ministry of Education, played an important part. Six years later, the first annual meeting of the Japanese Society of Hyperthermic Oncology (JSHO) was held in Kyoto, and the 23rd meeting was held in Nara in 2006. Over this period, the number of members as well as the number of scientific papers presented have decreased. However, new technologies such as immuno-stimulation, high temperature ablation, and mild hyperthermia have been introduced into clinics. The health insurance control committee of the JSHO conducted a survey on the clinical applications of hyperthermia. Data obtained through the use of questionnaires have been used to present the state of hyperthermic treatment in the major hospitals in Japan. An outline of the patients and diseases treated with hyperthermia, heating conditions including combination therapy, and clinical outcomes were summarized in this study. From the viewpoint of fiscal responsibility at each hospital, the difference between income and expenses for hyperthermic therapy is something which cannot be ignored. Further analysis of survey data and additional survey studies might be essential to resolve this problem.

Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function.

Elevations in temperature that are associated with inflammation or fever have been linked to improved survival from infections, enhanced immunological functions, and increased control of tumor growth. Over the past few years, several groups have begun to explore the possible linkage among these observations and have tested the hypothesis that various immune cells are especially sensitive to thermal stimulation. However, relatively little is known regarding the effects of thermal stimulation on antigen presenting cells (APCs), such as dendritic cells (DCs). Very recently, several groups have begun to examine the ability of thermal stimuli to regulate the function of these cells which are known to play a pivotal role in the efficacy of vaccines and other immunotherapies. In this review, we summarize what has been discovered about the role of mild thermal stress in regulating various Dendritic cell (DC) activities. Excitingly, it appears that mild elevations of temperature have the potential to enhance antigen uptake, activation associated migration, maturation, cytokine expression and T cell stimulatory activity of DCs. While these studies reveal that the timing, temperature and duration of heating is important, they also set the stage for essential questions that now need to be investigated regarding the molecular mechanisms by which elevated temperatures regulate DC function. With this information, we may soon be able to maximize the strategic use of thermal therapy as an adjuvant, i.e., combining its use with cancer immunotherapies such as vaccines, which depend upon the function of DCs. Several possible strategies and timepoints involving the clinical application of hyperthermia in combination with immunotherapy are presented.

Invited commentary

The use of heat to treat disease has existed as long as recorded history. Observations relevant to cancer show heat does the following: (1) selectively kills cells as a function of thermal dose (duration of exposure × degree of temperature elevation); (2) selectively kills S-phase and radiation-resistant cells; (3) partially inhibits DNA repair; (4) kills cells with a defective heat-shock response; and (5) is a stimulus for apoptosis. Tumor cells, therefore, are more vulnerable to heat than normal cells. The clinical application of hyperthermia, often in conjunction with chemotherapeutic agents, includes three general methods based on the extent of the body treated. Localized hyperthermia utilizes heat for primary and recurrent tumors and appears most successful for head and neck tumors. Regional or isolated organ/limb hyperthermia utilizes heat restricted to specific regions of the body. Response has been documented in select patients for tumors of the limbs, liver, pancreas, esophagus, gastrointestinal tract, colon, and rectum. Whole-body hyperthermia uses methods that heat the entire body to a target core temperature of approximately 42 degrees centigrade to treat metastatic disease. Effectiveness is still controversial because of the difficulty in administering and monitoring systemic hyperthermia and limited experience.

Clinical application of hyperthermia combined with anticancer drugs for the treatment of solid tumors

Hyperthermia is one of the modalities used to treat various forms of malignancies, including esophageal, stomach, or rectal cancers. The basic mechanism of synergism between hyperthermia and anticancer drugs, as well as the clinical result of hyperthermia for the treatment of gastrointestinal malignancy, was reviewed. Hyperthermia exerts a cytotoxic effect in combination with various mechanisms. Hyperthermia is applied in combination with chemotherapy and/or radiotherapy in the clinical setting. Among the anticancer drugs that are synergistic with hyperthermia is cisplatin, which is prevalent for clinical application. The mechanism of enhanced cytotoxicity of cisplatin includes increased intracellular drug accumulation, increased platinum-DNA adducts, and inhibition of DNA repair. At our institute, hyperthermochemoradiotherapy was conducted as a neoadjuvant therapy for either operative cases or as a palliative therapy for unresectable cases for esophageal and rectal cancers. In both situations, hyperthermochemoradiotherapy showed an excellent benefit in both the control of local recurrence and and in an improvement in patient survival. Regarding gastric cancer, the most popular application of hyperthermia was the intraoperative hyperthermic peritoneal lavage with cisplatin. This treatment modality demonstrated a better control of the disseminated lesion. Regarding the factors that influence thermosensitivity, in vitro experiments demonstrated the heat-shock proteins or tumor suppressor gene p53 to be related to thermosensitivity. In the clinical setting, these factors remain to be firmly established as predictive factors for thermosensitivity. It is evident that hyperthermia was effective in the control of far-advanced gastrointestinal malignancies. When more reliable factors for the prediction of the treatment response can be established, the standard guidelines for the application of hyperthermia can then be made.

Hyperthermia in oncology

The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44°C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.

Hyperthermia in oncology

The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44 degrees C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.

Inactivation of p53 and of pRb protects human colorectal carcinoma cells against hyperthermia-induced cytotoxicity and apoptosis.

Cell-cycle checkpoints are thought to govern the cellular response to external stimuli. The involvement of the p53 tumour-suppressor protein and the retinoblastoma protein (pRb) in the cell-cycle checkpoint in G1 phase is well established. However, little is known about the importance of these G1 checkpoint regulators in hyperthermia-induced cytotoxicity. Such information is relevant because of the clinical application of hyperthermia in combination with chemotherapy or with radiotherapy. The effects of p53 or pRb inactivation were studied in a well-established isogenic system using the human colorectal carcinoma cell line (RKO). The cells were treated with clinically relevant heat doses (60 min at 40-43 degrees C). Cell survival, cell-cycle redistribution and induction of apoptosis were investigated. Survival of the p53-inactivated transfectants was higher than that of the wild-type p53 cells. The pRb-inactivated transfectants showed an intermediate sensitivity to hyperthermia. All transfectants showed G2 arrest after hyperthermia and the appearance of a sub-G1 population. The induction of apoptosis was inhibited in p53-inactivated and pRb-inactivated transfectants. These results suggest that p53 and/or pRb status may be an important determinant of the clinical response to hyperthermia.

Chronic thermotolerance with continued cell proliferation.

The human colon adenocarcinoma cell line, NSY42129, is capable of proliferation at 41.1 degrees C. This ability appears to be due to a type of chronic thermotolerance, as opposed to selection or adaptation, that allows these cells to traverse S phase at elevated temperatures. Four other human cell lines were studied for their ability to proliferate at 41.1 degrees C. Of those only one, also a colon adenocarcinoma, showed the ability to sustain proliferation at 41.1 degrees C. While all the cell lines examined showed increased levels of the major heat shock proteins at 41.1 degrees C, the cellular amounts of these proteins did not correlate with their ability to proliferate at 41.1 degrees C. However, the ability of the cells to proliferate at 41.1 degrees C did correlate with their ability to sustain elevated rates of synthesis of hsp70 and hsp90. These results could have implications in the clinical application of hyperthermia, particularly the use of long duration moderate hyperthermia.

Pathophysiological aspects of hyperthermia

Blood flow in many rapidly growing tumors is sluggish leading to an impairment of convective heat dissipation which facilitates tumor heating compared to normal tissues. In addition, the compromised microcirculation causes a hostile metabolic micromilieu which can modulate the therapeutic effect of heat. After clinically relevant heat doses, a shut-down of tumor microcirculation is often observed creating a “heat-reservoir” and aggravating tumor hypoxia, acidosis, and substrate and energy depletion, factors which are known to greatly enhance tumor cell killing by heat. Since the mechanisms described are mostly derived from experimental results on fast-growing animal tumors, the clinical relevance, i.e., the applicability of these pathophysiological aspects to human tumors, has to be tested during clinical application of hyperthermia.

The Sensitivity of the Thoracolumbar Spinal Cord of the Mouse to Hyperthermia

Twelve millimeters of the thoracolumbar spinal cord of mice has been treated with a radiofrequency heating system which has been shown previously to produce localized and controllable elevation of temperature. The severity of neurological damage was assessed by measuring the reduction in the reflex leg extension of the hind legs of the mice from video-recorded images and by scoring the performance of the mice by a negative geotaxis test. The response to treatment was rapid with maximum paralysis occurring within a few days after treatment. Only minor symptoms were observed in those animals which had not developed paralysis within 2 weeks. A 40% reduction in the reflex leg extension was chosen as an end point, and the percentage of mice having reached the end point for different thermal doses was determined in groups of nine mice. The ED50 for heating for 1 h was 43.1 degrees C and for heating at 45 degrees C was 10.8 min. An increase in temperature by 1 degree C required a decrease in time by a factor of 2.25 to produce the same effect. Thermotolerance was observed 24 h after preheating at 45 degrees C for 1.9 min with a thermotolerance ratio of 1.7. The rapid response and high sensitivity of the spinal cord will have to be taken into consideration in the clinical application of hyperthermia.