Combination Of Local Hyperthermia Research Articles

Lower limb hyperthermia augments functional hyperaemia during small muscle mass exercise similarly in trained elderly and young humans.

What is the central question of the study? Ageing is postulated to lead to underperfusion of human limb tissues during passive and exertional hyperthermia, but findings to date have been equivocal. Thus, does age have an independent adverse effect on local haemodynamics during passive single-leg hyperthermia, single-leg knee-extensor exercise and their combination? What is the main finding and its importance? Local hyperthermia increased leg blood flow over three-fold and had an additive effect during knee-extensor exercise with no absolute differences in leg perfusion between the healthy, exercise-trained elderly and the young groups. Our findings indicate that age per se does not compromise lower limb hyperaemia during local hyperthermia and/or small muscle mass exercise. Heat and exercise therapies are recommended to improve vascular health across the lifespan. However, the haemodynamic effects of hyperthermia, exercise and their combination are inconsistent in young and elderly people. Here we investigated the acute effects of local-limb hyperthermia and exercise on limb haemodynamics in nine healthy, trained elderly (69±5 years) and 10 young (26±7 years) adults, hypothesising that the combination of local hyperthermia and exercise interact to increase leg perfusion, albeit to a lesser extent in the elderly. Participants underwent 90min of single whole-leg heating, with the contralateral leg remaining as control, followed by 10min of low-intensity incremental single-leg knee-extensor exercise with both the heated and control legs. Temperature profiles and leg haemodynamics at the femoral and popliteal arteries were measured. In both groups, heating increased whole-leg skin temperature and blood flow by 9.5±1.2°C and 0.7±0.2Lmin-1 (>3-fold), respectively (P<0.0001). Blood flow in the heated leg remained 0.7±0.6 and 1.0±0.8Lmin-1 higher during exercise at 6 and 12W, respectively (P<0.0001). However, there were no differences in limb haemodynamics between cohorts, other than the elderly group exhibiting a 16±6% larger arterial diameter and a 51±6% lower blood velocity following heating (P<0.0001). In conclusion, local hyperthermia-induced limb hyperperfusion and/or small muscle mass exercise hyperaemia are preserved in trained older people despite evident age-related structural and functional alterations in their leg conduit arteries.

Гипертермия как дополнительная опция в лечении больных плоскоклеточным раком анального канала

Purpose: to estimate the rate of locoregional recurrence and distant metastases, and the grade of chemoradiotherapy toxicity when in combination with local hyperthermia for treating squamous cell anal canal cancer T1-4N0,1-3M0-1. Materials and methods. 112 patients with squamous cell anal canal cancer were treated between 2011 and 2015 with chemotherapy, radiation therapy based on 3D CRT, intensity-modulated radiation therapy (IMRT) and volumetric intensity modulated arc therapy (VMAT), and local hypothermia. Staging was based on TNM (7th edition): I - 4 (3.6%) patients, II - 39 (34.8%) patients; IIIA - 33 (29.5%) patients, IIIB - 34 (30.3%) patients and IV - 2 (1.8%) patients. The median of mean follow-up was 32 months (range, 3-63 months). Local hyperthermia was performed in 81 (72.3%) patients. Results. 2-year local control was 73.2%. All recurrences, no matter which chemotherapy was performed, were in patients with advanced disease (IIIA/IIIB stages), from which 22.2% relapses were in group without local hyperthermia vs. 4.7% in group with radiomodification, p=0.038. Distant metastases were found in 9.4% patients with hyperthermia and in 11.1% patients without radiomodification, p=1. Usage of local hyperthermia is associated with increase II grade of dermatological toxicity (p=0.056). Conclusion. The combination of local hyperthermia and modern technologies of conformal radiation therapy has influenced the decrease of locoregional recurrences, but it is associated with lack of influence on distant metastases appearance regardless on chemotherapy regimen.

Proteotoxic stress targeted therapy (PSTT)

About a decade ago a multiple myeloma patient demonstrated a complete response to a proteasome inhibitor Bortezomib. This case generated a lot of hopes, and after successful clinical trials Bortezomib was approved by FDA and became the drug of choice for this disease. A high sensitivity of multiple myeloma to proteasome inhibition is probably related to extensive production immunoglobulins by the cancer cells. Bortezomib prevents degradation of these proteins, which accumulate and cause a strong ER stress, eventually triggering apoptosis [1, 2]. Unfortunately, many patients show only partial response to Bortezomib, in part due to the development of resistance [3]. Among multiple mechanism of resistance to Bortezomib, cells upregulate expression of molecular chaperones, e.g. Hsp27, which protect from the buildup of abnormal protein species [4-7]. The balance between toxicity of abnormal polypeptides and protective function of chaperones defines the outcome of the treatment with proteasome inhibitors. Bortezomib has also been tested in trials for treatment of solid tumors, either alone or in combination with other drugs, and results have been promising. The selective sensitivity of various cancer cells to proteasome inhibitors as compared to normal cells is probably because cancer cells have to handle higher levels of abnormal polypeptides, since they are exposed to adverse conditions of tumor microenvironments, oxidative stress and because of genetic instability and associated accumulation of mutant proteins [8]. Accordingly, cancer cells often have increased levels of molecular chaperones, like Hsp72 or Hsp27, as well as the heat shock transcription factor Hsf1 [9]. Furthermore, it was found that cancers have special requirements for these factors, since Hsf1 and hsp72 knockout mice demonstrate dramatic resistance to certain types of cancer, e.g. skin or breast cancer [10-12]. These data led to a concept of the “non-oncogene addiction” of cancers to Hsf1 and molecular chaperones, and predicted that inhibition of chaperones could be a potent novel approach towards development of therapeutics [8]. In fact, there have been number of publications that pharmacological inhibition or siRNA-mediated depletion of Hsf1, Hsp72 or Hsp27 can selectively cause apoptosis or growth inhibition in various types of cancer [9, 13]. Furthermore, anti-sense RNA against Hsp27 has been tested and demonstrated promising results with bladder cancer [14, 15]. Since downregulation of Hsf1 or chaperones increases the generation of abnormal proteins, while inhibition of proteasome blocks their degradation, the combination of these treatments could synergistically precipitate a selective demise of cancer cells. Indeed, it was demonstrated that downregulation or inhibition of Hsf1 can potently enhance sensitivity of cancer cells to Bortezomib [16, 17]. Accordingly, a lot of efforts and resources have been invested in academic labs and industry in development of inhibitors of Hsf1 and various chaperones, but so far there have been no breakthroughs. The paper by Neznanov et al. [18] offers an alternative approach towards sensitization of cancer cells to proteasome inhibitors. Instead of inhibition of chaperones, this group proposes to cause a buildup of abnormal polypeptides by heat shock. They demonstrated that a mild non-toxic heat shock strongly enhances apoptosis caused by sub-toxic concentrations of Bortezomib. Although there are no data on the effects of heat shock beyond cell culture models, an interesting possibility is that a combination of local hyperthermia and Bortezomib could be beneficial for treatment of localized tumors. Furthermore, since only mild heat treatment was necessary for the synergistic effect with Bortezomib, there is a possibility that the fever-range temperature, which could be triggered by pyrogenes can be sufficient for enhancement of Bortezomib-induced anti-cancer effects. This possibility opens up a range of approaches towards treatment. As an alternative way of generating abnormal proteins, the authors used puromycin. This inhibitor accepts growing polypeptide chains, and aborts further growth, leading to the release of incomplete chains, which of course cannot fold properly and are toxic. At low sub-toxic concentrations, puromycin could strongly potentiate killing of cancer cells by Bortezomib. In this set of experiments, the authors tested not only cell culture models, but also a mouse model of multiple myeloma. They demonstrated that Bortezomib alone only partially reduced growth of multiple myeloma tumors transplanted into syngenic animals. On the other hand, a combination of Bortezomib and low doses of puromycin led to almost complete inhibition. Overall, the combination of proteasome inhibitors with puromycin, heat shock or other treatments that generate a buildup of abnormal polypeptides represents a novel, and potentially powerful approach towards cancer treatment.

Optimization of radioimmunotherapy interactions with hyperthermia

The efficacy of radioimmunotherapy (RIT) employing radiolabelled monoclonal antibodies (MAb) is currently limited in most solid tumours. The combination of local hyperthermia (HT) with RIT has the potential to enhance tumour targeting of MAb; moreover, this approach may add an antitumour effect to radioresistant hypoxic and S-phase cells and may inhibit the cells from repairing sublethal damage or potentially lethal damage caused by ionizing radiation. There are distinct types of protocols in this combination. Hyperthermic temperature and timing relative to RIT administration appear to affect the efficacy of the combination therapy. Responses to heating at any particular condition are not always the same among different tumour types. There are many papers describing influence of HT on the biodistribution of radiolabelled MAb, but only limited information is currently available on ‘therapeutic’ outcomes regarding the dependency of combination protocols. A previous study suggested that the best therapeutic improvement would be achieved when HT was combined immediately after the administration of MAb, which significantly increases the radiation absorbed dose to tumours and produces a uniform intratumoural dose distribution. Further therapeutic investigation should be required to reach the optimal protocol of combining these two modalities.

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas

The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy

Purpose : To examine the possibility that hyperthermia would accelerate drug release from long-circulating liposomes, and enhance their antitumor activity. Methods and Materials : Liposomes were prepared by thin film hydration technique. Hyperthermia was induced by ultrasound apparatus and a water bath heating system. The antitumor efficacy of treatment against RIF-1 tumor in C3H mice was evaluated by the tumor growth delay assay. Results : In vitro drug release experiments demonstrated that increase in temperature from 37°C to 41°C resulted in about a sixfold increase in doxorubicin (DOX) release in a 1-h period. Increasing the temperature to 43°C, resulted in only a modest additional drug release. Drug uptake studies showed that local hyperthermic treatment immediately following the drug administration dramatically enhanced Stealth liposome-encapsulated doxorubicin (S-DOX) uptake by tumors, but did not do so for free DOX. At 42°C and at a dose of 10 mg/kg, the accumulation of S-DOX was about 10-fold and 2.5-fold higher than that with free drug and S-DOX at 37°C, respectively. The antitumor efficacy study confirmed our hypothesis that the addition of hyperthermia to the treatment of RIF-I tumors with doxorubicin encapsulated in long-circulating liposomes would enhance antitumor effects. Two hyperthermia treatments given at 24-h intervals appeared to be the most promising method of combining heat and long-circulating liposomes. The increased antitumor activity was not accompanied by increased toxicity, as determined by the body weight of the mice. Conclusion : Local hyperthermic treatment is able to accelerate DOX release from long-circulating liposomes, increase tumor uptake, and enhance their antitumor efficacy. The combination of local hyperthermia and long-circulating liposomes appears to show considerable promise in the treatment of localized diseases.

Combined hyperthermia and immunotherapy treatment of multiple pulmonary metastases in mice

The combination of immunotherapy and hyperthermia results in a greater reduction in tumour growth compared to either therapy used alone in a murine subcutaneous tumour model. To evaluate this combination further we tested it in a murine pulmonary metastasis model. Mice were given 5 × 10 5 MCA-105 sarcoma cells on day 0 intravenously resulting in the formation of pulmonary metastases. Mice were treated with local hyperthermia to the left hemithorax with a transcutaneous microwave applicator or with whole-body hyperthermia to 41 °C for 30 min on days 3 and 6. Immunotherapy included 5 × 10 7 syngeneic LAK cells administered on days 3 and 6 and interleukin-2 given intraperitoneally three times daily on days 3–7. Animals were killed on day 12 and pulmonary nodules enumerated. While the addtion of whole-body hyperthermia to immunotherapy had no significant effect on tumour growth, the combination of local hyperthermia and immunotherapy significantly decreased the number of pulmonary nodules by 94% compared to controls in combined experiments. The mechanism of this beneficial effect may be related to increased trafficking of immune active cells to the tumour-bearing site, an increase in the sensitivity of tumour cells to lysis, or perhaps a local release of cytokines induced by hyperthermia. This study established the efficacy of combined immunotherapy and hyperthermia for the treatment of visceral metastases and provides impetus for the initiation of clinical trials.

Localized thermo-cisplatin therapy: A pilot study in spontaneous canine and feline tumours

Local hyperthermia combined with intralesional cisplatin chemotherapy is a logical and potentially effective therapeutic approach for localized cancers. A trial using outbred animals with spontaneously occurring tumours was initiated to evaluate the toxicity and efficacy of this approach. Treatment consisted of injection of a colloidal suspension of cisplatin into the tumour prior to hyperthermia once a week for 4 weeks. Immediately after intratumoral injection of a mixture of cisplatin and collagen, thermotherapy was given. The goal temperature was 42 +/- 1 degrees C for 30 min. Ten animals (nine dogs and one cat) with soft tissue neoplasms were treated with one to four hyperthermia and cisplatin sessions for a total of 30 treatment sessions. Complete responses occurred in 4/10 cases (one carcinoma, two sarcomas, one melanoma). One dog with haemangiopericytoma had partial response. The lack of systemic toxicity and the minimal local normal tissue reactions indicate that the treatments were well tolerated. These data provide preliminary evidence that a combination of local hyperthermia and intratumoral cisplatin chemotherapy is a safe and effective method for the treatment of selected localized neoplasms.

Effect of a combination of local hyperthermia with irradiation on tumor tissue hydrolase activity

Effect of a combination of local hyperthermia with irradiation on tumor tissue hydrolase activity

The effects of some physical factors on the production of hyperthermia by ultrasound in neoplastic tissues.

A one-dimensional and a three-dimensional computer model have been built in order to study the importance of blood flow and ultrasonic absorption in tissues during local hyperthermia. The decreased blood flow in the interior of certain tumours and possibly the increased ultrasonic absorption of the malignant tissue in some cases may cause selectively higher temperatures inside the tumours though the heat input is the same as in the surrounding tissues. Also, the vasodilation of blood vessels in normal tissues as a response to heat causes a therapeutically useful temperature difference. These blood flow differences can lead to enhanced effects during sonication to produce hyperthermia in the tumour. The inhomogeneity of blood flow in the tumour causes a non-uniform temperature distribution leaving the well-perfused cells in the advancing front at a much lower temperature than the cells in the necrotic centre. Thus, the combination of local hyperthermia with radio-and chemotherapy seems to offer the most attractive means of destroying malignant tissue.