Fever-range Whole-body Hyperthermia Research Articles

Combined Radiotherapy and Hyperthermia: A Systematic Review of Immunological Synergies for Amplifying Radiation-Induced Abscopal Effects

Introduction: The abscopal effect is a systemic immune response characterized by metastases regression at sites distant from the irradiated lesion. This systematic review aims to explore the immunological mechanisms of action underlying the abscopal effect and to investigate how hyperthermia (HT) can increase the chances of radiotherapy (RT) triggering systemic anti-tumor immune responses. Methods: This review is created in accordance with the PRISMA guidelines. Results and Conclusion: HT and RT have both complementary and synergistic immunological effects. Both methods trigger danger signal release, promoting cytokine and chemokine secretion, which increases T-cell infiltration and facilitates cell death. Both treatments upregulate extracellular tumor HSP70, which could amplify DAMP recognition by macrophages and DCs, leading to stronger tumor antigen presentation and CTL-mediated immune responses. Additionally, the combined increase in cell adhesion molecules (VCAM-1, ICAM-1, E-selectin, L-selectin) could enhance leukocyte adhesion to tumors, improving lymphocyte trafficking and boosting systemic anti-tumor effects. Lastly, HT causes vasodilation and improves blood flow, which might exacerbate those distant effects. We suggest the combination of local radiotherapy with fever-range whole-body hyperthermia to optimally enhance the chances of triggering the abscopal effect mediated by the immune system.

Antitumor Effect of Fever Range Whole Body Hyperthermia with Curcumin in Breast Cancer-induced Mice

Breast cancer is a complex and heterogeneous disease and also one of the major cancer types among female worldwide. Fever range whole-body hyperthermia and curcumin as a single treatment have been tested against breast cancer and showed some promising anti-tumor effect. However, their combination as an effective anti- tumor treatment against breast cancer has never been explored. The effects of combined wholebody fever range hyperthermia and curcumin on tumor growth was examined in this study. Mice were inoculated with EMT6 cells subcutaneously and allocated to 4 treatment groups: (i) control (control), (ii) curcumin (50mg/kg bodyweight), (iii) twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes, (iv) a combination of curcumin (50mg/kg bodyweight) and twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes. Following treatment, mice body weight and tumor volume were measured. The greatest tumor growth inhibition exhibited in combination treatment (68.45%, p<0.05) and showed no general toxicity. As conclusion, the combination treatment can be a potential anti-tumor treatment of breast cancer.

Effect of preoperative fever-range whole-body hyperthermia on immunological markers in patients undergoing colorectal cancer surgery

Previous studies have demonstrated beneficial immunological effects of fever-range whole-body hyperthermia (FR-WBH) as an adjunct to non-surgical cancer therapy. We conducted a study of preoperative FR-WBH in patients undergoing colorectal cancer surgery to evaluate perioperative, hyperthermia-induced immunomodulation. The trial was conducted as a subject-blinded, controlled, randomized study. Subjects in the FR-WBH group (n=9) were treated with FR-WBH before operation under propofol sedation; the target core temperature was 39 (0.5)°C with 1 h warming and 2 h plateau phase. Subjects in the control group (n=9) were treated with propofol sedation only. Blood samples were acquired before and after treatment, after operation, and 24, 48 h, and 5 days after the end of surgery. The following parameters were measured: lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF)-α, procalcitonin (PCT), interleukin (IL)-6/10, heat shock proteins (HSPs) 60, 70, and 90, human leucocyte antigen-DR (HLA-DR), and LPS-binding protein (LBP). HSPs were increased in the FR-WBH group after treatment [HSP60, 48 h postop: 143 (41)% vs 89 (42)%, P=0.04; HSP90, postop: 111 (33)% vs 64 (31)%, P=0.04; HSP70: P=0.40; FR-WBH vs control, P-values for area under the level/time curve]. TNF-α levels were elevated after surgery in the control group and remained near baseline in the FR-WBH group [24 h postop: 73 (68)% vs 151 (72)%, P=0.04]. PCT increased in both groups 24 h after surgery; in the control group, this increase was significantly higher (P=0.02). There were no significant differences for IL, HLA-DR, or LBP. The immune system to react to surgical stress, as measured by a panel of laboratory indicators, might be improved by preoperative FR-WBH.

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2011 American Society of Anesthesiologists Annual Meeting

Thermal Facilitation of Lymphocyte Trafficking Involves Temporal Induction of Intravascular ICAM‐1

Fever is associated with improved survival, although its beneficial mechanisms are poorly understood. Previous studies indicate that the thermal element of fever augments lymphocyte migration across high endothelial venules (HEVs) of lymphoid organs by increasing the intravascular display of a gatekeeper trafficking molecule, intercellular adhesion molecule-1 (ICAM-1). Here, we evaluated the spatio-temporal relationship between the thermal induction of intravascular ICAM-1 and lymphocyte trafficking. Intravascular ICAM-1 density was quantified by immunofluorescence staining in mice exposed to fever-range whole-body hyperthermia (39.5+/-0.5 degrees C). ICAM-1-dependent lymphocyte trafficking was measured in short-term homing assays. A linear relationship was observed between the duration of heat treatment and intravascular ICAM-1 density in HEVs with maximal responses requiring sustained (i.e., five hours) thermal stress. Circulating lymphocytes were found to sense incremental changes in ICAM-1 on HEVs, such that trafficking is proportional to the intravascular density of ICAM-1. We further identified a hydroxamate-sensitive shedding mechanism that restores ICAM-1 expression to homeostatic levels following the cessation of thermal stress. The time-dependent response to thermal stress indicates that ICAM-1 density governs the efficiency of lymphocyte interactions with HEVs in vivo. These studies highlight the dynamic role of the microcirculation in promoting immune surveillance during febrile inflammatory responses.

Fever-range whole body hyperthermia prevents the onset of type 1 diabetes in non-obese diabetic mice

Purpose: Type 1 diabetes (T1D) is an autoimmune disease in which the insulin producing β cells of the pancreatic islets are destroyed by cytotoxic T lymphocytes (CTLs). It has been demonstrated that the injection of complete Freund's adjuvant (CFA) can prevent disease onset in non-obese diabetic (NOD) mice. This effect has been attributed to CFA-enhanced natural killer (NK) cell mediated control of autoimmune CTLs. Fever-range whole body hyperthermia (FR-WBH) has also been shown to stimulate NK cell cytotoxicity. This led to the hypothesis that FR-WBH can prevent disease onset in NOD mice by a thermally regulated mechanism.Methods: FR-WBH or mock treatment was administered weekly until the NOD mice reached 32 weeks of age. Blood glucose levels were monitored weekly, with measurements ≥33.5 mM indicating onset of diabetes, at which time the mice were euthanized for histological and cellular analyses.Results: Weekly FR-WBH prevented the onset of T1D in NOD mice and this effect correlated with increased NK cell cytotoxicity and control of blood glucose concentration. Histological analysis revealed significantly fewer lymphocytes infiltrating the pancreatic islets of FR-WBH treated mice than those of untreated mice, suggesting a relationship between thermally induced protection of β cells and their ability to regulate blood glucose concentrations.Conclusions: These studies show, for the first time, that mild systemic hyperthermia can prevent the generation of T1D in a clinically relevant mouse model. Further study of the thermally sensitive aspects of immunoregulation could lead to the development of heat-based therapies for the prevention or treatment of autoimmune diseases.

Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin

Purpose: Two major questions were addressed: (1) Can fever-range whole body hyperthermia (FR-WBH) affect the number of perfused tumor blood vessels? (2) Can pre-treatment with FR-WBH improve accumulation or anti-tumor efficacy of doxorubicin or DOXIL (liposomal doxorubicin)?Materials and methods: Perfused blood vessels were visualized by intravenous injection of the fluorescent dye (DiOC7(3)) and the number of labeled vessels in tumors and normal organs of unheated mice and those previously heated to 39.5°C for 6 hours were compared. Using three animal tumor models (one syngeneic murine model and two human tumor xenografts in SCID mice) we also compared tumor growth and amount of intratumoral doxorubicin (given as free drug or as DOXIL) in control mice or those given pre-treatment with FR-WBH.Results: FR-WBH had no effect on the number of CD-31 labeled blood vessels. However, in tumors, but not in normal organs of the same animals, FR-WBH resulted in a significant increase in those blood vessels which could take up dye over a prolonged period of time after heating. There was also an increase in DOXIL uptake in the tumors of mice given FR-WBH prior to drug injection as well as enhanced therapeutic efficacy in all three tumor models.Conclusions: FR-WBH increases the number of perfused blood vessels in tumors over a prolonged period following FR-WBH and thus may be useful for improving tumor targeting of cancer therapeutics. We discuss these data in relation to long-conserved thermoregulatory features in normal vasculature, which may be deficient in tumor vasculature.

An Important Role for Granulocytes in the Thermal Regulation of Colon Tumor Growth

Several lines of research show that cells of the immune response are sensitive to thermal variations in their microenvironment, such as that which occurs during inflammation and fever; these data have led to the hypothesis that strategic applications of heat could assist in controlling tumor growth in animal models. The innate immune response is known to play a critical role in the development of effective anti-tumor immunity and granulocytes such as polymorphonuclear neutrophils (PMNs), as key mediators of inflammation, have been suggested to have the potential to initiate immune response cascades against tumors. Thus, we hypothesized that PMNs may play a crucial role in mediating the anti-tumor effect of a mild, fever-range whole-body hyperthermia (FR-WBH) protocol, where core body temperatures are raised to 39.5–40°C for 8 hrs. Indeed, in BALB/c mice bearing the colon tumor CT26, the anti-tumor effects of WBH correlates with increased granulocytic infiltrate at the tumor site as determined using immunohistochemical analysis for Gr-1+ cells. In both BALB/c mice bearing CT26 and SCID mice bearing human colon tumors, PMN depletion in vivo using anti-Gr-1 ascites ablated the anti-tumor effect of mild WBH. Because mild thermal stress is also found to enhance the respiratory burst of granulocytes, these data collectively suggest that the thermal stimulation of granulocytes may help to prevent tumor establishment. Overall, these results may have implications for the design of thermal therapy protocols in cancer immunotherapy.

The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on rat mammary adenocarcinoma metastases

Many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumour diagnosis. The development and growth of these micro-metastases relies heavily on angiogenesis. Therefore, administering an angiogenesis-blocking treatment from the time of diagnosis could reduce the incidence of metastasis and, ultimately, increase patient survival. It is hypothesized that an antiangiogenesis strategy combining fever-range whole-body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the development of metastatic disease with minimal toxicity. To test this theory, a low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT-11) was administered over a prolonged period of time to rats bearing the highly metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day 12 after implantation. The metronomic CPT-11 was combined with long-duration, low-temperature, fever-range whole body hyperthermia (FR-WBH). This systemic hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological activity. Both the group treated with FR-WBH alone and the combined FR-WBH+CPT-11 group had delayed onset and reduced incidence of axillary lymph node metastases compared to control ( p < 0.05). Combination therapy of FR-WBH+CPT-11 resulted in a significantly greater inhibition of axillary lymph node metastasis volume compared to both control and CPT-11 alone ( p < 0.02) at day 16. Interestingly, none of the therapies significantly affected inguinal lymph node metastases. Lung metastases were decreased by 36% at the time of death in rats treated with FR-WBH+CPT-11, by 25% in the CPT-11 alone group and by 14% in the FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly longer (35%) than control animals ( p < 0.04). Neither significant body weight loss nor gastrointestinal toxicity was observed in any group. These data suggest that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be safely combined to reduce distant lymph node and lung metastases and, thus, to increase survival.

A phase I study of fever-range whole body hyperthermia (FR-WBH) in patients with advanced solid tumours: correlation with mouse models

Various studies in animal tumour models have revealed the potential of fever-range whole body hyperthermia (FR-WBH) to be used in cancer therapy. To determine the safety of FR-WBH treatment in the clinic, patients with advanced solid tumours were heated in the outpatient setting to 39-39.5°C for 3 or 6h, or 39.5-40°C for 6h using the Heckel-HT 2000 apparatus. These WBH treatments were well tolerated, with no significant adverse events related to cardiac, hepatic, renal or pulmonary systems. In the majority of patients, flow cytometric analysis of peripheral blood leukocyte populations indicated that there were transient decreases in the number of circulating T lymphocytes and a concomitant decrease in the number of L-selectin positive lymphocytes in the peripheral blood. These findings closely mimic the affects seen previously in pre-clinical murine studies in which this same fever-like treatment was shown to inhibit tumour growth. These studies have established the safety of this treatment and will allow for future clinical trials where application of FR-WBH treatment can be combined with other anti-cancer therapies, including immunotherapy and chemotherapy.

Regulatory Potential of Fever-Range Whole Body Hyperthermia on Langerhans Cells and Lymphocytes in an Antigen-Dependent Cellular Immune Response

The febrile response is one of the most common features of infection and inflammation. However, temperature is rarely a variable in experimental immunological investigations. To determine whether the thermal microenvironment has any immunoregulatory potential in an Ag-dependent response, we applied a mild fever-range whole body hyperthermia (FR-WBH) protocol to BALB/c mice experiencing the contact hypersensitivity (CHS) reaction. We observed that the timing of this FR-WBH treatment relative to the different phases of the CHS response was crucial to the outcome. FR-WBH treatment before sensitization with a 0.5% FITC solution resulted in a depressed CHS response. This appears to be due to direct effects of FR-WBH on epidermal Langerhans cell trafficking to the draining lymph nodes. In contrast, application of FR-WBH directly after application of the elicitation dose of FITC solution resulted in an enhanced reaction. This result correlates with increased homing of lymphocytes to the site of elicitation. Overall, these data have important implications regarding the role of thermal changes experienced during infection and the clinical use of FR-WBH relative to immunotherapeutic strategies.

Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response

The thermal component of fever is one of the most poorly understood aspects of inflammation. To evaluate the role of fever-range hyperthermia on acute inflammation, BALB/c and C57BL/6 mice were exposed to mild, long-duration whole-body hyperthermia (WBH), and serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and the acute phase proteins (APPs) alpha1-acid glycoprotein and haptoglobin were analyzed. WBH alone did not affect serum concentrations of these cytokines or APPs when compared with controls. In contrast, when WBH was applied just after intraperitoneal administration of lipopolysaccharide (LPS), serum concentrations of TNF-alpha and IL-6 were greater than or equal to threefold higher in BALB/c mice compared with LPS-treated controls. LPS-induced IL-6 levels were also enhanced in WBH-treated C57BL/6 mice. However, APP levels were prolonged only in WBH-treated BALB/c mice. It is interesting that in vitro hyperthermia treatment of LPS-stimulated peritoneal cells resulted in decreased cytokine production compared with controls. These results suggest that fever-range hyperthermia regulates acute inflammation in a mouse strain-specific manner that is more complex than that observed in vitro.