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

Background: 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. Methods: 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). Results: 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. Conclusions: The immune system to react to surgical stress, as measured by a panel of laboratory indicators, might be improved by preoperative FR-WBH.

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder – A Randomized Clinical Trial.

Importance: Limitations of current antidepressants highlight the need to identify novel treatments for major depressive disorder. A prior open trial found that a single session of whole-body hyperthermia (WBH) reduced depressive symptoms; however, the lack of a placebo control raises the possibility that the observed antidepressant effects resulted not from hyperthermia per se, but from nonspecific aspects of the intervention. Objective: To test whether WBH has specific antidepressant effects when compared with a sham condition and to evaluate the persistence of the antidepressant effects of a single treatment. Design, setting, and participants: A 6-week, randomized, double-blind study conducted between February 2013 and May 2015 at a university-based medical center comparing WBH with a sham condition. All research staff conducting screening and outcome procedures were blinded to randomization status. Of 338 individuals screened, 34 were randomized, 30 received a study intervention, and 29 provided at least 1 postintervention assessment and were included in a modified intent-to-treat efficacy analysis. Participants were medically healthy, aged 18 to 65 years, met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score of 16 or greater. Interventions: A single session of active WBH vs a sham condition matched for length of WBH that mimicked all aspects of WBH except intense heat. Main outcomes and measures: Between-group differences in postintervention Hamilton Depression Rating Scale scores. Results: The mean (SD) age was 36.7 (15.2) years in the WBH group and 41.47 (12.54) years in the sham group. Immediately following the intervention, 10 participants (71.4%) randomized to sham treatment believed they had received WBH compared with 15 (93.8%) randomized to WBH. When compared with the sham group, the active WBH group showed significantly reduced Hamilton Depression Rating Scale scores across the 6-week postintervention study period (WBH vs sham; week 1: -6.53, 95% CI, -9.90 to -3.16, P < .001; week 2: -6.35, 95% CI, -9.95 to -2.74, P = .001; week 4: -4.50, 95% CI, -8.17 to -0.84, P = .02; and week 6: -4.27, 95% CI, -7.94 to -0.61, P = .02). These outcomes remained significant after evaluating potential moderating effects of between-group differences in baseline expectancy scores. Adverse events in both groups were generally mild. Conclusions and relevance: Whole-body hyperthermia holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit.

Ganzkörperhyperthermie mit wasser – gefilterter Infrarot-A-Strahlung bei Patienten mit axialer Spondyloarthritis

Hyperthermia is an artificial induced increase of temperature of the whole body or single parts of the body by physical methods. A relatively new and rarely evaluated modality is the mild water filtered near infrared whole-body hyperthermia. According to our prospective controlled study this form of hyperthermia twice a week within a 3-week multimodal rehabilitation program can effect a sustainable pain reduction in patients with ankylosing spondylitis. Critical adverse effects could not be observed. Though we can not yet argue for an explicit recommendation because of missing evidence regarding other outcome variables like disease activity, functional capacity and independence in daily living. Furthermore the state of research is insufficient. More studies are needed.

Wirkung iterativer Ganzkörperhyperthermie mit wassergefilterter Infrarot-A-Strahlung bei Arthritis psoriatica – eine kontrollierte, randomisierte, prospektive Studie

This controlled, randomised and prospective study evaluated the effects of whole-body hyperthermia by mild water-filtered infrared A radiation (wIRAS) in patients with psoriatic arthritis. For this purpose, 35 acute inpatients were randomized into 2 groups: 15 received a standardised physical therapy (control group – KG), and 20 received additional serial whole-body hyperthermia by mild water-filtered infrared A radiation (intervention group – IG). The medication in both groups was comparable. The following outcome parameters were analysed before, immediately after and 3 months after the serial wIRAS therapy in the IG and at a temporally analogous point in the KG: pain (visual analogue scale – VAS), parameters of activity and function (Disease Activity Score 28 – DAS28, Health Assessment Questionnaire – HAQ, Funktionsfragebogen Hannover – FFbH, Psoriasis Area and Severity Index – PASI), inflammatory markers (erythrocyte sedimentation rate – ESR, C-reactive protein – CRP), and proinflammatory cytokines (TNF-α, IL-6, IL-1β). In the IG, VAS, HAQ, and DAS28 were measured also after 6 months. Compared to the KG the IG presented a significant pain relief over the observation period, reflected by a decrease in pain medication. Only the IG showed a significant decrease in the DAS28 (persistent up to 6 months) and the FFbH (partially persistent after 3 months). The HAQ was improved significantly in both groups (persistent up to 6 months only in the IG). Furthermore, in the IG the levels of TNF- α, IL-6, and IL-1β remained stable, matching the clinical course without exacerbation. The KG showed a significant decrease of TNF-α levels immediately, followed by a significant increase. IL-1 levels remained primarily stable, then increased significantly after 3 months, but without any clinical correlate. No changes were seen in ESR, CRP and PASI values in both groups. Whole-body hyperthermia by mild water-filtered ¬infrared A ¬radiation represents a valuable and well-tolerated physiotherapeutic tool. It can thus be regarded as a useful adjunct in the multimodal therapy concept for APS and to improves the medium-term treatment outcomes.

Wirkung iterativer Ganzkörperhyperthermie mit wassergefilterter Infrarot-A-Strahlung bei ankylosierender Spondylitis – eine kontrollierte, randomisierte, prospektive Studie

In der kontrollierten, randomisierten und prospektiven Studie galt das Interesse der Wirkung einer iterativen Ganzkorperhyperthermie mittels wassergefilterter Infrarot-A-Strahlung (wIRAS) bei Patienten mit ankylosierender Spondylitis (AS). Hierzu wurden 35 akut-stationare Patienten in 2 Gruppen randomisiert: 15 Patienten erhielten eine standardisierte physikalische Therapie (Kontrolle – KG) und 20 Patienten erhielten zusatzlich eine serielle Ganzkorperhyperthermie mittels wIRAS (Interventionsgruppe – IG, insgesamt 6 Anwendungen). Die Medikation in beiden Gruppen war vergleichbar. Folgende Outcomeparameter wurden vor, direkt nach sowie 3 Monate nach der seriellen wIRAS in der IG sowie zeitlich analog in der KG analysiert: Schmerzen (visuelle Analogskala – VAS), Aktivitats- und Funktionsparameter (Bath Ankylosing Spondylitis Disease Activity Index – BASDAI, Bath Ankylosing Spondylitis Disease Functional Index – BASFI, Health Assessment Questionnaire – HAQ, Funktionsfragebogen Hannover – FFbH), Patientenzufriedenheit, Entzundungswerte (BSG, CRP) und proinflammatorische Zytokine (TNF-α, IL-1s, IL-6). In der IG wurden nach 6 Monaten die Aktivitats- und Funktionsparameter sowie die Medikation nochmals erhoben. In der IG konnte im Vergleich zur KG eine signifikante Schmerzlinderung uber den Beobachtungszeitraum objektiviert werden, mit konsekutiver Abnahme der NSAR/Analgetika-Therapie. Nur die IG zeigte eine signifikante Abnahme des BASDAI und Verbesserung im BASFI (jeweils bis zu 6/3 Monate anhaltend) sowie beim FFbH (nach 3 Monaten vs. Baseline). Beim HAQ-Score war in beiden Gruppen keine signifikante Verbesserung objektivierbar. Bei den normwertigen BSG- und CRP-Werten zeigte sich in der IG bei der BSG ein signifikanter Abfall. In der IG fielen nach 3 Monaten die TNF-α- und IL-1s-Spiegel signifikant ab, in der KG zeigte sich nach 3 Monaten ebenfalls ein signifikanter Abfall beim TNF-α. Die IL-6-Spiegel blieben uber den Studienzeitraum in beiden Gruppen stabil. Das Verfahren der Ganzkorperhyperthermie stellt ein praktikables und vom Patienten gut toleriertes Physiotherapeutikum dar. Es kann somit als eine sinnvolle Erganzung im multimodalen Therapiekonzept der AS angesehen werden und unterstutzt die mittelfristigen Behandlungsergebnisse signifikant.

Whole body hyperthermia treatment increases interleukin 10 and toll-like receptor 4 expression in patients with ankylosing spondylitis: A pilot study

Purpose: Exposure to increased environmental temperatures is commonly used as a non-pharmacological treatment modality in ankylosing spondylitis (AS). We aimed to investigate systemic immunological effects of moderate whole body hyperthermia in patients with AS compared to healthy control subjects. Materials and methods: Ten healthy control subjects and six AS patients underwent whole body hyperthermia treatment with 38.7–39 °C body core temperature over 60 min. Numbers of polymorphonuclear leucocytes and lymphocyte subsets, plasma concentrations of several acute phase reactants and cytokines, and gene expression levels of toll-like receptor 4 (TLR-4), interleukin 10 (IL-10) and heat shock protein beta 1 (HSPB1) were determined during and up to 24 h after treatment. Results: TLR-4, IL-10 and HSPB1 gene expression increased significantly up to 3 h post treatment, with an earlier, higher and more pronounced increase of IL-10 in patients with AS. An increase of natural killer cells and CD8+ T lymphocytes was noted during active heating, with a subsequent decrease up to 2 h after treatment. CD4+ T lymphocytes showed a short increase during active treatment in AS patients, while decreasing immediately after start of treatment in control subjects. Neutrophil granulocytes increased significantly up to 3 h after treatment, monocytes and B lymphocytes remained unchanged. Likewise, no significant changes were found concerning systemic cytokine concentrations and acute phase reactants. Conclusions: Our data support the concept of systemic immunological effects of moderate whole body hyperthermia in patients with AS.

Small fibre pathology in patients with fibromyalgia syndrome

Fibromyalgia syndrome is a clinically well-characterized chronic pain condition of high socio-economic impact. Although the pathophysiology is still unclear, there is increasing evidence for nervous system dysfunction in patients with fibromyalgia syndrome. In this case-control study we investigated function and morphology of small nerve fibres in 25 patients with fibromyalgia syndrome. Patients underwent comprehensive neurological and neurophysiological assessment. We examined small fibre function by quantitative sensory testing and pain-related evoked potentials, and quantified intraepidermal nerve fibre density and regenerating intraepidermal nerve fibres in skin punch biopsies of the lower leg and upper thigh. The results were compared with data from 10 patients with monopolar depression without pain and with healthy control subjects matched for age and gender. Neurological and standard neurophysiological examination was normal in all patients, excluding large fibre polyneuropathy. Patients with fibromyalgia syndrome had increased scores in neuropathic pain questionnaires compared with patients with depression and with control subjects (P < 0.001 each). Compared with control subjects, patients with fibromyalgia syndrome but not patients with depression had impaired small fibre function with increased cold and warm detection thresholds in quantitative sensory testing (P < 0.001). Investigation of pain-related evoked potentials revealed increased N1 latencies upon stimulation at the feet (P < 0.001) and reduced amplitudes of pain-related evoked potentials upon stimulation of face, hands and feet (P < 0.001) in patients with fibromyalgia syndrome compared to patients with depression and to control subjects, indicating abnormalities of small fibres or their central afferents. In skin biopsies total (P < 0.001) and regenerating intraepidermal nerve fibres (P < 0.01) at the lower leg and upper thigh were reduced in patients with fibromyalgia syndrome compared with control subjects. Accordingly, a reduction in dermal unmyelinated nerve fibre bundles was found in skin samples of patients with fibromyalgia syndrome compared with patients with depression and with healthy control subjects, whereas myelinated nerve fibres were spared. All three methods used support the concept of impaired small fibre function in patients with fibromyalgia syndrome, pointing towards a neuropathic nature of pain in fibromyalgia syndrome.

Multi-modal pain therapy of fibromyalgia syndrome with integration of systemic whole-body hyperthermia – effects on pain intensity and mental state: A non-randomised controlled study.

Objectives: This controlled study evaluates a multi-modal pain therapy for treating severe progressions of fibromyalgia [FMS] syndrome. The aim is to establish whether the use of multi-modal therapy with inclusion of whole-body hyperthermia represents a useful therapeutic addition to inpatient therapy of FMS syndrome at a high level of chronification. Methods: The study involved 130 patients who fulfilled the criteria of the American College of Rheumatology [ACR] for FMS and whose disease showed severe progression. One group of patients [HTG] received whole-body hyperthermia, while the control group [CG] did not. The main parameters of the study were pain intensity and the mental state of the patients. Further study parameters were the diagnoses additional to FMS syndrome and the therapy density of the treatment provided in the two groups. Results: The integration of whole-body hyperthermia into the multi-modal pain therapy showed superior pain reduction [p = 0.023] and an improvement in the mental state of the patients [p = 0.055]. In addition to the primary disease, the patients presented with an average of 6.7 accompanying diseases, primarily from major diagnostic categories 8 [diseases and disturbances of the musculoskeletal system and connective tissues], 19 [mental diseases and disturbances] and 10 [endocrine, nutritional and metabolic diseases]. Analysis of the therapy density of the inpatient multi-modal pain therapy revealed a close-meshed and high-frequency therapy. Conclusions: Multi-modal pain therapy was also found to be a highly effective therapy option in the case of severely progressive FMS syndrome. Extension of the multi-modal therapy setting to include whole-body hyperthermia can be considered as a useful and effective complement for pain relief and stabilisation of the mental state.

Milde Ganzkörperhyperthermie in Kombination mit stationärer multimodal orientierter Schmerztherapie – Evaluation bei Patienten mit chronischem unspezifischem lumbalem Rückenschmerz.

Purpose: A randomized controlled clinical trial was implemented to evaluate the effectiveness of combined mild hyperthermia therapy (body core temperature 38.4 °C) and multimodal inpatient rehabilitation for patients suffering from chronic low back pain when compared to multimodal pain therapy alone. Patients and methods: A total of 88 patients were randomly assigned to the combined or single therapeutic schemes according to a block randomization scheme. According to the trial inclusion criteria all patients suffered from chronic low back pain and showed morphological degeneration. All patients underwent a 12-day inpatient multimodal pain therapy, which was complemented with a 6-session schedule of mild hyperthermia therapy for the intervention group (1 h at 38.6 °C). On admission and 3 months after treatment the study patients were asked to complete an interview assessment with the Oswestry low back pain disability questionnaire (Oswestry disability index). The change in the Oswestry disability index total score (%) 3 months after versus before therapy was defined as the primary clinical endpoint of the investigation. The patients in the control group and in the intervention group had a median age of 50 years. In the intervention group 70 % of the patients were female and 55 % reported having half to full time employment compared to 55 % and 43 % in the control group, respectively. Results: On admission the control patients reported a median Oswestry disability index of 64 % and on recall the same of 64 %. The intervention group showed median Oswestry disability index estimates of 60 % and 66 %, respectively. The changes in the overall Oswestry disability index after 3 months differed significantly with an estimated 6 % for the intervention group versus 0 % for the control group (Wilcoxon p = 0.050). Conclusion: When combined with a multimodal inpatient lower back pain functional therapy in patients showing morphological degeneration, the mild hyperthermia therapy demonstrated statistically significant, although not clinically relevant benefits in comparison to the multimodal treatment alone. However, regarding the moderate overall patient-related benefits as measured in terms of the Oswestry disability index, the benefit of the underlying multimodal therapy concept implementation must be critically discussed irrespective of its combination with mild hyperthermia therapy.

Influence of Frequency and Temperature on the Mechanisms of Nerve Conduction Block Induced by High-Frequency Biphasic Electrical Current

The influences of stimulation frequency and temperature on mechanisms of nerve conduction block induced by high-frequency biphasic electrical current were investigated using a lumped circuit model of the myelinated axon based on Schwarz and Eikhof (SE) equations. The simulation analysis showed that a temperature-frequency relationship was determined by the axonal membrane dynamics (i.e. how fast the ion channels can open or close.). At a certain temperature, the axonal conduction block always occurred when the period of biphasic stimulation was smaller than the action potential duration (APD). When the temperature decreased from 37°C to 15°C, the membrane dynamics slowed down resulting in an APD increase from 0.4 ms to 2.4 ms accompanied by a decrease in the minimal blocking frequency from 4 kHz to 0.5 kHz. The simulation results also indicated that as the stimulation frequency increased the mechanism of conduction block changed from a cathodal/anodal block to a block dependent upon continuous activation of potassium channels. Understanding the interaction between the minimal blocking frequency and temperature could promote a better understanding of the mechanisms of high frequency induced axonal conduction block and the clinical application of this method for blocking the nerve conduction.

Increasing temperature speeds intracellular PO2 kinetics during contractions in single xenupus skeletal fibers

Precise determination of the effect of muscle temperature (Tm) on mitochondrial oxygen consumption kinetics has proven difficult in humans, in part due to the complexities in controlling for Tm-related variations in blood flow, fiber recruitment, muscle metabolism, and contractile properties. To address this issue, intracellular Po2 (PiO2) was measured continuously by phosphorescence quenching following the onset of contractions in single Xenopus myofibers (n = 24) while controlling extracellular temperature. Fibers were subjected to two identical contraction bouts, in random order, at 15°C (cold, C) and 20°C (normal, N; n = 12), or at N and 25°C (hot, H; n = 12). Contractile properties were determined for every contraction. The time delay of the PiO2 response was significantly greater in C (59 ± 35 s) compared with N (35 ± 26 s, P = 0.01) and H (27 ± 14 s, P = 0.01). The time constant for the decline in PiO2 was significantly greater in C (89 ± 34 s) compared with N (52 ± 15 s; P < 0.01) and H (37 ± 10 s; P < 0.01). There was a linear relationship between the rate constant for PiO2 kinetics and Tm (r = 0.322, P = 0.03). Estimated ATP turnover was significantly greater in H than in C (P < 0.01), but this increased energy requirement alone with increased Tm could not account for the differences observed in PiO2 kinetics among conditions. These results demonstrate that PiO2 kinetics in single contracting myofibers are dependent on Tm, likely caused by temperature-induced differences in metabolic demand and by temperature-dependent processes underlying mitochondrial activation at the start of muscle contractions.

Entstehung und Metastasierung des Pankreaskarzinoms mit Fokus auf Tumorhypoxie, EMT und Krebsstammzellen (KSZ)

Due to new scientific findings, initiation, growth and metastasis of malignant tumors appear in new light today. The cancer stem cell (CSC) theory explains why tumors expand, invade and survive conventional tumor therapy. Using the example of aggressive and highly invasive pancreatic cancer the present article gives an overview about mechanisms of initiation and metastasis of this tumor entity. In the last years growing evidence underlines the importance of the tumor microenvironment as rout of tumor growth and metastasis. An important factor at this is tumor hypoxia, since an oxygen-depleted tumor region activates a signal transduction cascade, which favors tumor growth and metastasis. Under hypoxic growth conditions the presence of cancer stem cell markers is enhanced, which are thereafter induced to undergo epithelial-mesenchymal transition by oxygen-depletion. Several in vitro and animal examinations demonstrate that hypoxia creates the prerequisites for invasion of tumor cells to distant organs. Therapeutic aim of a new concept in therapy of pancreatic cancer does therefore not focus to elimination of cancer stem cells itself. Rather the rout of development of cancer stem cells should be targeted by elimination of tumor hypoxia.

Local tumour hyperthermia as immunotherapy for metastatic cancer

Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed.

Fever-range whole-body heat treatment stimulates antigen-specific T-cell responses in humans

Increase in body temperature has been thought to play an important role in the regulation of immune responses, although its precise mechanisms are still under investigation. Here, we examined the effects of physiologically relevant thermal stress on the cytokine production from human peripheral T cells. Volunteers were heated using a whole-body hyperthermia device, the rectal temperature was maintained above 38.5 °C for more than 60 min, and peripheral blood mononuclear cells (PBMCs) were obtained before and after the treatment. When T cells were stimulated with anti-CD3/CD28 antibodies, marked increases in the production of interferon-γ (IFN-γ) and interleukin-2 were observed in PBMCs prepared immediately after and 24h after the treatment. Similarly, enhanced production of IFN-γ in response to the tuberculin purified protein derivative or antigenic viral peptides was also observed immediately after and 24h after the treatment. Fluorescence photo-bleaching analyses showed heat-induced increase of membrane fluidity in T cells, which probably enables them to induce rapid and efficient cluster formation of molecules involved in antigen recognition and signal transduction for T-cell stimulation. We concluded that physiologically relevant thermal stress could efficiently modify T-cell responsiveness to various stimuli, including enhanced responses to specific antigens.

Effector CD8+ T cell IFN- γ production and cytotoxicity are enhanced by mild hyperthermia

Purpose: Clinical trials combining hyperthermia with radiation and/or chemotherapy for cancer treatment have resulted in improved overall survival and control of local recurrences. The contribution of thermally enhanced anti-immune function in these effects is of considerable interest, but not understood; studies on the fundamental effects of elevated temperature on immune effector cells are needed. The goal of this study is to investigate the potential of mild hyperthermia to impact tumour antigen-specific (Ag) effector CD8+ T cell functions. Method: Pmel-1 Ag-specific CD8+ T cells were exposed to mild hyperthermia and tested for changes in IFN-γ production and cytotoxicity. Additionally, overall plasma membrane organisation and the phosphorylation of signalling proteins were also investigated following heat treatment. Results: Exposing effector Pmel-1-specific CD8+ T cells to mild hyperthermia (39.5°C) resulted in significantly enhanced Ag-specific IFN-γ production and tumour target cell killing compared to that seen using lower temperatures (33° and 37°C). Further, inhibition of protein synthesis during hyperthermia did not reduce subsequent Ag-induced IFN-γ production by CD8+ T cells. Correlated with these effects, we observed a distinct clustering of GM1(+) lipid microdomains at the plasma membrane and enhanced phosphorylation of LAT and PKCθ which may be related to an observed enhancement of Ag-specific effector CD8+ T cell IFN-γ gene transcription following mild hyperthermia. However, mitogen-mediated production of IFN-γ, which bypasses T cell receptor activation with antigen, was not enhanced. Conclusions: Antigen-dependent effector T cell activity is enhanced following mild hyperthermia. These effects could potentially occur in patients being treated with thermal therapies. These data also provide support for the use of thermal therapy as an adjuvant for immunotherapies to improve CD8+ effector cell function.

IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells

Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor–α and thermally induced gp130 to promote E/P-selectin– and ICAM-1–dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor–α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6–dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6–rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell–mediated antitumor immunity and immunotherapy.

Differentiation of CD8+ T cells into effector cells is enhanced by physiological range hyperthermia

In this study, we asked whether exposure to different physiologically relevant temperatures (33°C, 37°C, and 39.5°C) could affect subsequent antigen-specific, activation-related events of naive CD8+ T cells. We observed that temporary exposure of CD62LhiCD44lo Pmel-1 CD8+ cells to 39.5°C prior to their antigen-dependent activation with gp10025–33 peptide-pulsed C57BL/6 splenocytes resulted in a greater percentage of cells, which eventually differentiated into CD62LloCD44hi effector cells compared with cells incubated at 33°C and 37°C. However, the proliferation rate of naive CD8+ T cells was not affected by mild heating. While exploring these effects further, we observed that mild heating of CD8+ T cells resulted in the reversible clustering of GM1+ CD-microdomains in the plasma membrane. This could be attributable to a decrease in line tension in the plasma membrane, as we also observed an increase in membrane fluidity at higher temperatures. Importantly, this same clustering phenomenon was observed in CD8+ T cells isolated from spleen, LNs, and peripheral blood following mild whole-body heating of mice. Further, we observed that mild heating also resulted in the clustering of TCRβ and the CD8 coreceptor but not CD71R. Finally, we observed an enhanced rate of antigen-specific conjugate formation with APCs following mild heating, which could account for the difference in the extent of differentiation. Overall, these novel findings may help us to further understand the impact of physiologically relevant temperature shifts on the regulation of antigen-specific CD8+ T cell activation and the subsequent generation of effector cells.

Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism

Fever is an evolutionarily conserved response during acute inflammation, although its physiological benefit is poorly understood. Here we show thermal stress in the range of fever temperatures increased the intravascular display of two ‚gatekeeper‘ homing molecules, intercellular adhesion molecule 1 (ICAM-1) and CCL21 chemokine, exclusively in high endothelial venules (HEVs) that are chief portals for the entry of blood-borne lymphocytes into lymphoid organs. Enhanced endothelial expression of ICAM-1 and CCL21 was linked to increased lymphocyte trafficking across HEVs. A bifurcation in the mechanisms controlling HEV adhesion was demonstrated by evidence that the thermal induction of ICAM-1 but not of CCL21 involved an interleukin 6 trans-signaling pathway. Our findings identify the ‚HEV axis‘ as a thermally sensitive alert system that heightens immune surveillance during inflammation by amplifying lymphocyte trafficking to lymphoid organs.

Fever-range hyperthermia enhances L-selectin-dependent adhesion of lymphocytes to vascular endothelium

The L-selectin leukocyte adhesion molecule plays an important role in controlling leukocyte extravasation in peripheral lymph nodes and at sites of tissue injury or infection. Although febrile responses during infection and inflammation are associated with enhanced immune activity, the contribution of fever-range temperatures to controlling lymphocyte recruitment to tissues has not been previously examined. In this report we provide evidence that direct exposure of lymphocytes to fever-range temperatures (38-41 degrees C) in vitro for 9 to 24 h resulted in a >100% increase in L-selectin-dependent adhesion of these cells to lymph node high endothelial venules (HEV). Moreover, culture of lymphocytes under hyperthermia conditions markedly enhanced the ability of these cells to traffic in an L-selectin-dependent manner to peripheral lymph nodes, mesenteric lymph nodes, and Peyer’s patches. In contrast, febrile temperatures did not increase LFA-1 function as assessed by measuring lymphocyte adhesion to ICAM-1-3T3 transfectants. Fever-range hyperthermia further did not increase L-selectin surface density on lymphocytes or L-selectin-dependent recognition of soluble carbohydrate substrates; however, a marked increase in ultrastructural immunogold-labeling of L-selectin was observed in response to thermal stimuli. These results suggest that elevated temperatures enhance L-selectin adhesion and/or avidity through the regulation of L-selectin conformation or organization in the plasma membrane. Finally, the observed thermal effects on L-selectin adhesion were attributed to soluble factors in the conditioned medium of heat-treated cells. Taken together, these data provide new insight into the potential physiologic role of the febrile response in enhancing lymphocyte recruitment to tissues through the regulation of L-selectin adhesion.

Effects of local and whole body hyperthermia on immunity

In this review, we summarized the historical and experimental basis of cancer immunity and the role of fever and of artificial elevation of temperature on immunity. The interactions of heat in vitro and in vivo on cytotoxicity of immune competent cells are discussed as their positive contribution on the various cancer immunotherapeutic strategies. Furthermore, we have described the link existing among Heat shock proteins, Toll like receptors and innate immunity justifying the use of temperature elevation for treating cancer. The disputed and life-threatening effect of local and whole body hyperthermia on metastasizing is also reviewed.

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.

Opposing roles for heat and heat shock proteins in macrophage fuctions during inflammation: a function of cell activation state?

Macrophages function both under normothermia and during periods of body temperature elevation (fever). Whether macrophages sense and respond to thermal signals in a manner which regulates their function in a specific manner is still not clear. In this brief review, we highlight recent studies which have analyzed the effects of mild heating on macrophage cytokine production, and summarize thermally sensitive molecular mechanisms, such as heat shock protein (HSP) expression, which have been identified. Mild, physiologically achievable, hyperthermia has been shown to have both pro- and anti-inflammatory effects on macrophage inflammatory cytokine production and overall it is not clear how hyperthermia or HSPs can exert opposing roles on macrophage function. We propose here that the stage of activation of macrophages predicts how they respond to mild heating and the specific manner in which HSPs function. Continuing research in this area is needed which will help us to better understand the immunological role of body temperature shifts. Such studies could provide a scientific basis for the use of heat in treatment of inflammatory diseases.

Sympathoadrenal regulation of circulatory responses to whole-body hyperthermia induced by the application of Piestany thermal water and thermal mud.

Application of warm substance during hyperthermic thermal procedures is accompanied by increase in body core temperature. Hyperthermia triggers thermoregulatory response in order to dissipate accumulating heat from body into ambient environment. Autonomic nervous system is a primary tool to regulate the organs involved in the thermal homeostasis: liver, skeletal muscle, respiratory system, cardiovascular system and sweat glands. In the present study the effect of non-immersion induced hyperthermia by mud pack versus hyperthermia induced by hyperthermic thermal bath on the sympathoadrenal activation and the cardiovascular response were clarified against the effects of water bath in thermoneutral water. Nine healthy men were exposed to mud application (15 minutes, 46°C), head-up hot (39°C) and thermoneutral (36°C) water bathes (25 minutes). Body temperature was measured sublingually and the blood was sampled immediately before and in the last minute of the procedure. Body temperature was increased after application of mud and after the bath in 39°C only. The study showed increased concentration of the catecholamines at the end of the procedure. After the bath in 36°C water, the noradrenaline levels and the blood pressure were decreased. The non-specific effects of hyperthermia, water immersion and their combination on the circulatory and sympathetic nervous system response should be considered before indicating the balneotherapy in spa.

Responses of growth hormone and prolactin to local and whole-body application of Piestany mud.

Hyperthermia is considered to be one of the most important releasing factors of growth hormone (GH) and prolactin (PRL). Thus, some effect of thermal procedures in Piestany may be promoted by the action of these adenopituitary hormones. The aim of the study was to evaluate the effect of local and whole body thermal mud application on the release of GH and PRL. Nine healthy men were exposed to whole body and one-forearm mud application (15 minutes, 46°C). Body temperature was measured in the external auditory channel and the blood samples were immediately before and in the last minute of the procedure. Whole body mud application produced increase of the core temperature. The study showed increased concentration of the hormones at the end of the procedure. Forearm application did not change the core temperature. The level of GH was elevated in five subjects. In any of the subjects no considerable elevation of PRL levels after treatment was observed. The results suggest that the release of growth hormones and prolactin accompanies whole body mud application when the core temperature is elevated. In some subjects the somatothrop response is observed despite no changes of core temperature. On the other hand the increase of core temperature is necessary for the release of prolactin.

Growth hormone and prolactin responses during partial and whole body warm-water immersions

Aim: To elucidate the role of core and skin thermoreceptors in the release of growth hormone (GH) and prolactin (PRL), a sequence of two experiments using whole-body (head-out) and partial (one forearm) hot water immersions was performed. Methods: Experiment 1: Nine healthy men were exposed to head-out and partial water immersions (25 min, 38-39 degrees C). Results: Head-out immersion increased the core temperature (38.0 +/- 0.1 vs. 36.7 +/- 0.1 degrees C, P < 0.001) and plasma concentration of the hormones (GH, 16.1 +/- 4.5 vs. 1.2 +/- 0.4 ng mL(-1), P < 0.01; PRL, 9.1 +/- 1.0 vs. 6.4 +/- 0.4 ng mL(-1), P < 0.05). During the partial immersion the core temperature was slightly elevated (36.8 +/- 0.1 vs. 36.6 +/- 0.1, P < 0.001), the concentration of GH increased (4.8 +/- 1.7 vs. 0.6 +/- 0.3, P < 0.05), while plasma PRL decreased (7.6 +/- 0.8, 6.0 +/- 0.6, 5.2 +/- 0.6, P < 0.01). Experiment 2: Seven volunteers immersed one forearm once in 39 degrees C and once in 38 degrees C water. The measurements were performed in 5-min intervals. The GH concentration increased gradually from the beginning of the immersions (min 10; 39 degrees C: 1.9 +/- 1.0 vs. 0.6 +/- 0.3 ng mL(-1), P < 0.01; 38 degrees C: 0.19 +/- 0.03 vs. 0.14 +/- 0.03, P < 0.05) and peaked after their completion (39 degrees C: +10 min, 3.7 +/- 2.0, P < 0.001; 38 degrees C: +15 min, 0.86 +/- 0.61, P < 0.01). The core temperature was unchanged until min 15 of the 39 degrees C bath. Thereafter, it increased about 0.15 degrees C above the baseline (P < 0.01). Immersion in 38 degrees C water did not induce core temperature changes. Conclusions: Peripheral thermoreceptors are involved in GH release when the body is exposed to elevated environmental temperature while a substantial elevation of core temperature is a precondition of PRL release.

Metabolic status and reaction to heat of normal and tumor tissue.

The occurrence of differential heating and differential thermal sensitivity between malignant tumors and normal tissues is thought to be due to limited heat dissipation and energy depletion in many solid tumors which in turn results from an inadequately functioning tumor microcirculation (Jain and Ward-Hartley 1984; Song 1984, 1991; Vaupel and Kallinowski 1987; Reinhold 1988; Vaupel et al. 1988a; Vaupel 1990). As a consequence of the latter pathophysiological condition, supply and drainage function are restricted in many solid tumors or, at least, in some tumor areas, thus creating a hostile metabolic microenvironment characterized by tissue hypoxia, acidosis, and energy depletion. Thermal sensitivity has been shown to depend greatly on tumor pH, and on energy and nutritional status of the tumors treated. Although no conclusive evidence is so far available concerning the ranking of these pivotal factors, there is no doubt that the rate and homogeneity of blood perfusion plays a paramount role in determining the metabolic and energy status.

Tissue physiology and the response to heat

The most important physiological parameter influencing tissue response to heat is blood flow. At mild hyperthermia temperatures blood perfusion increases in many tumours and this effect is heating time-, temperature- and tumour-dependent. These flow increases can improve tumour oxygenation.When heating is terminated, perfusion and oxygenation commonly recover, although how quickly this occurs appears to be tumour-specific. While these effects are unlikely to have any anti-tumour activity they can be exploited to improve the combination of heat with other therapies. However, since similar physiological effects should occur in normal tissues, such combination therapies must be carefully applied. Heating tumours to higher temperatures typically causes a transient increase in perfusion during heating, followed by vascular collapse which if sufficient will increase tumour necrosis. The speed and degree of vascular collapse is dependent on heating time, temperature and tumour model used. Such vascular collapse generally occurs at temperatures that cause a substantial blood flow increase in certain normal tissues, thus preferential anti-tumour effects can be achieved. The tumour vascular supply can also be exploited to improve the response to heat. Decreasing blood flow, using transient physiological modifiers or longer acting vascular disrupting agents prior to the initiation of heating, can both increase the accumulation of physical heat in the tumour, as well as increase heat sensitivity by changing the tumour micro-environmental parameters, primarily an increase in tumour acidity. Such changes are generally not seen in normal tissues, thus resulting in a therapeutic benefit.

Physiological effects of hyperthermia. In: Recent results in cancer research

Hyperthermia as a modality for the treatment of malignant tumors, either alone or in combination with radiation or anticancer drugs, is rapidly becoming a clinical reality. Three different mechanisms of action have provided the rationale for considering the use of hyperthermia as an antitumor agent. At moderate hyperthermia (T=40˚ -42.5˚ C), heat can increase cell killing in a synergistic way following exposure of a tumor to ionizing radiation. This radiosensitization is probably based on, among other things, the inhibited repair of radiation-induced DNA lesions. Elevated tissue temperatures at 40˚ -42.5˚ C also sensitize tumor cells to certain chemotherapeutic drugs, particularly to alkylating agents (chemosensitization). In this context it has been shown that the action of bleomycin, Adriamycin, and cis-platinum is also enhanced by heat treatment (see detailed literature data in: Bicher and Bruley 1982; Dethlefsen and Dewey 1982; Dietzel 1975; Hahn 1982; Hornback 1984; Jain and Gullino 1980; Nussbaum 1982; Overgaard 1984/85; Storm 1983; Streffer et al. 1978).

Effects of preoperative warming on the incidence of wound infection after clean surgery: a randomised controlled trial.

Background: Wound infection after clean surgery is an expensive and often underestimated cause of patient morbidity, and the benefits of using prophylactic antibiotics have not been proven. Warming patients during colorectal surgery has been shown to reduce infection rates. We aimed to assess whether warming patients before short duration, clean surgery would have the same effect. Methods: 421 patients having clean (breast, varicose vein, or hernia) surgery were randomly assigned to either a non- warmed (standard) group or one of two warmed groups (local and systemic). We applied warming for at least 30 min before surgery. Patients were followed up and masked outcome assessments made at 2 and 6 weeks. Finding: Analysis was done on an intention-to-treat basis. We identified 19 wound infections in 139 non-warmed patients (14%) but only 13 in 277 who received warming (5%; p=0·001). Wound scores were also significantly lower (p=0·007) in warmed patients. There was no significant difference in the development of haematomas or seromas after surgery but the non-warmed group were prescribed significantly more postoperative antibiotics (p=0·002). Interpretation: Warming patients before clean surgery seems to aid the prevention of postoperative wound infection. If applied according to the manufacturers guidelines these therapies have no known side-effects and might, with the support of further studies, provide an alternative to prophylactic antibiotics in this type of surgery.

Antibiotics and Increased Temperature against Borrelia burgdorferi in Vitro

In 1917, spirochaetal neurosyphilis was treated successfully with malariotherapy in combination with salvarsan or bismuth. Malariotherapy for spirochaetal Lyme disease has been discussed, but the mechanism of an antispirochaetal effect remains unclear. We cultured Borrelia burgdorferi at different temperatures, alone and in combination with antibiotics. Our data demonstrate that growth of the strains PKo and ATCC 35210 (B31) was impaired at temperatures of 37°C and inhibited at 39°C and 40°C, respectively. Strain ATCC 35211, however, grew well up to 39°C but did not multiply at 40°C. A bactericidal effect was seen at 41°C for the strains B31 and PKo and at 42°C for all strains. The susceptibility of all strains to penicillin and ceftriaxone was increased up to 16-fold by an elevation of temperature from 36°C to 38°C. These in vitro data suggest that elevated body temperature may be beneficial during antimicrobial treatment of Lyme disease. This may be particularly important in tissues where high concentrations of antibiotics are difficult to achieve.

Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity.

Several studies have confirmed that certain stress proteins can function as potent vaccines against a specific cancer when purified from the same tumor. Recent studies of two long-recognized but unstudied stress proteins, heat shock protein (hsp) 110 and glucose-regulated protein (grp) 170, have shown them to be efficient peptide chain-binding proteins. The present investigation examines the vaccine potential of hsp110 and grp170. First, it is shown that prior vaccination with hsp110 or grp170 purified from methylcholanthrene-induced fibrosarcoma caused complete regression of the tumor. In a second tumor model, hsp110 or grp170 purified from Colon 26 tumors led to a significant growth inhibition of this tumor. In addition, hsp110 or grp170 immunization significantly extended the life span of Colon 26 tumor-bearing mice when applied after tumor transplantation. A tumor-specific cytotoxic T lymphocyte response developed in the mice immunized with tumor-derived hsp110 or grp170. Furthermore, treatments of the mice with bone marrow-derived dendritic cells pulsed with these two proteins from tumor also elicited a strong antitumor response. Last, we showed that mild, fever-like hyperthermic conditions enhance the vaccine efficiency of hsp110 as well as heat shock cognate 70, but not grp170. These studies indicate that hsp110 and grp170 can be used in hsp-based cancer immunotherapy, that Ag-presenting dendritic cells can be used to mediate this therapeutic approach, and that fever-level hyperthermia can significantly enhance the vaccine efficiency of hsps.

Fever-range hyperthermia stimulates a4b7 integrin-dependent lymphozyte-endo­thelial adhesion.

Migration of blood-borne lymphocytes into lymphoid tissues is initiated by the L-selectin and alpha4¬-beta7 integrin adhesion molecules. Previous studies have shown that L-selectin adhesion is dynamically regulated by febrile temperatures. It is now reported that fever-range hyperthermia also acts directly on lymphocytes to enhance selected adhesive functions of alpha4-beta¬7 integrin. Fever-range hyperthermia treatment in vitro (408C, 12 h) of murine TK1 lymphoma cells and human peripheral blood lymphocytes (PBL) stimulates alpha4-beta¬7 integrin-dependent adhesion to high endothelial venules (HEV) in Peyer’s patch and mesenteric lymph node frozen sections. TK1 cells are alpha4-beta¬7 hi L-selectin, allowing for the analysis of alpha4-beta¬7 integrin without contributions from L-selectin. Adhesion was further shown to involve alpha4-beta¬7 integrin and its endothelial counter-receptor, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) using function-blocking anti-bodies (i.e. DATK32, HP2/1, MECA-367). Fever-range hyperthermia also promotes alpha4-beta¬7 integrin-mediated aggregation of TK1 cells. In sharp contrast, hyperthermia fails to increase alpha4-beta¬7 integrin adhesion to fibronectin by TK1 cells. Expression of the alpha4-beta¬7 heterodimer on TK1 cells or human PBL is not altered by hyperthermia, suggesting that hyperthermia stimulates adhesion by enhancing alpha4-beta¬7 integrin avidity rather than its cell surface density. These results provide a mechanism whereby febrile temperatures during infection or clinical hyperthermia potentially amplify the immune response by stimulating L-selectin and alpha4-beta¬7 integrin-dependent homing of immune effector cells to lymphoid tissues.

Effect of Fever-Like Whole-Body Hyperthermia on Lymphocyte Spectrin Distribution, Protein Kinase C Activity and Uropod Forma­tion.

Regional inflammation and systemic fever are hallmarks of host immune responses to pathogenic stimuli. Although the thermal element of fever is thought to enhance the activity of immune effector cells, it is unclear what the precise role of increased body temperatures is on the activation state and effector functions of lymphocytes. We report here that mild, fever-like whole body hyperthermia (WBH) treatment of mice results in a distinct increase in the numbers of tissue lymphocytes with polarized spectrin cytoskeletons and uropods, as visualized in situ. WBH also induces a coincident reorganization of protein kinase C (PKC) isozymes and increased PKC activity within T cells. These hyperthermia-induced cellular alterations are nearly identical with the previously described effects of Ag- and mitogen-induced activation on lymphocyte spectrin and PKC. Immunoprecipitation studies combined with dual staining and protein overlay assays confirmed the association of PKCb and PKCu with spectrin following its reorganization. The receptor for activated C kinase-1 was also found to associate with the spectrin-based cytoskeleton. Furthermore, all these molecules (spectrin, PKCb, PKCu, and receptor for activated C kinase-1) cotranslocate to the uropod. Enhanced intracellular spectrin phosphorylation upon WBH treatment of lymphocytes was also found and could be blocked by the PKC inhibitor bisindolylmaleimide I (GF109203X). These data suggest that the thermal element of fever, as mimicked by these studies, can modulate critical steps in the signal transduction pathways necessary for effective lymphocyte activation and function. Further work is needed to determine the cellular target(s) that transduces the signaling pathway(s) induced by hyperthermia.

Effect of in vivo hyperthermia on human natural killer cells.

Thirteen breast cancer patients were treated by hyperthermia. Natural killer (NK) activity and the frequency of large granular lymphocytes (LGL) were measured in their peripheral blood at various times before and after treatment. Immediately after the hyperthermia, significant increases in NK activities and numbers of LGL were observed.

Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer.

Hypoxia within the tumor microenvironment is correlated with poor treatment outcome after radiation and chemotherapy, and with decreased overall survival in cancer patients. Several molecular mechanisms by which hypoxia supports tumor growth and interferes with effective radiation and chemotherapies are now well established. However, several new lines of investigation are pointing to yet another ominous outcome of hypoxia in the tumor microenvironment: suppression of anti-tumor immune effector cells and enhancement of tumor escape from immune surveillance. This review summarizes this important information, and highlights mechanistic data by which hypoxia incapacitates several different types of immune effector cells, enhances the activity of immunosuppressive cells and provides new avenues which help “blind” immune cells to the presence of tumor cells. Finally, we discuss data which indicates that mild thermal therapy, through its physiologically-regulated ability to alter vascular perfusion and oxygen tensions within the tumor microenvironment, as well as its ability to enhance the function of some of the same immune effector activities that are inhibited by hypoxia,, could be used to rapidly and safely release the tight grip of hypoxia in the tumor microenvironment thereby reducing barriers to more effective immune-based therapies.

Fine-tuning immune surveillance by fever-range thermal stress.

An effectively orchestrated immune response to infection and disease depends on efficient trafficking of lymphocytes across vascular beds at distinct tissue sites. Local inflammation and systemic fever increase immune surveillance to immune-relevant sites throughout the body. During the initiation phase of inflammation, this tightly-regulated process improves leukocyte trafficking to the secondary lymphoid organs where they undergo activation and expansion in response to cognate antigen. In the resolution phase following the clearance of the invading pathogen, lymphocyte entry is rapidly returned to baseline conditions. Specialized blood vessels termed high endothelial venules (HEVs) have emerged as critical ‘hotspots’ controlling the rate of lymphocyte entry into lymphoid organs during both phases of inflammation. In this review we will examine the remarkably tight regulation of lymphocyte trafficking across HEVs conferred by inflammatory cues associated with the thermal element of fever. These studies have revealed a novel role for interleukin-6 (IL-6) trans-signaling in eliciting systemic effects on lymphocyte trafficking patterns to fine-tune immune surveillance.

Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia.

There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing the ability of heat shock temperatures (usually above 42 degrees C) to result in radio- or chemosensitization. However, these high temperatures are difficult to achieve in vivo, and new thermometry data in patients reveal that much of the tumor and surrounding region is only heated to 40-41 degrees C or less as a result of vascular drainage from the target zone of the heated tumor. Thus, there is now a growing appreciation of a role for mild hyperthermia in the stimulation of various arms of the immune system in contributing to long term protection from tumor growth. Indeed, a review of recent literature suggests the existence of an array of thermally sensitive functions which may exist naturally to help the organism to establish a new „set point“ of immune responsiveness during fever. This review summarizes recent literature identifying complex effects of temperature on immune cells and potential cellular mechanisms by which increased temperature may enhance immune surveillance.

Hyperthermia as an immunotherapy strategy for cancer.

The use of hyperthermia as an adjunct to cancer immunotherapy is supported by an increasing number of research data. Both preclinical and clinical data results have demonstrated improved antitumor immune responses with the addition of mild hyperthermia. The molecular mechanisms responsible for the improved immune reactivity observed in the presence of hyperthermia include the generation of Hsps, the activation of antigen presenting cells and changes in lymphocyte trafficking. Understanding these hyperthermia-induced processes can serve as the foundation for analyzing current clinical trials, as well as designing future trials in cancer immunotherapy.

How is the immune response affected by hyperthermia and heat shock proteins?

There is growing body of evidence linking the cellular response to heat stress with the response of the immune system to cancer. The anti-tumor immune response can be markedly enhanced by treatment with hyperthermia particularly in the fever range. In addition, the heat shock proteins (hsp) which are produced in abundant quantities in cells exposed to heat are potent immune modulators and can lead to stimulation of both the innate and adaptive immune responses to tumors. Immunostimulation by hyperthermia involves both direct effects of heat on the behavior of immune cells as well as indirect effects mediated through hsp release. In addition, the hsp can be deployed as components of antitumor vaccines in protocols that do not include hyperthermia. Understanding this process may permit the effective deployment of hyperthermia and hsp based vaccines in tumor treatment.

Die Beeinflussung des Immunsystems durch Thermotherapie.

In the last years many laboratory findings have been reported about immunologic activity in elevated body temperature and under in vitro conditions. In most cases, clinical importance still is not clear yet. In physical medicine thermotherapy has shown good results in several diseases, in which also immunologic reactions are believed to be of importance. Possible mechanisms in inflammatory rheumatism, infectious and allergic diseases and in oncology are discussed. Under an immunologic point of view, there is a strange difference between a natural fever and an elevation of body temperature by physical means (hyperthermia). Physiology of high frequency diathermia seems to be more similar to fever than that of a conductive heat transfer through the skin.

Antitumor effect of whole body hyperthermia with α-galactosylceramide in a subcutaneous tumor model of colon cancer.

Aim: Whole body hyperthermia (WBH) has been used clinically as an adjunct to radio- and chemotherapy in patients with various cancers. Recently, it has been reported that an activation of the immune system has recently been reported as a possible contributor to the therapeutic effects of WBH. Conversely, the glycolipid α-galactosylceramide (α-GalCer) is recognized by natural killer (NK) T cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. This study investigated the antitumor effects of WBH combined with α-GalCer in a mouse subcutaneous tumor model of colon cancer. Methods: Colon26 cells were inoculated subcutaneously into male BALB/c mice to establish subcutaneous tumor. Colon26-bearing mice were treated with WBH using far infrared rays three times/week. Rectal temperature was maintained for 60 min at 41°C. In some experimental groups, α-GalCer was intraperitoneally injected before WBH. We investigated the therapeutic effects of WBH, α-GalCer and combined therapy. Results: (1) Compared with controls, WBH alone resulted in significant inhibition of tumor growth. (2) No inhibitory effect on tumor growth was seen with α-GalCer. (3) The combination of WBH and α-GalCer showed significant inhibition of tumor growth and prolongation of survival. (4) Serum IFN-γ increased after 3 h and returned to basal levels by 24 h after α-GalCer administration. (5) CTL activity was enhanced following combination therapy with WBH and α-GalCer. Conclusion: WBH showed antitumor effects in a mouse subcutaneous tumor model of colon cancer. Addition of α-GalCer increased the efficacy of WBH, probably via enhancement of immune response.

Whole-body hyperthermia (WBH) in combination with carboplatin in patients with recurrent ovarian cancer – a phase II study.

Objective: Despite considerable progress in the front-line treatment in patient with advanced ovarian cancer, the outcome of patients with recurrent or refractory disease is still poor. Based on promising results of a pilot study, we initiated a phase II study with WBH and carboplatin in pretreated patients with advanced ovarian cancer to investigate the toxicity and efficacy of WBH in combination with carboplatin. Methods: 47 patients with histologically confirmed epithelial ovarian carcinoma were enrolled in the study. Patients were pretreated with at least one palliative chemotherapy regimen. Of 47 patients 24 were classified as platinum refractory or resistant and 16 as platinum sensitive. Results: Main toxicity was hematological with grade 3/4 anaemia, leukopenia and thrombocytopenia occurring in 49%, 49% and 65%, respectively. Cardiac complications occurred with grade 1/2 in 22 of 47 (47%) patients and with grade 3 in 1 patient (2%). In 35 patients evaluable for response, the overall response rate was 45% [CR: 4 / 35 (11%), PR: 12 / 35 (34%), NC: 9 / 35 (26%]. In platinum refractory and resistant patients we observed CR in 6%, PR in 24% and NC in 24%. The median overall survival and progression free survival were 61.5 weeks and 29 weeks, respectively. Conclusion: This study confirms that WBH in combination with carboplatin is an active salvage treatment option in patients with advanced ovarian cancer. However, significant hematological toxicity has to be considered and renders this regimen less suitable for palliative care setting. There is no evidence yet, that whole-body hyperthermia contributes to any clinical improvement beyond chemotherapy alone. This question can only be addressed in a randomized phase III trial.

Fever-range whole body thermotherapy combined with oxaliplatin: A curative regimen in a pre-clinical breast cancer model.

Purpose: Studies were conducted to test whether fever-range whole body hyperthermia, rationally combined with oxaliplatin chemotherapy, would boost its efficacy without substantial toxicity. Materials and Methods: The effect of heat on oxaliplatin cytotoxicity, cellular uptake, and platinum-DNA adduct formation was studied in vitro using the MTLn3 tumor cell line. In vivo, oxaliplatin was given with thermal therapy to rats bearing highly treatment-resistant MTLn3 mammary adenocarcinomas at various doses and times before, during, and after heating. Tumor growth, survival, and toxicity were measured to determine treatment outcome. Results: Heating for 6h at 40°C halved the oxaliplatin IC-50 dose for MTLn3 cells. Cellular uptake of platinum and platinum adducts increased by 34% and 36%, respectively, with heat. In vivo, 50% of all rats given 10 mg/kg oxaliplatin 24h before 6h of fever-range thermal therapy were completely, immunologically, cured while a further 11% regressed their primary tumor but ultimately succumbed to metastases, and 17% experienced a limited response with increased survival. The curative response occurred only in a narrow range of doses, with most cures at 10 mg/kg. Thermochemotherapy-treated, but uncured, animals had delayed incidence and slowed growth of metastases. Anti-tumor efficacy was greatest, and toxicity was least, when oxaliplatin was administered 12 or 24 hours before FR-WB-TT. Conclusions: When properly dosed and scheduled, oxaliplatin thermochemotherapy achieved permanent eradication of all primary and metastatic tumors in 50% of animals, seemingly through an immune response. Successful clinical translation of this protocol would yield hitherto unseen cures and substantial improvement in quality of life.

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Reirradiation combined with hyperthermia in breast cancer recurrences: Overview of experience in Erasmus MC.

For superficial hyperthermia a custom-built multi-applicator multi-amplifier superficial hyperthermia system operating at 433 MHz is utilised. Up to 6 Lucite Cone applicators can be used simultaneously to treat an area of 600 cm2. Temperatures are measured continuously with fibre optic multi-sensor probes. For patients with non-standard clinical problems, hyperthermia treatment planning is used to support decision making with regard to treatment strategy. In 74% of our patients with recurrent breast cancer treated with a reirradiation scheme of 8 fractions of 4 Gy in 4 weeks, combined with 4 or 8 hyperthermia treatments, a complete response is achieved, approximately twice as high as the CR rate following the same reirradation alone. The CR rate in tumours smaller than 30 mm is 80-90%, for larger tumours it is 65%. Hyperthermia appears beneficial for patients with microscopic residual tumour as well. To achieve high CR rates it is important to heat the whole radiotherapy field, and to use an adequate heating technique.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Fever-range whole-body thermal therapy combined with cisplatin, gemcitabine and daily interferon-α: A description of a phase I-II protocol.

Purpose: The purpose of the Phase I component of this study was to find the maximally tolerated dose (MTD) of cisplatin administered within a regimen of fever-range whole body thermal therapy (FR-WB-TT), cisplatin, gemcitabine, and low-dose interferon-alpha (IFN-α). The Phase II component aimed to assess which cancer diagnoses responded to the regimen, the response rate, and response duration. Materials and methods: The protocol design derived from a schedule-optimized preclinical regimen. Drugs were administered together, and also with thermal therapy in a schedule that optimized the therapeutic index. Eligible patients were those with therapy-resistant, metastatic or advanced solid malignancies. Beginning at 40 mg/m2, the cisplatin dose was escalated by 10 mg/m2 to the maximally tolerated dose (MTD) in successive cohorts of 3 patients. A treatment cycle consisted of cisplatin on day one, followed by thermal therapy and simultaneous gemcitabine 36 hours later; then a second dose of gemcitabine one week later; and daily IFN- α. Results: Thirty-seven patients were treated on protocol. The MTD of cisplatin in the thermochemotherapy regimen was established to be 60 mg/m2. The dose limiting toxicities (DLT) were peripheral neuropathy and ototoxicity. Complete and partial responses combined were 43%. The therapy improved the quality of life of responding patients. Conclusion: The protocol was well tolerated and was associated with antitumor activity in patients with a variety of advanced metastatic solid tumors. Tumor response occurred with the thermochemotherapy treatment despite treating malignancies that had progressed on the same chemotherapy drugs administered as standard treatment. Notably, good responses were observed in patients with high-grade neuroendocrine and pancreas cancers. This regimen will be tested in a phase II study.

Long-duration, mild whole body hyperthermia with cisplatin: tumour response and kinetics of apoptosis and necrosis in a metastatic rat mammary adenocarcino­ma.

This study examines antitumor effect and induction of apoptosis and necrosis after treatment with long-duration, mild whole-body hyperthermia (LL-WBH, 40–0°C, for 6 h) in simultaneous combination with cisplatin (CDDP) on primary and metastatic tumor growth in a rat mammary adenocarcinoma. A significantly greater delay in primary mammary tumor growth was observed after treatment with LL-WBH + CDDP, compared to either modality alone (p < 0.05). LL-WBH alone caused a significant delay in spontaneous metastasis to the axillary lymph node (ALN) and LL-WBH + CDDP tended to further increase the delay in ALN metastasis. Survival was longest in rats receiving LL-WBH + CDDP, compared to other groups (p < 0.05). CDDP induced a peak of tumor apoptosis at 24 h after treatment beginning that was significantly greater than LL-WBH alone (p < 0.05). The peak of tumor apoptosis induced by LL-WBH + CDDP from 12 to 24 h was significantly greater than any other group (p < 0.01). These results suggest that the extent of treatment-induced apoptosis seems to correlate positively with antitumor response and the combination of LL-WBH with CDDP may lead to a promising adjuvant therapy for breast cancer.

Comparison of the effects of two different whole-body hyperthermia protocols on the distribution of murine leucocyte populations.

Two predominant WBH protocols presently being used in clinical trials include a low temperature, long duration (LL) WBH, where core body temperature is raised to 39.5-40 degrees C for 6h or more, and a high temperature, short duration (HS) WBH, where core body temperature is raised to 41.8 degrees C for up to 2h. Here, the effects of LL-WBH and HS-WBH on leukocyte populations in the blood, spleen, lymph node (LN) and peritoneal cavity (PerC) of Balb/c mice were compared using flow cytometry. The total numbers of peripheral blood leukocytes decreased up to 2-fold immediately after LL-WBH, reflecting a decrease of lymphocyte numbers compared to controls. In contrast, the numbers of blood leukocytes are increased 2.7-fold immediately after HS-WBH compared to controls, reflecting an increase in lymphocytes, monocytes and granulocytes. After both LL- and HS-WBH treatment, leukocyte numbers in the spleen are decreased approximately 2-fold, again reflecting decreases in lymphocyte numbers. In the PerC, total numbers of leukocytes are also significantly decreased (2-fold) during LL-WBH but not HS-WBH. Total numbers of leukocytes in the LNs were unaffected by both LL- and HS-WBH. Overall, these data reveal differential effects of the LL- and HS-WBH protocols on leukocyte populations in the blood, spleen, LN and PerC of Balb/c mice.

Prophylactic treatment of seasonal affective disorder (SAD) by using light visors: Bright white or infrared light?.

Background: Thirty-eight patients with SAD participated in a light visor study addressing two questions. 1. Can the development of a depressive episode be prevented by daily exposure to bright light started before symptom onset in early fall and continued throughout the winter? 2. Does the light have to be visible in order to have beneficial effects? Methods: Three groups participated in the study: I (n = 14) received bright white light (2500 lux); II, (n = 15) received infrared light (0.18 lux); III (n = 9, control group) did not receive any light treatment at all. Results: Infrared light is just as effective as bright white light. Both are more effective than the control condition. Conclusions: Light visors can be effectively used to prevent the development of SAD. The fact that exposure to infrared light was as effective as exposure to bright white light questions the specific role of visible light in the treatment of SAD.

Erfahrungen beim Asthma bronchiale und anderen Atemwegserkrankungen mit Sauerstoff-Mehrschritt-Therapie und Hyperthermie.

Insufficient fever reaction and sometimes use of antipyretica in recent infection of airways seems to be one reason of asthma. On the other side, calorific means show favorable effects on recent and chronic bronchitis and asthma, which is reinforced by oxygen application. 48 patients with chronic asthma and high drug consumption including cortisone, treated with hyperthermia and oxygen application, showed improvement of lung-function and reduced drug consumption.

Heat shock protein 72 protects insulin-secreting beta cells from lipopolysaccharide-induced endoplasmic reticulum stress.

Purpose: Hyperthermia-induced activation of stress response proteins allows cells to withstand metabolic insults. In this study we set out to determine whether insulin secretion by pancreatic beta cells was affected by the acute inflammatory response, systemic inflammation-induced hyperglycaemia, and whole-body hyperthermia. Given that systemic-inflammation induces ER stress, we further examined whether hyperthermia can attenuate the extent of LPS-induced ER stress. Materials and methods: Rats were randomised and divided into three treatment groups. Control rats received a 0.9% NaCl solution. Rats in the lipopolysaccharide (LPS) group received 7.5 mg of LPS/kg. Rats in the whole-body hyperthermia (WBH) + LPS group were exposed to 42 degrees C for 15 min, followed by injection with 7.5 mg of LPS/kg after 48 h. Glucose-potentiated insulin release and extent of ER stress were measured in beta cells. Results: LPS inhibited glucose-induced insulin release from islet cells and induced the expression of Bip/GRP78, XBP-1, and CHOP transcripts. The inhibition of glucose-induced insulin release and induction of ER stress proteins by LPS was attenuated by WBH. Conclusions: Our findings suggest that LPS-induced systemic inflammation decreased insulin release due to the effects of ER stress proteins on insulin secretion. Furthermore, the induction of ER stress proteins was prevented by pretreating rats with WBH. This may suggest that inhibiting the induction of ER stress proteins through WBH can restore insulin release in various disease states.

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 ≥33.5mM 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 heatbased therapies for the prevention or treatment of autoimmune diseases.

Induction of the putative protein ferritin by infrared radiation: Implications in skin repair.

The modification of ferritin in human skin cells in vitro and in vivo following infrared-A irradiation by immunohistochemical analysis and ELISA were evaluated. In addition, we observed that IR-A is not capable of inducing frank damage to DNA (pyrimidine dimers, p53), induction of oxidative stress proteins (heme oxygenase, nitric oxide, superoxide dismutase, heat shock proteins) or proteases (collagenase, stromelysin, gelatinase) involved in carcinogenesis and photoaging of the skin. in vivo, basal levels of ferritin were heterogeneous for all individuals tested but all showed ferritin to stain precisely in the basal layer of unirradiated epidermis. Following IR-A radiation, the ferritin increase was localized to epidermal tissue and showed an increase from 120 to 220%. Parallel to the in vivo analysis, dermal fibroblasts were cultured from six individuals. Quantitative analysis for ferritin in cultured fibroblasts was assessed by ELISA and increases were seen to be dose-dependent and up to 130% of basal levels of ferritin following infrared-A. Our findings indicate that the putative defense system of ferritin that exists in human skin in vivo can be induced by infrared-A radiation and that these wavelengths may prove to be beneficial for human skin. Importantly, following the same doses of IR-A that induced ferritin levels, there was no alteration seen for nuclear DNA type damage, oxidative stress proteins or proteases involved in the degradation of skin. The increased concentrations of this antioxidant in human skin following acute UV radiation could afford increased protection against subsequent oxidative stress.

Infrared-Mediated Hyperthermia is Effective in the Treatment of Scleroderma-Associated Raynaud’s Phenomenon.

To the Editor: Scleroderma is a systemic autoimmune disease featuring variable organ involvement as well as Raynaud’s phenomenon (RP). To date, no studies exist on the effect of systemic body temperature elevation on the severity of RP. Water-filtered near-infrared (infrared A (IRA)) irradiation is particularly effective in transdermal heat delivery (Meffert and Sonnichsen, 1974;Meffert et al, 1989;Meffert and Meffert, 2000). Prompted by preliminary findings (Meffert et al, 1990), we here examined the effect of IRA treatment on RP. We employed fingertip rewarming in response to cold challenge (Wise et al, 2004;Foerster et al, in press) as well as a clinical activity score (Merkel et al, 2002) as outcome variables. In addition, we explored the effect of IRA treatment on skin thickness and scleroderma-associated joint pain. Methods, a study flow chart, as well as immediate effects of IRA treatment are detailed in the online supplement. Because of the specified inclusion criteria (see Tables S1–S3), patients were in stable-disease phase.

Rechnergesteuerte Infrarot-A-Hyperthermie zur Behandlung der systemischen Sklerodermie.

Die bei systemischer Sklerodermie verengten peripheren Blutgefäße können durch Erhöhung der Körperkerntemperatur weitgestellt werden. Zur Untersuchung einer möglichen Therapiesteuerung sind Patienten mit systemischer Sklerodermie einer seriellen Infrarot-A-Ganzkörperbestrahlung unterzogen worden. Der Durchblutungszustand während und nach der Therapie ist über die akrale Wiedererwärmung der Haut und über die Formunterschiede des peripheren Pulses einschätzbar. Beide Größen haben sich für die Therapiekontrolle und -steuerung als prinzipiell geeignet erwiesen und werden zur Diagnostik und Therapiekontrolle bzw. -steuerung von Erkrankungen der kleinen Blutgefäße empfohlen.

Milde Infrarot-A-Hyperthermie zur Behandlung der systemischen Sklerodermie.

Seven female systemic sclerosis patients (all from acrosclerosis type, with intestinal involvement, and marked Raynaud phenomenon) were treated with infrared A whole body irradiations (wavelengths between 800 and 1,400 nm, 12 W/dm2 maximally). The single exposure lasted for 30 minutes and resulted in an 0.9 degrees C rise of central body temperature. Acral skin rewarming became regular immediately after irradiation and kept improved, as compared with pre-treatment values, for at least 18 weeks. All the patients told about a comfortable feeling of warmth after each treatment lasting for one two days. Three out of the seven reported lower frequency and severity of Raynaud attacks.

Hyperthermia for the treatment of articular cartilage with osteoarthritis.

Osteoarthritis (OA) is one of the most frequent musculoskeletal disorders in the elderly population. OA is characterised by a gradual loss of extracellular matrix in the articular cartilage of joints. OA can only be managed by artificial joint replacement when joint destruction becomes severe. Therefore, it is preferable to administer conservative therapy that is easy, simple and effective in inhibiting OA progression at the early stage. Heat shock protein 70 (Hsp70) has a protective effect on the cartilage and inhibits the apoptosis of chondrocytes. Heat stimulation by microwave to the joints can increase Hsp70 expression in chondrocytes, and at the same time, Hsp70 expression partially enhances matrix metabolism of the cartilage. These findings suggest that hyperthermia can be positively applied to the treatment of OA. Hyperthermia is therefore expected to be an inexpensive and less-invasive conservative therapy for OA.

Milde Infrarot-A-Hyperthermie zur Behandlung von Erkrankungen des rheumatischen Formenkreises – Anhaltende Verminderung der Aktivität polymorphkerniger Granulozyten.

Due to serial applications of Mild Infrared-A-Hyperthermia (increase of rectal temperature up to 38.5°C provoked by near infrared whole body-irradiation) in ex vivo isolated polymorphonuclear leukocytes concentration of activated oxygen species – as measured by stimulated chemiluminescence and INT test – was depressed markedly and longstanding. 11 healthy women underwent Mild Infrared-A-Hyperthermia 6 times a week for 2 weeks. That depression of the concentration of activated oxygen species was measurable by stimulation with opsonized zymosan or aggregated human gamma-globulin even on day 22 following the end of irradiation serial. These results at least partially explain reports on favorable results of Mild Infrared-A-Hyperthermia in cases of painful joint disorders. Furthermore, they call for systemic investigation of therapeutic efficiency in diseases like rheumatoid arthritis and arthopathia psoriatica.

The effect of mild whole-body hyperthermia on systemic levels of TNF-alpha, IL-1 beta and IL-6 in patients with ankylosing spondylitis.

Serial mild whole-body hyperthermia is a widely used balneotherapy modality for clinically inactive ankylosing spondylitis (AS) in rehabilitative medicine. Thus far, the mechanisms of its favorable influence on the symptoms of AS are not completely understood. We therefore analyzed the effect of mild whole-body hyperthermia on the systemic levels of pivotal proinflammatory cytokines. Twelve male subjects with AS and 12 healthy control subjects received nine cycles of whole-body hyperthermia (target body core temperature, 38.5 degrees C; duration, 50 min). Serum samples were taken at the beginning of the last cycle and at 1, 6, and 24 h for measurement of tumor necrosis factor alpha, interleukin 1beta and interleukin 6. Significant differences of cytokine levels were found between both groups. In AS patients, hyperthermia caused a significant reduction of all cytokines by 40-50%. Thus, serial mild whole-body hyperthermia in AS results in heat-induced changes of the proinflammatory cytokine network.

Zur Wirkung einer Ganzkörperhyperthermie auf Entzündungen und Immunreaktionen: experimentelle Grundlagen.

Purpose, material and methods: Review of the scientific literature about experimental effects of whole body hyperthermia on immune reactions and inflammations. Results: Numerous animal experiments demonstrated, that an intense elevation of body temperature (above 41 °C) has an immunosuppressive effect and after repeated applications induces an involution of lymphatic organs. However, a moderate hyperthermia of 39 – 40 °C (for a short-time also 41 °C) is immune-stimulating and promotes different physiological functions of immunocompetent cells. Under experimental conditions also a preventive hyperthermia-induced immunosuppression is possible and may inhibit a lateron occurring autoimmune-disease like adjuvant arthritis of rats. Thus, intense and moderate whole body hyperthermia have opposite effects on the immune system. There is no doubt, that hyperthermia has antiphlogistic effects in chronic inflammations whereas acute inflammations, similar to local heating, are aggravated. Trying to interpret these effects of hyperthermia heat-induced changes of the cytokine network seem to be important. Conclusions: Conclusions for therapeutic aspects in men must be drawn with reservation. An advantage of hyperthermia treatment of inflammations could be that all sites of inflammation may be reached. However, therapeutic effects depend on the kind of inflammation and its actual activity. Therapeutic immunosuppression is possible only with very high body temperatures. This would be contraindicated in general autoimmune diseases on behalf of possible additional damage of organs. Furthermore, there exist only few informations about therapeutic tolerance, effects on cytokine network and dosage. Nevertheless, traditional hyperthermia treatment should not disappear in the fog of medical history, because many kinds of treatments (hyperthermic water baths, mud baths, sauna, infrared radiation cabins) use hyperthermia still today. Thus, further investigations seem to be necessary as well as controlled therapeutic studies.

Mild hyperthermia modulates biological activities of interferons.

A significant enhancement of antiviral activity of human IFN-alpha, -beta and -gamma and murine IFN-gamma is observed when cells are treated with mild hyperthermia (398C) during antiviral assays. Treatment of primary human fibroblast cells with mild hyperthermia for 4 and 24 hours prior to interferon antiviral assays (pre-assay hyperthermia) further enhances interferon antiviral activity. An enhancement of interferon induced enzyme, 2,5-oligoadenylate synthetase, is also observed in cells treated with interferon and mild hyperthermia. This increase in enzyme activity is, in part, responsible for the observed increase in interferon antiviral activity with hyperthermia. Besides antiviral activity, mild hyperthermia also increases interferon antiproliferative activity on different tumor cells beyond its effect at nor-mal physiological temperatures. On the other hand, mild hyperthermia decreases human interferon production in both human and murine cells when challenged with a viral or non-viral inducer. Also, mild hyperthermia suppresses interferon- mediated enhancement of natural killer (NK) cell activity in human and murine cells. The findings demonstrate that, although mild hyperthermia has suppressive effects upon interferon production and NK cell activity, it significantly increases both antiviral and antiproliferative activities of all three human interferons. These observations have direct bearing upon clinical utilization of exogenously administered interferons to late stage cancer patients who for the most part have a weaker immune system. In these patients, the antiviral and antiproliferative efficacies of administered interferon can be enhanced by combining interferon and hyperthermia.

Heat shock proteins in neurodegenerative diseases: Pathogenic roles and therapeutic implications.

Neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, and polyglutamine (polyQ) diseases are thought to be caused by protein misfolding. Heat shock proteins (HSPs), which function mainly as molecular chaperones, play an important role in the folding and quality control of proteins. The histopathological hallmark of neurodegenerative diseases is accumulation and/or inclusions of the disease-causing proteins in residual neurons in targeted regions of the nervous system. The inclusions combine with many components of molecular chaperone pathways and ubiquitin-proteasome, raising the possibility that misfolding and altered degradation of mutant proteins may be involved in the pathogenesis of neurodegenerative diseases. Overexpression of HSPs has been reported to reduce the number and size of inclusions and accumulation of disease-causing proteins, and ameliorate the phenotypes in neuronal cell and mouse models. Hsp90 inhibitors also exert therapeutic effects through selective proteasome degradation of its client proteins. Elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, i.e., Hsp90 inhibitor and HSP inducer, which inhibit the pathogenic process of neuronal degeneration. These findings may provide the basis for development of an HSP-related therapy for neurodegenerative diseases.

Microcirculation abnormalities in patients with fibromyalgia – measured by capillary and laser fluxmetry.

This unblinded preliminary case-control study was done to demonstrate functional and structural changes in the microcirculation of patients with primary fibromyalgia (FM). We studied 10 women (54.0 ± 3.7 years of age) with FM diagnosed in accordance with the classification criteria of the American College of Rheumatology, and controls in three groups (n = 10 in each group) – age-matched women who were healthy or who had rheumatoid arthritis or systemic scleroderma (SSc). All 40 subjects were tested within a 5-week period by the same investigators, using two noninvasive methods, laser fluxmetry and capillary microscopy. The FM patients were compared with the healthy controls (negative controls) and with rheumatoid arthritis patients and SSc patients (positive controls). FM patients had fewer capillaries in the nail fold (P < 0.001) and significantly more capillary dilatations (P < 0.05) and irregular formations (P < 0.01) than the healthy controls. Interestingly, the peripheral blood flow in FM patients was much less (P < 0.001) than in healthy controls but did not differ from that of SSc patients (P = 0.73). The data suggest that functional disturbances of microcirculation are present in FM patients and that morphological abnormalities may also influence their microcirculation.

Ganzkörperhyperthermie in der Schmerztherapie – eine kontrollierte Studie an Patienten mit Fibromyalgiesyndrom.

Hintergrund: Ziel der Studie war es, zu prüfen, ob die milde wassergefilterte Infrarot-A-Ganzkörperhyperthermie als Zusatzbehandlung im Rahmen einer medizinischen Rehabilitation gegenüber der rehabilitativen Standardtherapie bei Patienten mit Fibromyalgiesyndrom (FMS) einen langfristigen Nutzen erbringt. Material und Methode: 67 FMS-Patienten einer deutschen Rehabilitationsklinik wurden 3 Studiengruppen zugewiesen. Zwei Interventionsgruppen erhielten über 3 Wochen zusätzlich 1-mal bzw. 2-mal wöchentlich eine Hyperthermieanwendung. Die Kontrollgruppe erhielt die rehabilitative Standardtherapie. Wichtigste Zielgröße war die Schmerzintensität, die bei Aufnahme, Entlassung und 6 Monate nach Entlassung gemessen wurde. Ergebnisse: Die Behandlung mit einer Hyperthermieanwendung pro Woche erwies sich gegenüber den anderen Studiengruppen hinsichtlich der Schmerzreduktion und der affektiven Schmerzempfindung als signifikant überlegen. Tendenzielle Vorteile erzielte diese Gruppe in der FMS-bezogenen Lebensqualität und bezüglich der Depressivität. Schlussfolgerung: Die Anwendung der Ganzkörperhyperthermie im Rahmen einer stationären Rehabilitation scheint geeignet, die langfristigen Behandlungsergebnisse beim FMS zu verbessern.

Eine randomisierte, kontrollierte Studie zur Wirksamkeit und Ver­träglichkeit einer milden wassergefi lterten Infrarot-A-Ganz­körperhyperthermie als Zusatzbehandlung zu einer multimo­dalen rehabiliitativen Standardtherapie bei der Behandlung der Fibromyalgie.

Ziel: Die Studie evaluiert, ob bei Patienten mit Fibromyalgie (FM) die milde wassergefilterte Infrarot-A-Ganzkörperhyperthermie (NI-WBH) als Zusatzbehandlung zu einer multimodalen rehabilitativen Standardtherapie (MR) gegen überalleiniger MR einen therapeutischen Nutzen erbringt. Methoden: 139 stationäre Patienten einer deutschen Rehabilitationsklinik, welche die
Kriterien des American College of Rheumatology (ACR, 1990) f ü r eine FM erfüllten, wurden in die Studie eingeschlossen und randomisiert einer Versuchs- oder Kontrollgruppe zugewiesen. Die Patienten der Versuchsgruppe erhielten neben einer MR zusätzlich eine Behandlungsserie NI-WBH (6 Behandlungen insgesamt, 2 Behandlungen pro Woche, Erwärmung auf 38,1 °C Körperkerntemperatur, gefolgt von 15 min Wärmestauphase), während die Patienten der Kontrollgruppe ausschließlich eine MR erhielten. Hauptzielparameter waren das affektive und sensorische Schmerzempfinden, gemessen mit der deutschen Version des McGill Pain Questionnaire (Schmerzempfindungsskala), erhoben zur Baseline, zum Interventionsende sowie 3 und 6 Monate nach Interventionsende und analysiert nach dem Intention-to-Treat-Prinzip. Ergebnisse: In der Kovarianzanalyse mit Meßwiederholungen ergaben sich in der Primäranalyse signifikante Differenzen zwischen den Gruppen für beide Hauptzielparameter zugunsten von NI-WBH plus MR im Vergleich zu alleiniger MR (p < 0,001 für affektives Schmerzempfinden, p = 0,001 für sensorischen Schmerzempfinden). Die Sekundäranalyse zu Schmerzintensität, FMbezogener Lebensqualität und Tenderpoint-Assessment erbrachte der Primäranalyse entsprechende Resultate. Mittlere Effektstärken wurden für alle Zielparameter beobachtet (Spannbreite, 0,41 – 0,75). NI-WBH bezogene Nebenwirkungen traten bei 14 von 69 Studienpatienten (20 %) auf, die jedoch alle in weniger als 30 min nach Interventionsende nicht mehr vorhanden waren. Diskussion: Die Studie zeigt, dass NI-WBH eine wertvolle Ergänzung zur MR bei der rehabilitativen Behandlung der FM darstellt.

A Randomized Controlled Trial on the Effectiveness of Mild Water-filtered Near Infrared Whole-body Hyperthermia as a n Adjunct to a Standard Multimodal Rehabilitation in the treatment of Fibromyalgia.

Objectives: To evaluate whether mild water-filtered near infrared whole-body hyperthermia (NI-WBH) produces an additional benefit when applied as an adjunct to a standard multimodal rehabilitation (MR) compared with MR only in patients with fibromyalgia (FM). Methods: One hundred thirty-nine patients of a German inpatient rehabilitation hospital meeting the ACR 1990 criteria for FM were randomly allocated to NI-WBH (heating-up to 38.1 degrees C body core temperature followed by a 15 min heat retention period) and MR or MR only, twice a week over 3 weeks. Main outcome measures were affective and sensory pain assessed by a German version of the McGill Pain Questionnaire, measured at baseline, postintervention, 3 and 6 months postintervention and analyzed by intention to treat. Results: Repeated measures analysis of covariance showed significant differences between groups for both primary outcome measures in favor of NI-WBH and MR compared with MR only (P<0.001 for affective pain, P=0.001 for sensory pain). Secondary analyses on pain intensity, FM-related quality of life and tender point assessment yielded similar results. Moderate effect sizes were observed for all outcome measures considered (range, 0.41 to 0.75). NI-WBH related side effects were observed in 14 of 69 participants (20%) but all disappeared in less than 30 minutes. Discussion: The study indicates that NI-WBH is a worthwhile adjunct to MR in the treatment of FM.

Zur Wirkung einer iterativen milden Ganzkörperhyperthermie auf den Fibromyalgieschmerz.

Fibromyalgia is a very common non-inflammatory rheumatic disease. Main symptoms are wide-spread pain, multiple tender points, and irritations of autonomous nervous system which are often accompanied by depression and sleep disturbances. The disease is very resistant against pharmacological as well as physical treatment, but may be ameliorated by heat applications. Objective: Investigations about a possible influence of repeated moderate hyperthermia on pain. Methods: Using Iratherm 1000 (von Ardenne GmbH, Dresden) whole-body hyperthermia was induced (duration: 30 min, mean body temperature: 38±0,32°C, 3 treatments per week for 3 weeks). In addition, all patients received an identical standardized drug and a physical treatment program. Pain threshold was measured at 42 tender points using a dolorimeter (Pain Diagnostics and Thermography Inc., Great Neck, USA). For subjective pain intensity, a pain score and a visual pain analog scala were used. Results: Immediately after a single hyperthermia treatment, pain was significantly reduced. At the end of 3 weeks‘ treatment, pain no longer reached the pretreatment level. Conclusions: Moderate whole body hyperthermia has a significant analgesic effect in fibromyalgia, especially under repeated application. Further investigations in controlled studies are necessary.

Behandlung einer Radikulopathie bei ossärer Metastasierung der Lendenwirbelsäule durch Infrarot-A-Ganzkörperhyperthermie.

Introduction: Cancer metastases can be the reason of neuropathic pain. It can be caused by infiltration and compression of nerves. Cytokines released by tumor cells and the affected nerve structures induce an inflammatory reaction that enhances the neuropathic pain. Case report: We report the case of a 67-year-old female patient. She suffered from a persisting and acutely exacerbated radiculopathy (L5/S1 right) due to metastases of breast cancer (pT1bL0N1R1G2M1/osseous; ER 95%, PR 95%, Her2-new-score 3+) in the lumbar spine. Traditional treatments had failed to yield sufficient therapeutic effects. Methods: We performed 6 sessions of water-filtered infrared-A whole-body hyperthermia using a commercial system (Iratherm 1000; Von Ardenne Institute for Applied Medical Research, Dresden, Germany). The wave-length was 600-1300 nm, the aimed body core temperature was 38.5 degrees C. The intensity of pain was assessed by visual analog scale. Results: Pain intensity (VAS) decreased from 9 (initial) to 3 points after the first 3 treatment sessions. The patient was completely free of pain after 6 sessions. No side-effects were observed. At follow up after 3 and 24 weeks the patient was still free of pain. Conclusion: Infrared-A whole-body hyperthermia might be an effective therapeutic procedure with rare side-effects for tumor-induced neuropathic pain. Its use should be investigated further in controlled clinical trials.

Milde Infrarot-A-Hyperthermie. Auswirkungen von Serienbestrahlungen mit wassergefilterter Infrarotstrahlung auf Gesunde und Kranke mit arterieller Hypertonie bzw. systemischer Sklerodermie.

Short-wave infrared radiation (near infrared, Infrared A, IRA; wavelengths between 760 and 1400 nm) becomes converted into heat just at the level of superficial capillaries, which is then distributed by flowing blood throughout the human body. Hence, it is feasible to induce hyperthermia in a manner that is both smooth and efficient. In case of Mild Infrared A-Hyperthermia rectal temperatures do not exceed 38.5 °C. Because of the rapid rise of core temperature, the functional small blood vessel diameter and muscle clearance enlarge, and function and reactivity of small blood vessels improve. This was confirmed by Fourier analysis of peripheral pulse curves and acral skin rewarming. Following serial infrared irradiations, long-term effects occurred. For example, diastolle blood pressure remained normalised for another 6 weeks after the end of the irradiation serial, and in patients with systemic scleroderma clinical improvement and relative acceleration of acral skin rewarming remained noticeable for several months. Mild infrared A-hyperthermia is an update version of classical heat treatment. Its possible indications range from rheumatic diseases via migraine to vasomotoric impotentia coeundi.

Physikalische Therapie der arteriellen Hypertonie- Eine einmalige milde Infrarot-A-Hyperthermie gestattet Voraussagen hinsichtlich des Besprechens auf weitere Behandlungen.

Hypertensive patients in stages I and II according to WHO definition can be successfully treated by series of irradiation with short-wave infrared (infrared-A). In 5 out of 40 patients, the therapeutic effect was not satisfactory. It was found that only in these patients the diastolic blood pressure reached values of 100 mmHg and more as early as 30 minutes after the first infrared-A irradiation. This, a single infrared-A hyperthermia can be used as a functional test to select hypertensive patients suitable for series of infrared-A irradiation.

Effects of a multiple mild infrared a induced hyperthermia on central and peripheral pulse waves in hypertensive patients.

The paper reports on the effects of multiple whole-body infra-red-A irradiational (IRA) on 13 male patients known to have stage I or stage II essential arterial hypertension (WHO definition). The peripheral blood pressure was decreased significantly by IRA exposures. The lowered diastolic blood pressure lasted into posttreatment time. This effect is regarded as a consequence of an improvement in peripheral haemodynamics. A measure of this improvement is the different shape of the blood pressure pulse waves. Calculation and comparison of the spectral components of the recorded pulse signals show that these components are useful for a prediction of the blood pressure lowering effect.

Wirkung einer einmaligen milden Infrarot-A-Hyperthermie auf Körpertemperatur, Herzfrequenz, Blutdruck und Blutviskosität bei Gesunden und Patienten mit arterieller Hypertonie der Stadien I und II.

Report on mild and single whole body-irradations with near infrared (IRA). The central body temperature went up to 38.5°C in 9 healthy subjects and 9 patients known as having essential arterial hypertension of the stages I or II. In case of hypertensive patients, a single exposure decreased significantly both arterial and venous blood pressure as well as the resulting mean arterial blood pressure. This beneficial effect lasted for at least 24 hours. Beside that, improved peripheral hemodynamics is linked to that blood pressure lowering effect which happens due to dilatation of peripheral blood vessels.

Mild Elevation of Body Temperature Reduces Tumor

Human and rodent solid tumors often exhibit elevated interstitial fluid pressure (IFP). This condition is recognized as a prognostic indicator for reduced responses to therapy and decreased disease-free survival rate. In the present study, we tested whether induction of a thermoregulatory-mediated increase in tissue blood flow, induced by exposure of mice to mild environmental heat stress, could influence IFP and other vascular parameters within tumors. Using several murine tumor models, we found that heating results in a sustained reduction in tumor IFP correlating with increased tumor vascular perfusion (measured by fluorescent imaging of perfused vessels, laser Doppler flowmetry, and MRI) as well as a sustained reduction in tumor hypoxia. Furthermore, when radiation therapy was administered 24 hours postheating, we observed a significant improvement in efficacy that may be a result of the sustained reduction in tumor hypoxia. These data suggest, for the first time, that environmental manipulation of normal vasomotor function is capable of achieving therapeutically beneficial changes in IFP and microvascular function in the tumor microenvironment.

Einfluß einer Serie von Infrarot-Ganzkörperbestrahlungen auf Fließeigenschaften des Blutes und die Hämodynamik.

The reaction of volunteers (normoton and borderline hyperton: p_s= 15.0 +/- 1.8 kPa) on the increase of the body temperature (rectal) up to 38.5°C with respect to hemorheological and hemodynamical parameters was investigated. 11 volunteers were treated with a series of 12 whole body near-infrared irradiation (IR; 700-1400nm). Apparent viscosity of blood, plasma viscosity, and the aggregation kinetics od red blood cells (RBC) were determined. The blood circulation was characterized by means of radionuclide ventriculography (central) and of Xe_133 muscle clearance (peripheral). Viscosities and parameters of RBC aggregation were significantly reduced after the IR series as well as 4 weeks thereafter. The central circulation did not significantly change. The clearance parameter of peripheral circulation was improved similar as the rheological parameters but less pronounced. It is concluded that there is an adaption to heat leading to a better perfusion to the periphery.

Moderate Hyperthermie als Behandlungsmethode mit vielen Indikationen.

The principles and design of equipment for moderate whole-body hyperthermic therapy (up to 39°C) are reported on. Hyperthermy of the patient, who lies in a net, is achieved with the Iratherm 1000 system by means of irradiation from below that is filtered through water and has an energy density factor of 10 W/dm^2. The filtering process reduces the stress level for the skin – the radiation also reaches dermal vessels. The most important indications for such treatment are: systemic sclerodermatitis, degenerative non-articular rheumatism, acute muscle pain, rhinitis, bronchitis, muscle spasticity in multiple sclerosis, poor circulation in tissues and organs, therapy-resistant chronic inflammations, chronic back pains, hypertension, activation of immunological system.

Biophysikalische Ergebnisse des klinischen Tests der IRA-Therm-Hyperthermietechnik der 2. Generation.

Results of clinical evaluation of a new whole-body infrared-A irradiation machine are presented. Irradiance is continuously unable between 1.7 and 12 W/dm^2. The 8 volunteers reached central body temperatures of 40°C within 70 minutes and tolerated that treatment well. Whereas irradiance was distributed quite homogenously over the body’s surface, maximal skin temperatures of 45°C situated at the abdomen, at buttocks and the proximal upper legs. On the other hand, ventral thorax skin exhibited minimal temperatures (36.9°C). Relations between central body temperature, skin temperature (infrared camera), irradiance (energy balance), pulse rate, peripheral blood pressure are body weight are depicted. So, the established thermic efficiency was about 10%. The precondition of that was homogenization of irradiation at skin surface. Increase of peripheral systolic blood pressure declined immediately after reduction of applied energy. On the other hand, decrease of diastolic blood pressure lasted into post-treatment time. Speed of increase in body temperature was not or just marginally related to body weight (range 47 to 89 kg).

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