Systemic Hyperthermia Research Articles

Harnessing Hyperthermia: Molecular, Cellular, and Immunological Insights for Enhanced Anticancer Therapies.

Hyperthermia, the raising of tumor temperature (≥39°C), holds great promise as an adjuvant treatment for cancer therapy. This review focuses on 2 key aspects of hyperthermia: its molecular and cellular effects and its impact on the immune system. Hyperthermia has profound effects on critical biological processes. Increased temperatures inhibit DNA repair enzymes, making cancer cells more sensitive to chemotherapy and radiation. Elevated temperatures also induce cell cycle arrest and trigger apoptotic pathways. Furthermore, hyperthermia modifies the expression of heat shock proteins, which play vital roles in cancer therapy, including enhancing immune responses. Hyperthermic treatments also have a significant impact on the body's immune response against tumors, potentially improving the efficacy of immune checkpoint inhibitors. Mild systemic hyperthermia (39°C-41°C) mimics fever, activating immune cells and raising metabolic rates. Intense heat above 50°C can release tumor antigens, enhancing immune reactions. Using photothermal nanoparticles for targeted heating and drug delivery can also modulate the immune response. Hyperthermia emerges as a cost-effective and well-tolerated adjuvant therapy when integrated with immunotherapy. This comprehensive review serves as a valuable resource for the selection of patient-specific treatments and the guidance of future experimental studies.

The Role of Hyperthermia in Potentiation of Anti-Angiogenic Effect of Cisplatin and Resveratrol in Mice Bearing Solid Form of Ehrlich Ascites Tumour

The aim of this study was to investigate the therapeutic potential of resveratrol in combination with cisplatin on the inhibition of tumour angiogenesis, growth, and macrophage polarization in mice bearing the solid form of an Ehrlich ascites tumour (EAT) that were exposed to whole-body hyperthermia treatment. In addition, we investigated whether a multimodal approach with hyperthermia and resveratrol could abolish cisplatin resistance in tumour cells through the modulation of histone deacetylase (HDAC) activity and levels of heat shock proteins (HSP70/HSP90) and contribute to the direct toxicity of cisplatin on tumour cells. The tumour was induced by injecting 1 × 106 EAT cells subcutaneously (sc) into the thighs of Balb/c mice. The mice were treated with resveratrol per os for five consecutive days beginning on day 2 after tumour injection and/or by injecting cisplatin intraperitoneally (ip) at a dose of 2.5 mg/kg on days 10 and 12 and at a dose of 5 mg/kg on day 15. Immediately thereafter, the mice were exposed to systemic hyperthermia for 15 min at a temperature of 41 °C. The obtained results showed that the administration of resveratrol did not significantly contribute to the antitumour effect of cisplatin and hyperthermia, but it partially contributed to the immunomodulatory effect and to the reduction of cisplatin toxicity and to a slight increase in animal survival. This treatment schedule did not affect microvessel density, but it inhibited tumour growth and modulated macrophage polarization to the M1 phenotype. Furthermore, it abolished the resistance of tumour cells to cisplatin by modulating HDAC activity and the concentration of HSP70 and HSP90 chaperones, contributing to the increased lifespan of mice. However, the precise mechanism of the interaction between resveratrol, cisplatin, and hyperthermia needs to be investigated further.

Effect of ferroparticles clustering on magnetic hyperthermia in non-liquid systems

Effect of ferroparticles clustering on magnetic hyperthermia in non-liquid systems

BIO23: Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®) for Treatment of Advanced, Unresponsive, Hospice Eligible Cancer Patients: Update

Purpose: HEATT® is veno-venous perfusion-induced systemic hyperthermia with a heart-lung pump, dialysis, blood sorbent, and CO2/pH control with flow at 20% of cardiac output to homogeneously increase core temperature to 42°C for 120 min while normalizing fluid and electrolyte changes. Two Phase 1 FDA trials (advanced lung, ovarian cancer), demonstrated safety and efficacy. We are reporting progress on an open label, non-randomized, early feasibility, single dose of HEATT® to treat select cancer patients with persistent or recurrent unresectable cancers unresponsive to chemo-, immuno-, and/or curative therapy. Method: Informed consent was obtained. Exclusion criteria: recent brain surgery, metastasis or stroke; organ failure; sepsis; or active bleeding. HEATT® uses 13-17 Fr Femoral-Jugular cannulas placed by image guidance in a veno-venous circuit. All individual components are FDA approved. Upon general anesthesia and systemic anticoagulation, Interventional Radiology placed a triple lumen central line, arterial line, and IVC/SVC venous cannula at L2 for drainage and at SVC/RA junction for infusion of heated blood for a targeted 20% cardiac output flow to increase core temperature to 42°C for 120 min. Patients are cooled to 38°C, then recovered. Results: All patients met criteria and were hospice eligible with a mean predicted survival of 90 days. Primary cancers included ovarian (5), colon (2), breast (2), lung (1), pancreatic (1), cholangiocarcinoma (1), and lipo-sarcoma (1). All achieved 42°C core temperature for 120 min with stable hemodynamics, heat transfer, and circuit dynamics. No complications were identified specific to HEATT®. Length of stay was 2-4 days including treatment, 12/13 survived to 30-day all-cause mortality, while 1/13 died of pulmonary hemorrhage from multiple metastasis. Eight of 13 exceeded expected median survival, 6/13 exceeded 180 day predicted maximum end-of-life. Four are alive and active at 500, 386, 360, and 288 days (Max 530). Twelve of 13 recovered to receive additional therapies. Frailty, age >80, and immobility negatively impact recovery. HEATT® does not predictably relieve tumor obstruction. Summary: We recommend HEATT® for treatment of advanced cancer patients unresponsive to conventional treatments.

Malignant hyperthermia (literature review)

The objective – to summarize the current literature data on the etiology, pathogenesis, diagnosis and treatment of malignant hyperthermia. The search and analysis of literature data on malignant hyperthermia in the medical information systems PubMed, Сochrane librarу, Cyberleninka for the last 10 years was performed with using the keywords: «malignant hyperthermia», «dantrolene», «general anesthesia», «succinylcholine», «inhalation anesthetics». The search criteria were met by 96 publications. In addition, references to selected articles were manually checked for applicable articles including recent reports of malignant hyperthermia, in addition to works of historical significance. It was shown that malignant hyperthermia develops in susceptible individuals during or after general anesthesia with the use of trigger agents – inhaled halogen-containing anesthetics and succinylcholine. Until recently, the problem of treatment in Russia remained unresolved, since specific therapy for this syndrome was not available. In connection with the official registration of Dantrolene in the Russian Federation, this problem no longer has a life-threatening potential. Doctors should recognize the symptoms of this disease as early as possible in order to quickly begin the pathogenetic treatment of malignant hyperthermia in order to prevent fatal complications. The material is intended for a wide audience of anesthesiologists, resuscitators and surgeons who may encounter this pathology in clinical practice.

Temperature management during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

In addition to attaining complete or near complete cytoreduction, the instillation of select heated chemotherapeutic agents into the abdominal cavity has offered a chance for cure or longer survival inpatients with peritoneal surface malignancies. While the heating of chemotherapeutic agents enhances cytotoxicity, the resulting systemic hyperthermia has been associated with an increased risk of severe hyperthermia and its associated complications. Factors that have been associated with an increased risk of severe hyperthermia include intraoperative blood transfusions and longer perfusion duration. However, the development of severe hyperthermia still remains largely unpredictable. Thus, at several institutions, cooling protocols are employed during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Cooling protocols for CRS-HIPEC are not standardized and may be associated with episodes of severe hyperthermia or alternatively hypothermia. In theory, excessive cooling could result in a decreased effectiveness of the intraperitoneal chemotherapeutic agents. This presumption has been supported by a recent study of 214 adults undergoing CRS-HIPEC, where failure to attain a temperature of 38° C at the end of chemo-perfusion was associated with worse survival. Although not statistically significant, failure to maintain a temperature of 38° C for at least 30 minutes was associated with worse survival. Although studies are limited in this regard, the importance of maintaining a steady state of temperature during the hyperthermic phase of intraperitoneal chemotherapy administration cannot be disregarded. The following article describes the processes and physiological mechanisms responsible for hyperthermia during CRS-HIPEC. The challenges associated with temperature management during CRS-HIPEC and methods to avoid severe hypothermia and hyperthermia are also described.

Hyperthermic Extr thermic Extracorpor acorporeal Applied T eal Applied Tumor Ther umor Therapy (HEATT®) in Advanced Unresponsive Cancer

Hyperthermia has been utilized for cancer therapy, including metastatic cancer, for decades with isolated success. Previous research has indicated that the elevated temperature of 42°C induces cell death, apoptosis, or senescence of responsive cancers, providing a mechanism for tumor destruction and management. Veno-venous perfusion-induced systemic hyperthermia (V-V PISH) may be the key to improving advanced tumor responsiveness to previously failed chemotherapy and/or radiation as combination therapy. The most recent iteration of V-V PISH, Hyperthermic Extracorporeal Applied Tumor Therapy (HEATT®), provides homogeneous heating of all tissues with electrolyte and pH control and continues to prove safe and effective. The utilization of HEATT® in advanced, unresponsive cancers should be further explored as a part of integrative oncology care.

Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia.

Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity.

Systemic Hyperthermia in Traumatic Brain Injury-Relation to Intracranial Pressure Dynamics, Cerebral Energy Metabolism, and Clinical Outcome.

Systemic hyperthermia is common after traumatic brain injury (TBI) and may induce secondary brain injury, although the pathophysiology is not fully understood. In this study, our aim was to determine the incidence and temporal course of hyperthermia after TBI and its relation to intracranial pressure dynamics, cerebral metabolism, and clinical outcomes. This retrospective study included 115 TBI patients. Data from systemic physiology (body temperature, blood pressure, and arterial glucose), intracranial pressure dynamics (intracranial pressure, cerebral perfusion pressure, compliance, and pressure reactivity), and cerebral microdialysis (glucose, pyruvate, lactate, glycerol, glutamate, and urea) were analyzed during the first 10 days after injury. Overall, 6% of patients did not have hyperthermia (T>38°C) during the first 10 days after injury, whereas 20% had hyperthermia for >50% of the time. Hyperthermia increased from 21% (±27%) of monitoring time on day 1 to 36% (±29%) on days 6 to 10 after injury. In univariate analyses, higher body temperature was not associated with higher intracranial pressure nor lower cerebral perfusion pressure, but was associated with lower cerebral glucose concentration (P=0.001) and higher percentage of lactate-pyruvate ratio>25 (P=0.02) on days 6 to 10 after injury. Higher body temperature and lower arterial glucose concentration were associated with lower cerebral glucose in a multiple linear regression analysis (P=0.02 for both). There was no association between hyperthermia and worse clinical outcomes. Hyperthermia was most common between days 6 and 10 following TBI, and associated with disturbances in cerebral energy metabolism but not worse clinical outcome.

Direct and Cross Effects of Adaptation to Systemic Hyperthermia: Impact on Quality of Life, Neurohormonal and Psychophysiological Human Status

Direct and Cross Effects of Adaptation to Systemic Hyperthermia: Impact on Quality of Life, Neurohormonal and Psychophysiological Human Status

Effect of internal chain-like structures on magnetic hyperthermia in non-liquid media.

This paper deals with a theoretical study of the effect of chain-like aggregates on magnetic hyperthermia in systems of single-domain ferromagnetic particles immobilized in a non-magnetic medium. We assume that the particles form linear chain-like aggregates and the characteristic time of the Néel remagnetization is much longer than the time of medium heating (time of process observation). This is applicable to magnetite particles when the particle diameter exceeds 20-25 nm. Our results show that the appearance of the chains significantly decreases the intensity of heat production. This article is part of the theme issue 'Heterogeneous materials: metastable and non-ergodic internal structures'.

Size-selected Fe3O4-Au hybrid nanoparticles for improved magnetism-based theranostics.

Size-selected Fe3O4–Au hybrid nanoparticles with diameters of 6–44 nm (Fe3O4) and 3–11 nm (Au) were prepared by high temperature, wet chemical synthesis. High-quality Fe3O4 nanocrystals with bulk-like magnetic behavior were obtained as confirmed by the presence of the Verwey transition. The 25 nm diameter Fe3O4–Au hybrid nanomaterial sample (in aqueous and agarose phantom systems) showed the best characteristics for application as contrast agents in magnetic resonance imaging and for local heating using magnetic particle hyperthermia. Due to the octahedral shape and the large saturation magnetization of the magnetite particles, we obtained an extraordinarily high r2-relaxivity of 495 mM−1·s−1 along with a specific loss power of 617 W·gFe−1 and 327 W·gFe−1 for hyperthermia in aqueous and agarose systems, respectively. The functional in vitro hyperthermia test for the 4T1 mouse breast cancer cell line demonstrated 80% and 100% cell death for immediate exposure and after precultivation of the cells for 6 h with 25 nm Fe3O4–Au hybrid nanomaterials, respectively. This confirms that the improved magnetic properties of the bifunctional particles present a next step in magnetic-particle-based theranostics.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy

Introduction: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex therapeutic procedure used to complement cytoreductive surgery and intravenous chemotherapy for the management of primary peritoneal neoplasms and peritoneal carcinomatosis. Objectives: To review considerations regarding the surgical procedure, physiological changes associated with fluid, blood and protein loss, increase in intra-abdominal pressure, metabolic rate, and systemic hyperthermia, from the perspective of the anesthetist. Methods: A nonsystematic search was conducted in the Medline/PUBMED and Google Academics databases using the terms cytoreductive surgery, hyperthermia, HIPEC, peritoneal carcinomatosis, and Sugarbaker. No limits for publication dates were used. The articles were reviewed independently by each of the authors, and the final text was edited and approved by the main author. Results: Overall, 151 articles were identified, and, of these, 64 were included in the review. The aspects studied included the surgical technique, physiological changes during the procedure, and anesthetic management. Conclusion: Cytoreductive surgery with hyperthermic intra-peritoneal chemotherapy is a therapeutic option for patients with peritoneal carcinomatosis. This procedure involves risks for the patient, first because of an initial phase which involves fluid and blood loss, and, second, because the hyperthermic phase gives rise to a hyperdynamic state with hemodynamic instability. Anesthetists must be familiar with the basic aspects of management to reduce complications and improve patient outcomes.

Magnetic hyperthermia in solid magnetic colloids

Abstract We present results of theoretical study of magnetic hyperthermia in systems of single-domain ferromagnetic particles homogeneously distributed in a solid matrix. The heat effect is induced by linearly polarized alternating magnetic field. The effect of magnetic interaction between the particles as well as influence of orientation of the particles magnetic axes are in a focus of our consideration. Analysis shows that the interparticle interaction increases intensity of the heat production. The thermal effect in the systems with parallel orientation of the particles axes of easy magnetization is significantly higher than that in the case of random orientation of these axes.

Venovenous perfusion-induced systemic hyperthermia: Five-day sheep survival studies

Since hyperthermia selectively kills lung cancer cells, we developed a venovenous perfusion-induced systemic hyperthermia system for advanced lung cancer therapy. Our objective was to test the safety and accuracy of our venovenous perfusion-induced systemic hyperthermia system in 5-day sheep survival studies, following Good Laboratory Practice standards. Our venovenous perfusion-induced systemic hyperthermia system, which included a double-lumen cannula (Avalon Elite, Rancho Dominguez, Calif), a centrifugal pump (Bio-Pump 560; Medtronic Inc, Minneapolis, Minn), a heat exchanger (BIOtherm; Medtronic Perfusion Systems, Brooklyn Park, Minn), and a heater/cooler (modified Blanketrol IIIl Cincinnati Subzero, Cincinnati, Ohio), was tested in healthy adult sheep (n=5). The perfusion circuit was primed with prewarmed Plasma-Lyte A (Baxter Healthcare Corp, Deerfield, Ill) and de-aired. Calibrated temperature probes were placed in the right and left sides of the nasopharynx, bladder, and blood in/out tubing in the animal. The double-lumen cannula was inserted through the jugular vein into the superior vena cava, with the tip in the inferior vena cava. Therapeutic core temperature (42°C-42.5°C), calculated from the right and left sides of the nasopharynx and bladder temperatures, was achieved in all sheep. Heating time was 21±5 minutes. Therapeutic core temperature was maintained for 120 minutes followed by a cooling phase (35±6 minutes) to reach baseline temperature. All sheep recovered from anesthesia with spontaneous breathing within 4 hours. Arterial, pulmonary, and central venous pressures were stable. Transient increases in heart rate, cardiac output, and blood glucose occurred during hyperthermia but returned to normal range after venovenous perfusion-induced systemic hyperthermia termination. Electrolytes, complete blood counts, and metabolism enzymes were within normal to near normal range throughout the study. No significant venovenous perfusion-induced systemic hyperthermia-related hemolysis was observed. Neurologic assessment showed normal brain function all 5 days. Our venovenous perfusion-induced systemic hyperthermia system safely delivered the hyperthermia dose with no significant hyperthermia-related complications.

Effects of ulinastatin administered at different time points on the pathological morphologies of the lung tissues of rats with hyperthermia.

Hyperthermia not only directly induces cell injury of body tissues, but also causes the body to release large amounts of inflammatory mediators and cells with extensive biological activities to induce a systemic inflammatory response and immune dysfunction. Thus, hyperthermia causes systemic inflammatory response syndrome, aggravating injuries to various organs. This study aimed to observe the effects of ulinastatin (UTI) administered at different time points on the cellular morphologies of the lung tissues of rats with systemic hyperthermia. A total of 40 male Sprague Dawley rats were randomly divided into five groups: The normal control group (C group), the hyperthermia group without medication (H group), the hyperthermia and UTI pre-treatment group (HU group), the group treated with UTI at 1 h after hyperthermia (HU1 group), and the group treated with UTI at 2 h after hyperthermia (HU2 group). The systemic hyperthermia rat model was established in a heating chamber with a biological oxygen supply. For the HU, HU1 and HU2 groups, UTI (5×104 U/kg) was administered at different time points. For the C and H groups, an equivalent volume of normal saline was administered. During heating, the respiratory frequency and rectal temperature were measured and recorded once every 30 min. After 2.5 h of heating, the wet/dry weight (W/D) ratio of the lung tissues of the rats was measured. Additionally, the cellular morphologies of the lung tissues were observed under light and electron microscopes. The respiratory frequencies and lung tissue W/D ratios of the rats in the various hyperthermia groups were significantly higher than those of the rats in the C group (all P<0.05). The respiratory frequencies and lung tissue W/D values of the HU and HU1 groups were significantly lower than those of the H group (all P<0.05). Under the light microscope, the bronchial surrounding tissues of the HU and HU1 groups were loose, and the majority of the pulmonary alveolar structures were normal; the H and HU2 groups presented a number of changes, including pulmonary interstitial hyperemia, alveolar epithelial swelling and emphysema. Under the electron microscope, it was observed in the type II epithelial cells of the pulmonary alveoli of the H group that the mitochondria were swollen, the cell ridges were shortened, the microvilli were thin and increased, and the alveolar wall was thickened. Also, an increased number of infiltrating neutrophils were visible. In addition, the type II epithelial cells of the HU2 group also presented these changes to different extents and the changes in the HU and HU1 groups were the mildest. These results indicate that the early application of UTI relieves edema and the extent of cell injury of the lung tissue in rats with systemic hyperthermia.

The possible role of peripherally generated cross-reactive IgG in breakdown of the blood–brain barrier and initiation of multiple sclerosis

Abstract The initiating event in multiple sclerosis (MS) pathogenesis is not known yet. However, in general, breakdown of the blood-brain barrier (BBB) and subsequent infiltration of immune cells into the central nervous system (CNS) has been thought to be the main initiating event. Nonetheless, the mechanism by which the BBB gets disrupted and allows immune cells to infiltrate into the CNS is not fully understood. Evidence indicates that prior to cellular infiltration, over passing peripherally generated cross-reactive immunoglobulin G (IgG) through the transiently permeable BBB during systemic inflammation, hypoxia, hyperthermia, transient hypertension or acute stresses may cause CNS inflammation, BBB breakdown and then initiation of MS disease. Here, we discuss the possible detailed mechanisms that may be involved in cross-reactive IgG-mediated MS autoimmunity.

Resolution of Pulmonary Hypertension Complication During Venovenous Perfusion-Induced Systemic Hyperthermia Application

We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment.

臨床現場における高精度体温制御装置を用いた全身加温の検討

臨床現場における高精度体温制御装置を用いた全身加温の検討

Physiologic Response to a Simplified Venovenous Perfusion-Induced Systemic Hyperthermia System

Our original venovenous perfusion-induced systemic hyperthermia (vv-PISH) system appeared to significantly improve the survival of patients with lung cancer, but was too complex with numerous dialysis problems. We tested a simplified vv-PISH circuit that includes the Avalon Elite (Avalon Laboratories, LLC, Rancho Dominguez, CA) double lumen cannula, a modified heat exchanger, a water heater/cooler, and a centrifugal pump. The purpose of this study was to evaluate this simplified vv-PISH system (without hemodialyzer) and to investigate the physiologic response to whole-body hyperthermia in pigs. We tested our vv-PISH circuit in healthy adult female swine (n = 7, 55-68 kg). The therapeutic core temperature (42°C), calculated as mean of rectal, bladder, and esophageal temperatures, was achieved in six swine. A maximum difference of 0.5°C was observed between the individual temperature sensor readings, indicating homogeneous heat distribution. Heart rate and mean arterial pressure were transiently altered, but were safely managed. A significant elevation in pulmonary artery pressure occurred during the heating phase, resulting in death of one pig. In all other pigs, pulmonary artery pressure returned to physiologic values during the therapeutic phase. Arterial blood electrolytes were maintained without the need of a dialyzer. Major organ function was within normal parameters. The simplified vv-PISH circuit reliably delivered the hyperthermic dose with no need of dialysis.