Focal Hyperthermia Research Articles

Microwave Radiothermometry in Evaluating Brain Temperature Changes (Review)

Aim. This review aims to inform physicians of different specialties (anesthesiologists, intensivists, neurologists, neurosurgeons, oncologists) about the diagnostic capabilities of microwave radiothermometry, which enables to identify and analyze features of alterations of cerebral temperature in brain damage.The review displays a critical analysis of 80 recent Russian and foreign open access publications found by keywords.The review presents major clinical features and pathophysiological mechanisms of cerebral thermal balance disruptions in brain lesions. Slow responsiveness and vulnerability of cerebral thermal homeostasis regulation mechanisms that underlie development of different temperature heterogeneity levels in the cerebral cortex in healthy brain and brain lesions are highlighted. The authors postulate their concept about the critical role of hyperthermia in the pathogenesis of brain damage and disruption of interconnections in the global central regulation system. A body of evidence explaining direct association between the depth of consciousness impairment and degree of cerebral cortex temperature heterogeneity manifestation is presented. It is emphasized that a significant increase in temperature heterogeneity with areas of focal hyperthermia accompanies an acute period of ischemic stroke, while in post-comatose state usually associated with prolonged impairment of consciousness, the temperature heterogeneity significantly subsides. It has been suggested that lowering of an increased and rising of the reduced temperature heterogeneity, for example by using temperature exposure, can improve altered level of consciousness in patients with brain damage. The diagnostic capabilities of various technologies used for cerebral temperature measurement, including microwave radiothermometry (MWR), are evaluated. Data on high accuracy of MWR in measurement of the cerebral cortex temperature in comparison with invasive methods are presented.Conclusion. In healthy individuals MWR revealed a distinct daily rhythmic changes of the cerebral cortex temperature, and badly violated circadian rhythms in patients with brain lesions. Since MWR is an easy-toperform, non-invasive and objective diagnostic tool, it is feasible to use this technology to detect latent cerebral hyperthermia and assess the level of temperature heterogeneity disruption, as well as to study the circadian rhythm of temperature changes.

A New Pharmacokinetic Model Describing the Biodistribution of Intravenously and Intratumorally Administered Superparamagnetic Iron Oxide Nanoparticles (SPIONs) in a GL261 Xenograft Glioblastoma Model.

BackgroundSuperparamagnetic iron oxide nanoparticles (SPIONs) have displayed multifunctional applications in cancer theranostics following systemic delivery. In an effort to increase the therapeutic potential of local therapies (including focal hyperthermia), nanoparticles can also be administered intratumorally. Therefore, the development of a reliable pharmacokinetic model for the prediction of nanoparticle distribution for both clinically relevant routes of delivery is of high importance.Materials and MethodsThe biodistribution of SPIONs (of two different sizes – 130 nm and 60 nm) radiolabeled with zirconium-89 or technetium-99m following intratumoral or intravenous injection was investigated in C57/Bl6 mice bearing subcutaneous GL261 glioblastomas. Based on PET/CT biodistribution data, a novel pharmacokinetic model was established for a better understanding of the pharmacokinetics of the SPIONs after both administration routes.ResultsThe PET image analysis of the nanoparticles (confirmed by histology) demonstrated the presence of radiolabeled nanoparticles within the glioma site (with low amounts in the liver and spleen) at all investigated time points following intratumoral injection. The mathematical model confirmed the dynamic nanoparticle redistribution in the organism over a period of 72 h with an equilibrium reached after 100 h. Intravenous injection of nanoparticles demonstrated a different distribution pattern with a rapid particle retention in all organs (particularly in liver and spleen) and a subsequent slow release rate.ConclusionThe mathematical model demonstrated good agreement with experimental data derived from tumor mouse models suggesting the value of this tool to predict the real-time pharmacokinetic features of SPIONs in vivo. In the future, it is planned to adapt our model to other nanoparticle formulations to more precisely describe their biodistribution in in vivo model systems.

Impact of 68Ga-PSMA-11 PET/CT on staging and management of prostate cancer patients in various clinical settings.

26 Background: The goal of this study was to determine the impact of 68Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications excluding the two main classical indications: BCR and pre-surgical staging. Methods: This is a prospective study of 197 patients that aimed to determine the impact of 68Ga-PSMA-11 PET/CT on PCa stage and management. Indications for PSMA PET/CT were initial staging of non-surgical candidates (30 patients) and re-staging after definitive treatment (n=168). The re-staging cohort comprised: patients re-staged with known advanced metastatic disease (n=103), after androgen deprivation therapy only (n=16), after surgery with serum PSA levels <0.2 ng/ml (n=13), after radiation therapy (RT) not meeting the Phoenix criteria (n=22) and after other primary local treatments [i.e. HIFU, focal laser ablation, cryoablation, hyperthermia or irreversible electroporation] (n=13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review and/or patient telephone encounters. Results: PSMA PET/CT changed disease stage in 135/197 (69%) patients (38% up-stage, 30% down-stage and no changes in stage in 32%). Management was affected in 104/182 (57%) patients. PSMA PET/CT had its greatest management impact in patients who were re-staged after RT. Conclusions: PSMA PET/CT has a profound impact on stage and management of PCa patients outside of the two main classical indications (BCR and presurgical staging) across all examined clinical scenarios. Clinical trial information: NCT04050215.

Tubulopapillary Carcinoma of the Mammary Gland in a Mare

Background: Mammary gland neoplasia are often observed in bitches and cats, rarely in cows, goats, sheep, sows, and mares. Among the neoplasia that affect mares, breast tumors are rare, as they occur more frequently in older animals. In horses, mammary gland tumors occur more frequently in older animals. In this species there are reports of cases describing carcinomas and adenocarcinomas and several subtypes. Mammary neoplasms in equines tend to be locally aggressive and promote metastases to the regional lymph nodes and other organs, including the lungs, and may cause pleural effusion. The aim objective of the present case report was to describe the clinical-pathological and immunohistochemical findings of a tubulopapillary carcinoma of the mammary gland in mare.Case: Was received a biopsy of a tumor mass of the mammary gland of a 15-year-old Quarter Horse mare. According to the veterinarian, the mare presented an increase in volume with ulceration of the mammary gland three months before the biopsy. Macroscopically, the mass was firm to the cut with white surface measuring 12x12 cm. The fragment was fixed in 10% formalin, routinely processed for histology, paraffin embedded, and stained with hematoxylin and eosin. Microscopically, we observed proliferation of epithelial neoplastic cells arranged in tubules and papillary projections, some with two to three layers of cells. Neoplastic cells had oval, moderate and distinct cytoplasm. The nuclei were rounded with dense chromatin and an apparent nucleolus. There were two figures of mitosis per field of high magnification. Proliferation of neoplastic cells invaded adjacent tissues, and in lymph vessels of the region, neoplastic cells were observed as well as inflammation in adjacent tissue. In addition, the breast fragment was submitted to the immunohistochemistry technique using anti-pancytokeratin and anti-vimentin antibody. In immunohistochemistry for pancytokeratin, there was immunoreactivity with marked cytoplasm in neoplastic epithelial cells. In immunohistochemistry for vimentin, there was cytoplasmic labeling in cells of the supporting tissue (fibroblasts and endothelial cells). After approximately six months of the initial diagnosis, the mare died.Discussion: The diagnosis of tubulopapillary carcinoma of the mammary gland in a mare was based on the clinical-pathological and immunohistochemical findings. In mares, descriptions of breasts neoplasia are uncommon and found in animals aged over 12 years. In a study carried out in slaughterhouses in France, with approximately 40,000 horses slaughtered, only 45 breast neoplasms (0.11%) were observed, most of them consisting of carcinomas. In these equines, the absolute incidence of neoplasia of the reproductive system increases with age and tumors generally appear as deep, multifocal, and ulcerating skin nodules. Thus, important differential diagnoses include chronic mastitis and prepartum breast edema. In mares with neoplasia of the mammary gland, unilateral or bilateral volume increase, pain, warm area, redness and suppurative serous discharge are frequently observed. There are also reports of skin ulceration or necrosis. In the present report, the mare showed increased volume of the mammary gland, with focal hyperthermia, fistulated area and serum-blood secretion. The literature suggests a reserved prognosis for any mare presenting mammary neoplasia. Histopathology and immunohistochemistry were fundamental for the diagnosis of tubulopapillary carcinoma of the mammary gland in the present study. Mammary neoplasiss in mares are rare, but should be considered in the diagnosis of mammary pathologies in this species.

Thrombolysis induced by intravenous administration of plasminogen activator in magnetoliposomes: dual targeting by magnetic and thermal manipulation

In previously published studies, intra-arterial (i.a.), but not intravenous (i.v.) delivery of recombinant tissue-type plasminogen activator (rtPA) immobilized on the surface of magnetic nanoparticles induces thrombolysis by magnetic targeting. We asked whether i.v. delivery of protected rtPA in a thermosensitive magnetoliposome (TML@rtPA) may achieve target thrombolysis. PEGylated TML@rtPA was optimized and characterized; controlled release of rtPA was achieved by thermodynamic and magnetic manipulation in vitro. The lysis index of TML@rtPA incubated with blood at 43 °C vs. 37 °C was 53 ± 11% vs. 81 ± 3% in thromboelastograms, suggesting thermosensitive thrombolysis of TML@rtPA. In a rat embolic model with superfusion of 43 °C saline on a focal spot on the iliac artery with clot lodging, release of rtPA equivalent to 20% regular dose from TML@rtPA administered i.a. vs. i.v. significantly restored iliac blood flow 15 vs. 55 min after clot lodging, respectively. TML@rtPA with magnetic guiding and focal hyperthermia may be potentially amendable to target thrombolysis.

Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells

Currently, there are very few therapeutic options for treatment of metastatic disease, as it often remains undetected until the burden of disease is too high. Microporous poly(ε-caprolactone) biomaterials have been shown to attract metastasizing breast cancer cells in vivo early in tumor progression. In order to enhance the therapeutic potential of these scaffolds, they were modified such that infiltrating cells could be eliminated with non-invasive focal hyperthermia. Metal disks were incorporated into poly(ε-caprolactone) scaffolds to generate heat through electromagnetic induction by an oscillating magnetic field within a radiofrequency coil. Heat generation was modulated by varying the size of the metal disk, the strength of the magnetic field (at a fixed frequency), or the type of metal. When implanted subcutaneously in mice, the modified scaffolds were biocompatible and became properly integrated with the host tissue. Optimal parameters for in vivo heating were identified through a combination of computational modeling and ex vivo characterization to both predict and verify heat transfer dynamics and cell death kinetics during inductive heating. In vivo inductive heating of implanted, tissue-laden composite scaffolds led to tissue necrosis as seen by histological analysis. The ability to thermally ablate captured cells non-invasively using biomaterial scaffolds has the potential to extend the application of focal thermal therapies to disseminated cancers.

Abstract 5398: Nanoparticles for image guided focused ultrasound drug delivery

Abstract Thermally triggered, PEGylated drug- liposomes are currently in clinical trials. Conventional thermosensitive liposomes (TSLs) lack the labels that would allow tumor imaging upon intravenous injection and a better mark for tissue specific applied hyperthermia (image guidance). We suggest dual- labelled thermosensitive liposomes for focused ultrasound (FUS) induced hyperthermia, triggered-release and functional delivery of the therapeutic anti-cancer drugs to xenograft tumors in response to thermal stimuli in vivo. In addition to labeling for MR Imaging we introduce the use of near infrared (NIR) fluorophores that allow for real time imaging of nanoparticle behavior in the absence of any significant intrinsic tissue background fluorescence, with good to excellent transmission and reduced scattering throughout tissues. We have synthesized these labels as lipid-probe conjugates and using these labels and thermosensitive lipids we have prepared TSL nanoparticles. N`-XenoLight750-N,N-distearylamidomethylamine (XLA750.DSA) and Gadolinium(III) 2-{4,7-Bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amidomethyl]-1,4,7,10-tetraazacyclododec-1-yl}acetic Acid (Gd.DOTA.DSA) were synthesized and characterized. Both lipids were used to prepare TSL nanoparticles carrying the anticancer drugs at substantial encapsulation efficiency. Nanoparticles were tested for their biophysical characteristics (thermal drug release, stability in plasma, size) in vitro. MRI contrast enhancement ability and Near-IR signal were tested in vitro and in vivo. Nanoparticles carrying drugs were injected intravenously in mice bearing tumors. Nanoparticle kinetics in tumors were assessed with optical imaging and at defined time intervals (post injection), FUS (TIPS Phillips: 1.4MHz) was applied for 3-5 min to induce a small increase in temperature from 37°C to 41°C. Optical imaging revealed both substantial nanoparticle accumulation and drug release immediately after and only in tumors treated with focused ultrasound induced (focal) hyperthermia. Tumors treated with both nanoparticles and FUS post injection showed substantial growth inhibition compared to tumors treated with nanoparticles only. The applications of these multifunctional nanoparticles with short and mild hyperthermia could have a transformative effect on cancer chemotherapy. Citation Format: Maya Thanou, Michael Wright, Miguel Centelles. Nanoparticles for image guided focused ultrasound drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2014-5398

Effects of temperature on simulated electrotonic potentials and their current kinetics of human motor axons at 20°C–42°C

To expand our studies on accommodation in human motor nerve axons, the effects of temperature on polarizing nodal and internodal electrotonic potentials and their current kinetics are investigated. The computations use our temperature dependent multi-layered model of the myelinated human motor nerve fiber and the temperature is increased from 20°C to 42°C. The results show that for temperatures from 28°C to 37°C, the polarizing electrotonic potentials almost coincide, as the kinetics of their ionic currents is changed a little. The normal (at 37°C) resting membrane potential is further depolarized or hyperpolarized during hypothermia (≤ 25°C) or hyperthermia (≥ 40°C), respectively and its change is determined by the flow of ionic currents through the internodal axolemma during the polarizing current stimuli. The polarizing electrotonic potentials are more altered during hypothermia and are most altered during hyperthermia. During hyperthermia, the depolarizing nodal and internodal electrotonic potentials are determined by the nodal slow (I Ks ) and internodal fast (I Kf ) and slow (I Ks ) potassium currents. The hyperpolarizing internodal electrotonic potentials are determined by the activation of internodal channels, which are different during hyperthermia at 40°C and 42°C. These potentials are determined by the internodal I Ks current at 40°C and by the internodal inward rectifier (I IR ) and leakage (I Lk ) currents at 42°C. The difference in accommodation to hyperpolarizing currents during focal and uniform hyperthermia at 42°C is discussed. The present results are essential for the interpretation of mechanisms of threshold electrotonus measurements in subjects with symptoms of cooling, warming and fever, which can result from alterations in body temperature.

Excitability and the safety margin in human axons during hyperthermia

Abstract Hyperthermia challenges the nervous system's ability to transmit action potentials faithfully. Neuromuscular diseases, particularly those involving demyelination have an impaired safety margin for action potential generation and propagation, and symptoms are commonly accentuated by increases in temperature. The aim of this study was to examine the mechanisms responsible for reduced excitability during hyperthermia. Additionally, we sought to determine if motor and sensory axons differ in their propensity for conduction block during hyperthermia. Recordings of axonal excitability were performed at normal temperatures and during focal hyperthermia for motor and sensory axons in six healthy subjects. There were clear changes in excitability during hyperthermia, with reduced superexcitability following an action potential, faster accommodation to long-lasting depolarization and reduced accommodation to hyperpolarization. A verified model of human motor and sensory axons was used to clarify the effects of hyperthermia. The hyperthermia-induced changes in excitability could be accounted for by increasing the modelled temperature by 6°C (and adjusting the maximum conductances and activation kinetics according to their Q10 values; producing a 2 mV hyperpolarization of resting membrane potential), further hyperpolarizing the voltage dependence of Ih (motor, 11 mV; sensory, 7 mV) and adding a small depolarizing current at the internode (motor, 20 pA; sensory, 30 pA). The modelling suggested that slow K(+) channels play a significant role in reducing axonal excitability during hyperthermia. The further hyperpolarization of the activation of Ih would limit its ability to counter the hyperpolarization produced by activity, thereby allowing conduction block to occur during hyperthermia.

Reduced excitability and the safety margin in human axons during hyperthermia

Hyperthermia challenges the nervous system's ability to transmit action potentials faithfully. Neuromuscular diseases, particularly those involving demyelination have impaired safety margins for axonal generation and propagation, and symptoms are commonly accentuated by elevations in temperature. The aim of this study was to examine the mechanisms responsible for reduced excitability during hyperthermia in both motor and sensory axons. Recordings of axonal excitability were performed at normal temperatures and during focal hyperthermia for motor and sensory axons in six healthy subjects. The results show a marked decrease in excitability during hyperthermia, with reduced superexcitability following an action potential, faster accommodation to long-lasting depolarization and reduced accommodation to hyperpolarization. An existing model of human motor and sensory axons was used to model the effects of hyperthermia. The modelling suggested that slow K+ channels play a significant role in reducing excitability during hyperthermia. The further hyperpolarization of the activation of I h could limit its ability to counter the hyperpolarization produced by activity, thereby allowing conduction block to occur during hyperthermia.

Modelo experimental de termoterapia ultrassônica em ratos inoculados com tumor de Walker-236

To develop a model to evaluate the effects of focal pulsed ultrasound (US) waves as a source of heat for treatment of murine subcutaneous implanted Walker tumor.An experimental, controlled, comparative study was conducted. Twenty male Wistar rats (160-300 g) randomized in 2 equal groups (G-1: Control and G-2: Hyperthermia) were inoculated with Walker-256 carcinosarcoma tumor. After 5 days G-2 rats were submitted to 45ºC hyperthermia. Heat was delivered directly to the tumor by an ultrasound (US) equipment (3 MHz frequency, 1,5W/cm³). Tumor temperature reached 45º C in 3 minutes and was maintained at this level for 5 minutes. Tumor volume was measured on days 5, 8, 11, 14 e 17 post inoculation in both groups. Unpaired t-test was used for comparison. P<0.05 was considered significant.Tumor volume was significantly greater in day 5 and decreased in days 11, 14 and 17 in treated rats. Rats treated with hyperthermia survived longer than control animals. On the 29th day following tumor inoculation, 40% of control rats and 77.78% of hyperthermia-treated rats remained alive.The proposed model is quite simple and may be used in less sophisticated laboratory settings for studying the effects of focal hyperthermia in the treatment of malignant implanted tumours or in survival studies.

Experimental model of ultrasound thermotherapy in rats inoculated with Walker-236 tumor

To develop a model to evaluate the effects of focal pulsed ultrasound (US) waves as a source of heat for treatment of murine subcutaneous implanted Walker tumor. An experimental, controlled, comparative study was conducted. Twenty male Wistar rats (160-300 g) randomized in 2 equal groups (G-1: Control and G-2: Hyperthermia) were inoculated with Walker-256 carcinosarcoma tumor. After 5 days G-2 rats were submitted to 45ºC hyperthermia. Heat was delivered directly to the tumor by an ultrasound (US) equipment (3 MHz frequency, 1,5W/cm³). Tumor temperature reached 45º C in 3 minutes and was maintained at this level for 5 minutes. Tumor volume was measured on days 5, 8, 11, 14 e 17 post inoculation in both groups. Unpaired t-test was used for comparison. P<0.05 was considered significant. Tumor volume was significantly greater in day 5 and decreased in days 11, 14 and 17 in treated rats. Rats treated with hyperthermia survived longer than control animals. On the 29th day following tumor inoculation, 40% of control rats and 77.78% of hyperthermia-treated rats remained alive. The proposed model is quite simple and may be used in less sophisticated laboratory settings for studying the effects of focal hyperthermia in the treatment of malignant implanted tumours or in survival studies.

Morphologic evaluation of breast neoplasia in experimental focal hyperthermia

Focal thermotherapy (FT) is a new modality for cancer treatment under study.The objective of this study was to evaluate the morphological changes of breast tumors induced by 7,12‐dimethylbenz[a]anthrace (DMBA).At 53 days of age 24 virgin SD female rats were orally given a single dose of DMBA (65 mg/Kg). Twenty‐six weeks later, animals were randomly allocated to two groups: control group (n=12) and treated group (n=12). The treated group was submitted to FT applied on the largest tumor 60 seconds for two days. The animals were ethically euthanized one week after treatment.Tumors were grouped on: I‐tumors of non‐treated animals; II‐non‐treated tumors of treated animals and III‐tumors injected with ferromagnetic cement heated with electromagnetic energy.The malignant breast tumors were evaluated by histopathology. Apoptosis, necrosis and hemorrhage did not differ significantly between groups I and II, although the frequency of these parameters was higher on group II. On group III there is a significant increase of necrosis compared to group I, and a higher frequency of necrosis and hemorrhage to group II.This preliminary study suggests that FT of one breast carcinoma leads to an increase of necrosis in all tumors of one rat experimental model. Although further studies are needed, FT has great potential for future clinical applications in breast cancer therapy.Grant: FCT‐ PTDC/SAU‐BEB/69497/2006

Synergistic Effect of a Novel Focal Hyperthermia on the Efficacy of Rifampin in Staphylococcal Experimental Foreign-Body Infection

This study was designed to evaluate the efficacy of focal hyperthermia and rifampin in vitro and in vivo using a rabbit model of foreign-body infection by methicillin-resistant Staphylococcus aureus (MRSA). In vitro studies demonstrated bacterial re-growth and development of rifampin resistance after 24 h with rifampin alone, which was prevented under hyperthermic conditions. For the in vivo studies, rifampin was administered intraperitoneally every 12 h for 7 days to rabbits with MRSA-containing cages implanted into their flanks. When combined with hyperthermia at 39 degrees C, 41 degrees C and 43 degrees C, rifampin significantly reduced in-cage bacterial counts by > 3.0 log(10) colony forming units/ml compared with rifampin alone. Eradication of cage-associated infection was achieved more effectively when rifampin was combined with hyperthermia, with cure rates of 70-95% on day 10. Focal hyperthermia combined with rifampin prevented the emergence of rifampin resistance and maintained rifampin efficacy. These findings might have implications for orthopaedic surgery.

Mechanisms of Focal Heat Destruction of Liver Tumors

Focal heat destruction has emerged as an effective treatment strategy in selected patients with malignant liver tumors. Radiofrequency ablation, interstitial laser thermotherapy, and microwave treatment are currently the most widely applied thermal ablative techniques. A major limitation of these therapies is incomplete tumor destruction and overall high recurrences. An understanding of the mechanisms of tissue injury induced by focal hyperthermia is essential to ensure more complete tumor destruction. Here, the currently available scientific literature concerning the underlying mechanisms involved in the destruction of liver tumors by focal hyperthermia is reviewed. Medline was searched from 1960 to 2004 for literature regarding the use of focal hyperthermia for the treatment of liver tumors. All relevant literature was searched for further references. Experimental evidence suggests that focal hyperthermic injury occurs in two distinct phases. The first phase results in direct heat injury that is determined by the total thermal energy applied, tumor biology, and the tumor microenvironment. Tumors are more susceptible to heat injury than normal cells as the result of specific biological features, reduced heat dissipating ability, and lower interstitial pH. The second phase of hyperthermic injury is indirect tissue damage that produces a progression of tissue injury after the cessation of the initial heat stimulus. This progressive injury may involve a balance of several factors, including apoptosis, microvascular damage, ischemia-reperfusion injury, Kupffer cell activation, altered cytokine expression, and alterations in the immune response. Blood flow modulation and administration of thermosensitizing agents are two methods currently used to increase the extent of direct thermal injury. The processes involved in the progression of thermal injury and therapies that may potentially modulate them remain poorly understood. Focal hyperthermia for the treatment of liver tumors involves complex mechanisms. Evidence suggests that focal hyperthermia produces both direct and indirect tissue injury by differing underlying processes. Methods to enhance the effects of treatment to achieve complete tumor destruction should focus on manipulating these processes.

Focal Hyperthermia Produces Progressive Tumor Necrosis Independent of the Initial Thermal Effects

Focal hyperthermia, produced using laser, radio frequency, and microwave, is used to treat liver tumors. The exact mechanisms of tissue destruction using focal hyperthermia are, however, unknown. Clinical and experimental studies suggest a progression of injury after cessation of the initial heat stimulus. This study investigates the mechanisms and time sequence of progressive tissue necrosis induced using focal hyperthermia in a murine model of colorectal liver metastases. Focal hyperthermia produced using a neodymium-yttrium aluminum garnet (Nd-YAG) laser source was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice. The extent of direct lethal thermal injury was assessed histochemically using vital stain for nicotinamide adenine dinucleotide (NADH) diaphorase immediately after laser application. Tissue injury at subsequent time points was assessed using both NADH diaphorase staining and routine histology to determine the temporal relationship between tissue necrosis and time. Thermal injury occurring immediately after the application of 100 joules of energy was greater in the tumor tissue than in the normal liver (mean [standard error of the mean (SEM)]), measuring 23.5 (3.4) and 16.3 (2.6) mm(3), respectively (P=0.046), despite similar tissue temperature profiles. There was a significant increase in tissue necrosis after initial injury that was greater in the normal liver than in the tumor tissue. In the normal liver, the peak volume of necrosis was 137.4 (9.8) mm(3) and occurred at 3 days, whereas in the tumor tissue the peak was 49.0 (3.5) mm(3) at 4.5 days (P < 0.001). Focal hyperthermia produces tissue necrosis that occurs in two phases. The first phase is caused by the direct lethal thermal injury followed by a second phase involving a progression of necrosis beyond the initial thermal effects. The normal liver and the tumor tissue responded differently to focal hyperthermia. In the tumor tissue, the direct injury is more pronounced, whereas the progression of injury is more rapid and extensive in the normal liver.

Progressive microvascular injury in liver and colorectal liver metastases following laser induced focal hyperthermia therapy

Focal hyperthermia by laser or radiofrequency is currently the preferred method for local ablation of liver tumors. The underlying mechanism of action of focal hyperthermia, in particular the relationship between the microvascular and tissue effect is uncertain and was investigated in a murine model. Focal hyperthermia produced by a Neodymium-Yttrium-Aluminium-Garnet laser (wavelength 1,064 nm) was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice at 2 W for 50 seconds (100 J). Tissue injury was assessed at 0, 24, 48, 72, 120, and 168 hours following therapy by measurements of necrosis in tissue sections stained for nicotinamide adenine dinucleotide (NADH) diaphorase activity. Characteristics of microvascular injury were assessed at the various time points by scanning electron microscopy (SEM) of vascular resin casts, Laser Doppler flowmetry, and confocal in vivo microscopy. Focal hyperthermia produced progressive tissue and vascular injury. There was an initial reduction in blood flow and increased vascular permeability in the microcirculation of both tumor and liver tissue immediately following heat application as assessed by laser Doppler flowmetry and confocal in vivo microscopy, respectively. SEM of vascular casts showed heterogeneous regions of microvascular injury immediately following heat application. The extent of initial vascular disruption or occlusion on SEM of vascular resin casts (mean+/-SE) was significantly less than the tissue necrosis in liver (1.9+/-0.1 mm vs. 3.0 mm+/-0.2 mm P<0.001), but was equivalent to the tissue injury in tumor tissue (3.5 mm+/-0.2 mm vs. 3.6 mm+/-0.1 mm P = 0.907). This was followed by a progressive increase in both microvascular and tissue injury in liver and tumor that peaked by 72 hours following treatment. The peak microvascular injury and tissue damage in liver (6.6 mm+/-0.2 and 6.3 mm+/-0.2 mm, respectively) was significantly greater than the extent of microvascular and tissue damage in tumors (4.8 mm+/-0.2 mm and 4.5 mm+/-0.2 mm, respectively) (P<0.001). The progression of microvascular injury in liver and tumor at times preceded the tissue injury. Focal hyperthermia produces both progressive microvascular and tissue damage in liver and colorectal liver metastases. An increase in tissue injury following focal hyperthermia may be a direct result of progressive microvascular damage. Tumor vessels appear more susceptible to direct focal hyperthermia destruction than liver sinusoids. The liver sinusoids are however more susceptible to progressive damage or occlusion following the initial laser thermal stimulus.

Selective occlusion and focal hyperthermia therapy of V-2 tumors in the rabbit hindlimb.

Utilizing technology recently developed in our laboratory, hypervascular, heat-resistant V-2 tumors growing in the rabbit hindlimb were variously subjected to selective vascular occlusion by embolization with Dextran M microspheres and focal hyperthermia to minimum intratumor temperatures of 43 degrees C X 40 minutes (OH), focal 43 degrees C X 40 minutes hyperthermia alone (H), selective occlusion plus sham hyperthermia (O), and sham treatment. Regional toxicity observed consisted of skin burns and muscle fibrosis in the H and OH groups and peripheral embolization in the O alone group. Tumors subjected to a single OH treatment had significantly reduced growth rate over a 28-day period of observation compared with all other treatment groups and sham-treated controls (P less than or equal to .05). Our findings suggest that the combination of selective vascular embolization and focused hyperthermia may be useful in therapy of hypervascular, heat-resistant human tumors in anatomic locations where selective occlusion and relatively intense focal heating can be performed. The regional toxicity encountered in this model reemphasizes the need for extensive thermal mapping over the heated region.

Reversible focal hyperthermic effects on evoked auditory cerebral responses

The click-induced cerebral response recorded as three positive and three negative waves (P 1, P 2, P 3, and N 1, N 2, N 3) from the auditory receiving cortex of cat was selectively modified by focal hyperthermia (FBF). (a) In the posterior ectosylvian gyrus with FBF of 41°C, there was enhanced amplitude of P 2 (24 to 40 ms, latency) and N 2 (44 to 62 ms) waves compared with responses recorded from cortex prior to treatment. (b) Similar enhancement occurred in the middle ectosylvian gyrus with FBF but the effect on the N 2 wave was less prominent. (c) In the anterior ectosylvian gyrus, the amplitude of the N 2 wave was enhanced to a greater extent than the P 2 wave by FBF. (d) In gyrus ansatus, adjacent to the anterior ectosylvian gyrus, FBF resulted in enhancement of the N 1 (16 to 22 ms) wave with smaller increases in the P 2 wave. P 3 N 3 waves showed increased amplitudes but with less stability than those described above. These observations indicate that focally elevated temperatures of auditory receiving cortex result in increased activities which can be recorded as selective enhancement of components of the click-evoked response. Compatible observations, obtained during FBF of the cerebellar auditory receiving area, show increased amplitudes and frequencies of efferent discharges in the superior cerebellar penduncle.

Hyperthermia for Brain Tumors

Hyperthermia has great potential as an antineoplastic agent because: (a) it is effective against relatively radioresistant hypoxic cells and cells in S phase; (b) unlike most chemotherapeutic agents, it is effective against poorly vascularized and metabolically quiescent tissues; (c) as a physical agent, its biological effect is related to the duration and intensity of its application; (d) it seems to have no cumulative toxicity; and (e) it potentiates the effects of both chemotherapy and ionizing radiation at the cellular level. The use of hyperthermia for malignant brain tumors is constrained by a relatively narrow therapeutic index and the considerable thermal sensitivity of normal neural tissue. Glioblastoma multiforme, by virtue of its low growth fraction and heterogeneous cell populations, seems to be an ideal candidate for hyperthermia administered as part of a combined modality treatment program. Focal hyperthermia can be produced by a number of energy sources, including those utilizing ultrasound, microwave, and radiofrequency generators. The clinical safety and feasibility of a miniature microwave radiator/sensor system for direct implantation have been demonstrated. In comparison to normal feline brain, malignant brain tumors in humans are unable to dissipate heat efficiently.