Ferromagnetic Hyperthermia Research Articles

Tumor bed brachytherapy for locally advanced laryngeal cancer: a feasibility assessment of combination with ferromagnetic hyperthermia

Purpose. To assess the feasibility of adding hyperthermia to an original method of organ-preserving brachytherapy treatment for locally advanced head and neck tumors. Methods and materials. The method involves organ-preserving tumor resection and adjunctive high-dose-rate (HDR) brachytherapy delivered via afterloading catheters. These catheters are embedded in a polymeric implant prepared intraoperatively to fill the resection cavity, allowing precise computer planning of dose distribution in the surrounding at-risk tumor bed tissue. Theoretical and experimental analyzes address the feasibility of heating the tumor bed implant by coupling energy from a 100 kHz magnetic field applied externally into ferromagnetic particles, which are uniformly distributed within the implant. The goal is to combine adjuvant hyperthermia (40 °C–45 °C) to at-risk tissue within 5 mm of the resection cavity for thermal enhancement of radiation and chemotherapy response. Results. A five-year relapse free survival rate of 95.8% was obtained for a select group of 48 male patients with T3N0M0 larynx tumors, when combining organ-preserving surgery with HDR brachytherapy from a tumor bed implant. Anticipating the need for additional treatment in patients with more advanced disease, a theoretical analysis demonstrates the ability to heat at-risk tissue up to 10 mm from the surface of an implant filled with magnetically coupled ferromagnetic balls. Using a laboratory induction heating system, it takes just over 2 min to increase the target tissue temperature by 10 °C using a 19% volume fraction of ferromagnetic spheres in a 2 cm diameter silicone implant. Conclusion. The promising clinical results of a 48 patient pilot study demonstrate the feasibility of a new organ sparing treatment for laryngeal cancer. Anticipating the need for additional therapy, theoretical estimations of potential implant heating are confirmed with laboratory experiments, preparing the way for future implementation of a thermobrachytherapy implant approach for organ-sparing treatment of locally advanced laryngeal cancer.

Numerical modeling and simulation of temperature distribution uncertainty subject to ferromagnetic thermoseeds hyperthermia

In the process of ferromagnetic thermoseeds mediated magnetic induction hyperthermia, the temperature distribution in the tumor region is a key factor to determine the therapy effect. During the preoperative treatment planning, discrepancies of the treatment parameters may lead to the temperature distribution uncertainty within the target area. Inaccurate prediction of temperature distribution may induce the treatment failure; therefore, it would be significant to investigate the uncertainty of tissue temperature prediction caused by the disturbance of calculation parameters. In this paper, 3D temperature field and necrosis zone of tissues in ferromagnetic thermoseeds hyperthermia are simulated by the finite volume algorithm, and effects of parameter uncertainties on the temperature distribution are revealed. Results show that selecting appropriate magnetic field parameters for treatment is a priority to guarantee therapeutic effect. Thermoseed properties and blood perfusion rate are the obvious disturbing terms for temperature distribution, while the metabolic heat of bio-tissues can often be ignored within limits. Our investigation is of importance for guiding reasonable and optimal preoperative treatment planning.

Determination of the 3D temperature distribution during ferromagnetic hyperthermia under the influence of blood flow

A numerical simulation of tissue heating during thermo-seed ferromagnetic hyperthermia was performed to determine the temperature distribution of treated tumor tissues under the influence of three large blood vessels at different locations. The effects of the blood velocity waveform, blood vessel size, Curie point of the thermo-seeds and the thermo-seed number on temperature distributions were analyzed. The results indicate that the existence of a blood vessel inside the tumor has a significant cooling effect on the temperature distribution in a treated tumor tissue, which is enhanced with an increase in blood velocity. However, the pulsatile blood flow does not have apparently different effects on the outcomes of uniformly heating target tissues in comparison with the steady blood flow during the hyperthermia process. It is also concluded that a higher Curie point temperature and an increase in the number of thermo-seeds can result in profound increases in the temperature variations of the tumor tissue. In addition, tissue-equivalent phantom experiments were conducted to confirm the cooling effects of the blood vessels, and to validate the effectiveness and accuracy of the proposed heat transfer model for the ferromagnetic hyperthermia.

Influence of Co amount on the efficiency of energy absorption of Fe–Co ferrite nanoparticles

We present the chemical synthesis, structural characterization and efficiency of AC field energy absorption of Fe–Co ferrite particles sized between 35 and 100 nm and containing different cobalt amounts up to 3 wt%. Dynamic magnetic measurements in an AC field with frequency of 430 Hz and amplitude of up to 1200 Oe were performed for both solid and liquid dispersions of obtained particles. The energy absorption per one field cycle in function of the field amplitude and Co content was always bigger in liquid systems, under the same conditions, than in solid systems. The obtained results are of significance for the technology of low-frequency ferromagnetic hyperthermia of tumors.

Study of cobalt ferrite nanosuspensions for low-frequency ferromagnetic hyperthermia

High-coercive cobalt ferrite nanoparticles were synthesized and studied for magnetic hyperthermia by direct injection of their suspension into a tumor and application of a strong audio-frequency magnetic field for heating. Physical (dynamic magnetic hysteresis and heat generation in both liquid and solid dispersions), biological (toxicity and penetration of particles in therapeutic quantities into mouse tumor tissue) as well as other properties of the particles were studied. A model was developed to describe the magnetodynamics in suspensions of magnetic nanoclusters with an account for both Brownian and regular rotations, to provide understanding of observed phenomena. The experimental and theoretical techniques developed have formed a basis for controllable synthesis of the magnetic nanoparticles for low-frequency heat generation in medical and other applications.

Concurrent vs sequential application of ferromagnetic hyperthermia and 125I brachytherapy of melanoma in an animal model : Meiler WF. Trans Am Ophthalmol Soc 1997;95:611–628

Concurrent vs sequential application of ferromagnetic hyperthermia and 125I brachytherapy of melanoma in an animal model : Meiler WF. Trans Am Ophthalmol Soc 1997;95:611–628

Temperature distributions during thermoradiotherapy: a sensitivity study with a transient numerical model of the rabbit eye.

An approach to the treatment of medium-sized choroidal melanomas combines radiation with ferromagnetic hyperthermia. The study herein discusses results with a numerical thermal model of a choroidal melanoma in the rabbit eye as treated with episcleral, thermoradiotherapy plaques. The sensitivity of a temperature-dependent blood perfusion model is investigated.

Ferromagnetic hyperthermia: Functional and histopathologic effects on normal rabbit ocular tissue

Ferromagnetic (FM) hyperthermia has previously been evaluated in a rabbit tumour model of ocular melanoma. To study the effect of focal heating in normal rabbit eyes, FM seeds were implanted into a 14-mm episcleral plaque and heated to operating temperatures of 48 or 54°C. Thermal induction was performed by placing rabbits in a uniform, oscillating (100 kHz) magnetic field operating at 1200 W and an H-field strength of 265A/m. Eyes were heated for 60min with continuous scleral temperature monitoring. Hyperthermic effects were monitored by direct ophthalmic examination, fundus photography, serial electroretinography and histopathology. Intraocular temperatures were mapped with direct fiberoptic thermometry. All treatment effects were confined to the area covered by the episcleral plaque. Direct ophthalmoscopic examination revealed early retinal whitening during heat induction followed by localized exudative retinal detachments, limited to the area of the retinal surface overlying the plaque, that resolved spontaneously. Serial electroretinography was virtually indistinguishable between the 48 and 54°C treatment groups. We noted a minimal alteration in a- and b-wave amplitudes with no changes in implicit times. Histopathology at 3 weeks post-treatment documented chorioretinal scarring overlying the thermal plaque treatment zone. No evidence of haemorrhage, infection, cataract or scleral thinning was noted. This study documents the apparent focal containment of thermal effects with FM heating utilizing operating temperatures as high as 54°C for 60 min, and discloses no evidence of diffuse ocular toxicity.

Radiation therapy and ferromagnetic hyperthermia in the treatment of murine transgenic retinoblastoma.

Combined modality therapy for childhood retinoblastoma holds the potential of decreasing treatment-related morbidity while maintaining excellent tumor control rates. To evaluate the efficacy of external beam radiation therapy (EBRT), ferromagnetic hyperthermia (FMH), and the combination of both modalities in the control of ocular tumors in a transgenic murine model of retinoblastoma. One hundred sixty-six mouse eyes from 4-week-old animals transgenically positive for simian virus 40 large T antigen were treated with a total dose of 10, 15, 20, 30, 40, 45, or 50 Gy of EBRT in 5-Gy fractions twice daily, with 48 degrees C or 54 degrees C FMH for 20 minutes, or with combined EBRT at 10 or 30 Gy and 48 degrees C or 54 degrees C FMH for 20 minutes. Serial histologic sections, obtained 8 weeks after treatment, were examined for the presence of tumor. The tumor control dose for 50% of eyes (TCD50) treated with EBRT occurred at 27.6 Gy. Ferromagnetic hyperthermia at 48 degrees C cured 30% (6/20) of eyes, while 54 degrees C FMH resulted in a 100% (20/20) cure rate. Combined treatment with 48 degrees C FMH and EBRT exhibited a TCD50 at 3.3 Gy. The thermal enhancement ratio was 8.4. Ferromagnetic hyperthermia at 54 degrees C exhibited tumor cure in all animals, but 25% of eyes were lost owing to secondary treatment complications. This represents the first documentation of tumor control via EBRT, ocular FMH, and a combination of these treatment modalities in this murine transgenic retinoblastoma model. The extent of treatment synergy in this model suggests that combined treatment application may allow a reduction in total ocular and periocular radiation dose while maintaining excellent local tumor control.

Characteristics of cell damage in breast cancer with the use of modifiers of radiotherapy

Ultrastructural peculiarities of breast tumor cells damaged by radiotherapy modulated by thermomodifiers are studied. The destructive changes are characteristically more pronounced in the center of nodes rather than in their peripheral parts after hyperthermia of superhigh frequency. Alterations induced by high-frequency interstitial hyperthermia are distributed more evenly in the central and peripheral regions. Ferromagnetic hyperthermia activates phagolysosomes containig iron particles, while hyperthermia with current-conducting fluids causes intra- and intercellular edema.

Thermoradiotherapy of intraocular tumors in an animal model: Concurrent vs. sequential brachytherapy and ferromagnetic hyperthermia

Purpose : To compare concurrent vs. sequential ferromagnetic thermoradiotherapy in vivo. Methods and materials : Greene melanomas were implanted subretinally in rabbits and observed until they were 3–5 mm in diameter. Episcleral plaques were assembled with 125I seeds for radiation therapy, or with ferromagnetic (FM) theremoseeds and nonradioactive I seeds for hyperthermia. Rabbits were implanted by centering a plaque over the intraocular melanoma. After a given dose of radiation had been delivered, the plaque was removed and a nonradioactive plaque containing FM thermoseeds was inserted into the same extrascleral space. One hour later, hyperthermia (46–47°C at the plaque-scleral interface) was initiated and continued for a period of 1 h by placing the rabbits in a magnetic induction coil powered to 1200 W. Tumor size was determined at 1-to 2-week intervals by indirect ophthalmoscopy and by ultrasound. Results : Dose-response analysis of 27 treated eye melanomas showed 50% local tumor control at 43 Gy for 125I alone and 29.4 Gy for 125I followed by FM hyperthermia. the thermal enhancement ratio was 1.4. Conclusion : Comparison with a previously published thermal enhancement ratio of 4.4 (for concurrent 125I and FM hyperthermia) leads us to conclude that thermal enhancement of 125I brachytherapy is more efficient in this tumor model system when hyperthermia is delivered during, rather than after, the irradiation process.

The use of generalized cell-survival data in a physiologically based objective function for hyperthermia treatment planning: A sensitivity study with a simple tissue model implanted with an array of ferromagnetic thermoseeds

Purpose : A physiologically based objective function for identifying a combination of ferromagnetic seed temperatures and locations that maximizes the fraction of tumor cells killed in pretreatment planning of local hyperthermia. Methods and Materials : An objective-function is developed and coupled to finite element software that solves the bioheat transfer equation. The sensitivity of the objective function is studied in the optimization of a ferromagnetic hyperthermia treatment. The objective function has several salient features including (a) a physiological basis that considers increasing the fraction of cells killed with increasing temperatures above a minimum therapeutic temperature ( T mia,thera), (b) a term to penalize for heating of normal tissues above T min,thera, and (c) a scalar weighting factor (γ) that has treatment implications. Reasonable estimates for γ are provided and their influence on the objective function is demonstrated. The cell-kill algorithm formulated in the objective function is based empirically upon the behavior of published hyperthermic cell-survival data. The objective function is shown to be independent of normal tissue size and shape when subjected to a known outer-surface, thermal boundary condition. Therefore, fractions of cells killed in tumors of different shapes and sizes can be compared to determine the relative performance of thermoseed arrays to heat different tumors. Results : In simulations with an idealized tissue model perfused by blood at various rates, maxima of the objective function are unique and identify seed spacings and Curie-point temperatures that maximize the fraction of tumor cells killed. In ferromagnetic hyperthermia treatment planning, seed spacing can be based on maximizing the minimum tumor temperature and minimizing the maximum normal tissue temperature. It is shown that this treatment plan is less effective than a plan based on seed spacings that maximize the objective function. Conclusions : It is shown that under the assumptions of the model and based on a desired therapeutic goal, the objective function identifies a combination of thermoseed temperatures and locations that maximizes the fraction of tumor cells killed.

Effect of interseed spacing, tissue perfusion, thermoseed temperatures and catheters in ferromagnetic hyperthermia: results from simulations using finite element models of thermoseeds and catheters.

Finite element heat-transfer models of ferromagnetic thermoseeds and catheters are developed for simulating ferromagnetic hyperthermia. These models are implemented into a general purpose, finite element computer program to solve the bioheat transfer equation. The seed and catheter models are unique in that they have fewer modeling constraints than other previously developed thermal models. Simulations are conducted with a 4 x 4 array of seeds in a multicompartment tissue model. The heat transfer model predicts that fractions of tumor greater than 43 degrees C are between 8 and 40% lower when seed temperatures depend on power versus models which assume a constant seed temperature. Fractions of tumor greater than 42 degrees C, in simulations using seed and catheter models, are between 3.3 and 25% lower than in simulations with bare seeds. It is demonstrated that an array of seeds with Curie points of 62.6 degrees C heats the tumor very well over nearly all blood perfusion cases studied. In summary, results herein suggest that thermal models simulating ferromagnetic hyperthermia should consider the power-temperature dependence of seeds and include explicit models of catheters.

Use of thermocouples in the intense fields of ferromagnetic implant hyperthermia.

Thermocouples have been used in the intense fields of ferromagnetic implant hyperthermia for extensive temperature measurements. Electromagnetic interference at 100 kHz is minimized with feed-through filters mounted on a copper plate in a shielded assembly. The thermocouples are temperature compensated in the software by monitoring the temperature of the copper plate. D-shell connectors are used for multiple sensor thermocouple connections and to provide proper shield termination of external cables. The technical approaches of grounding, shielding and filtering are examined, and experiments have been conducted to determine the proper usage of thermocouple during ferromagnetic implant treatments. The dependence of filter performance on thermocouple impedance and the effect of D-shell connections on temperature accuracy have been studied. The results indicate that self-heating due to electromagnetic energy coupled into 51 microns thermocouple leads and unbalanced current along 76 microns leads are insignificant at 100 kHz. But severe heating has been observed in 511 and 813 microns leads, especially in high-conductivity copper wires. By using 25-50 microns thermocouple leads, better than 0.1 degree C accuracy and 0.05 degree C resolution have been achieved during ferromagnetic hyperthermia. At field strength of 1500 A/m, artifacts of 0.03-0.05 degree C are observed.

Effect of implant variables on temperatures achieved during ferromagnetic hyperthermia

Effects of ferromagnetic implant variables on steady-state temperature were studied in both in vitro (phantom) and in vivo (rabbit hind limb musculature) models. Thermoseed implant variables included: (1) the presence and number of thermoseed sleeves; (2) variations in thermoseed alignment within the oscillating electromagnetic field; (3) generator power levels of 300 W, 600 W, and 1200 W; and (4) separation of thermoseed tracks by 0.8 cm versus 1 cm. When the thermoseeds were aligned parallel to the electromagnetic field, temperature distributions in the in vivo model using bare thermoseeds and thermoseeds encased in a single sleeve (0.1 mm wall thickness) of polyethylene tubing were statistically higher than in tests performed with thermoseeds encased in a double sleeve (0.25 mm over 0.1 mm wall thickness) of tubing (p = 0.006). Nonetheless, average steady-state temperatures above a therapeutic minimum (greater than or equal to 42 degrees C) were achieved at all generator power levels using thermoseeds encased in a double sleeve of tubing and aligned parallel to the electromagnetic field. Gross misalignment of thermoseeds with the electromagnetic field was partly compensated for by utilizing higher generator power levels. Thermoseed tracks separated by 0.8 cm and aligned parallel to the electromagnetic field yielded average steady-state temperatures that were 0.4-2.2 degrees C higher than those obtained with a thermoseed track separation of 1 cm.

A gap type RF induction heating system for ferromagnetic hyperthermia

A gap type RF induction heating system for ferromagnetic hyperthermia

Ferromagnetic hyperthermia and iodine 125 brachytherapy in the treatment of choroidal melanoma in a rabbit model.

Hyperthermia has been combined with conventional radiation methods to achieve enhanced tumor destruction. We combined iodine 125 seeds with ferromagnetic thermoseeds in a single plaque to simultaneously deliver radiation and heat in a rabbit model of choroidal melanoma. Initially, six ferromagnetic thermoseeds were placed in parallel on a 14-mm episcleral plaque. The plaques were placed on normal rabbit eyes and on eyes containing transvitreally implanted choroidal melanoma. The heating response was assessed in both normal and tumor-containing eyes. Rigid copper-constantan and flexible Baily thermocouples were used to monitor temperature responses. The animals were subjected to an electromagnetic field of 100 kHz, with power of 1100 to 1500 W. The thermoseeds autoregulated at 48.2 degrees C. Scleral temperatures stabilized at 45.8 degrees C +/- 0.4 degrees C (SD), while temperatures at the base of the tumor stabilized at 43.6 degrees C +/- 0.1 degrees C. Ferromagnetic thermoseeds were then combined with iodine 125 seeds. Similar temperature responses were recorded, and autoradiographic findings confirmed a uniform radiation distribution. Varying the amount or type of ferromagnetic material in the thermoseeds allows the delivery of heat at virtually any temperature. Ferromagnetic hyperthermia may provide a more simplified approach over currently available methods of heat delivery.