This PDF file contains the front matter associated with SPIE Proceedings Volume 7181, including the Title Page, Copyright information, Table of Contents, Introduction, and the Conference Committee listing.

The basic unit of life and death is the cell. The two main modes of cell death, cell death with necrosis and apoptosis, are characterized by relatively easily recognizable, different morphologic changes before, during and after the cell has died. However, more recent advanced investigations of the physiologic, biochemical and genetic aspects of cell death have produced a wealth of information. But, the final analysis of this embarrassment of riches awaits the accumulation of more knowledge and understanding of how all the pieces fit together and relate to each other. Currently, the analyses are complicated by the isolated and narrow scope of the experimental subjects, a lack of uniformity of nomenclature and missing information that would allow successful understanding of the "big picture." Some causes and mechanisms of heat-induced cellular and tissue death will be considered from anatomical, pathological, physiological, biochemical and genetic aspects.

Minimally invasive, thermally ablative, interventional technologies have been changing the practice of medicine since before the turn of the 20th century. More recently, cryothermic and hyperthermic therapies have expanded in terms of their spectrum of thermal generators, modes for controlling and monitoring the treatment zone and both benign and malignant medical applications. The final tissue, and hence clinical outcome, of a thermal ablation is determined by the summation of direct primary (thermal) and secondary (apoptosis, ischemia, free radical, inflammation, wound healing, etc.) injury followed by possible cellular regeneration and scar formation. The initial thermal lesion can be broadly divided into two major zones of cellular death: 1) the complete ablation zone closer to the thermal source and 2) the peripheral transition zone with a decreasing gradient of cell death. While not applicable to cryotherapy, hyperthermic complete ablation zones are subdivided into two zones: 1) thermal or heat fixation and 2) coagulative necrosis. It is important to clearly differentiate these tissue zones because of their substantially different healing responses. Therefore, the development of clinically successful thermal therapies requires an understanding of tissue healing responses. The healing responses can be affected by a number of additional factors such as the tissue's anatomy, organ specific healing differences, blood supply, protein vs. lipid content, and other factors. Thus, effective biomedical instrument development requires both an understanding of thermal cell injury/death and the body's subsequent healing responses. This paper provides a general overview of the healing pathways that follow thermal tissue treatment.

Thermal Dose, expressed as equivalent minutes of exposure at 43 °C, is typically used as the measure of relative treatment effectiveness in tumor hyperthermia work while an Arrhenius model is more typical in skin burn and other higher temperature studies. The two methods are closely related, mathematically, but yield very different styles of prediction. Arrhenius calculations in numerical models can be used to predict the probability of irreversible thermal damage and are capable of making such predictions for several different markers of thermal damage simultaneously. CEM 43 contours are not probabilistic by nature, though they do contain that information. If one additional data point is known - i.e. D0 at 43 °C - a probability plot identical to the Arrhenius result may be created from a CEM 43 result. Absent that value, it is not possible to do. This paper de-constructs both measures of irreversible thermal alteration, showing their inter-relationship, and presents methods to convert one measure into the other. Specific examples of damage predictions using thermal damage coefficients from published data are discussed with particular emphasis on the original pathologic data from 1947. Obtaining probabilistic predictions from the two methods is presented, and strongly advocated.

A treatment system was developed utilizing a microwave-based procedure capable of treating myopia and offering a less invasive alternative to laser vision correction without cutting the eye. Microwave thermal treatment elevates the temperature of the paracentral stroma of the cornea to create a predictable refractive change while preserving the epithelium and deeper structures of the eye. A pattern of shrinkage outside of the optical zone may be sufficient to flatten the central cornea. A numerical model was set up to investigate both the electromagnetic field and the resultant transient temperature distribution. A finite element model of the eye was created and the axisymmetric distribution of temperature calculated to characterize the combination of controlled power deposition combined with surface cooling to spare the epithelium, yet shrink the cornea, in a circularly symmetric fashion. The model variables included microwave power levels and pulse width, cooling timing, dielectric material and thickness, and electrode configuration and gap. Results showed that power is totally contained within the cornea and no significant temperature rise was found outside the anterior cornea, due to the near-field design of the applicator and limited thermal conduction with the short on-time. Target isothermal regions were plotted as a result of common energy parameters along with a variety of electrode shapes and sizes, which were compared. Dose plots showed the relationship between energy and target isothermic regions.

Technology is in development to correct vision without the use of lasers or cutting of the eye. Many current technologies used to reshape the cornea are invasive, in that either RF needles are placed into the cornea or a flap is cut and then a laser used to ablate the cornea in the optical zone. Keraflex, a therapeutic microwave treatment, is a noninvasive, non-incisional refractive surgery procedure capable of treating myopia (nearsightedness). The goal is to create a predictable refractive change in the optical zone, while preserving the epithelium and deeper structures of the eye. A further goal is to avoid incisions and damage to the epithelium which both require a post-treatment healing period. Experimental work with fresh porcine eyes examined the following variables: duration of the RF pulse, RF power level, coolant amount and timing, electrode spacing, applanation force against the eye, initial eye temperature, and age of eye. We measured curvature changes of the eye with topography, Scheimpflug, Wavefront aberrometry or other means to characterize diopter change as an important endpoint. Other assessment includes evaluation of a fine white ring seen in the cornea following treatment. Dose studies have been done to correlate the treated region with energy delivered. The timing and dosing of energy and cooling were investigated to achieve the target diopter change in vision.

The use of conformal antenna array in the treatment of superficial diseases can significantly increase patient comfort while enhancing the local control of large treatment area with irregular shapes. Originally a regular square multi-fed slot antenna (Dual Concentric Conductor - DCC) was proposed as basic unit cell of the array. The square DCC works well when the outline of the treatment area is rectangular such as in the main chest or back area but is not suitable to outline diseases spreading along the armpit and neck area. In addition as the area of the patch increases, the overall power density decreases affecting the efficiency and thus the ability to deliver the necessary thermal dose with medium power amplifier (<50W). A large number of small efficient antennas is preferable as the disease is more accurately contoured and the lower power requirement for the amplifiers correlates with system reliability, durability, linearity and overall reduced cost. For such reason we developed a set of design rules for multi-fed slot antennas with irregular contours and we implemented a design that reduce the area while increasing the perimeter of the slot, thus increasing the antenna efficiency and the power density. The simulation performed with several commercial packages (Ansoft HFSS, Imst Empire, SemcadX and CST Microwave Studio) show that the size reducing method can be applied to several shapes and for different frequencies. The SAR measurements of several DCCs are performed using an in-house high resolution scanning system with tumor equivalent liquid phantom both at 915 MHz for superficial hyperthermia systems in US) and 433 MHz (Europe). The experimental results are compared with the expected theoretical predictions and both simulated and measured patterns of single antennas of various size and shapes are then summed in various combinations using Matlab to show possible treatment irregular contours of complex diseases. The local control is expected to significantly improve while maintaining the patient comfort.

Microwave applicators are becoming more prevalent in cancer ablation therapy due to factors of penetration, high power, and shortened treatment time. These applicators create the largest zones of necrosis of available energy sources. Progress has been made both with interstitial applicators for surgical, laparoscopic, or radiological approaches, as well as surface applicators that provide hemostasis or precoagulation prior to resection. Most commonly, the applicators operate at 915 MHz or 2450 MHz, and are well matched to tissue. Surgical applicators are as large as 5.6 mm and have the capability to operate at 100-200 W. With smaller applicators, internal cooling may be required to avoid heating sensitive skin surfaces if used percutaneously or laparoscopically. With the interstitial applicators, animal studies have shown a strong relationship between power and ablation volume, including reaching a steady-state plateau in performance based more on power level and less on time. As shown in-vivo, MW surface applicators are very efficient in surface coagulation for hemostasis or precoagulation and in the treatment of surface breaking lesions. These applicators are also capable of deep penetration as applied from the surface. Characteristic treatment times for interstitial applicators are four minutes and for surface applicators, one minute or less is sufficient. Examples will be shown of multi-organ results with surface coagulation using high-power microwaves. Finally, future trends will be discussed that include treatment planning, multiple applicators, and navigation.

A clinical treatment delivery platform has been developed for providing 3D controlled hyperthermia with catheter-based ultrasound applicators in conjunction with high dose rate (HDR) brachytherapy. This integrated system consists of hardware and software components required for thermal therapy delivery, treatment monitoring and control, and realtime and post-treatment analysis; and interstitial and endocavity ultrasound heating applicators. Hardware includes a 32-channel RF amplifier with independent power (0-25 W) and frequency (5-10 MHz) control for ultrasound power delivery and a 48-channel thermometry system compatible with 0.4 mm OD multi-sensor thermocouple probes. Software graphical user interfaces (GUI) are used to monitor and control both the amplifier and the thermometry system. The amplifier GUI controls, monitors, and records individual channel frequency and power values in real-time; the thermometry GUI monitors and records temperature and thermal dose values in real-time, as well as displaying and allowing dynamic control for temperature and thermal dose target thresholds. The thermometry GUI also incorporates registration of thermocouple positions relative to target anatomy and applicator transducers based on HDR planning tools (CT/MRI/US overlays) for improved treatment control and documentation. The interstitial (2.4 mm) and endocavity (6 mm) ultrasound hyperthermia applicators are composed of linear arrays of 1-4 tubular piezoceramic transducers - sectored at 90°, 180°, 270°, and 360° for single or dual directional heating patterns - that are compatible with plastic implant catheters. QA techniques specific to these catheter-based ultrasound applicators have been devised and implemented, and include rotational beam plots and dynamic force balance efficiency measurements, which are critical to establish applicator performance. A quality assurance test matrix has been devised and used to evaluate and characterize all components of this system prior to clinical implementation.

Investigators reporting RF ablation (RFA) studies often use different initial and dynamic conditions, often in porcine or bovine liver models. This study examines the effects of initial temperature, prior freezing, and perfusion in these models. Understanding how these variables affect RFA size provides some basis for comparing data from different studies. We obtained porcine and bovine livers from a slaughterhouse and divided them into experimental groups each with discrete initial temperatures set in the range of 12 to 37°C. The livers were used either the day of harvest or frozen within 1-3 days prior to RFA treatment. A perfused liver model was developed to simulate human blood flow rates and allowed accurate control of the temperature and flow rate. Saline (0.9%) was substituted for blood. The non-perfused liver model group included bovine and porcine tissue; whereas the perfused liver model group included only porcine tissue. One experiment included porcine livers that were perfused at different flow rates and with different saline concentrations. Harvested tissue from this group was examined under a light microscope and the level of edema was assessed using image processing software. The results demonstrate no significant difference in RF lesion sizes between porcine and bovine livers. Freezing the tissue prior to treatment has no significant effect but the initial temperature does significantly affect the size of ablation. The ablation size in perfused liver is similar to in vivo results (earlier study) but is significantly smaller then non-perfused liver. Morphological analysis indicates that perfusion, freezing, and saline concentration cause significant tissue edema.

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3± 0.001% and 2.95±0.03 % using an ion chamber and OneDose™ dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic.

As a part of an ongoing program to develop computerized tools for surgery, the current study focuses on the design of optimal cryoprobe layouts for prostate cryosurgery. Once a decision to treat the prostate with cryosurgery has been made, its application can be presented as a four-stage process: (i) 3D reconstruction of the target region; (ii) evaluation of the optimum number of cryoprobes and their layout; (iii) insertion of cryoprobes according to that plan; and, (iv) orchestrating cryoprobe operation to achieve the optimum match between the target region and the forming frozen region. Cryosurgical success equals the sum of the successes of each of the above stages. To date, this four-stage process is performed manually, relying upon the cryosurgeon's experience and "rules of thumb". This manuscript reviews recent efforts to develop the necessary building blocks for an integrated computerized surgical tool for prostate cryosurgery, which includes methods for prostate model reconstruction, schemes for bioheat transfer simulation, and optimization techniques for cryoprobe placement; experimental verification of these building blocks are also presented. The emphasis in this line of development is on performing a full-scale planning in less than one minute, while the patient is on the operation table. It can be concluded from the current manuscript that the above goals are achievable. The current manuscript concludes with a review of current challenges in the development of related computerized means.

A 3D optimization-based thermal treatment planning platform has been developed for the application of catheter-based ultrasound hyperthermia in conjunction with high dose rate (HDR) brachytherapy for treating advanced pelvic tumors. Optimal selection of applied power levels to each independently controlled transducer segment can be used to conform and maximize therapeutic heating and thermal dose coverage to the target region, providing significant advantages over current hyperthermia technology and improving treatment response. Critical anatomic structures, clinical target outlines, and implant/applicator geometries were acquired from sequential multi-slice 2D images obtained from HDR treatment planning and used to reconstruct patient specific 3D biothermal models. A constrained optimization algorithm was devised and integrated within a finite element thermal solver to determine a priori the optimal applied power levels and the resulting 3D temperature distributions such that therapeutic heating is maximized within the target, while placing constraints on maximum tissue temperature and thermal exposure of surrounding non-targeted tissue. This optimizationbased treatment planning and modeling system was applied on representative cases of clinical implants for HDR treatment of cervix and prostate to evaluate the utility of this planning approach. The planning provided significant improvement in achievable temperature distributions for all cases, with substantial increase in T90 and thermal dose (CEM43T90) coverage to the hyperthermia target volume while decreasing maximum treatment temperature and reducing thermal dose exposure to surrounding non-targeted tissues and thermally sensitive rectum and bladder. This optimization based treatment planning platform with catheter-based ultrasound applicators is a useful tool that has potential to significantly improve the delivery of hyperthermia in conjunction with HDR brachytherapy. The planning platform has been extended to model thermal ablation, including the addition of temperature dependent attenuation, perfusion, and tissue damage. Pilot point control at the target boundaries was implemented to control power delivery to each transducer section, simulating an approach feasible for MR guided procedures. The computer model of thermal ablation was evaluated on representative patient anatomies to demonstrate the feasibility of using catheter-based ultrasound thermal ablation for treatment of benign prostate hyperplasia (BPH) and prostate cancer, and to assist in designing applicators and treatment delivery strategies.

Purpose: Blood perfusion is a well-known factor that complicates accurate control of heating during hyperthermia treatments of cancer. Since blood perfusion varies as a function of time, temperature and location, determination of appropriate power deposition pattern from multiple antenna array Hyperthermia systems and heterogeneous tissues is a difficult control problem. Therefore, we investigate the applicability of a real-time eigenvalue model reduction (virtual source - VS) reduced-order controller for hyperthermic treatments of tissue with nonlinearly varying perfusion. Methods: We impose a piecewise linear approximation to a set of heat pulses, each consisting of a 1-min heat-up, followed by a 2-min cool-down. The controller is designed for feedback from magnetic resonance temperature images (MRTI) obtained after each iteration of heat pulses to adjust the projected optimal setting of antenna phase and magnitude for selective tumor heating. Simulated temperature patterns with additive Gaussian noise with a standard deviation of 1.0°C and zero mean were used as a surrogate for MRTI. Robustness tests were conducted numerically for a patient's right leg placed at the middle of a water bolus surrounded by a 10-antenna applicator driven at 150 MHz. Robustness tests included added discrepancies in perfusion, electrical and thermal properties, and patient model simplifications. Results: The controller improved selective tumor heating after an average of 4-9 iterative adjustments of power and phase, and fulfilled satisfactory therapeutic outcomes with approximately 75% of tumor volumes heated to temperatures >43°C while maintaining about 93% of healthy tissue volume < 41°C. Adequate sarcoma heating was realized by using only 2 to 3 VSs rather than a much larger number of control signals for all 10 antennas, which reduced the convergence time to only 4 to 9% of the original value. Conclusions: Using a piecewise linear approximation to a set of heat pulses in a VS reduced-order controller, the proposed algorithm greatly improves the efficiency of hyperthermic treatment of leg sarcomas while accommodating practical nonlinear variation of tissue properties such as perfusion.

A transrectal MRgFUS system was tested in a canine prostate model. Focal volumes in each half of the prostate were targeted, with high energy in one half of the gland for ablation and in the other with lower-energy sonications to test our ability to localize the focal spot before causing thermal tissue damage. All sonications (n=155) were readily observed with proton resonance frequency (PRF) MR temperature imaging, contrast enhanced MRI and histology. The prostate gland moved during the experiments, demonstrating the need for motion tracking. The resultant focal temperature changes during the experiments were 24.2 ± 8.2°C.

A critical need has emerged for volumetric thermometry to visualize 3D temperature distributions in real time during deep hyperthermia treatments used as an adjuvant to radiation or chemotherapy for cancer. For the current effort, magnetic resonance thermal imaging (MRTI) is used to measure 2D temperature rise distributions in four cross sections of large extremity soft tissue sarcomas during hyperthermia treatments. Novel hardware and software techniques are described which improve the signal to noise ratio of MR images, minimize motion artifact from circulating coupling fluids, and provide accurate high resolution volumetric thermal dosimetry. For the first 10 extremity sarcoma patients, the mean difference between MRTI region of interest and adjacent interstitial point measurements during the period of steady state temperature was 0.85°C. With 1min temporal resolution of measurements in four image planes, this noninvasive MRTI approach has demonstrated its utility for accurate monitoring and realtime steering of heat into tumors at depth in the body.

We are developing a microwave tomographic imaging system for non-invasive monitoring of temperature changes during thermal therapy, based on the known tissue conductivity temperature dependence. As with any monitoring system, the actual integration with a therapy device is a significant challenge. The combined high intensity focused ultrasound (HIFU)/microwave imaging approach is intriguing because the necessary characteristics for the microwave data gathering (highly EM attenuating coupling liquid) are not compromised by the HIFU requirements (low ultrasound attenuating coupling liquid) since the physics of the two wave propagations are quite different. We have previously reported results for a configuration for use in breast cancer treatment where the HIFU transducer was positioned within the array of coaxial support rods of the antennas which surrounded the breast while the ultrasound beam propagated towards the breast without being obstructed by the antennas. For our new implementation, we have positioned the heating device outside the antenna array and aimed the beam directly past the monopole antennas to the target tissue within. This configuration is particularly useful for various other anatomical sites where it is not possible to position the transducer inside the antenna array, such as for vital organs in the torso. Our initial results illustrate that the ultrasound beam is not significantly impaired by the presence of the microwave antennas and that the beam is readily steerable to desired locations. Additional dynamic experiments demonstrate good correlation between actual temperature rise and conductivity decreases in targeted positions. These results set the stage for actual animal experiments.

The development of medical grade iron oxide nanoparticles (IONP) has renewed interest in hyperthermia cancer therapy. Because of their modifiable size and heating capabilities under an AC magnetic field (alternating magnetic field, AMF), IONPs have the potential to damage or kill cells in a manner more therapeutically efficient than previous hyperthermia techniques. The use of IONPs in hyperthermia cancer therapy has prompted numerous questions regarding the cytotoxic mechanism associated with IONP heat therapy and if such mechanism is different (more or less effective) with respect to conventional hyperthermia techniques. In this in vitro study, we determine the immediate and long-term (24 hours) cytotoxic effects of isothermal IONP hyperthermia treatment versus a conventional global heating technique (water bath). Using the same heating time and temperature we showed significantly greater cytotoxicity in IONP-heated cells as opposed to water bath-treated cells. We postulate that the difference in treatment efficacy is due to the spatial relationship of particle-induced thermal damage within cells. Although the exact mechanism is still unclear, it appears likely that intracellular IONPs have to achieve a very high temperature in order to heat the surrounding environment; therefore it is reasonable to assume that particles localized to specific areas of the cell such as the membrane can deliver exacerbated injury to those areas. In this experiment, although detectable global temperature for the particle-heated cells stands comparable to the conventional heat treatment, particle-induced cell death is higher. From the results of this study, we propose that the mechanism of IONP hyperthermia renders enhanced cytotoxicity compared to conventional waterbath hyperthermia at the same measured thermal dose.

The use of nanoparticles in medical treatment has prompted the question of their safety. In this study, the pathophysiology and biodistribution of three different concentrations of intravenously-delivered dextran-coated Fe3O4 iron oxide nanoparticles (IONP) were evaluated in mice. Some groups of mice were exposed to an AC magnetic field (AMF) at levels comparable with those proposed for cancer treatments. Iron biodistribution analysis for both AMF and non-AMF treated mice was performed for all three concentrations used (.6 mg Fe/mouse, 1.8 mg Fe/mouse, and 5.6 mg Fe/mouse). Blood urea nitrogen, alanine transaminase, alkaline phosphatase, total serum protein, and creatinine were also assessed at 4 hours, 7 days, and 14 days post-injection. Histological analysis of lung, spleen, heart, liver, and kidney tissue was conducted at 7 and 14 days post-injection. Prussian blue and H&E stains were used to histomorphometrically assess iron content in the tissues studied. Preliminary results demonstrate small temporary elevation in liver enzymes and hepatocyte vacuolization at all iron concentrations studied. Liver and spleen were the primary sites of IONP deposition. None of the animals demonstrated systemic or local toxicity or illness, with or without AMF activation.

Investigators are just beginning to use hyperthermia generated by alternating magnetic field (AMF) activated iron oxide nanoparticles (IONPs) as a promising avenue for targeted cancer therapy. An important step in understanding cell death mechanisms in nanoparticle AMF treatments is to determine the location of these nanoparticles in relation to cellular organelles. In this paper, we report on transmission electron microscopy (TEM) studies designed to define the position of 100 nm diameter dextran-coated iron oxide nanoparticles in murine breast adenocarcinoma (MTG-B) and human colon adenocarcinoma tumors propagated in mice. METHODS: Iron oxide nanoparticles (5 mg/g tumor) were injected into intradermal MTG-B flank tumors on female C3H/HEJ mice and into HT-29 flank tumors on female Nu/Nu mice. The IONPs were allowed to incubate for various times. The tumors were then excised and examined using TEM. RESULTS: In the MTG-B tumors, most of the nanoparticles reside in aggregates adjacent to cell plasma membranes prior to three hours post-injection. By four hours post injection, however, most of the nanoparticles have been endocytosed by the cells. At time periods after four hours post injection, few visible extracellular nanoparticles remain and intracellular nanoparticles have densely aggregated within endosomes. In the HT-29 tumor, however, endocytosis of nanoparticles has not progressed to the same extent as in the MTG-B tumors by four hours post injection. CONCLUSIONS: The time at which most of the nanoparticles transition from being extracellular to intracellular in the MTG-B system appears to be between two and four hours. The HT-29 cells, however, display different and delayed uptake pattern. These data show that there are IONP uptake differences between tumor types (cell lines) and that, based on known uptake kinetics, nanoparticle hyperthermia can be employed as an extracellular or intracellular modality. These data will be important in guiding future nanoparticle hyperthermia cancer treatments.

The benefit of combining hyperthermia and chemotherapy to treat cancer is well established. However, combined therapy has not yet achieved standard of care status. The reasons are numerous and varied, however the lack of significantly greater tumor cell sensitivity to heat (as compared to normal cells) and the inability to deliver heat to the tumor in a precise manner have been major factors. Iron oxide nanoparticle (IONP) hyperthermia, alone and combined with other modalities, offers a new direction in hyperthermia cancer therapy via improved tumor targeting and an improved therapeutic ratio. Our preliminary studies have demonstrated tumor cell cytotoxicity (in vitro and in vivo) with IONP heat and cisplatinum (CDDP) doses lower than those necessary when using conventional heating techniques or cisplatinum alone. Ongoing studies suggest such treatment could be further improved through the use of targeted nanoparticles.

It is established that heat can enhance the effect of radiation cancer treatment. Due to the ability to localize thermal energy using nanoparticle hyperthermia, as opposed to other, less targeted, hyperthermia modalities, it appears such enhancement could be accomplished without complications normally associated with systemic or regional hyperthermia. This study employs non-curative (suboptimal), doses of heat and radiation, in an effort to determine the therapeutic enhancement potential for IONP hyperthermia and radiation. Methods: MTG-B murine breast adenocarcinoma cell are inoculated into the right flanks of female CH3/HEJ mice and grown to volumes of 150mm³⁺ /_- 40 mm³. A single dose of 15 Gy (6 MeV) radiation was uniformly delivered to the tumor. A pre-defined thermal dose is delivered by direct injection of iron oxide nanoparticles into the tumor. By adjusting the field strength of the 160 KHz alternating magnetic field (AMF) an intra-tumoral temperature between 41.5 and 43 degrees Celsius was maintained for 10min. The alternating magnetic field was delivered by a water-cooled 36mm diameter square copper tube induction coil operating at 160 kHz with variable magnet field strengths up to 450 Oe . The primary endpoint of the study is the number of days required for the tumor to achieve a volume 3 fold greater than the volume at the time of treatment (tumor regrowth delay). Results: Preliminary results suggest the addition of a modest IONP hyperthermia to 15 Gy radiation achieved an approximate 50% increase in tumor regrowth delay as compared to a 15 Gy radiation treatment alone. The therapeutic effects of IONP heat and radiation combined were considered additive, however in mice that demonstrated complete response (no tumor present after 30 days), the effect was considered superadditive or synergistic. Although this data is very encouraging from a multimodality cancer therapy standpoint, additional temporal and dose related information is clearly necessary to optimize the therapy.

Hyperthermia, as an independent modality or in combination with standard cancer treatments such as chemotherapy and radiation, has been established in vitro and in vivo as an effective cancer treatment. However, despite efforts over the past 25 years, such therapies have never been optimized or widelyaccepted clinically. Although methods continue to improve, conventionally-delivered heat (RF, ultrasound, microwave etc) can not be delivered in a tumor selective manner. The development of antibody-targeted, or even nontargeted, biocompatible iron oxide nanoparticles (IONP) now allows delivery of cytotoxic heat to individual cancer cells. Using a murine mouse mammary adenocarcinoma (MTGB) and human colon carcinoma (HT29) cells, we studied the biology and treatment of IONP hyperthermia tumor treatment. Methods: Cancer cells (1 x 10⁶) with or without iron oxide nanoparticles (IONP) were studied in culture or in vivo via implanted subcutaneously in female C3H mice, Tumors were grown to a treatment size of 150 mm³ and tumors volumes were measured using standard 3-D caliper measurement techniques. Mouse tumors were heated via delivery of an alternating magnetic field, which activated the nanoparticles, using a cooled 36 mm diameter square copper tube induction coil which provided optimal heating in 1.5 cm wide region of the coil. The IONPs were dextran coated and had a hydrodynamic radius of approximately 100 nm. For the in vivo studies, intra-tumor, peritumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Although some eddy current heating was generated in non-target tissues at the higher field strengths, our preliminary IONP hyperthermia studies show that whole mouse AMF exposure @160 KHz and 400 or 550 Oe, for a 20 minutes (heat-up and protocol heating), provides a safe and efficacious tumor treatment. Initial electron and light microscopic studies (in vitro and in vivo) showed the 100 nm used in our studies are rapidly taken up and retained by the tumor cells. Additional in vitro studies suggest antibodies can significantly enhance the cellular uptake of IONPs.

The use of near-infrared absorbing nanoparticles recently has been proposed for the minimally invasive photothermal ablation of solid tumors, and this approach currently is being investigated in the clinic. One class of nanoparticles, gold nanorods, has been investigated for the ablation of various cancer types using both direct injection and systemic delivery. Here we investigate the photothermal ablation of colon cancer in an animal model using intravenously delivered gold nanorods. Nanorods with an aspect ratio of ~3.2 and an extinction peak of 774 nm were PEGylated, suspended in an isotonic solution, and infused into the tail vein of BALB/c mice bearing subcutaneous CT26.wt murine colon cancer tumors. After 24 hrs, an isotropic laser fiber was inserted through a small incision in the skin to a point proximate to and beneath the tumor. The area was illuminated with 3.5 W average power for 3 minutes. Control groups consisted of laser-only, nanorod-only and untreated tumored animals. The survival of the animals receiving nanorod-based photothermal ablation was statistically longer than the control groups with >44% complete response. This work demonstrates the promise of systemically delivering nanoparticles to tumors for thermal ablation

Tumor ablation using radiofrequency (RF) energy is clinically used for treatment of various cancer types. During RF ablation, an electrode is inserted into a tumor under imaging-guidance, and the tumor is heated by RF electric current and cancer cells killed above temperatures of ~50 °C. One of the major factors affecting tissue temperature and ablation zone dimensions is tissue perfusion. To examine perfusion effects, we created Finite Element Method computer models of a clinically used RF ablation device, including temperature-dependent electrical and thermal tissue properties. Microvascular perfusion was modeled according to Pennes' Bioheat Equation, and was varied with temperature to include perfusion cessation due to coagulation at high temperatures. Microvascular perfusion rate was varied to represent variations between patients by +/-1 standard deviation based on prior data measured in humans. Macro-vascular perfusion was modeled by including a large vessel (10 mm diameter) in the model geometry, and assigning a convective heat transfer coefficient as a boundary condition at the vessel wall. The vessel resulted in local deviation of the ablation zone around the vessel, and resulted in a region of viable tissue near the vessel wall. Microvascular perfusion affected overall size and geometry of the ablation zone. Ablation zone volume for average microvascular perfusion was 20.1 cm³, and was 16.6 and 25.3 cm³ when perfusion rate was increased or reduced by 1 standard deviation. Both micro- and macrovascular perfusion considerably affect tissue temperature and ablation zone. Patient-specific data on perfusion would allow for more accurate estimates of ablation zone dimensions and improved treatment planning.

Using micro-fabrication techniques a micro thermal probe has been developed in our laboratory to measure the thermal conductivity of biological tissues. This paper presents our latest experimental results which demonstrate the usefulness of the micro thermal probe in mapping the complicated perfusion field inside biological tissues. A perfused pig liver model has been constructed to simulate in vivo conditions. The portal vein and hepatic artery of a porcine liver were intubated and connected to a perfusion circuit. Saline water was perfused through the liver driven by a peristaltic pump. By varying the pumping rate of the perfused model, we measured the effective thermal conductivity at different perfusion rates in different locations. The results show that the effective thermal conductivity varies with the square root of the perfusion rate. Also, by rotating the micro probes, we observed a strong directional dependence of the effective thermal conductivity, revealing that perfusion is not a scalar but a vector field.

An intracavitary hyperthermia applicator for targeted heat delivery to the cervix was developed based on a linear array of sectored tubular ultrasound transducers that provides truly 3-D heating control (angular and along the length). A central conduit can incorporate an HDR source for sequential or simultaneous delivery of heat and radiation. Hyperthermia treatment volumes were determined from brachytherapy treatment planning data and used as a basis for biothermal simulations analyzing the effects of device parameters, tissue properties, and catheter materials on heating patterns. Devices were then developed with 1-3 elements at 6.5-8 MHz with 90-180° sectors and a 15-35 mm heating length, housed within a 6-mm diameter water-cooled PET catheter. Directional heating from sectored transducers could extend lateral penetration of therapeutic heating (41°C) >2 cm while maintaining rectum and bladder temperatures within 12 mm below thermal damage thresholds. Imaging artifacts were evaluated with standard CT, cone beam CT, and MR images. MR thermal imaging was used to demonstrate shaping of heating profiles in axial and coronal slices with artifact <2 mm from the device. The impact of the high-Z applicator materials on the HDR dose distribution was assessed using a well-type ionization chamber and was found to be less than 6% attenuation, which can readily be accounted for with treatment planning software. The intrauterine ultrasound device has demonstrated potential for 3-D conformal heating of clinical tumors in the delivery of targeted hyperthermia in conjunction with brachytherapy to the cervix.