The discovery of new treatments for cancer is imperative. Recently, we showed in a proof-of-concept study that SYnergistic IMmuno PHOtothermal NanotherapY (SYMPHONY) is a powerful treatment for metastatic bladder cancer and brain tumor in mouse models. Our work has recently demonstrated that combining immunotherapy checkpoint inhibitors and gold nanostar (AuNS) photothermal therapy (PTT) is more effective in killing primary tumors and activating the immune system to eradicate tumors at distant sites, than each individual treatment alone. When the tumor is being ablated via PTT in mice models, using low intensity heat from a near infrared laser, the dying tumor releases proteins that trigger the immune system to destroy remaining tumor cells. Immune checkpoint inhibitors prevent the tumor cells from hiding from the immune system’s mechanisms; thus, the immune system becomes capable of attacking distant secondary tumors, after the primary tumor has been eradicated using AuNS mediated PTT. The data shows that after the cured mice were rechallenged with bladder cancer cells, no tumor formation was observed after 60 days; hence these results indicate that the SYMPHONY treatment can function as a cancer vaccine and lead to long-lasting immunity.
Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). Their multiple sharp branches acting like “lightning rods” can convert safely and efficiently light into heat. As with other nanoparticles, GNS sizes can be controlled so that they passively accumulate in tumors due to the enhanced permeability and retention (EPR) effect of tumor vasculature. This feature improves tumor-targeting precision and permits the use of reduced laser energy required to destroy the targeted cancer cells. The ability to selectively heat tumor areas where GNS are located while keeping surrounding healthy tissues at significantly lower temperatures offers significant advantages over other thermal therapies. GNS-mediated photothermal therapy combined with checkpoint immunotherapy was shown to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer ‘vaccine’ effect.
Background: Brown adipose tissue (BAT) plays an important role in whole body metabolism and could potentially
mediate weight gain and insulin sensitivity. Although some imaging techniques allow BAT detection, there are currently
no viable methods for continuous acquisition of BAT energy expenditure. We present a non-invasive technique for long
term monitoring of BAT metabolism using microwave radiometry.
Methods: A multilayer 3D computational model was created in HFSSTM with 1.5 mm skin, 3-10 mm subcutaneous fat,
200 mm muscle and a BAT region (2-6 cm3) located between fat and muscle. Based on this model, a log-spiral antenna
was designed and optimized to maximize reception of thermal emissions from the target (BAT). The power absorption
patterns calculated in HFSSTM were combined with simulated thermal distributions computed in COMSOL® to predict
radiometric signal measured from an ultra-low-noise microwave radiometer. The power received by the antenna was
characterized as a function of different levels of BAT metabolism under cold and noradrenergic stimulation.
Results: The optimized frequency band was 1.5-2.2 GHz, with averaged antenna efficiency of 19%. The simulated
power received by the radiometric antenna increased 2-9 mdBm (noradrenergic stimulus) and 4-15 mdBm (cold
stimulus) corresponding to increased 15-fold BAT metabolism.
Conclusions: Results demonstrated the ability to detect thermal radiation from small volumes (2-6 cm3) of BAT located up to 12 mm deep and to monitor small changes (0.5 °C) in BAT metabolism. As such, the developed miniature
radiometric antenna sensor appears suitable for non-invasive long term monitoring of BAT metabolism.
Background: There are numerous clinical applications for non-invasive monitoring of deep tissue temperature. We
present the design and experimental performance of a miniature radiometric thermometry system for measuring volume
average temperature of tissue regions located up to 5cm deep in the body.
Methods: We constructed a miniature sensor consisting of EMI-shielded log spiral microstrip antenna with high gain onaxis
and integrated high-sensitivity 1.35GHz total power radiometer with 500 MHz bandwidth. We tested performance
of the radiometry system in both simulated and experimental multilayer phantom models of several intended clinical
measurement sites: i) brown adipose tissue (BAT) depots within 2cm of the skin surface, ii) 3-5cm deep kidney, and iii)
human brain underlying intact scalp and skull. The physical models included layers of circulating tissue-mimicking
liquids controlled at different temperatures to characterize our ability to quantify small changes in target temperature at
depth under normothermic surface tissues.
Results: We report SAR patterns that characterize the sense region of a 2.6cm diameter receive antenna, and radiometric
power measurements as a function of deep tissue temperature that quantify radiometer sensitivity. The data demonstrate:
i) our ability to accurately track temperature rise in realistic tissue targets such as urine refluxed from prewarmed bladder
into kidney, and 10°C drop in brain temperature underlying normothermic scalp and skull, and ii) long term accuracy
and stability of +0.4°C over 4.5 hours as needed for monitoring core body temperature over extended surgery or
monitoring effects of brown fat metabolism over an extended sleep/wake cycle.
Conclusions: A non-invasive sensor consisting of 2.6cm diameter receive antenna and integral 1.35GHz total power
radiometer has demonstrated sufficient sensitivity to track clinically significant changes in temperature of deep tissue
targets underlying normothermic surface tissues for clinical applications like the detection of vesicoureteral reflux, and
long term monitoring of brown fat metabolism or brain core temperature during extended surgery.
KEYWORDS: Bladder, Magnetism, Nanoparticles, Magnetic resonance imaging, Tissues, Temperature metrology, Bladder cancer, In vivo imaging, Control systems, Iron
Background
Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field
penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the
body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been
demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the
feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of
nanoparticle heating in a rat bladder model.
Methods
The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium
Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after
injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen,
Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder
CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were
measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to
characterize our ability to localize heat within the bladder target.
Results
The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles
throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder
>1°C/min to a steady-state of 42°C.
Conclusion
Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of
temperature in the bladder and minimal heating of surrounding tissues.
Paul Stauffer, Paolo Maccarini, Kavitha Arunachalam, Valeria De Luca, Sara Salahi, Alina Boico, Oystein Klemetsen, Yngve Birkelund, Svein Jacobsen, Fernando Bardati, Piero Tognolotti, Brent Snow
Background: Vesicoureteral reflux (VUR) is a serious health problem leading to renal scarring in children. Current
VUR detection involves traumatic x-ray imaging of kidneys following injection of contrast agent into bladder via
invasive Foley catheter. We present an alternative non-invasive approach for detecting VUR by radiometric monitoring
of kidney temperature while gently warming the bladder.
Methods: We report the design and testing of: i) 915MHz square slot antenna array for heating bladder, ii) EMI-shielded
log spiral microstrip receive antenna, iii) high-sensitivity 1.375GHz total power radiometer, iv) power
modulation approach to increase urine temperature relative to overlying perfused tissues, and v) invivo porcine
experiments characterizing bladder heating and radiometric temperature of aaline filled 30mL balloon "kidney"
implanted 3-4cm deep in thorax and varied 2-6°C from core temperature.
Results: SAR distributions are presented for two novel antennas designed to heat bladder and monitor deep kidney
temperatures radiometrically. We demonstrate the ability to heat 180mL saline in in vivo porcine bladder to 40-44°C
while maintaining overlying tissues <38°C using time-modulated square slot antennas coupled to the abdomen with
room temperature water pad. Pathologic evaluations confirmed lack of acute thermal damage in pelvic tissues for up to
three 20min bladder heat exposures. The radiometer clearly recorded 2-6°C changes of 30mL "kidney" targets at depth
in 34°C invivo pig thorax.
Conclusion: A 915MHz antenna array can gently warm in vivo pig bladder without toxicity while a 1.375GHz
radiometer with log spiral receive antenna detects ≥2°C rise in 30mL "urine" located 3-4cm deep in thorax,
demonstrating more than sufficient sensitivity to detect Grade 4-5 reflux of warmed urine for non-invasive detection of
VUR.
P. Stauffer, Oana Craciunescu, P. Maccarini, Cory Wyatt, K. Arunachalam, O. Arabe, V. Stakhursky, B. Soher, J. MacFall, Z. Li, William Joines, S. Rangarao, K. Cheng, S. Das, Carlos Martins, Cecil Charles, Mark Dewhirst, T. Wong, E. Jones, Z. Vujaskovic
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.
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.
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.
Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy, the CMA applicator resulting from these enhancements should expand the number of patients that can benefit from effective heating of superficial disease in combination with radiation or chemotherapy.
Laboratory experiments have shown that thermal enhancement of radiation response increases substantially for higher thermal dose (approaching 100 CEM43) and when hyperthermia and radiation are delivered simultaneously. Unfortunately, equipment capable of delivering uniform doses of heat and radiation simultaneously has not been available to test the clinical potential of this approach. We present recent progress on the clinical implementation of a system that combines the uniform heating capabilities of flexible printed circuit board microwave array applicators with an array of brachytherapy catheters held a fixed distance from the skin for uniform radiation of tissue <1.5 cm deep with a scanning high dose rate (HDR) brachytherapy source. The system is based on the Combination Applicator which consists of an array of up to 32 Dual Concentric Conductor (DCC) apertures driven at 915 MHz for heating tissue, coupled with an array of 1 cm spaced catheters for HDR therapy. Efforts to optimize the clinical interface and move from rectangular to more complex shape applicators that accommodate the entire disease in a larger number of patients are described. Improvements to the system for powering and controlling the applicator are also described. Radiation dosimetry and experimental performance results of a prototype 15 x 15 cm dual-purpose applicator demonstrate dose distributions with good homogeneity under large contoured surfaces typical of diffuse chestwall recurrence of breast carcinoma. Investigations of potential interaction between heat and brachytherapy components of a Combination Applicator demonstrate no perceptible perturbation of the heating field from an HDR source or leadwire, no perceptible effect of a scanning HDR source on fiberoptic thermometry, and <0.5% variation of radiation dose delivered through the CMA applicator. By applying heat and radiation simultaneously for maximum synergism of modalities, this dual therapy system should expand the number of patients that can benefit from effective thermoradiotherapy treatments.
The large variance of survival in the treatment of large superficial tumors indicates that the efficacy of current therapies can be dramatically improved. Hyperthermia has shown significant enhancement of response when used in combination with chemotherapy and/or radiation. Control of temperature is a critical factor for treatment quality (and thus effectiveness), since the response of tumor and normal cells is significantly different over a range of just a few degrees (41-45°). For diffuse spreading tumors, microwave conformal arrays have been shown to be a sound solution to deposit the power necessary to reach the goal temperature throughout the targeted tissue. Continuous temperature monitoring is required for feedback control of power to compensate for physiologic (e.g. blood perfusion and dielectric properties) changes. Microwave radiometric thermometry has been proposed to complement individual fluoroptic probes to non-invasively map superficial and sub-surface temperatures. The challenge is to integrate the broadband antenna used for radiometric sensing with the high power antenna used for power deposition. A modified version of the dual concentric conductor antenna presented previously is optimized for such use. Several design challenges are presented including preventing unwanted radiating modes and thermal and electromagnetic coupling between the two antennas, and accommodating dielectric changes of the target tissue. Advanced 3D and planar 2D simulation software are used to achieve an initial optimized design, focused on maintaining appropriate radiation efficiency and pattern for both heating and radiometry antennas. A cutting edge automated measurement system has been realized to characterize the antennas in a tissue equivalent material and to confirm the simulation results. Finally, the guidelines for further development and improvement of this initial design are presented together with a preliminary implementation of the feedback program to be used to control the temperature distribution in variable, inhomogeneous tissue.
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