Cumulative Equivalent Minutes Research Articles

Preclinical assessment of a noncooled MR thermometry-based neurosurgical laser therapy system.

MRI-guided laser interstitial thermal therapy (MRgLITT) has recently gained interest as an ablative stereotactic procedure for intractable epilepsy, movement disorders, and brain tumors. Conventionally, a LITT system consists of a laser generator and cooled laser applicator, which is a fiber optic core surrounded by a sheath through which cooled fluid is pumped. However, this footprint can make the system bulky and nonmobile, limit the maximum depth of targeting, and increase the chances of breakdown. Herein, the authors conduct a preclinical assessment of a noncooled MRgLITT system in a porcine model. Three-tesla MRI was used to guide the in vivo placement of noncooled laser applicators in the porcine brain. The study consisted of a survival arm and terminal arm. The laser was activated at a power of 4-7 W for ≤ 180 seconds. Temperature changes were monitored using the MR thermometry software ThermoGuide in the survival arm (n = 5) or both ThermoGuide software and adjacently inserted thermal probes in the terminal arm (n = 3). Thermal damage was determined by the software using the temperature-time relationship of cumulative equivalent minutes at 43°C (CEM43). Temperatures calculated by the software were compared with those recorded by the temperature probes. The dimensions of thermal damage thresholds (TDTs; 2-9, 10-59, 60-239, ≥ 240 CEM43 isolines) given by MR thermometry were compared with the dimensions of irreversible damage on histopathological analysis. There was a strong correlation between temperature recordings by ThermoGuide and those by thermal probes at both 4 mm (r = 0.96) and 8 mm (r = 0.80), with a mean absolute error of 0.76°C ± 2.13°C and 0.17°C ± 1.65°C at 4 and 8 mm, respectively. The area of 2-9 CEM43 was larger than the area of irreversible damage seen on histopathological analysis. The dimensions of the 10 and 60 CEM43 correlated well with dimensions of the lesion on histopathological analysis. A well-defined border (≤ 1 mm) was observed between the area of irreversible damage and healthy brain tissue. This preclinical assessment showed that the noncooled LITT system was able to precisely reach the target and create well-defined lesions within a margin of safety, without any adverse effects. MR thermometry software provided an accurate near-real-time temperature of the brain tissue, and dimensions of the lesion as visualized by the software correlated well with histopathological findings. Further studies to test the system's efficacy and safety in human subjects are in progress.

A Non-Contrast Multi-Parametric MRI Biomarker for Assessment of MR-Guided Focused Ultrasound Thermal Therapies.

We present the development of a non-contrast multi-parametric magnetic resonance (MPMR) imaging biomarker to assess treatment outcomes for magnetic resonance-guided focused ultrasound (MRgFUS) ablations of localized tumors. Images obtained immediately following MRgFUS ablation were inputs for voxel-wise supervised learning classifiers, trained using registered histology as a label for thermal necrosis. VX2 tumors in New Zealand white rabbits quadriceps were thermally ablated using an MRgFUS system under 3 T MRI guidance. Animals were re-imaged three days post-ablation and euthanized. Histological necrosis labels were created by 3D registration between MR images and digitized H&E segmentations of thermal necrosis to enable voxel-wise classification of necrosis. Supervised MPMR classifier inputs included maximum temperature rise, cumulative thermal dose (CTD), post-FUS differences in T2-weighted images, and apparent diffusion coefficient, or ADC, maps. A logistic regression, support vector machine, and random forest classifier were trained in red a leave-one-out strategy in test data from four subjects. In the validation dataset, the MPMR classifiers achieved higher recall and Dice than a clinically adopted 240 cumulative equivalent minutes at 43 °C (CEM 43) threshold (0.43) in all subjects. The average Dice scores of overlap with the registered histological label for the logistic regression (0.63) and support vector machine (0.63) MPMR classifiers were within 6% of the acute contrast-enhanced non-perfused volume (0.67). Voxel-wise registration of MPMR data to histological outcomes facilitated supervised learning of an accurate non-contrast MR biomarker for MRgFUS ablations in a rabbit VX2 tumor model.

Influence of different heat transfer models on therapeutic temperature prediction and heat-induced damage during magnetic hyperthermia

Magnetic hyperthermia regulates the therapeutic temperature within a specific range to damage malignant cells after exposing the magnetic nanoparticles inside tumor tissue to an alternating magnetic field. The therapeutic temperature of living tissues can be generally predicted using Pennes' bio-heat equation after ignoring both the inhomogeneity of biological structure and the microstructural responses. Although various of the bio-heat transfer models proposed in literature fix these shortages, there is still a lack of a comprehensive report on investigating the discrepancy for different models when applied in the magnetic hyperthermia context. This study compares four different bio-heat equations in terms of the therapeutic temperature distribution and the heat-induced damage situation for a proposed geometric model, which is established based on computed tomography images of a tumor bearing mouse. The therapeutic temperature is also used as an index to evaluate the effect of two key relaxation times for the phase lag behavior on bio-heat transfer. Moreover, this work evaluates the effects of two blood perfusion rates on both the treatment temperature and the cumulative equivalent heating minutes at 43 °C. Numerical analysis results reveal that relaxation times for phase-lag behavior as well as the porosity for living tissues directly affect the therapeutic temperature variation and ultimately the thermal damage for the malignant tissue during magnetic hyperthermia. The dual-phase-lag equation can be converted into Pennes’ equation and simple-phase-lag equation when relaxation times meet specific conditions during the process of heat transfer. In addition, different blood perfusion rates can result in an amplitude discrepancy for treatment temperature, but this parameter does not change the characteristics of thermal propagation during therapy.

Radiotherapy combined with deep regional hyperthermia in elderly and frail patients with muscle-invasive bladder cancer: quality analysis of hyperthermia and impact on clinical results

Purpose: Radiotherapy (RT) in combination with deep regional hyperthermia (HT) after transurethral removal of bladder tumor (TURBT) can be offered to elderly and frail patients with muscle-invasive bladder cancer (MIBC). Methods: In total, 21 patients (mean age 84 years) with unifocal or multifocal MIBC received radiation to a dose of 48–50 Gy/16–20 fractions with weekly HT. The primary endpoint was the variation in temperature metrics, thermal dose expressed as cumulative equivalent minutes at 43 °C when the measured temperature is T90 (CEM43T90) and net power applied in target volume per each HT session. Secondary endpoints were three-year overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS) and toxicity. Results: The temperature metrics, CEM43T90, mean and maximum net power applied did not differ significantly among the HT sessions of the 21 patients. With a median follow-up of 65 months, 52% (95% CI 32–72%) of patients had died 3 years after treatment. The three-year DFS and LPFS rates were 62% (95%CI 41–79%) and 81% (95%CI 60–92%), respectively. The three-year bladder preservation rate was 100%. Three out of four patients with local failure received a thermal dose CEM43T90 below a median of 2.4 min. The rates of acute and late grade-3 toxicities were 10% and 14%, respectively. Conclusion: The reproducibility of HT parameters between sessions was high. A moderately high CEM43T90 (> 2.4 min) for each HT session seems to be preferable for local control. RT combined with HT is a promising organ-preservation therapy for elderly and frail MIBC patients.

Direct Temperature Measurements of Cardiac Stent during MRI Examinations

Nowadays, Magnetic Resonance Imaging (MRI) is considered the gold standard for imaging the brain, spinal cord, musculoskeletal system, head and neck, and complex congenital heart malformations; consequentially, the number of MRI scans in patients with implantable electronic devices has simultaneously increased. During the entire length of the MRI exam, patients are exposed to electromagnetic fields with different characteristics (static, low frequency, radiofrequency fields), which are related to different risks. The scarce available literature about MRI-induced heating on cardiac stents suggests that excessive temperature rise occurs only in unfavorable cases. Ideally, RF safety assessment could be performed during the anamnestic process, but this simulation process’s results are too slow to be performed before patient MRI examination. In this context, we developed a dedicated measurement set-up by focusing our target on the measurement of the heating of a cardiac stent during an MRI examination. Results for the temperature rise trend along the entire stent length during a clinical MRI protocol are shown together with the local Specific Absorption Rate (SAR) values and cumulative equivalent minutes at 43 °C (CEM43°C), in order to ensure the safety of patients with MR-conditional devices, also with a view to not inappropriately preclude their access to MRI scans. The obtained results show that the maximum temperature rise (4.12 °C) is within the limit of 5 °C stated in the stent manual for 15 min of continued scanning with the specific conditions. The maximum temperature rise was in correspondence with the stent tips and calculated SAR confirms the fact that two hotspots are present near the tips of the stent. Finally, the calculated CEM43°C remained well below the proposed threshold for muscle tissue.

Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells

IntroductionIrreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. Aim: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. MethodsSeveral IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using “Non-linear-least-squares”-analysis. ResultsMild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. ConclusionBoth mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

Holographic Focused Ultrasound Hyperthermia System for Uniform Simultaneous Thermal Exposure of Multiple Tumor Spheroids.

Hyperthermia is currently used to treat cancer due to its ability to radio- and chemo-sensitize and to stimulate the immune response. While ultrasound is non-ionizing and can induce hyperthermia deep within the body non-invasively, achieving uniform and volumetric hyperthermia is challenging. This work presents a novel focused ultrasound hyperthermia system based on 3D-printed acoustic holograms combined with a high-intensity focused ultrasound (HIFU) transducer to produce a uniform iso-thermal dose in multiple targets. The system is designed with the aim of treating several 3D cell aggregates contained in an International Electrotechnical Commission (IEC) tissue-mimicking phantom with multiple wells, each holding a single tumor spheroid, with real-time temperature and thermal dose monitoring. System performance was validated using acoustic and thermal methods, ultimately yielding thermal doses in three wells that differed by less than 4%. The system was tested in vitro for delivery of thermal doses of 0-120 cumulative equivalent minutes at 43 °C (CEM43) to spheroids of U87-MG glioma cells. The effects of ultrasound-induced heating on the growth of these spheroids were compared with heating using a polymerase chain reaction (PCR) thermocycler. Results showed that exposing U87-MG spheroids to an ultrasound-induced thermal dose of 120 CEM43 shrank them by 15% and decreased their growth and metabolic activity more than seen in those exposed to a thermocycler-induced heating. This low-cost approach of modifying a HIFU transducer to deliver ultrasound hyperthermia opens new avenues for accurately controlling thermal dose delivery to complex therapeutic targets using tailored acoustic holograms. Spheroid data show that thermal and non-thermal mechanisms are implicated in the response of cancer cells to non-ablative ultrasound heating.

209 What Happens to Brain Outside the Thermal Ablation Zones? An Assessment of Needle-Based Therapeutic Ultrasound in Survival Swine

INTRODUCTION: For stereotactic radiosurgery, isodense lines must be considered to determine how surrounding tissue is affected. In thermal ablative therapy, such as laser interstitial thermal therapy (LITT) transcranial MR-guided focused ultrasound (tcMRgFUS) and needle-based therapeutic ultrasound (NBTU) how the surrounding area is effected has not been well studies in large animal models. METHODS: Four swine underwent MRgRA NBTU using varying treatment doses. Neurological evaluation of swine was performed up to 30 days post-procedure. Serial MRI images were obtained, and the most representative were overlaid with isodose lines and compared to brain tissue acquired post-mortem which underwent histopathologic analysis. These results were also compared to predicted volumes using a finite element analysis (FEA). RESULTS: NBTU applicator orientation at 360° induced smaller lesion volumes (33.19 mm3; 120 s, 3 W; 30.05 mm3, 180 s, 4 W) versus 180o (77.20 mm3, 120 s, 3 W; 109.29 mm3; 180 s; 4 W). The ablation-zone was characterized by dense macrophage infiltration and glial/neuronal loss as demonstrated by glial fibrillary acidic protein (GFAP) and neurofilament (NF) absence and avid CD163 staining. The transition-zone between lesion and normal brain demonstrated decreased macrophage infiltration and measured ∼345 microns. None of the experimental swine suffered any long-term neurologic or behavioral complications. MRTI/histology overlay demonstrated the boundary of ablation at ∼200 (cumulative equivalent minutes) CEM43 isodose boundary. CONCLUSIONS: We successfully performed MRgRA NBTU ablation in swine and demonstrated minimal histologic changes extended past the ablation-zone. The lesion was characterized by macrophage infiltration and glial/neuronal loss which decreased through the transition-zone. Whether NBTU offers advantage over tcMRgFUS and LITT in this regard warrants further study.

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer

Purpose In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. Methods and materials The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. Results Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8–41.1) °C and 3.1 (IQR 0.9–2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). Conclusions No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

Validation of a Temperature-Feedback Controlled Automated Magnetic Hyperthermia Therapy Device.

We present in vivo validation of an automated magnetic hyperthermia therapy (MHT) device that uses real-time temperature input measured at the target to control tissue heating. MHT is a thermal therapy that uses heat generated by magnetic materials exposed to an alternating magnetic field. For temperature monitoring, we integrated a commercial fiber optic temperature probe containing four gallium arsenide (GaAs) temperature sensors. The controller device used temperature from the sensors as input to manage power to the magnetic field applicator. We developed a robust, multi-objective, proportional-integral-derivative (PID) algorithm to control the target thermal dose by modulating power delivered to the magnetic field applicator. The magnetic field applicator was a 20 cm diameter Maxwell-type induction coil powered by a 120 kW induction heating power supply operating at 160 kHz. Finite element (FE) simulations were performed to determine values of the PID gain factors prior to verification and validation trials. Ex vivo verification and validation were conducted in gel phantoms and sectioned bovine liver, respectively. In vivo validation of the controller was achieved in a canine research subject following infusion of magnetic nanoparticles (MNPs) into the brain. In all cases, performance matched controller design criteria, while also achieving a thermal dose measured as cumulative equivalent minutes at 43 °C (CEM43) 60 ± 5 min within 30 min.

Assessing critical temperature dose areas in the kidney by magnetic resonance imaging thermometry in an ex vivo Holmium:YAG laser lithotripsy model

PurposeWe aimed to assess critical temperature areas in the kidney parenchyma using magnetic resonance thermometry (MRT) in an ex vivo Holmium:YAG laser lithotripsy model.MethodsThermal effects of Ho:YAG laser irradiation of 14 W and 30 W were investigated in the calyx and renal pelvis of an ex vivo kidney with different laser application times (tL) followed by a delay time (tD) of tL/tD = 5/5 s, 5/10 s, 10/5 s, 10/10 s, and 20/0 s, with irrigation rates of 10, 30, 50, 70, and 100 ml/min. Using MRT, the size of the area was determined in which the thermal dose as measured by the Cumulative Equivalent Minutes (CEM43) method exceeded a value of 120 min.ResultsIn the calyx, CEM43 never exceeded 120 min for flow rates ≥ 70 ml/min at 14 W, and longer tL (10 s vs. 5 s) lead to exponentially lower thermal affection of tissue (3.6 vs. 21.9 mm2). Similarly at 30 W and ≥ 70 ml/min CEM43 was below 120 min. Interestingly, at irrigation rates of 10 ml/min, tL = 10 s and tD = 10 s CEM43 were observed > 120 min in an area of 84.4 mm2 and 49.1 mm2 at tD = 5 s. Here, tL = 5 s revealed relevant thermal affection of 29.1 mm2 at 10 ml/min.ConclusionWe demonstrate that critical temperature dose areas in the kidney parenchyma were associated with high laser power and application times, a low irrigation rate, and anatomical volume of the targeted calyx.

High-contrast spectroscopic photoacoustic characterization of thermal tissue ablation in the visible spectrum.

High-contrast tissue characterization of thermal ablation has been desired to evaluate therapeutic outcomes accurately. This paper presents a photoacoustic (PA) characterization of thermal tissue ablation in the visible spectrum, in which higher light absorbance can produce spectral contrast starker than in the near-infrared range. Ex vivo experiments were performed to measure visible PA spectra (480-700 nm) from fresh porcine liver tissues that received a thermal dose in a range of cumulative equivalent minutes at 43°C (CEM43). The local hemoglobin lobe area between 510-600 nm and wholespectral area under the curve were evaluated to represent the transition of hemoglobin into methemoglobin (MetHb) in the target tissue. The thermal process below an estimated therapeutic CEM43 threshold (80-340 minutes) presented a progressive elevation of the PA spectrum and an eventual loss of local hemoglobin peaks in the visible spectrum, closer to the MetHb spectrum. Interestingly, an excessive CEM43 produced a substantial drop in the PA spectrum. In the spectral analysis, the visible spectrum yielded 13.9-34.1 times higher PA sensitivity and 1.42 times higher contrast change than at a near-infrared wavelength. This novel method of PA tissue characterization in the visible spectrum could be a potential modality to evaluate various thermal therapeutic modalities at high-contrast resolution.

Correction of heat-induced susceptibility changes in respiratory-triggered 2D-PRF-based thermometry for monitoring of magnetic resonance-guided hepatic microwave ablation in a human-like in vivo porcine model

Purpose To develop and evaluate susceptibility corrected 2D proton resonance frequency (PRF)-based magnetic resonance (MR)-thermometry for the accurate assessment of the ablation zone of hepatic microwave ablation (MWA). Methods and materials Twelve hepatic MWA were performed in five LEWE minipigs with human-like fissure-free liver. Temperature maps during ablation of PRF-based MR-thermometry were corrected by modeling heat induced susceptibility changes. Ablation zones were determined using cumulative equivalent minutes at 43 °C (CEM43) as tissue damage model. T1 weighted (w) post-ablation contrast-enhanced (CE) MR-imaging and manually segmented postmortem histology were used for validation. The agreement of uncorrected (raw) and susceptibility corrected (corr) MR-thermometry with T1w post-ablation CE MR-imaging and histology was evaluated. The Wilcoxon-signed rank test and Bland–Altman analysis were applied. Results With the susceptibility corrected MR-thermometry a significantly increased dice coefficient (raw: 77% vs. corr: 83%, p < 0.01) and sensitivity (raw: 72% vs. corr: 82%, p < 0.01) was found for the comparison to T1w-CE imaging as well as histopathology (dice coefficients: raw: 76% vs. corr: 79%, p < 0.001; sensitivity: raw: 72% vs. corr: 74%, p < 0.001). While major axis length was significantly increased (7.1 mm, p < 0.001) and minor axis length significantly decreased (2.2 mm, p < 0.001) in uncorrected MR-thermometry compared to T1w-CE MR-imaging, no significant bias was found after susceptibility correction. Conclusion Using susceptibility corrected 2D PRF-based MR-thermometry to predict the ablation zones of hepatic MWA provided a good agreement in comparison to T1w post-ablation CE MR-imaging and histopathology.

Computational investigation of the tumor position and ambient conditions on magnetic nanoparticle thermo-therapy

• Estimation of effects of tumor position beneath the skin on magnetic nanoparticle hyperthermia (MNPH). • Estimation of effects of therapeutic environmental conditions on MNPH. • Quantification of thermal damage in tumor as well healthy tissues in diverse therapeutic environmental conditions. • Estimation of the critical depth of the tumor up to which the variations in the therapeutic effects of MNPH are significant. The present study elucidate the effects of tumor position and clinical environmental conditions on the therapeutic effects of magnetic nanoparticle hyperthermia (MNH) in superficial like breast tumor tissue. Effects of these two factors are investigated through a three-dimensional (3D) tumor model. The position of the tumor tissue (of size 1.5 cm) within the 3D model as well as the heat transfer rate through the skin is altered to evaluate their effects on MNH. Six different positions of tumor ranging from zero-depth to the tumor depth of 1.5 times the tumor size from the skin are considered. Similarly, three different heat transfer coefficients ( h c = 2.5, 5.5, 7.5 W / m 2 K ) on the skin during thermotherapy are considered to simulate a wide range of clinical environmental conditions. MNH is induced for 1 hour using two different heating powers (with amplitudes of 10 k A / m and 12.5 k A / m at 130 k H z ) to evaluate the thermal damage (Arrhenius ( Ω =4.6) and cumulative equivalent minutes C E M 43 60 in the tissue. Results show that there exists a critical depth, which is nearly half of the tumor size, up to which the MNH is influenced by the position of the tumor. Similarly, the effects of the ambient conditions during this thermotherapy on thermal dosimetry, also cease beyond this critical depth. The estimation of the critical depth of the tumor will help in predicting the therapeutic effects of magnetic hyperthermia applicators for specifically positioned tumors in actual environmental conditions.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers

PurposeThe combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT.MethodsA questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods.ResultsThe response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3–100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter “cumulative equivalent minutes at 43 °C” (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order.ConclusionThere is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

425 Defining the Optimal Thermal Parameters for Sub-threshold Testing With Focused Ultrasound

INTRODUCTION: Focused ultrasound ablation (FUSA) relies on accurate subthreshold testing to physiologically explore the presumed target before permanent ablation. However, the optimal thermal parameters for subthreshold testing (i.e., thermal dose and spot size thresholds) are not yet defined. METHODS: We performed a retrospective analysis of intraoperative testing data of essential tremor patients undergoing FUSA. Sonications with a thermal dose of less than 25 cumulative equivalent minutes (CEM) were classified as sub-threshold. The intraoperative writing samples were independently rated by two raters using the clinical rating scale for tremor. The association between thermal dose and tremor scores was statistically analyzed, and the thermal dose and spot size thresholds for tremor improvement were computed using leave-one-out cross-validation analysis. RESULTS: From the 331 pairs of sonications and tremor assessments, 97 sonications were classified as subthreshold sonications. Intraoperative tremor improvement was observed in 23 (24%) subthreshold sonications with a median tremor improvement of 20% (interquartile range = 41.6) from the baseline. The thermal dose threshold for tremor improvement was 0.67 CEM (equivalent to 30 seconds thermal exposure at 430C). The spot size threshold for tremor improvement was 2.46 mm. VIM was exposed to TN thermal dose during sub-ablative and ablative sonications. CONCLUSION: The optimal thermal dose and spot size thresholds for subthreshold testing are significantly higher than the current FUSA standard-of-care. We recommend long duration (&gt;30 seconds), subthreshold sonications for intraoperative testing during FUSA. Future investigations should test whether the thermal dose threshold is tissue-specific and determine the mechanisms underlying focused ultrasound TN.

Parameterizing the Effects of Tumor Shape in Magnetic Nanoparticle Thermotherapy Through a Computational Approach

Abstract In this work, effects of tumor shape on magnetic nanoparticle hyperthermia (MNPH) are investigated and evaluated using four categories (spherical, oblate, prolate, and egg-shape) of tumor models having different morphologies. These tumors have equal volume; however, due to the differences in their shapes, they have different surface areas. The shape of tumors is quantified in terms of shape factor (ζ). Simulations for MNPH are done on the physical model constituting tumor tissue enclosed within the healthy tissue. Magnetic hyperthermia is applied (frequency 150 kHz, and magnetic field amplitude 20.5 kA/m) to all tumor models, for 1 h, after injection of magnetic nanoparticles (MNPs) at the respective tumor centroids. The distribution of MNPs after injection is considered Gaussian. The governing model (Pennes' bioheat model) of heat transfer in biological media is solved with the finite volume-immersed boundary (FV-IB) method to simulate MNPH. Therapeutic effects are calculated using the Arrhenius tissue damage model, cumulative equivalent minutes at 43 °C (CEM 43), and heterogeneity in temperature profiles of the tumors. Results show that the therapeutic effects of MNPH depend significantly on the shape of a tumor. Tumors with higher shape factors receive less therapeutic effects in comparison to the tumors having lower shape factors. An empirical thermal damage model is also developed to assess the MNPH efficacy in real complex-shaped tumors.

Post-operative re-irradiation with hyperthermia in locoregional breast cancer recurrence: Temperature matters

PurposeTo investigate the impact of hyperthermia thermal dose (TD) on locoregional control (LRC), overall survival (OS) and toxicity in locoregional recurrent breast cancer patients treated with postoperative re-irradiation and hyperthermia. MethodsIn this retrospective study, 112 women with resected locoregional recurrent breast cancer treated in 2010–2017 with postoperative re-irradiation 8frx4Gy (n = 34) or 23frx2Gy (n = 78), combined with 4–5 weekly hyperthermia sessions guided by invasive thermometry, were subdivided into ‘low’ (n = 56) and ‘high’ TD (n = 56) groups by the best session with highest median cumulative equivalent minutes at 43 °C (Best CEM43T50) < 7.2 min and ≥7.2 min, respectively. Actuarial LRC, OS and late toxicity incidence were analyzed. Backward multivariable Cox regression and inverse probability weighting (IPW) analysis were performed. ResultsTD subgroups showed no significant differences in patient/treatment characteristics. Median follow-up was 43 months (range 1–107 months). High vs. low TD was associated with LRC (p = 0.0013), but not with OS (p = 0.29) or late toxicity (p = 0.58). Three-year LRC was 74.0% vs. 92.3% in the low and high TD group, respectively (p = 0.008). After three years, 25.0% and 0.9% of the patients had late toxicity grade 3 and 4, respectively. Multivariable analysis showed that distant metastasis (HR 17.6; 95%CI 5.2–60.2), lymph node involvement (HR 2.9; 95%CI 1.2–7.2), recurrence site (chest wall vs. breast; HR 4.6; 95%CI 1.8–11.6) and TD (low vs. high; HR 4.1; 95%CI 1.4–11.5) were associated with LRC. TD was associated with LRC in IPW analysis (p = 0.0018). ConclusionsHigh thermal dose (best CEM43T50 ≥ 7.2 min) was associated with significantly higher LRC for patients with locoregional recurrent breast cancer treated with postoperative re-irradiation and hyperthermia, without augmenting toxicity.

Safety of MRI in patients with retained cardiac leads.

PurposeTo evaluate the safety of MRI in patients with fragmented retained leads (FRLs) through numerical simulation and phantom experiments.MethodsElectromagnetic and thermal simulations were performed to determine the worst‐case RF heating of 10 patient‐derived FRL models during MRI at 1.5 T and 3 T and at imaging landmarks corresponding to head, chest, and abdomen. RF heating measurements were performed in phantoms implanted with reconstructed FRL models that produced highest heating in numerical simulations. The potential for unintended tissue stimulation was assessed through a conservative estimation of the electric field induced in the tissue due to gradient‐induced voltages developed along the length of FRLs.ResultsIn simulations under conservative approach, RF exposure at B1 + ≤ 2 µT generated cumulative equivalent minutes (CEM)43 < 40 at all imaging landmarks at both 1.5 T and 3 T, indicating no thermal damage for acquisition times (TAs) < 10 min. In experiments, the maximum temperature rise when FRLs were positioned at the location of maximum electric field exposure was measured to be 2.4°C at 3 T and 2.1°C at 1.5 T. Electric fields induced in the tissue due to gradient‐induced voltages remained below the threshold for cardiac tissue stimulation in all cases.ConclusionsSimulation and experimental results indicate that patients with FRLs can be scanned safely at both 1.5 T and 3 T with most clinical pulse sequences.

Using kinetic Monte Carlo simulations to design efficient magnetic nanoparticles for clinical hyperthermia.

The purpose of this study was to identify the properties of magnetite nanoparticles that deliver optimal heating efficiency, predict the geometrical characteristics to get these target properties, and determine the concentrations of nanoparticles required to optimize thermotherapy. Kinetic Monte Carlo simulations were employed to identify the properties of magnetic nanoparticles that deliver high Specific Absorption Rate (SAR) values. Optimal volumes were determined for anisotropies ranging between 11 and 40kJ/m3 under clinically relevant magnetic field conditions. Atomistic spin simulations were employed to determine the aspect ratios of ellipsoidal magnetite nanoparticles that deliver the target properties. A numerical model was developed using the extended cardiac-torso (XCAT) phantom to simulate low-field (4 kA/m) and high-field (18 kA/m) prostate cancer thermotherapy. A stationary optimization study exploiting the Method of Moving Asymptotes (MMA) was carried out to calculate the concentration fields that deliver homogenous temperature distributions within target thermotherapy range constrained by the optimization objective function. A time-dependent study was used to compute the thermal dose of a 30-min session. Prolate ellipsoidal magnetite nanoparticles with a volume of 3922 ± 35 nm3 and aspect ratio of 1.56, which yields an effective anisotropy of 20kJ/m3 , constituted the optimal design at current maximum clinical field properties (H0 =18 kA/m, f=100kHz), with SAR=342.0 ± 2.7 W/g, while nanoparticles with a volume of 4147 ± 36 nm3 , aspect ratio of 1.29, and effective anisotropy 11kJ/m3 were optimal for low-field applications (H0 =4 kA/m, f=100kHz), with SAR=50.2 ± 0.5 W/g. The average concentration of 3.86 ± 0.10 and 0.57 ± 0.01mg/cm3 at 4 and 18 kA/m, respectively, were sufficient to reach therapeutic temperatures of 42-44°C throughout the prostate volume. The thermal dose delivered during a 30-min session exceeded 5.8 Cumulative Equivalent Minutes at 43°C within 90% of the prostate volume (CEM43T90 ). The optimal properties and design specifications of magnetite nanoparticles vary with magnetic field properties. Application-specific magnetic nanoparticles or nanoparticles that are optimized at low fields are indicated for optimal thermal dose delivery at low concentrations.