Heating technology for malignant tumors: a review

The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39-45 degrees C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 degrees C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors

A study of the properties of an oil-based drilling fluid with using emulsifier EM-4

The issue of maintaining the potential productivity of the well is one of the most urgent tasks of the oil and gas industry nowadays. Due to the development of deposits with complex deposits and low-permeability productive layers, the issues of increasing the flow rate of wells due to the qualitative opening of reservoirs were of fundamental importance. The drilling fluid with an oil base (OBM) does not adversely affect the properties of oil and gas collectors, also it has good lubricating properties, reducing the wear of drill bits and bits. This paper is devoted to comparing the properties of drilling muds prepared using the industrial emulsifier Cleave FM and the new synthesized emulsifier EM-4. Emulsifier EM-4 is a solution of N- (2-hydroxyethyl) amides of fatty acids in a mixture of mono- and diglycerides of fatty acids

Interleaved Mapping of Temperature and Longitudinal Relaxation Rate to Monitor Drug Delivery During Magnetic Resonance-Guided High-Intensity Focused Ultrasound-Induced Hyperthermia

Objectives: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a method to heat lesions noninvasively to a stable, elevated temperature and a well-suited method to induce local hyperthermia (41 degrees C-43 degrees C) in deep-seated tissues. Magnetic Resonance (MR) imaging provides therapy planning on anatomical images and offers temperature feedback based on near-realtime MR thermometry. Although constant acquisition of MR thermometry data is crucial to ensure prolonged hyperthermia, it limits the freedom to perform measurements of other MR parameters, which are of interest during hyperthermia treatments. In image-guided drug delivery applications, co-encapsulation of paramagnetic MR contrast agents with a drug inside temperature-sensitive liposomes (TSLs) allows to visualize hyperthermia-triggered drug delivery through changes of the longitudinal relaxation rate R-1. While the drug accumulates in the heated tumor tissue, R1 changes can be used for an estimate of the tumor drug concentration. The main objective of this study was to demonstrate that interleaved MR sequences are able to monitor temperature with an adequate temporal resolution and could give a reasonable estimate of the achieved tumor drug concentration through R-1 changes. To this aim, in vitro validation tests and an in vivo proof-of- concept study were performed. Materials and Methods: All experiments were performed on a clinical 3-T MR-HIFU system adapted with a preclinical setup. The validity of the R-1 values and the temperature maps stability were evaluated in phantom experiments and in ex vivo porcine muscle tissue. In vivo experiments were performed on rats bearing a 9L glioma tumor on their hind limb. All animals (n = 4 HIFU-treated, n = 4 no HIFU) were injected intravenously with TSLs co-encapsulating doxorubicin and gadoteridol as contrast agent. The TSL injection was followed by either 2 times 15 minutes of MR-HIFU-induced hyperthermia or a sham treatment. R-1 maps were acquired before, during, and after sonication, using a single slice Inversion Recovery Look-Locker (IR-LL) sequence (field of view [FOV], 50 x 69 mm(2); in-plane resolution, 0.52 x 0.71 mm2; slice thickness, 3 mm; 23 phases of 130 milliseconds; 1 full R1 map every 2 minutes). The R1 maps acquired during treatment were interleaved with 2 perpendicular proton resonance frequency shift (PRFS) MR thermometry slices (dynamic repetition time, 8.6 seconds; FOV, 250 x 250 mm(2); 1.4 x 1.4 mm(2) in-plane resolution; 4 mm slice thickness). Tumor doxorubicin concentrations were determined fluorometrically. Results: In vitro results showed a slight but consistent overestimation of the measured R1 values compared with calibrated R-1 values, regardless whether the R1 was acquired with noninterleaved IR-LL or interleaved. The average treatment cell temperature had a slightly higher temporal standard deviation for the interleaved PRFS sequence compared with the noninterleaved PRFS sequence (0.186 degrees C vs 0.101 degrees C, respectively). The prolonged time in between temperature maps due to the interleaved IR-LL sequence did not degrade the temperature stability during MR-HIFU treatment (T-average = 40.9 degrees C +/- 0.3 degrees C). Upon heat treatment, some tumors showed an R-1 increase in a large part of the tumor while other tumors hardly showed any Delta R-1. The tumor doxorubicin concentration showed a linear correlation with the average Delta R-1 during both sonications (n = 8, R-adj(2) = 0.933), which was higher than for the Delta R1 measured after tumor cooldown (averaged for both sonications, n = 8, R-adj(2) = 0.877). Conclusions: The new approach of interleaving different MR sequences was applied to simultaneously acquire R-1 maps and PRFS thermometry scans during a feedback-controlled MR-HIFU-induced hyperthermia treatment. Interleaved acquisition did not compromise speed or accuracy of each scan. The Delta R-1 acquired during treatment was used to visualize and quantify hyperthermia-triggered release of gadoteridol from TSLs and better reflected the intratumoral doxorubicin concentrations than the Delta R-1 measured after cooldown of the tumor, exemplifying the benefit of interleaving R-1 maps with temperature maps during drug delivery. Our study serves as an example for interleaved MR acquisition schemes, which introduce a higher flexibility in speed, sequence optimization, and timing

Development and evaluation of an isolated limb infusion model for investigation of drug delivery kinetics to solid tumors by thermosensitive liposomes and hyperthermia

The combined administration of thermosensitive liposomes (TSLs) and hyperthermia (HT) has been increasingly shown to be a powerful tool for the treatment of solid tumors. At present, it is hypothesized that the circulation of TSLs through the vasculature of a heated tumor results in the rapid release of the entrapped drug, followed by its uptake and distribution within the tumor microenvironment. However, simple questions on the transport kinetics of TSLs through the heated tumor and how much drug is retained upon passage of TSLs through the tumor microcirculation have not been investigated in an experimental setting to-date. The present work describes a novel methodology for investigating these parameters by isolated limb infusion (ILI), developed in a rat model of sarcoma. This approach was used to assess the efficacy of Doxorubicin (Dox) delivery by TSL in a heated (42 degrees C) tumor following a single passage of TSL through the tumor vasculature. Analysis of the effluent post-ILI, whole-tumor histological sections, and tissue homogenates revealed that upon a single passage, Dox delivery by TSL at 42 degrees C did not exceed delivery under conventional (i.e. free Dox) or physiological (i.e. TSL at 37 degrees C, or normothermia; NT) conditions. In fact, mathematical modeling demonstrated that at least thirteen passages are required to obtain the intratumoral Dox levels typically achieved using TSL (i.e. similar to 5% ID/g). Overall, this work investigates TSL-based determinants for achieving efficacious drug delivery using a model of ILI in tumor-bearing rats and the results bear important implications for TSL disposition in vivo

A time-driven activity-based costing approach of magnetic resonance-guided high-intensity focused ultrasound for cancer-induced bone pain

Objective To determine resource consumption and total costs for providing magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) treatment to a patient with cancer-induced bone pain (CIBP). Methods We conducted a time-driven activity-based costing (TD-ABC) of MR-HIFU treatments for CIBP from a hospital perspective. A European care-pathway (including a macro-, meso-, and micro-level) was designed to incorporate the care-delivery value chain. Time estimates were obtained from medical records and from prospective direct observations. To calculate the capacity cost rate, data from the controlling department of a German university hospital were allocated to the modules of the care pathway. Best- and worst-case scenarios were calculated by applying lower and upper bounds of time measurements. Results The macro-level care pathway consisted of eight modules (i.e., outpatient consultations, pretreatment imaging, preparation, optimization, sonication, post-treatment, recovery, and anesthesia). The total cost of an MR-HIFU treatment amounted to euro5147 per patient. Best- and worst-case scenarios yielded a total cost of euro4092 and to euro5876. According to cost categories, costs due to equipment accounted for 41% of total costs, followed by costs with personnel (32%), overhead (16%) and materials (11%). Conclusion MR-HIFU is an emerging noninvasive treatment for alleviating CIBP, with increasing evidence on treatment efficacy. This costing study can support MR-HIFU reimbursement negotiations and facilitate the adoption of MR-HIFU as first-line treatment for CIBP. The present TD-ABC model creates the opportunity of benchmarking the provision of MR-HIFU to bone tumor

Field drift correction of proton resonance frequency shift temperature mapping with multichannel fast alternating nonselective free induction decay readouts

Purpose To demonstrate that proton resonance frequency shift MR thermometry (PRFS-MRT) acquisition with nonselective free induction decay (FID), combined with coil sensitivity profiles, allows spatially resolved B-0 drift-corrected thermometry. Methods Phantom experiments were performed at 1.5T and 3T. Acquisition of PRFS-MRT and FID were performed during MR-guided high-intensity focused ultrasound heating. The phase of the FIDs was used to estimate the change in angular frequency delta omega(drift) per coil element. Two correction methods were investigated: (1) using the average delta omega(drift) over all coil elements (0th-order) and (2) using coil sensitivity profiles for spatially resolved correction. Optical probes were used for independent temperature verification. In-vivo feasibility of the methods was evaluated in the leg of 1 healthy volunteer at 1.5T. Results In 30 minutes, B-0 drift led to an apparent temperature change of up to -18 degrees C and -98 degrees C at 1.5T and 3T, respectively. In the sonicated area, both corrections had a median error of 0.19 degrees C at 1.5T and -0.54 degrees C at 3T. At 1.5T, the measured median error with respect to the optical probe was -1.28 degrees C with the 0th-order correction and improved to 0.43 degrees C with the spatially resolved correction. In vivo, without correction the spatiotemporal median of the apparent temperature was at -4.3 degrees C and interquartile range (IQR) of 9.31 degrees C. The 0th-order correction had a median of 0.75 degrees C and IQR of 0.96 degrees C. The spatially resolved method had the lowest median at 0.33 degrees C and IQR of 0.80 degrees C. Conclusion FID phase information from individual receive coil elements allows spatially resolved B-0 drift correction in PRFS-based MRT

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2)

Background High-intensity focused ultrasound (HIFU) allows noninvasive heating of deep-seated tissues. Guidance under magnetic resonance imaging (MR-HIFU) offers spatial targeting based on anatomical MR images as well as MR-based near-real-time temperature maps. Temperature feedback allows delivery of a well-defined thermal dose enabling new applications such as the ablation of malignant tissue. Methods Peer-reviewed publications on MR-HIFU were studied and are summarized in this review. Literature was restricted to applications in oncology. Results Several MR-HIFU-based applications for the treatment of malignant diseases are currently part of clinical trials or translational research. Recent trials regarding the treatment of prostate cancer with MR-HIFU have already shown this to be a safe and patient-friendly method. For the treatment of breast cancer and malignancies within abdominal organs, MR-HIFU has been applied so far only in proof of concept studies. Conclusion MR-HIFU is currently being investigated for the ablative treatment of malignant tissue in a variety of oncological applications. For example, the transrectal as well as transurethral ablation of prostate cancer using MR-HIFU was shown to be a patient-friendly, safe alternative to other local treatment options with low side effects. Key points: MR guidance offers high soft tissue contrast for treatment planning, near-real-time temperature monitoring, and post-interventional therapy evaluation. Special HIFU transducers and technological solutions are available for the treatment of e.g. prostate cancer, breast cancer or abdominal malignancies

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1)

Background Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation. Methods This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given. Results Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tremor as a first neurological application. Conclusion MR-HIFU is a patient-friendly noninvasive method for thermal ablation which has received clinical approval for several applications. Overall, clinical data demonstrate treatment efficacy, safety and cost efficiency. Key Points: HIFU is a promising technique for noninvasive thermal ablation of tissue. HIFU is typically performed under image guidance using either diagnostic ultrasound (US-HIFU) or MRI (MR-HIFU). The preferred image guidance modality depends on the application. MR guidance offers improved soft-tissue contrast for treatment planning, near real-time and noninvasive temperature monitoring and post-interventional therapy evaluation. MR-HIFU is CE-approved for treatment of uterine fibroids, alleviation of bone pain, prostate tissue ablation and treatment of essential tremor

Comparing the therapeutic potential of thermosensitive liposomes and hyperthermia in two distinct subtypes of breast cancer

Local drug delivery of Doxorubicin (Dox) with thermosensitive liposomes (TSL) and hyperthermia (HT) has shown preclinically to achieve high local drug concentrations with good therapeutic efficacy. Currently, this is clinically studied for treatment of chest wall recurrence of breast cancer, however with various outcomes. This study examines the potency of neoadjuvant TSL HT combination therapy in two orthotopic mouse models of human breast cancer, MDA-MB-231 and T-47D, which morphologically correlate to mesenchymal and epithelial phenotypes, respectively. Both cell lines showed improved in vitro chemosensitivity and Dox uptake at HT. Doxloaded TSL (TSLDox) was stable in vitro in FBS, BALB/c-nu plasma and human plasma, although release of the drug at HT was incomplete for the latter two. Combination treatment with TSLDox and HT in vivo was significantly more effective against MDA-MB-231 tumors, whereas T-47D tumors showed no significant therapeutic response. Ex vivo investigation revealed a higher mean vessel density and poorly differentiated extracellular matrix (ECM) in MDA-MB-231 tumors relative to T-47D tumors. Although in vitro results of the TSLDox and HT treatment were favorable for both cell types, the therapeutic efficacy in vivo was remarkably different. The well-differentiated and slowly-growing T-47D tumors may provide a microenvironment that limits drug delivery to the target cell and therefore renders the therapy ineffective. Mesenchymal and invasive MDAMB- 231 tumors display higher vascularization and less mature ECM, significantly enhancing tumor response to TSLDox and HT treatment. These results yield insight into the efficacy of TSL treatment within different tumor microenvironments, and further advance our understanding of factors that contribute to heterogeneous therapeutic outcomes in clinical trials

Imaging of Tumor Spheroids, Dual-Isotope SPECT, and Autoradiographic Analysis to Assess the Tumor Uptake and Distribution of Different Nanobodies (vol 31, pg 1079, 2020)

This article was corrected/updated to include the complete graphic legend of Fig. 3