Editorial

4 pages, 210 KiB

Open AccessEditorial

Hyperthermia-Based Anti-Cancer Treatments

by Johannes Crezee, Nicolaas A. P. Franken and Arlene L. Oei

Cancers 2021, 13(6), 1240; https://doi.org/10.3390/cancers13061240 - 12 Mar 2021

Cited by 35 | Viewed by 2895

Hyperthermia is an adjuvant local anti-cancer treatment using temperatures exceeding the physiologically optimal level, typically 40–43 °C for approximately one hour [...] Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

Research

Jump to: Editorial, Review

25 pages, 8623 KiB

Open AccessArticle

Design, Implementation, Evaluation and Application of a 32-Channel Radio Frequency Signal Generator for Thermal Magnetic Resonance Based Anti-Cancer Treatment

by Haopeng Han, Thomas Wilhelm Eigentler, Shuailin Wang, Egor Kretov, Lukas Winter, Werner Hoffmann, Eckhard Grass and Thoralf Niendorf

Cancers 2020, 12(7), 1720; https://doi.org/10.3390/cancers12071720 - 28 Jun 2020

Cited by 8 | Viewed by 2985

Abstract

Thermal Magnetic Resonance (ThermalMR) leverages radio frequency (RF)-induced heating to examine the role of temperature in biological systems and disease. To advance RF heating with multi-channel RF antenna arrays and overcome the shortcomings of current RF signal sources, this work reports on a [...] Read more.

Thermal Magnetic Resonance (ThermalMR) leverages radio frequency (RF)-induced heating to examine the role of temperature in biological systems and disease. To advance RF heating with multi-channel RF antenna arrays and overcome the shortcomings of current RF signal sources, this work reports on a 32-channel modular signal generator (SG_PLL). The SG_PLL was designed around phase-locked loop (PLL) chips and a field-programmable gate array chip. To examine the system properties, switching/settling times, accuracy of RF power level and phase shifting were characterized. Electric field manipulation was successfully demonstrated in deionized water. RF heating was conducted in a phantom setup using self-grounded bow-tie RF antennae driven by the SG_PLL. Commercial signal generators limited to a lower number of RF channels were used for comparison. RF heating was evaluated with numerical temperature simulations and experimentally validated with MR thermometry. Numerical temperature simulations and heating experiments controlled by the SG_PLL revealed the same RF interference patterns. Upon RF heating similar temperature changes across the phantom were observed for the SG_PLL and for the commercial devices. To conclude, this work presents the first 32-channel modular signal source for RF heating. The large number of coherent RF channels, wide frequency range and accurate phase shift provided by the SG_PLL form a technological basis for ThermalMR controlled hyperthermia anti-cancer treatment. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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17 pages, 3967 KiB

Open AccessArticle

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

by Yiyi Ji, Lukas Winter, Lucila Navarro, Min-Chi Ku, João S. Periquito, Michal Pham, Werner Hoffmann, Loryn E. Theune, Marcelo Calderón and Thoralf Niendorf

Cancers 2020, 12(6), 1380; https://doi.org/10.3390/cancers12061380 - 27 May 2020

Cited by 15 | Viewed by 2803

Abstract

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a [...] Read more.

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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33 pages, 12863 KiB

Open AccessArticle

Differences of the Immune Phenotype of Breast Cancer Cells after Ex Vivo Hyperthermia by Warm-Water or Microwave Radiation in a Closed-Loop System Alone or in Combination with Radiotherapy

by Michael Hader, Deniz Pinar Savcigil, Andreas Rosin, Philipp Ponfick, Stephan Gekle, Martin Wadepohl, Sander Bekeschus, Rainer Fietkau, Benjamin Frey, Eberhard Schlücker and Udo S. Gaipl

Cancers 2020, 12(5), 1082; https://doi.org/10.3390/cancers12051082 - 27 Apr 2020

Cited by 20 | Viewed by 4125

Abstract

The treatment of breast cancer by radiotherapy can be complemented by hyperthermia. Little is known about how the immune phenotype of tumor cells is changed thereby, also in terms of a dependence on the heating method. We developed a sterile closed-loop system, using [...] Read more.

The treatment of breast cancer by radiotherapy can be complemented by hyperthermia. Little is known about how the immune phenotype of tumor cells is changed thereby, also in terms of a dependence on the heating method. We developed a sterile closed-loop system, using either a warm-water bath or a microwave at 2.45 GHz to examine the impact of ex vivo hyperthermia on cell death, the release of HSP70, and the expression of immune checkpoint molecules (ICMs) on MCF-7 and MDA-MB-231 breast cancer cells by multicolor flow cytometry and ELISA. Heating was performed between 39 and 44 °C. Numerical process simulations identified temperature distributions. Additionally, irradiation with 2 × 5 Gy or 5 × 2 Gy was applied. We observed a release of HSP70 after hyperthermia at all examined temperatures and independently of the heating method, but microwave heating was more effective in cell killing, and microwave heating with and without radiotherapy increased subsequent HSP70 concentrations. Adding hyperthermia to radiotherapy, dynamically or individually, affected the expression of the ICM PD-L1, PD-L2, HVEM, ICOS-L, CD137-L, OX40-L, CD27-L, and EGFR on breast cancer cells. Well-characterized pre-clinical heating systems are mandatory to screen the immune phenotype of tumor cells in clinically relevant settings to define immune matrices for therapy adaption. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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23 pages, 4060 KiB

Open AccessArticle

Solving the Time- and Frequency-Multiplexed Problem of Constrained Radiofrequency Induced Hyperthermia

by Andre Kuehne, Eva Oberacker, Helmar Waiczies and Thoralf Niendorf

Cancers 2020, 12(5), 1072; https://doi.org/10.3390/cancers12051072 - 25 Apr 2020

Cited by 17 | Viewed by 3917

Abstract

Targeted radiofrequency (RF) heating induced hyperthermia has a wide range of applications, ranging from adjunct anti-cancer treatment to localized release of drugs. Focal RF heating is usually approached using time-consuming nonconvex optimization procedures or approximations, which significantly hampers its application. To address this [...] Read more.

Targeted radiofrequency (RF) heating induced hyperthermia has a wide range of applications, ranging from adjunct anti-cancer treatment to localized release of drugs. Focal RF heating is usually approached using time-consuming nonconvex optimization procedures or approximations, which significantly hampers its application. To address this limitation, this work presents an algorithm that recasts the problem as a semidefinite program and quickly solves it to global optimality, even for very large (human voxel) models. The target region and a desired RF power deposition pattern as well as constraints can be freely defined on a voxel level, and the optimum application RF frequencies and time-multiplexed RF excitations are automatically determined. 2D and 3D example applications conducted for test objects containing pure water (r_target = 19 mm, frequency range: 500–2000 MHz) and for human brain models including brain tumors of various size (r₁ = 20 mm, r₂ = 30 mm, frequency range 100–1000 MHz) and locations (center, off-center, disjoint) demonstrate the applicability and capabilities of the proposed approach. Due to its high performance, the algorithm can solve typical clinical problems in a few seconds, making the presented approach ideally suited for interactive hyperthermia treatment planning, thermal dose and safety management, and the design, rapid evaluation, and comparison of RF applicator configurations. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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14 pages, 2877 KiB

Open AccessArticle

MR Thermometry Data Correlate with Pathological Response for Soft Tissue Sarcoma of the Lower Extremity in a Single Center Analysis of Prospectively Registered Patients

by Michaela Unsoeld, Ulf Lamprecht, Frank Traub, Barbara Hermes, Marcus Scharpf, Vlatko Potkrajcic, Daniel Zips, Frank Paulsen and Franziska Eckert

Cancers 2020, 12(4), 959; https://doi.org/10.3390/cancers12040959 - 13 Apr 2020

Cited by 11 | Viewed by 2787

Abstract

Background: There is a strong biologic rationale for using locoregional hyperthermia in soft tissue sarcoma and a randomized trial reported significant improvements with hyperthermia. The aim of this study was to describe the opportunities of magnetic resonance (MR)-based thermometry in a cohort [...] Read more.

Background: There is a strong biologic rationale for using locoregional hyperthermia in soft tissue sarcoma and a randomized trial reported significant improvements with hyperthermia. The aim of this study was to describe the opportunities of magnetic resonance (MR)-based thermometry in a cohort of soft tissue sarcoma patients undergoing combined radiotherapy and locoregional hyperthermia. Patients and Methods: For eleven evaluable patients, tumor volume (V_Tu) and a separate volume for temperature analysis with reliable temperature distribution (V_therm) were contoured for every hyperthermia treatment (103 therapies). Temperature data were recorded for all tumors and were correlated with clinical features and pathologic response data. Results: Of 48 patients with high-risk soft tissue sarcomas treated with radio(chemo)therapy and locoregional hyperthermia, MR thermometry was possible in 11 (23%) patients. For all patients, the temperature superseded by 90% of V_Tu (T90(V_Tu)) and T90 (V_therm) were in the range of 37–43 °C and 40–45 °C, respectively. Larger tumors tended to reach higher temperatures. For tumors showing a pathologic response in the resection specimen after preoperative treatment, temperature (T90 (V_therm)) was significantly higher than in tumors without pathologic response. Conclusion: Lower extremity sarcomas undergoing preoperative treatment with locoregional hyperthermia are especially suitable for MR thermometry. MR thermometry is a promising non-invasive way for temperature measurement during locoregional hyperthermia, showing a positive dose-response relationship. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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15 pages, 3878 KiB

Open AccessArticle

Modelling Curved Contact Flexible Microstrip Applicators for Patient-Specific Superficial Hyperthermia Treatment Planning

by H. Petra Kok, Jort Groen, Akke Bakker and Johannes Crezee

Cancers 2020, 12(3), 656; https://doi.org/10.3390/cancers12030656 - 11 Mar 2020

Cited by 7 | Viewed by 3046

Abstract

This paper describes a method to reconstruct bendable superficial hyperthermia applicators for routine clinical patient-specific treatment planning. The reconstruction uses a CT scan with a flexible silicone dummy applicator positioned on the patient. The curvature was approximated by two second-degree polynomial functions. A [...] Read more.

This paper describes a method to reconstruct bendable superficial hyperthermia applicators for routine clinical patient-specific treatment planning. The reconstruction uses a CT scan with a flexible silicone dummy applicator positioned on the patient. The curvature was approximated by two second-degree polynomial functions. A realistic treatment series was mimicked using a standard Alderson radiation therapy phantom and a treatment planning model was reconstructed from a CT scan. The variation among treatment curvatures was compared to the modelled curvature. The mathematical approximation of the applicator curvature was validated for this phantom experiment, as well as for clinical treatments. The average maximum variation among the successive mimicked sessions was 3.67 ± 0.69 mm (range 2.98–4.60 mm). The maximum deviation between the treatment curvature and the modelled curvature was 4.35 mm. Comparing the treatment and approximated curvature yielded a maximum deviation between 2.98 mm and 4.12 mm. For clinical treatments the maximum deviation of the treatment and approximated curvature varied between 0.48 mm and 1.98 mm. These results allow adequate reconstruction of bendable hyperthermia applicators for treatment planning, which can further improve treatment quality, for example by optimizing the water bolus temperature for patient-specific tumor depths. Predictive parameters for hyperthermia treatment outcome can easily be evaluated and compared for various input parameters. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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14 pages, 2741 KiB

Open AccessArticle

Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification

by Markus Notter, Andreas R. Thomsen, Mirko Nitsche, Robert M. Hermann, Hendrik A. Wolff, Gregor Habl, Karin Münch, Anca-L. Grosu and Peter Vaupel

Cancers 2020, 12(3), 606; https://doi.org/10.3390/cancers12030606 - 06 Mar 2020

Cited by 37 | Viewed by 12251

Abstract

Effective tumor control in patients suffering from unresectable locally recurrent breast cancer (LRBC) in pre-irradiated areas can be achieved by re-irradiation combined with superficial hyperthermia. Using this combined modality, total re-irradiation dose and toxicity can be significantly reduced compared to conventionally fractionated treatment [...] Read more.

Effective tumor control in patients suffering from unresectable locally recurrent breast cancer (LRBC) in pre-irradiated areas can be achieved by re-irradiation combined with superficial hyperthermia. Using this combined modality, total re-irradiation dose and toxicity can be significantly reduced compared to conventionally fractionated treatment schedules with total doses of 60–66 Gy. Applying contact-free, thermography-controlled water-filtered infrared-A superficial hyperthermia, immediately followed by hypofractionated re-irradiation, consisting of 4 Gy once per week up to a total dose of 20 Gy, resulted in high overall response rates even in large-sized tumors. Comparability of clinical data between different combined Hyperthermia (HT)/Radiotherapy (RT) treatment schedules is impeded by the highly individual characteristics of this disease. Tumor size, ranging from microscopic disease and small lesions to large-sized cancer en cuirasse, is described as one of the most important prognostic factors. However, in clinical studies and analyses of LRBC, tumor size has so far been reported in a very heterogeneous way. Therefore, we suggest a novel, simple and feasible size classification (rClasses 0–IV). Applying this classification for the evaluation of 201 patients with pre-irradiated LRBC allowed for a stratification into distinct prognostic groups. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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18 pages, 4266 KiB

Open AccessArticle

Radiosensitization by Hyperthermia: The Effects of Temperature, Sequence, and Time Interval in Cervical Cell Lines

by Xionge Mei, Rosemarie ten Cate, Caspar M. van Leeuwen, Hans M. Rodermond, Lidewij de Leeuw, Dionysia Dimitrakopoulou, Lukas J. A. Stalpers, Johannes Crezee, H. Petra Kok, Nicolaas A. P. Franken and Arlene L. Oei

Cancers 2020, 12(3), 582; https://doi.org/10.3390/cancers12030582 - 03 Mar 2020

Cited by 25 | Viewed by 3488

Abstract

Cervical cancers are almost exclusively caused by an infection with the human papillomavirus (HPV). When patients suffering from cervical cancer have contraindications for chemoradiotherapy, radiotherapy combined with hyperthermia is a good treatment option. Radiation-induced DNA breaks can be repaired by nonhomologous end-joining (NHEJ) [...] Read more.

Cervical cancers are almost exclusively caused by an infection with the human papillomavirus (HPV). When patients suffering from cervical cancer have contraindications for chemoradiotherapy, radiotherapy combined with hyperthermia is a good treatment option. Radiation-induced DNA breaks can be repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Hyperthermia can temporarily inactivate homologous recombination. Therefore, combining radiotherapy with hyperthermia can result in the persistence of more fatal radiation-induced DNA breaks. However, there is no consensus on the optimal sequence of radiotherapy and hyperthermia and the optimal time interval between these modalities. Moreover, the temperature of hyperthermia and HPV-type may also be important in radiosensitization by hyperthermia. In this study we thoroughly investigated the impact of different temperatures (37–42 °C), and the sequence of and time interval (0 up to 4 h) between ionizing radiation and hyperthermia on HPV16⁺: SiHa, Caski; HPV18⁺: HeLa, C4I; and HPV⁻: C33A, HT3 cervical cancer cell lines. Our results demonstrate that a short time interval between treatments caused more unrepaired DNA damages and more cell kill, especially at higher temperatures. Although hyperthermia before ionizing radiation may result in slightly more DNA damage, the sequence between hyperthermia and ionizing radiation yielded similar effects on cell survival. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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7 pages, 1326 KiB

Open AccessArticle

Anti-Metastatic Benefits Produced by Hyperthermia and a CCL3 Derivative

by Liqiu Ma, Ryosuke Kambe, Tomoko Tsuchiya, Shiro Kanegasaki and Akihisa Takahashi

Cancers 2019, 11(11), 1770; https://doi.org/10.3390/cancers11111770 - 11 Nov 2019

Cited by 2 | Viewed by 2379

Abstract

Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, [...] Read more.

Significant numbers of malignant tumor cells that have spread to surrounding tissues and other distant organs are often too small to be picked up in a diagnostic test, and prevention of even such small metastases should improve patient outcomes. Using a mouse model, we show in this article that intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia not only induces tumor growth inhibition at the treated site but also inhibits metastasis. Colon26 adenocarcinoma cells (1 × 10⁵ cells/mouse) were grafted subcutaneously into the right hind leg of syngeneic BALB/c mice and after nine days, when tumor size reached ~11 mm in diameter, the local tumor mass was exposed to high-frequency waves, by which intratumoral temperature was maintained at 42 °C for 30 min. Mice received the CCL3 variant named eMIP (2 μg/mouse/day) intravenously for five consecutive days starting one day after heat treatment. We found that tumor growth in eMIP recipients after hyperthermia was inhibited markedly but no effect was seen in animals treated with either hyperthermia or eMIP alone. Furthermore, the number of lung metastases evaluated at 18 days after hyperthermia treatment was dramatically reduced in animals receiving the combination therapy compared with all other controls. These results encourage future clinical application of this combination therapy. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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19 pages, 6240 KiB

Open AccessArticle

Quantitative, Multi-institutional Evaluation of MR Thermometry Accuracy for Deep-Pelvic MR-Hyperthermia Systems Operating in Multi-vendor MR-systems Using a New Anthropomorphic Phantom

by Sergio Curto, Bassim Aklan, Tim Mulder, Oliver Mils, Manfred Schmidt, Ulf Lamprecht, Michael Peller, Ruediger Wessalowski, Lars H. Lindner, Rainer Fietkau, Daniel Zips, Gennaro G. Bellizzi, Netteke van Holthe, Martine Franckena, Margarethus M. Paulides and Gerard C. van Rhoon

Cancers 2019, 11(11), 1709; https://doi.org/10.3390/cancers11111709 - 02 Nov 2019

Cited by 28 | Viewed by 3691

Abstract

Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique [...] Read more.

Clinical outcome of hyperthermia depends on the achieved target temperature, therefore target conformal heating is essential. Currently, invasive temperature probe measurements are the gold standard for temperature monitoring, however, they only provide limited sparse data. In contrast, magnetic resonance thermometry (MRT) provides unique capabilities to non-invasively measure the 3D-temperature. This study investigates MRT accuracy for MR-hyperthermia hybrid systems located at five European institutions while heating a centric or eccentric target in anthropomorphic phantoms with pelvic and spine structures. Scatter plots, root mean square error (RMSE) and Bland–Altman analysis were used to quantify accuracy of MRT compared to high resistance thermistor probe measurements. For all institutions, a linear relation between MRT and thermistor probes measurements was found with R² (mean ± standard deviation) of 0.97 ± 0.03 and 0.97 ± 0.02, respectively for centric and eccentric heating targets. The RMSE was found to be 0.52 ± 0.31 °C and 0.30 ± 0.20 °C, respectively. The Bland-Altman evaluation showed a mean difference of 0.46 ± 0.20 °C and 0.13 ± 0.08 °C, respectively. This first multi-institutional evaluation of MR-hyperthermia hybrid systems indicates comparable device performance and good agreement between MRT and thermistor probes measurements. This forms the basis to standardize treatments in multi-institution studies of MR-guided hyperthermia and to elucidate thermal dose-effect relations. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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16 pages, 2033 KiB

Open AccessArticle

Tumor Drug Distribution after Local Drug Delivery by Hyperthermia, In Vivo

by Helena C. Besse, Angelique D. Barten-van Rijbroek, Kim M.G. van der Wurff-Jacobs, Clemens Bos, Chrit T.W. Moonen and Roel Deckers

Cancers 2019, 11(10), 1512; https://doi.org/10.3390/cancers11101512 - 09 Oct 2019

Cited by 28 | Viewed by 4098

Abstract

Tumor drug distribution and concentration are important factors for effective tumor treatment. A promising method to enhance the distribution and the concentration of the drug in the tumor is to encapsulate the drug in a temperature sensitive liposome. The aim of this study [...] Read more.

Tumor drug distribution and concentration are important factors for effective tumor treatment. A promising method to enhance the distribution and the concentration of the drug in the tumor is to encapsulate the drug in a temperature sensitive liposome. The aim of this study was to investigate the tumor drug distribution after treatment with various injected doses of different liposomal formulations of doxorubicin, ThermoDox (temperature sensitive liposomes) and DOXIL (non-temperature sensitive liposomes), and free doxorubicin at macroscopic and microscopic levels. Only ThermoDox treatment was combined with hyperthermia. Experiments were performed in mice bearing a human fibrosarcoma. At low and intermediate doses, the largest growth delay was obtained with ThermoDox, and at the largest dose, the largest growth delay was obtained with DOXIL. On histology, tumor areas with increased doxorubicin concentration correlated with decreased cell proliferation, and substantial variations in doxorubicin heterogeneity were observed. ThermoDox treatment resulted in higher tissue drug levels than DOXIL and free doxorubicin for the same dose. A relation with the distance to the vasculature was shown, but vessel perfusion was not always sufficient to determine doxorubicin delivery. Our results indicate that tumor drug distribution is an important factor for effective tumor treatment and that its dependence on delivery formulation merits further systemic investigation. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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23 pages, 4695 KiB

Open AccessArticle

Hyperthermia Treatment Planning Including Convective Flow in Cerebrospinal Fluid for Brain Tumour Hyperthermia Treatment Using a Novel Dedicated Paediatric Brain Applicator

by Gerben Schooneveldt, Hana Dobšíček Trefná, Mikael Persson, Theo M. de Reijke, Klas Blomgren, H. Petra Kok and Hans Crezee

Cancers 2019, 11(8), 1183; https://doi.org/10.3390/cancers11081183 - 15 Aug 2019

Cited by 27 | Viewed by 3807

Abstract

Hyperthermia therapy (40–44 °C) is a promising option to increase efficacy of radiotherapy/chemotherapy for brain tumours, in particular paediatric brain tumours. The Chalmers Hyperthermia Helmet is developed for this purpose. Hyperthermia treatment planning is required for treatment optimisation, but current planning systems do [...] Read more.

Hyperthermia therapy (40–44 °C) is a promising option to increase efficacy of radiotherapy/chemotherapy for brain tumours, in particular paediatric brain tumours. The Chalmers Hyperthermia Helmet is developed for this purpose. Hyperthermia treatment planning is required for treatment optimisation, but current planning systems do not involve a physically correct model of cerebrospinal fluid (CSF). This study investigates the necessity of fluid modelling for treatment planning. We made treatments plans using the Helmet for both pre-operative and post-operative cases, comparing temperature distributions predicted with three CSF models: a convective “fluid” model, a non-convective “solid” CSF model, and CSF models with increased effective thermal conductivity (“high-k”). Treatment plans were evaluated by T₉₀, T₅₀ and T₁₀ target temperatures and treatment-limiting hot spots. Adequate heating is possible with the helmet. In the pre-operative case, treatment plan quality was comparable for all three models. In the post-operative case, the high-k models were more accurate than the solid model. Predictions to within ±1 °C were obtained by a 10–20-fold increased effective thermal conductivity. Accurate modelling of the temperature in CSF requires fluid dynamics, but modelling CSF as a solid with enhanced effective thermal conductivity might be a practical alternative for a convective fluid model for many applications. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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11 pages, 1440 KiB

Open AccessArticle

Impact of Technique and Schedule of Reirradiation Plus Hyperthermia on Outcome after Surgery for Patients with Recurrent Breast Cancer

by Sabine Oldenborg, Rob van Os, Bing Oei and Philip Poortmans

Cancers 2019, 11(6), 782; https://doi.org/10.3390/cancers11060782 - 05 Jun 2019

Cited by 9 | Viewed by 3196

Abstract

Purpose: Combining reirradiation (reRT) with hyperthermia (HT) has shown to be of high therapeutic value for patients with loco-regionally recurrent breast cancer. The purpose of this study was to compare the long-term therapeutic effect and toxicity of reRT + HT following surgery of [...] Read more.

Purpose: Combining reirradiation (reRT) with hyperthermia (HT) has shown to be of high therapeutic value for patients with loco-regionally recurrent breast cancer. The purpose of this study was to compare the long-term therapeutic effect and toxicity of reRT + HT following surgery of loco-regionally recurrent breast cancer using two different reRT regimens. Methods: The reRT regimen of the 78 patients treated in Institute A consisted of 8 × 4 Gy twice a week using mostly abutted photon-electron fields. The 78 patients treated in Institute B received a reRT regimen of 12 × 3 Gy, four times a week with single or multiple electron fields. Superficial hyperthermia was applied once a week in Institute A and twice a week in Institute B. Both institutes started HT treatment within 1 hour after reRT and used the same 434-MHz systems to heat the tumor area to 41–43 °C. Results: The 5-year-infield local control (LC) rates were similar; however, the 5-year-survival rates were 13% lower in Institute A. Most remarkable was the difference in risk with respect to 5-year ≥ grade 3 toxicity, which was more than twice as high in Institute A. Conclusion: The combination of reirradiation and hyperthermia after macroscopically complete excision of loco-regional breast cancer recurrences provides durable local control in patients at risk for locoregional recurrent breast cancer. Treatment is well tolerated with the 12 × 3 Gy schedule with limited-sized electron fields. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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19 pages, 11547 KiB

Open AccessArticle

Numerical Study on Effective Conditions for the Induction of Apoptotic Temperatures for Various Tumor Aspect Ratios Using a Single Continuous-Wave Laser in Photothermal Therapy Using Gold Nanorods

by Moojoong Kim, Gwantaek Kim, Donghyuk Kim, Jaisuk Yoo, Dong-Kwon Kim and Hyunjung Kim

Cancers 2019, 11(6), 764; https://doi.org/10.3390/cancers11060764 - 31 May 2019

Cited by 38 | Viewed by 3877

Abstract

Photothermal therapy can serve as an alternative to classic surgery in the treatment of patients with cancer. However, using photothermal therapy can result in local overheating and damage to normal tissues. Therefore, it is important to determine effective heating conditions based on heat [...] Read more.

Photothermal therapy can serve as an alternative to classic surgery in the treatment of patients with cancer. However, using photothermal therapy can result in local overheating and damage to normal tissues. Therefore, it is important to determine effective heating conditions based on heat transfer. In this study, we analyzed laser–tissue interactions in gold nanoparticle (GNP)-enhanced photothermal therapy based on the theory of heat transfer. The thermal behavior inside tissues during photothermal therapy was analyzed using numerical analysis. The apoptosis ratio was defined by deriving the area having a temperature distribution between 43 °C and 50 °C, which is required for inducing apoptosis. Thermal damage, caused by local heating, was defined using the thermal hazard value. Using this approach, we confirmed that apoptosis can be predicted with respect to tumor size (aspect ratio) and heating conditions (laser intensity and radius) in photothermal therapy with a continuous-wave laser. Finally, we determined the effective apoptosis ratio and thermal hazard value of normal tissue according to tumor size and heating conditions, thereby establishing conditions for inducing maximal levels of cell apoptosis with minimal damage to normal tissue. The optimization conditions proposed in this study can be a gentle and effective treatment option for photothermal therapy. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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20 pages, 3993 KiB

Open AccessArticle

Hydroxyethyl Starch-Based Nanoparticles Featured with Redox-Sensitivity and Chemo-Photothermal Therapy for Synergized Tumor Eradication

by Chan Yu, Chuqi Liu, Shaocong Wang, Zheng Li, Hang Hu, Ying Wan and Xiangliang Yang

Cancers 2019, 11(2), 207; https://doi.org/10.3390/cancers11020207 - 11 Feb 2019

Cited by 16 | Viewed by 3599

Abstract

Chemo-photothermal combination therapy could achieve synergistically enhanced efficiency against tumors. Nanocarriers with good safety and high efficiency for chemo- photothermal therapy are pressingly needed. A new type of hydroxyethyl starch (HES) based on nanoparticles (NPs) loaded with doxorubicin (DOX) and indocyanine green (ICG) [...] Read more.

Chemo-photothermal combination therapy could achieve synergistically enhanced efficiency against tumors. Nanocarriers with good safety and high efficiency for chemo- photothermal therapy are pressingly needed. A new type of hydroxyethyl starch (HES) based on nanoparticles (NPs) loaded with doxorubicin (DOX) and indocyanine green (ICG) was, thus, developed in this study. DOX-loaded HES conjugates with redox-sensitivity (HES-SS-DOX) were first synthesized and they were then combined with ICG to self-assemble into HES-SS-DOX@ICG NPs with controlled compositions and sizes via collaborative interactions. The optimal HES-SS-DOX@ICG NPs had good physical and photothermal stability in aqueous media and showed high photothermal efficiency in vivo. They were able to fast release the loaded DOX in response to the redox stimulus and the applied laser irradiation. Based on the H22-tumor-bearing mouse model, these NPs were found to tendentiously accumulate inside tumors in comparison to other major organs. The HES-SS-DOX@ICG NPs together with dose-designated laser irradiation were able to fully eradicate tumors with only one injection and one single subsequent laser irradiation on the tumor site during a 14-day treatment period. In addition, they showed almost no impairment to the body. The presently developed HES-SS-DOX@ICG NPs have good in vivo safety and highly efficient anti-tumor capability. These NPs in conjugation with laser irradiation have promising potential for chemo-photothermal cancer therapy in the clinic. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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26 pages, 2327 KiB

Open AccessArticle

On the Mechanism of Hyperthermia-Induced BRCA2 Protein Degradation

by Nathalie van den Tempel, Alex N. Zelensky, Hanny Odijk, Charlie Laffeber, Christine K. Schmidt, Inger Brandsma, Jeroen Demmers, Przemek M. Krawczyk and Roland Kanaar

Cancers 2019, 11(1), 97; https://doi.org/10.3390/cancers11010097 - 15 Jan 2019

Cited by 15 | Viewed by 4699

Abstract

The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. [...] Read more.

The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment—it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 —one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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18 pages, 3128 KiB

Open AccessReview

Variation in Clinical Application of Hyperthermic Intraperitoneal Chemotherapy: A Review

by Roxan F. C. P. A. Helderman, Daan R. Löke, H. Petra Kok, Arlene L. Oei, Pieter J. Tanis, Nicolaas A. P. Klaas Franken and Johannes Crezee

Cancers 2019, 11(1), 78; https://doi.org/10.3390/cancers11010078 - 11 Jan 2019

Cited by 64 | Viewed by 6433

Abstract

Peritoneal metastasis (PM) originating from gastrointestinal and gynecological malignancies are associated with a poor prognosis and rapid disease progression. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment option with curative intent. Hyperthermia enhances the cytotoxicity of chemotherapeutic drugs, thereby [...] Read more.

Peritoneal metastasis (PM) originating from gastrointestinal and gynecological malignancies are associated with a poor prognosis and rapid disease progression. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective treatment option with curative intent. Hyperthermia enhances the cytotoxicity of chemotherapeutic drugs, thereby killing microscopic tumors and reducing the risk of tumor recurrence. Eight parameters potentially have an impact on the efficacy of HIPEC: the type of drug, drug concentrations, carrier solution, volume of the perfusate, temperature of the perfusate, duration of the treatment, the technique of delivery, and patient selection. In this review, a literature search was performed on PubMed, and a total of 564 articles were screened of which 168 articles were included. Although HIPEC is a successful treatment, there is no standardized method for delivering HIPEC: the choice of parameters is presently largely determined by institutional preferences. We discuss the current choice of the parameters and hypothesize about improvements toward uniform standardization. Quantifying the effect of each parameter separately is necessary to determine the optimal way to perform HIPEC procedures. In vivo, in vitro, in silico, and other experimental studies should shed light on the role of each of the eight parameters. Full article

(This article belongs to the Special Issue Hyperthermia-based Anticancer Treatments)

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