Infrared heat, a transient receptor potential vanilloid type-3 (TRPV3) sensitive stimulus, may have potential physiological effects beneficial to treating metabolic syndrome.
Materials and methods
Obesity prone (OP) and obesity resistant (OR) rats were fed for seven days on a high-fat diet. Heat treated OP rats were exposed twice daily to infrared light for 20 min each, separated by 80 min of rest. Food intake, blood pressure, blood glucose, and body weight measurements were taken daily and compared between treated OP rats, untreated OP rats, and OR controls. The animals were perfused with 4% paraformaldehyde, and immunohistochemistry was performed on the coronal brainstem sections with polyclonal antibodies against TRPV3 and pro-opiomelanocortin (POMC). The positive-staining cells in the medulla nuclei were quantified using a microscope with reticule grid.
Food intake, body weight, and mean arterial blood pressure (MAP) were higher in OP rats, a diet-induced metabolic syndrome model, accompanied by a reduced expression of POMC, an anorectic agent, in the hypoglossal nucleus (HN) and medial nucleus tractus solitarius (mNTS). Food intake in heat-treated OP rats was significantly decreased. POMC positive neuron count was increased in the HN and mNTS of OP rats following treatment. TRPV3 positive staining neurons were increased in the HN and mNTS of OP control rats and decreased following the heat treatments.
Lowered POMC and heightened TRPV3 expressions in the HN and mNTS are involved in development of hyperphagia and obesity in OP rats. Exposure to infrared heat modifies TRPV3 and POMC expression in the brainstem, reducing food intake.
dorsal medulla; food intake; infrared heat; metabolic syndrome; POMC; TRPV3
Purpose: An investigation of the thermal effect and the potential for injury at the lung surface following thermal vapour ablation (InterVapor), an energy-based method of achieving endoscopic lung volume reduction.
Methods: Heated water vapour was delivered to fifteen ex vivo human lungs using standard clinical procedure, and the thermal effect at the visceral pleura was monitored with an infrared camera. The time–temperature response was analysed mathematically to determine a cumulative injury quotient, which was compared to published thresholds.
Results: The cumulative injury quotients for all 71 treatments of ex vivo tissue were found to be below the threshold for first degree burn and no other markers of tissue injury at the lung surface were observed.
Conclusion: The safety profile for thermal vapour ablation is further supported by the demonstration that the thermal effect in a worst-case model is not expected to cause injury at the lung surface.
Cumulative injury; lung; thermal effect; vapour ablation
Objectives of this study were to: 1) develop iLTSL, a low temperature sensitive liposome co-loaded with an MRI contrast agent (ProHance® Gd-HP-DO3A) and doxorubicin, 2) characterise doxorubicin and Gd-HP-DO3A release from iLTSL and 3) investigate the ability of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) to induce and monitor iLTSL content release in phantoms and in vivo.
iLTSL was passively loaded with Gd-HP-DO3A and actively loaded with doxorubicin. Doxorubicin and Gd-HP-DO3A release was quantified by fluorescence and spectroscopic techniques, respectively. Release with MR-HIFU was examined in tissue-mimicking phantoms containing iLTSL and in a VX2 rabbit tumour model.
iLTSL demonstrated consistent size and doxorubicin release kinetics after storage at 4°C for 7 days. Release of doxorubicin and Gd-HP-DO3A from iLTSL was minimal at 37°C but fast when heated to 41.3°C. The magnitude of release was not significantly different between doxorubicin and Gd-HP-DO3A over 10 min in HEPES buffer and plasma at 37°, 40° and 41.3°C (p>0.05). Relaxivity of iLTSL increased significantly (p <0.0001) from 1.95 ± 0.05 to 4.01 ± 0.1 mMs−1 when heated above the transition temperature. Signal increase corresponded spatially and temporally to MR-HIFU-heated locations in phantoms. Signal increase was also observed in vivo after iLTSL injection and after each 10-min heating (41°C), with greatest increase in the heated tumour region.
An MR imageable liposome formulation co-loaded with doxorubicin and an MR contrast agent was developed. Stability, imageability, and MR-HIFU monitoring and control of content release suggest that MR-HIFU combined with iLTSL may enable real-time monitoring and spatial control of content release.
doxorubicin (Adriamycin); heat targeted drug delivery (nanoparticles; liposomes); high intensity focused ultrasound; MR imaging; imageable temperature sensitive liposomes
To investigate the effect of heat shock protein (HSP) modulation on tumour coagulation by combining radiofrequency (RF) ablation with adjuvant liposomal quercetin and/or doxorubicin in a rat tumour model.
Sixty R3230 breast adenocarcinoma tumours/animals were used in this IACUC-approved study. Initially, 60 tumours (n = 6, each subgroup) were randomised into five groups: (1) RF alone, (2) intravenous (IV) liposomal quercetin alone (1 mg/kg), (3) IV liposomal quercetin followed 24 h later with RF, (4) RF followed 15 min later by IV liposomal doxorubicin (8 mg/kg), (5) IV liposomal quercetin 24 h before RF followed by IV liposomal doxorubicin 15 min post-ablation. Animals were sacrificed 4 or 24 h post-treatment and gross coagulation diameters were compared. Next, immunohistochemistry staining was performed for Hsp70 and cleaved caspase-3 expression. Comparisons were performed by using Student t-tests or ANOVA.
Combination RF-quercetin significantly increased coagulation size compared with either RF or liposomal quercetin alone (13.1 ± 0.7 mm vs. 8.8 ± 1.2 mm or 2.3 ± 1.3 mm, respectively, P < 0.001 for all comparisons). Triple therapy (quercetin-RF-doxorubicin) showed larger coagulation diameter (14.5 ± 1.0mm) at 24 h than quercetin-RF (P = 0.016) or RF-doxorubicin (13.2 ± 1.3 mm, P = 0.042). Combination quercetin-RF decreased Hsp70 expression compared with RF alone at both 4 h (percentage of stained cells/hpf 22.4 ± 13.9% vs. 38.8 ± 16.1%, P < 0.03) and 24 h (45.2 ± 10.5% vs. 81.1 ± 3.6%, P < 0.001). Quercetin-RF increased cleaved caspase-3 expression at both 4 h (percentage of stained cells/hpf 50.7 ± 13.4% vs. 41.9 ± 15.1%, P < 0.03) and 24 h (37.4 ± 7.8% vs. 33.2 ± 6.5%, P = 0.045); with, triple therapy (quercetin-RF-doxorubicin) resulting in the highest levels of apoptosis (45.1 ± 10.7%) at 24 h. Similar trends were observed for rim thickness.
Suppression of HSP production using adjuvant liposomal quercetin can increase apoptosis and improve RF ablation-induced tumour destruction. Further increases in tumour coagulation can be seen including an additional antitumour adjuvant agent such as liposomal doxorubicin.
apoptosis; heat shock protein; liposomal quercetin; liposomal doxorubicin; radiofrequency; tumour ablation
To determine the impact of including dynamic changes in tissue physical properties during heating on feedback controlled thermal ablation with catheter-based ultrasound. Additionally, we compared impact several indicators of thermal damage on predicted extents of ablation zones for planning and monitoring ablations with this modality.
A 3D model of ultrasound ablation with interstitial and transurethral applicators incorporating temperature based feedback control was used to simulate thermal ablations in prostate and liver tissue. We investigated five coupled models of heat dependent changes in tissue acoustic attenuation/absorption and blood perfusion of varying degrees of complexity.. Dimensions of the ablation zone were computed using temperature, thermal dose, and Arrhenius thermal damage indicators of coagulative necrosis. A comparison of the predictions by each of these models was illustrated on a patient-specific anatomy in the treatment planning setting.
Models including dynamic changes in blood perfusion and acoustic attenuation as a function of thermal dose/damage predicted near-identical ablation zone volumes (maximum variation < 2.5%). Accounting for dynamic acoustic attenuation appeared to play a critical role in estimating ablation zone size, as models using constant values for acoustic attenuation predicted ablation zone volumes up to 50% larger or 47% smaller in liver and prostate tissue, respectively. Thermal dose (t43 ≥ 240min) and thermal damage (Ω ≥ 4.6) thresholds for coagulative necrosis are in good agreement for all heating durations, temperature thresholds in the range of 54 °C for short (< 5 min) duration ablations and 50 °C for long (15 min) ablations may serve as surrogates for determination of the outer treatment boundary.
Accounting for dynamic changes in acoustic attenuation/absorption appeared to play a critical role in predicted extents of ablation zones. For typical 5—15 min ablations with this modality, thermal dose and Arrhenius damage measures of ablation zone dimensions are in good agreement, while appropriately selected temperature thresholds provide a computationally cheaper surrogate.
thermal ablation; high intensity ultrasound; ultrasound ablation; theoretical model; treatment planning
The purpose of this study was to quantify hypoxia changes in viable tumour volumes after thermal ablation of a murine breast carcinoma.
Murine breast 4T1 tumours were grown in the rear leg of BALB/c mice to an average diameter of 10–12 mm. Tumours were treated with conductive interstitial thermal therapy (CITT) at a peak temperature of 80–90° C for 10 min. The animals were euthanised 72 h later, and the tumours were removed for immunohistochemical staining with pimonidazole – a marker of partial pressure of oxygen. The levels of pimonidazole staining intensity were used to quantify changes in hypoxia gradients in terms of strong, medium and weak positive pixel fractions.
The pimonidazole staining ratio of viable control tumour tissue to viable tissue in tumours that were ablated was 0.7 for weak staining, 2.7 for medium staining and 8.0 (p < 0.03) for strong pimonidazole staining.
This shift of pimonidazole staining toward lower intensity pixels in the remaining tumour indicates that tumour ablation with CITT may increase radiosensitivity of the remaining tumour tissue and presents a rationale for combination therapy.
Ablation; 4T1; hypoxia; perinecrotic zone
The goal of this study was to evaluate the relationship between previously demonstrated thermosensitising effects of the block copolymer, Pluronic, and heat shock protein 70 (Hsp70) expression in an experimental colorectal cancer model in vitro and in vivo.
Materials and methods
Rat colorectal carcinoma cells were treated with low-grade hyperthermia (43°C) alone or in combination with Pluronics L10 (3 mg/mL), L61 (0.3 mg/mL), or L64 (0.5 mg/mL) for 20 min. Adinosine triphosphate (ATP) levels and cell viability were determined using standard assays. Hsp70 expression was quantified by western blot for cells treated with L10, L61, and L64 at doses specified above and Pluronic P85 (10 mg/mL) alone and in combination with heat. BDIX rats with flank tumours were used to study the effect of L61 and hyperthermia on Hsp70 expression in vivo.
In vitro, treatment with L10, L61, and L64 plus low-grade hyperthermia lead to depletion of ATP levels to between 8 and 66% of untreated control after 24 h. Maximum expression of Hsp70 was observed at 9 h following hyperthermia alone. The combination of low-grade hyperthermia and Pluronic treatment reduced Hsp70 expression for up to 6 hours, and L10 appeared to completely inhibit the Hsp70 expression. In vivo, Hsp70 expression was increased 5 h after hyperthermia in BDIX rat tumour models and no Hsp70 expression was observed in L61 pre-treated and control groups.
Pluronic effectively improves hyperthermic and low-grade hyperthermic treatment in part due to reduction of Hsp70 expression.
heat shock protein; low-grade hyperthermia; pluronic
To identify specific Pluronic triblock copolymer structural properties which are critical to its function as a sensitiser in hyperthermia treatment of experimental colorectal adenocarcinoma.
Materials and methods
DHD/K12/TRb rat colorectal adenocarcinoma cells were exposed to Pluronics, a family of triblock copolymers with the general structure EOx-POy-EOx (EO: ethylene oxide, and PO: propylene oxide), at a range of molecular weights (Mw) and EO:PO:EO sub-unit lengths and then submitted to sublethal heat (43°C) treatment. Outcomes indicating Pluronic performance as a thermal sensitiser were correlated with its structural properties; lead candidates were determined accordingly. Finally, one of the lead candidates, Pluronic L61, a 2000 Da copolymer, was used to assess sensitising functionality in vivo in a subcutaneous rat model of colorectal carcinoma.
Pluronics with 1100 ≤ Mw ≤ 3200 Da and hydrophilic lipophilic balance (HLB) between 1–8 demonstrated the highest thermosensitising ability. Pluronics L31, L61, L62, L10 and L64 were found to be among the most effective copolymers for hyperthermia sensitisation under tested conditions. Most encouraging, L61 in synergy with hyperthermia significantly reduced tumour growth progression in vivo compared to tumours treated with hyperthermia alone.
Pluronic copolymer structure properties including, Mw, HLB and PO length are essential to its hyperthermia sensitising function.
colorectal adenocarcinoma; hyperthermia therapy; pluronic triblock copolymer; radiofrequency ablation; thermosensitiser
Clinical trials combining hyperthermia with radiation and/or chemotherapy for cancer treatment have resulted in improved overall survival and control of local recurrences. The contribution of thermally enhanced anti-immune function in these effects is of considerable interest, but not understood; studies on the fundamental effects of elevated temperature on immune effector cells are needed. The goal of this study is to investigate the potential of mild hyperthermia to impact tumor antigen-specific (Ag) effector CD8+ T cell functions.
Pmel-1 Ag-specific CD8+ T cells were exposed to mild hyperthermia and tested for changes in IFN-γ production and cytotoxicity. Additionally, overall plasma membrane organization and the phosphorylation of signaling proteins were also investigated following heat treatment.
Exposing effector Pmel-1 specific CD8+ T cells to mild hyperthermia (39.5°C) resulted in significantly enhanced Ag-specific IFN-γ production and tumor target cell killing compared to that seen using lower temperatures (33 and 37°C). Further, inhibition of protein synthesis during hyperthermia did not reduce subsequent Ag-induced IFN-γ production by CD8+ T cells. Correlated with these effects, we observed a distinct clustering of GM1+ lipid microdomains at the plasma membrane and enhanced phosphorylation of LAT and PKCθ which may be related to an observed enhancement of Ag-specific effector CD8+ T cell IFN-γ gene transcription following mild hyperthermia. However, mitogen–mediated production of IFN-γ, which bypasses T cell receptor activation with antigen, was not enhanced.
Antigen-dependent effector T cell activity is enhanced following mild hyperthermia. These effects could potentially occur in patients being treated with thermal therapies. These data also provide support for the use of thermal therapy as an adjuvant for immunotherapies to improve CD8+ effector cell function.
T lymphocytes; fever; hyperthermia; cytotoxicity; interferon-γ
Heat shock proteins (HSP) and heat shock factor 1 (HSF1), key factors in the heat shock response (HSR) have been implicated in the etiology of breast cancer. At least two members of the HSP family, Hsp27 and Hsp70 undergo significant increases in cellular concentration during the transformation of mammary cells. These changes result in HSP-mediated inhibition of tumor cell inactivation through blockade of the apoptosis and replicative senescence pathways. The increases in HSP thus mediate two of the common hallmarks of cancer and favor cell birth over cell death. In addition, Hsp90 plays a role in facilitating transformation by stabilizing the mutated and overexpressed oncoproteins found in breast tumors, and permitting the activation of growth stimulatory and transforming pathways in the absence of growth factors. HSF1 appears to play a similar role as a facilitator of transformation in mammary carcinoma. Induction of some facets of the HSR in breast cancer cells therefore leads to growth stimulation and inhibits cell death. Pharmacological targeting of HSP and HSF1 is therefore indicated and in the case of Hsp90, inhibitory drugs are undergoing clinical trial for treatment of breast carcinoma and other cancers.
heat; shock; protein; HSF1; breast; cancer
A review of MRI temperature imaging methods based on intermolecular multiple quantum coherences (iMQCs) is presented. Temperature imaging based on iMQCs can provide absolute temperature maps that circumvent the artefacts that other proton frequency shift techniques suffer from such as distortions to the detected temperature due to susceptibility changes and magnetic field inhomogeneities. Thermometry based on iMQCs is promising in high-fat tissues such as the breast, since it relies on the fat signal as an internal reference. This review covers the theoretical background of iMQCs, and the necessary adaptations for temperature imaging using iMQCs.
Materials and methods
Data is presented from several papers on iMQC temperature imaging. These studies were done at 7T in both phantoms and in vivo. Results from phantoms of cream (homogeneous mixture of water and fat) are presented as well as in vivo temperature maps in obese mice.
Thermometry based on iMQCs offers the potential to provide temperature maps which are free of artefacts due to susceptibility and magnetic field inhomogeneities, and detect temperature on an absolute scale.
The data presented in the papers reviewed highlights the promise of iMQC-based temperature imaging in fatty tissues such as the breast. The change in susceptibility of fat with temperature makes standard proton frequency shift methods (even with fat suppression) challenging and iMQC-based imaging offers an alternative approach.
CRAZED; intermolecular multiple quantum coherences; magnetic resonance temperature imaging; proton resonance frequency shift; thermometry
We employed a grp170-secreting tumor cell system to determine whether tumor cells engineered to secrete grp170 generate an anti-tumor specific immune response. Further, we examine the possibility that secreted grp170 can bind to and co-transport out of tumor cells full-length tumor antigens that may play a role in the anti-tumor immune response.
Materials and Methods
Wild type Colon-26 and Colon-26 engineered to secrete grp170 were subcutaneously inoculated into BALB/c mice. Tumor growth was monitored, and variations in immunoregulatory mechanisms were evaluated using immunohistochemistry, lymphocyte depletion, ELISpot assays, and Western blot analysis.
Immunization of animals with grp170-secreting tumor cells results in rejection of the tumor by induction of antigen-specific, CD8-dependent immune responses. The secreted grp170 is able to deliver full-length tumor antigens to the tumor microenvironment, thus making them available for uptake by antigen presenting cells (APCs) to initiate tumor-specific immune responses.
These data parallel our studies showing that hsp110 or grp170 are able to chaperone full-length proteins, and when complexed with protein antigens and used as vaccines, these complexes elicit immune responses in vivo against the protein antigens. This cell-based approach has the potential to be utilized as a tumor-specific vaccine in tumors of various histological origins.
vaccines; tumor immunotherapy; molecular chaperones; heat shock proteins; tumor antigens
The purpose of this study was to delineate the mechanisms by which stromal components of cancer may induce tumour thermotolerance and exploit alterations in stromal and tumour physiology to enhance radiation therapy. The vascular thermoresponse was monitored by daily one-hour 41.5°C heatings in two murine solid tumour models, SCK murine mammary carcinoma and B16F10 melanoma. A transient increase was seen in overall tumour oxygenation for 2–3 days, followed by a progressive decline in tumour pO2 upon continued daily heatings. Vascular thermotolerance was further studied by treating tumours with different heating strategies, i.e. (1) a single 60 min 41.5°C treatment; (2) two consecutive daily treatments of 41.5°C for 60 min; (3) a single 60 min 43°C treatment or (4) two days of 41.5°C for 60 min followed by treatment with 43°C for 60 min on the third day. Pre-heating tumours with mild temperature hyperthermia induced vascular thermotolerance, which was accompanied by evidence of vessel normalisation, i.e. a decrease in microvessel density and an increase in pericyte coverage. Rational scheduling of fractionated radiation during heat-induced increases in tumour oxygen levels rendered a significantly greater, synergistic, tumour growth inhibition. In vitro clonogenic survival responses of the individual cell types associated (endothelial cells, fibroblasts, pericytes and tumour cells) indicated only a direct cellular thermotolerance in endothelial cells. Overall, this suggests that tumour thermotolerance is a physiological phenomenon mediated through improvement of functional vasculature.
Hyperthermia; radiation; thermotolerance; tumour microenvironment; vessel normalisation
Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles with different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customized gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumors or preferential accumulation in tumors following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia.
Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanoparticles in the reticuloendothelial system when administered systemically, the inability to visualize or quantify the global concentration and spatial distribution of these particles within tumors, the lack of standardized thermal modeling and dosimetry algorithms, and the concerns regarding their biocompatibility. Nevertheless, novel particle compositions, geometries, activation strategies, targeting techniques, payload delivery strategies, and radiation dose enhancement concepts are unique attributes of this form of hyperthermia that warrant further exploration. Capitalizing on these opportunities and overcoming these challenges offers the possibility of seamless and logical translation of this nanoparticle-mediated hyperthermia paradigm from the bench to the bedside.
Nanoparticles; magnetic; optical; activatable; hyperthermia; prostate cancer
This article explores the feasibility of using coupled electromagnetic and thermodynamic simulations to improve planning and control of hyperthermia treatments for cancer. The study investigates the usefulness of preplanning to improve heat localization in tumor targets in treatments monitored with PRFS-based Magnetic Resonance Thermal Imaging (MRTI). .
Heating capabilities of a cylindrical radiofrequency (RF) mini-annular phased array (MAPA) applicator were investigated with electromagnetic and thermal simulations of SAR in homogeneous phantom models and two human leg sarcomas. HFSS (Ansoft Corp) was used for electromagnetic simulations and SAR patterns were coupled into EPhysics (Ansoft Corp) for thermal modeling with temperature dependent variable perfusion. Simulations were accelerated by integrating tumor specific anatomy into a pre-gridded whole body tissue model. To validate this treatment planning approach, simulations were compared with MR thermal images in both homogenous phantoms and heterogeneous tumors.
SAR simulations demonstrated excellent agreement with temperature rise distributions obtained with MR thermal imaging in homogeneous phantoms, and clinical treatments of large soft-tissue sarcomas. The results demonstrate feasibility of preplanning appropriate relative phases of antennas for localizing heat in tumor.
Advances in the accuracy of computer simulation and non-invasive thermometry via MR thermal imaging have provided powerful new tools for optimization of clinical hyperthermia treatments. Simulations agree well with MR thermal images in both homogeneous tissue models and patients with lower leg tumors. This work demonstrates that better quality hyperthermia treatments should be possible when simplified hybrid model simulations are performed routinely as part of the clinical pretreatment plan.
Electromagnetic simulation; thermodynamic simulation; Proton Resonance Frequency Shift; PRFS; MRI; RF phased array heat applicator; treatment planning; non-invasive temperature measurement
This article summarizes the evolution of microwave array applicators for heating large area chestwall disease as an adjuvant to external beam radiation, systemic chemotherapy, and potentially simultaneous brachytherapy.
Current devices used for thermotherapy of chestwall recurrence are reviewed. The largest conformal array applicator to date is evaluated in four studies: i) ability to conform to the torso is demonstrated with a CT scan of a torso phantom and MR scan of the conformal waterbolus component on a mastectomy patient; ii) Specific Absorption Rate (SAR) and temperature distributions are calculated with electromagnetic and thermal simulation software for a mastectomy patient; iii). SAR patterns are measured with a scanning SAR probe in liquid muscle phantom for a buried coplanar waveguide CMA; and iv) heating patterns and patient tolerance of CMA applicators are characterized in a clinical pilot study with 13 patients.
CT and MR scans demonstrate excellent conformity of CMA applicators to contoured anatomy. Simulations demonstrate effective control of heating over contoured anatomy. Measurements confirm effective coverage of large treatment areas with no gaps. In 42 hyperthermia treatments, CMA applicators provided well-tolerated effective heating of up to 500cm2 regions, achieving target temperatures of Tmin=41.4±0.7°C, T90=42.1±0.6°C, Tave=42.8±0.6°C, and Tmax=44.3±0.8°C as measured in an average of 90 points per treatment.
The CMA applicator is an effective thermal therapy device for heating large-area superficial disease such as diffuse chestwall recurrence. It is able to cover over three times the treatment area of conventional hyperthermia devices while conforming to typical body contours.
Microwave array; conformal applicator; superficial hyperthermia; chestwall recurrence
The purpose of this review is to examine the roles that functional imaging may play in prediction of treatment response and determination of overall prognosis in patients who are enrolled in thermotherapy trials, either in combination with radiotherapy, chemotherapy or both. Most of the historical work that has been done in this field has focused on MRI/MRS methods, so the emphasis will be there, although some discussion of the role that PET might play will also be examined. New optical technologies also hold promise for obtaining low cost, yet valuable physiologic data from optically accessible sites. The review is organized by traditional outcome parameters: local response, local control and progression free or overall survival. Included in the review is a discussion of future directions for this type of translational work.
Hypoxia within the tumor microenvironment is correlated with poor treatment outcome after radiation and chemotherapy, and with decreased overall survival in cancer patients. Several molecular mechanisms by which hypoxia supports tumor growth and interferes with effective radiation and chemotherapies are now well established. However, several new lines of investigation are pointing to yet another ominous outcome of hypoxia in the tumor microenvironment: suppression of anti-tumor immune effector cells and enhancement of tumor escape from immune surveillance. This review summarizes this important information, and highlights mechanistic data by which hypoxia incapacitates several different types of immune effector cells, enhances the activity of immunosuppressive cells and provides new avenues which help “blind” immune cells to the presence of tumor cells. Finally, we discuss data which indicates that mild thermal therapy, through its physiologically-regulated ability to alter vascular perfusion and oxygen tensions within the tumor microenvironment, as well as its ability to enhance the function of some of the same immune effector activities that are inhibited by hypoxia,, could be used to rapidly and safely release the tight grip of hypoxia in the tumor microenvironment thereby reducing barriers to more effective immune-based therapies.
hypoxia; anti-tumor immunity; thermoregulation; hyperthermia; tumor microenvironment
This paper reviews systems and techniques to deliver simultaneous thermoradiotherapy of breast cancer. It first covers the clinical implementation of simultaneous delivery of superficial (microwave or ultrasound) hyperthermia and external photon beam radiotherapy, first using a Co-60 teletherapy unit and later medical linear accelerators. The parallel development and related studies of the SURLAS, an advanced system specifically designed and developed for simultaneous thermoradiotherapy, follows. The performance characteristics of the SURLAS are reviewed and power limitation problems at high acoustic frequencies (> 3MHz) are discussed along with potential solutions. Next, the feasibility of simultaneous SURLAS hyperthermia and IMRT/IGRT is established based on published and newly presented studies. Finally, based on the encouraging clinical results thus far, it is concluded that new trials employing the latest technologies are warranted along with further developments in treatment planning.
breast; cancer; chest wall; heat; hyperthermia; radiation therapy; radiotherapy; radiosensitization; recurrence; thermoradiotherapy; simultaneous; ultrasound; intensity modulated
Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.
hyperthermia; locally advanced breast cancer; radiation
Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.
breast cancer recurrence; hyperthermia; radiation
The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50–60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia.
Materials and methods
Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30–75 mg/m2), paclitaxel (100–175 mg/m2), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy.
Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%–76%) and the four-year overall survival was 75% (95% CI, 58–86%).
Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.
locally advanced breast cancer; liposomal doxorubicin; hyperthermia
In previous reports, laboratory-made lysolecithin-containing thermosensitive liposome encapsulating doxorubicin (LTSL-DOX) showed potent anticancer effects in FaDu human squamous cell carcinoma. To further study the spectrum of LTSL-DOX activity, the efficacy of its commercial formulation was re-examined in FaDu and compared in HCT116, PC3, SKOV-3 and 4T07 cancer cell lines. Factors that may influence differences in HT-LTSL-DOX efficacy were also examined.
Anticancer effect was measured using standard growth delay methods. We measured doubling time and clonogenic survival after doxorubicin exposure in vitro, and interstitial pH and drug concentrations in vivo.
In all five tumour types, HT-LTSL-DOX increased median tumour growth time compared with untreated controls ( p < 0.0006) and HT alone ( p < 0.01), and compared with LTSL-DOX alone in FaDu, PC-3 and HCT-116 ( p < 0.0006). HT-LTSL-DOX yielded significantly higher drug concentrations than LTSL-DOX ( p < 0.0001). FaDu was most sensitive ( p < 0.0014) to doxorubicin (IC50 = 90 nM) in vitro, compared to the other cell lines (IC50 = 129–168 nM). Of the parameters tested for correlation with efficacy, only the correlation of in vitro doubling time and in vivo median growth time was significant (Pearson r = 0.98, p = 0.0035). Slower-growing SKOV-3 and PC-3 had the greatest numbers of complete regressions and longest tumour growth delays, which are clinically important parameters.
These results strongly suggest that variations in anti-tumour effect of HT-LTSL-DOX are primarily related to in vitro doubling time. In the clinic, the rate of tumour progression must be considered in design of treatment regimens involving HT-LTSL-DOX.
temperature sensitive liposome; LTSL; doxil; doxorubicin; hyperthermia
The poor overall survival for patients with locally advanced breast cancers has led over the past decade to the introduction of numerous neoadjuvant combined therapy regimens to down-stage the disease before surgery. At the same time, more evidence suggests the need for treatment individualisation with a wide variety of new targets for cancer therapeutics and also multi modality therapies. In this context, early determination of whether the patient will fail to respond can enable the use of alternative therapies that can be more beneficial. The purpose of this review is to examine the potential role of magnetic resonance imaging (MRI) in early prediction of treatment response and prognosis of overall survival in locally advanced breast cancer patients enrolled on multi modality therapy trials that include hyperthermia. The material is organised with a review of dynamic contrast (DCE)-MRI and diffusion weighted (DW)-MRI for characterisation of phenomenological parameters of tumour physiology and their potential role in estimating therapy response. Most of the work published in this field has focused on responses to neoadjuvant chemotherapy regimens alone, so the emphasis will be there, however the available data that involves the addition of hyperthermia to the regimen will be discussed The review will also include future directions that include the potential use of MRI imaging techniques in establishing the role of hyperthermia alone in modifying breast tumour microenvironment, together with specific challenges related to performing such studies.
imaging (DCE-MRI-DW-MRI); locally advanced breast cancer; physiological effects of hyperthermia; prediction and monitoring of tumour response
There is widespread recognition among both patients and caregivers that breast cancer patients often experience debilitating deficiencies in their ability to achieve thermal comfort, feeling excessively hot or cold under circumstances when others are comfortable. However, this symptom receives little clinical or scientific attention beyond identification and testing of drugs that minimise menopausal-like symptoms. Could some of these symptoms represent an important prognostic signal? Could thermal discomfort be among other cytokine-driven sickness behaviour symptoms seen in many breast cancer patients? While the literature reveals a strong link between treatment for breast cancer and some menopausal vasomotor symptoms (e.g. hot flashes also known as “hot flushes”), there is little data on quantitative assessment of severity of different types of symptoms and their possible prognostic potential. However, recent, intriguing studies indicating a correlation between the presence of hot flashes and reduced development of breast cancer recurrence strongly suggests that more study on this topic is needed. In comparison to reports on the phenomenon of breast cancer-associated hot flashes, there is essentially no scientific study on the large number of women who report feeling excessively cold after breast cancer treatment. Since similar acquired thermal discomfort symptoms can occur in patients with cancers other than breast cancer, there may be as yet unidentified cancer – or treatment-driven factor related to temperature dysregulation. In general, there is surprisingly little information on the physiological relationship between body temperature regulation, vasomotor symptoms, and cancer growth and progression. The goal of this article is twofold: (1) to review the scientific literature egarding acquired deficits inthermoregulation among breast cancer survivors and (2) to propose some speculative ideas regarding the possible basis for thermal discomfort among some of these women. Specifically, we suggest a potential association with excessive proinflammatory cytokine activity, similar to other cytokine-driven symptoms experienced after breast cancer, including fatigue and depression. We highlight the similarity of some breast cancer-associated thermal discomfort symptoms to those which occur during fever, suggesting the possibility that there may be common underlying changes in pro-inflammatory cytokine activity in both conditions. We anticipate that this contribution will stimulate additional scientific interest among researchers in identifying potential mechanisms and prognostic significance of this under-studied aspect of breast cancer biology and survivorship.
fever; menopausal vasomotor symptoms; pro-inflammatory cytokines; sickness behaviour symptoms