Precooling prevents overheating of subcutaneous fat in the use of RF capacitive heating

The usefulness of precooling subcutaneous tissue in the hyperthermic treatment of deep-seated human tumors with capacitive application of radio-frequency (RF) was investigated. A capacitive hyperthermia unit operated at 8 MHz of radiofrequency was used to heat deep-seated human tumors. The electrode surfaces were covered with flexible vinyl sheets and the space between the electrode and the vinyl sheets perfused with 0.4% saline. The temperature of the saline was controlled by circulating the saline through built-in heat exchangers. The depth of heating was controlled by pairing electrodes of different diameters. When subcutaneous fat was less than 1 cm thick, various deep-seated tumors could be heated to a therapeutic temperature without significant discomfort in the subcutaneous tissue as long as the skin was properly cooled with the cold saline bolus. However, the same cooling method could not prevent the occurrence of pain in subcutaneous tissue in obese patients. The pain usually developed when the temperature of subcutaneous fat 1-2 cm below the skin surface exceeded 42 degrees C. We observed that cooling the human skin surface with 10 degrees C bolus for 20 min could substantially lower the temperature of fat as deep as 2.0-2.5 cm. Therefore, when the subcutaneous tissue was precooled with 10 degrees C saline for 20 min or longer before heating, it was possible to prevent successfully the overheating of subcutaneous fat as thick as 2.0-2.5 cm and to raise the temperature of deep-seated tumors to therapeutic levels.     

Radiofrequency capacitive hyperthermia for deep-seated tumors. I. Studies on thermometry

The thermometry results of radiofrequency (RF) capacitive hyperthermia for 60 deep-seated tumors in 59 patients are reported. Hyperthermia was administered regionally using two RF capacitive heating equipments which the authors have developed in cooperation with Yamamoto Vinyter Company Ltd., (Osaka, Japan). Intratumor temperatures were measured by thermocouples inserted through angiocatheters which were placed 5 cm to 12 cm deep into the tissues. Tumor center temperatures were measured for 307 treatments in all tumors; thermal distributions within tumors and surrounding normal tissues were obtained for 266 treatments of 53 tumors by microthermocouples. Thermometry results obtained were summarized as follows. A maximum tumor center temperature greater than 43 degrees C and 42 degrees C to 43 degrees C was obtained in 23 (38%) and 14 (23%) of the 60 tumors respectively. The time required to reach 43 degrees C in the tumor center was within 20 minutes after the start of hyperthermia in 87% of tumors heated to more than 43 degrees C. Temperature variations within a tumor exceeded 2 degrees C in 81% of tumors heated to more than 43 degrees C. The lowest tumor temperature greater than 42 degrees C was achieved in six of the 53 tumors (11%). Of 42 tumors in which temperatures of the subcutaneous fat, surrounding normal tissues, and the tumor center were compared, 24 (57%) showed the highest temperature in the tumor center and ten (24%) in the subcutaneous fat. When the heating efficacy was assessed in terms of a maximum tumor center, it great deal depended on the treatment site, tumor size, thickness of subcutaneous fat, and tumor type. Tumors in the head and neck, thorax, lower abdomen, and pelvis could be heated better than tumors in the upper abdomen. Greater heating efficacy was shown in patients with large, hypovascular tumors, and with the subcutaneous fat measuring less than 15 mm thick. The predominant limiting factor for power elevation was pain associated with heating. Systemic signs including increases in pulse rate and body temperature were not serious and seldom became limiting factors for power elevation. Our thermometry results indicate that the advantages of deep RF capacitive heating are its applicability to various anatomic sites and negligible systemic effects. The disadvantages are that its primary usefulness is limited to patients with thin subcutaneous fat and with large or hypovascular tumors.     

Regional hyperthermia combined with radiotherapy in the treatment of lung cancers.

Twenty locally advanced lung cancers were treated by hyperthermia in combination with radiotherapy between November 1980 and January 1990. All tumors selected had invaded or were in contact with the chest wall, so that transcutaneous insertion of thermal probes into the tumor was possible. Using an 8 or 13.56 MHZ RF capacitive heating device, hyperthermia was given once or twice a week after irradiation for 30-60 min per session (1-12 sessions in total). Radiotherapy was delivered at dose of 13.6-70 Gy. The thermal parameters analyzed were a) maximum, average, and minimum intratumor temperatures (Tmax, Tav, and Tmin), which were recorded at the termination of each treatment, and b) the percentages of the intratumor points that exceeded 41 C (%T greater than or equal to 41 C). The mean +/- SD for Tmax, Tav, Tmin, and %T greater than or equal to 41 C was 42.9 +/- 1.7 C, 41.6 +/- 1.2 C, 39.7 +/- 1.1 C, and 56.2 +/- 25.8, respectively. Larger tumors showed higher thermal parameters than the smaller tumors. Of the 12 tumors treated by definitive therapy, 2 (17%) achieved CR, 7 (58%) PR, and 3 (25%) NR. Four of 10 tumors that did not achieve CR showed large intratumor low density areas on post-treatment CT, reflecting massive coagulation necrosis. Higher thermal parameters were closely related to the appearance of low-density areas but not to changes in tumor size. Four tumors treated preoperatively were successfully resected 2 weeks after thermoradiotherapy, whereas four palliatively-treated tumors showed no regression. The side effects associated with hyperthermia were pain in 12 patients (60%) and dyspnea in 3 (15%), all of which resolved after termination of treatment. A skin abscess and a pneumothorax attributed to thermal probe insertion were observed in one patient each. These results indicate that regional RF capacitive hyperthermia is clinically feasible for local treatment of selected lung cancers.     

Deep-heating characteristics of an RF capacitive heating device

An RF capacitive heating device was constructed and its deep-heating characteristics were studied using three mini-pigs. The deep-heating ability of RF capacitive heating was found to be improved by enlarging the electrodes, driving at 8 MHz, cooling the skin under the electrodes, inserting a bolus between the body and the electrodes and considering the anatomical structure of the body. The heating characteristics obtained were as follows. When applicators were placed on both sides of the abdomen of a mini-pig, 7 mm in fat layer thickness and 23 cm in lateral chest thickness, the increase in temperature of the deep part was greater than that of the fat layer. When applicators were placed on the posterior and anterior abdomen, overheating was noted in the fat and muscle near the back. The temperature was highest in a mock tumour, made by blocking blood flow to the spleen. The bio-heat equation revealed that RF capacitive heating accompanied by surface cooling at 10 degrees C could heat the deep portion of the body to 42 degrees C without excessive heating of a 1.6 cm thick fat layer.     

Capacitive heating of phantom and human tumors with an 8 MHz radiofrequency applicator (Thermotron RF-8)

The thermal profile was investigated in agar phantoms and in human tumors heated capacitively with 8 MHz RF. Deep and homogeneous heating could be achieved in a large homogeneous phantom of 25 cm diameter and 24 cm thick when heated with a pair of 25 cm diameter electrodes, coupled to both bases of the phantom. When the size of the two electrodes was not the same, the region near the smaller electrode was preferentially heated. It was, therefore, possible to control the depth of heating by choosing properly sized electrodes. Therapeutic temperature (greater than 42 degrees C) could be obtained in 7 out of 9 small, as well as, bulky superficial human tumors as large as 8 X 8 X 10 cm. Indications are that heating of some deep-seated human tumors might be achieved by the capacitive method, provided that subcutaneous fat layer is cooled by temperature controlled bolus and large electrodes are used. The effect of the anatomical structure on the power deposition in the human body during capacitive heating should be further investigated.     

A phase I and II clinical trial of a newly developed ultrasound hyperthermia system with an improved planar transducer

: The clinical usefulness of a newly developed ultrasound hyperthermia system was evaluated.

: The hyperthermia system uses a modified planer transducer operated at frequencies of 0.5, 1.0, and 1.5 MHz. The transducer has a nonvibrating part at the center to reduce the central hot spot. Frequency sweeping technique is also used to eliminate the annular hot spot around the center. Thirty-eight tumors in 29 patients were examined in this study. In 35 tumors, hyperthermia was given in conjunction with irradiation and/or chemotherapy, and in the remaining 3 tumors, hyperthermia alone was given. In all, a total of 153 hyperthermia sessions were performed.

: The number of hyperthermia sessions per tumor ranged from 1 to 7 (mean, 4.0 ± 1.3). The number of intratumor thermometr points per session ranged from 1 to 8 (mean, 4.3 ± 1.5). The average intratumor temperature for tumors with a maximum depth of <3 cm, 3–6 cm, and >6 cm was 42.1 ± 1.2, 41.7 ± 1.4, and 39.9 ± 2.0°C, respectively. The percentage of monitored intratumor points with temperature exceeding 42°C was 56 ± 31%, 43 ± 34%, and 21 ± 24%, respectively. Of the 30 evaluable tumors treated with combined irradiation, 12 showed complete response, 14 partial response, and 4 no change. Observed complications included pain at the treatment site in 13 of the 153 treatment sessions and vesicle formation in 3 of the 38 treatment sites. No serious complication was seen.

: These results indicate that the newly developed ultrasound hyperthermia system is clinically useful for the treatment of localized superficial and subsurface tumors with a maximum tumor depth of no more than 6 cm.     

Heating efficiency of radiofrequency capacitive hyperthermia for treatment of deep-seated tumors in the peritoneal cavity

We analyzed heating profiles from 318 hyperthermic treatments of 39 patients with recurrent or inoperable cancers of the digestive organs whose deep-seated tumors were treated by radiofrequency (RF) capacitive heating of the abdominal region, and we investigated the heating efficiency and antitumor effect of such treatment. It was apparent that heating with a mean maximum RF output of 1,000 watts (700 watts at least), repeated four times or more, was necessary for a high rate of response by the tumor. Although it was difficult to heat tumors of the bile duct/pancreas to 42 degrees C or more, there was a strong positive correlation between maximum output of RF energy and maximum temperature of tumors (r = 0.839, P less than 0.001). The antitumor effect of RF hyperthermia was augmented with increasing output of RF energy. Therefore, the maximum level of RF output may be a useful index for expressing the heating efficiency with respect to intra-abdominal deep-seated tumors.     

Edta Clearance in Monitoring Cisplatin Dose Escalation in Patients with Bulky Metastatic Germ Cell Tumors of the Testis

A fast cisplatin clearance may reduce exposure time of tumor cells to the drug, and thus impair the expected effects of dose escalation. This hypothesis was tested in 23 patients with bulky metastatic germ cell tumors of the testis, treated with etoposide, bleomycin and high-dose cisplatin (60 mg/m²/24 h×4). The daily dose was retrospectively calculated in mg/1 EDTA clearance/24 h. A daily dose of 60 mg/m² of cisplatin in a person with a body surface of 1.7 m² and EDTA clearance of 100 ml/min was equivalent to 0.69 mg cisplatin/l EDTA clearance/24 h. In the whole group, 10 patients had complete remission (CR), 10 partial response (PR) and 3 progressive disease (PD). The mean daily cisplatin dose (×) in the whole group was 0.86 mg/1 EDTA clearance/24 h (range 0.35-2.00). For patients with CR, × × SD was 1.00±0.46, for those with PR 0.80±0.44, and for those with PD only 0.61±0.07. A cisplatin dose over 0.86 mg/1 EDTA clearance/24 h × 4 was obtained in 6/10 patients with CR versus 2/13 patients with PR + PD. Patients with PD received a significantly lower cisplatin dose than the whole group (0.61 versus 0.86 mg cisplatin/l EDTA clearance/24 h × 4.) The difference between the average toxicity grade after cisplatin dose over and below 0.69 mg/l EDTA clearance/24 h × 4 was significant only for leukocytes (WHO grade 2.17 versus 1.36). Thus, the effective escalated dose of cisplatin should preferably be calculated not per m² body surface but per 1 liter EDTA clearance. The 'ideal' escalated dose might be about 0.86-1.0 mg cisplatin/l EDTA clearance 24 h × 4.     

Effect of Functional Magnetic Particles on Radiofrequency Capacitive Heating: An in vivo Study

Specific heating of magnetic particles in radiofrequency (RF) capacitive hyperthermia and its hyper-thermic effect were investigated in an in vivo study. Magnetite cationic liposomes (MCLs) were injected into a rat tumor on the femur and 8 MHz-RF capacitive heating was applied to the rat under'mild heating' conditions. Although the input power of RF capacitive heating was low under the same power conditions, the MCLs-injected tumor was heated over 43°C, whereas it was only heated to 41°C in the case of the rats not injected with MCLs. A necrotic area in the tumor was observed in the heated rats. From the results of histological observation of the removed tissue, the necrotic area in the MCLs-injected tumor was wider than that in MCLs-free tumor. Complete tumor suppression was observed in 71% (5/7) of MCLs-injected rats, and the hyperthermic effect was greatly improved by the MCLs.     

Effect of functional magnetic particles on radiofrequency capacitive heating: an in vivo study.

Specific heating of magnetic particles in radiofrequency (RF) capacitive hyperthermia and its hyperthermic effect were investigated in an in vivo study. Magnetite cationic liposomes (MCLs) were injected into a rat tumor on the femur and 8 MHz-RF capacitive heating was applied to the rat under "mild heating" conditions. Although the input power of RF capacitive heating was low under the same power conditions, the MCLs-injected tumor was heated over 43 degrees C, whereas it was only heated to 41 degrees C in the case of the rats not injected with MCLs. A necrotic area in the tumor was observed in the heated rats. From the results of histological observation of the removed tissue, the necrotic area in the MCLs-injected tumor was wider than that in MCLs-free tumor. Complete tumor suppression was observed in 71% (5 / 7) of MCLs-injected rats, and the hyperthermic effect was greatly improved by the MCLs.     

Radiofrequency (RF) capacitive hyperthermia combined with radiotherapy in the treatment of abdominal and pelvic deep-seated tumors

Thermal parameters and tumor response were determined in 33 abdominal and pelvic deep-seated tumors which were treated with hyperthermia in combination with radiation therapy. Hyperthermia was applied regionally for a total of 3-14 sessions (mean; 6.4 sessions), using an 8 MHz radiofrequency (RF) capacitive heating device. An average tumor temperature (Tav) of more than 42 degrees C was achieved in 17 (52%) tumors, and intratumor temperatures above 42 degrees C could be maintained for more than 20 min (effective heat session) in 103 (52%) of the 198 heat sessions. Of the 33 tumors, 4 tumors exhibited complete regression (CR), 7 PRa (80-99% regression), 7 PRb (50-79% regression) and 15 NR (less than 50% regression). Tumor response (CR + PRa) was apparently dependent on the thermal parameters. Tumors with Tav of more than 42 degrees C or those receiving more than three effective heat sessions showed a significantly higher response rate than those heated less effectively. This trend was also noted in minimum tumor temperature. As to radiation dose, most of the responders received a total of 60-70 Gy irradiation. The two characteristic features in tumor response in effectively heated tumors, were slow tumor regression and appearance of an intratumor low density area on post-treatment computed tomography.     

Clinical research on hyperthermia of cancer using microwave heating equipment of lens applicator type

Ninety cases with 96 tumors were treated by the 430 MHz microwave heating systems, HTS-100, at Tokyo Metropolitan Komagome Hospital, Kyoto University and Aichi Cancer Center. The results of treatment were analyzed, and the following have been clarified. Three cases are demonstrated showing feature of HTS-100. 1) The results of 383 sessions of heating by HTS-100 were analyzed, and it has been clarified that even the larger tumors, more than 5 cm both in size and depth, can be heated satisfactorily to temperatures higher than 42 degrees C. This system is capable of heating remarkably wider areas compared with the conventional microwave heating systems. 2) Hyperthermia by HTS-100 and radiotherapy were combined for treatment. The success rate (total percentage of CR plus PRa) of 89 cases analyzed was as high as 66.3%. Furthermore, local heating was successful for 60.7% of tumors, larger than 5 cm and deeper than 4 cm. 3) Combination of microwave heating and RF wave heating is a new method which is helpful for expansion of indications. 4) The frequencies of side effects of HTS-100 heating were: pain, 15.6%; sensation of heat, 6.3%; burns, 3.6%. Most of side effects were transient and slight. The higher frequency of pain than the conventional microwave heating is attributable to expansion of heating area.     

Study of Ill-conditioning of Linac Stereotactic Irradiation Subspaces using Singular Values Decomposition Analysis

A Linac stereotactic irradiation space is characterized by different angular separations of beams because of the geometry of the stereotactic irradiation. The regions of the stereotactic space characterized by low angular separations are one of the causes of ill-conditioning of the stereotactic irradiation inverse problem. The singular value decomposition (SVD) is a powerful mathematical analysis that permits the measurement of the ill-conditioning of the stereotactic irradiation problem. This study examines the ill-conditioning of the stereotactic irradiation space, provoked by the different angular separations of beams, using the SVD analysis. We subdivided the maximum irradiation space (MIS: (AA)_AP×(AA)_RL=180°×180°) into irradiation subspaces (ISSs), each characterized by its own angular separation. We studied the influence of ISSs on the SVD analysis and the evolution of the reconstruction quality of well defined three-dimensional dose matrices in each configuration. The more the ISS is characterized by low angular separation the more the condition number and the reconstruction inaccuracy are increased. Based on the above results we created two reduced irradiation spaces (RIS: (AA)_AP×(AA)_RL=180°×140° and (AA)_AP×(AA)_RL=180°×120°) and compared the reconstruction quality of the RISs with respect to the MIS. The more an irradiation space is free of low angular separations the more the irradiation space contains useful singular components.     

Clinical results of radiofrequency hyperthermia combined with radiation in the treatment of radioresistant cancers

Clinical results of radiothermotherapy applied to 40 radioresistant tumors in 36 patients were reported. Hyperthermia was administered locally using two radiofrequency (RF) capacitive heating equipment systems developed in our institution under the collaboration of Yamamoto Vinyter Co. Ltd. Hyperthermia was given twice weekly immediately after irradiation. Intratumor temperatures of 41 degrees C to 44 degrees C were maintained for 30 to 60 minutes. Radiation doses varied from 32 Gy to 60 Gy. Of the 40 tumors treated, 21 (53%) showed complete response, 16 (40%) partial response, and 3 (7%) no response when the tumor response was assessed by tumor size measurement. Of eight patients who had matched tumors treated with either radiation alone or radiation plus hyperthermia, six patients showed better response in tumors treated with radiothermotherapy than in tumors treated with radiation alone. Skin reactions following radiothermotherapy and radiation alone were comparable. The tumor response was greatly dependent on the tumor size. Greater response was observed in small tumors, although histologic examinations and long-term follow-up studies revealed an excellent effect of radiothermotherapy on the large tumors as well as on the small tumors. Tumor responses correlated with tumor center temperatures but not with histologic features. Our clinical results indicate that RF hyperthermia combined with radiation has a therapeutic benefit in the treatment of radioresistant cancers.     

OMRON RF hyperthermia treatment system HEH-500 C

The RF capacitive type hyperthermia system "HEH-500 C" enables regional heating for superficial and deep seated tumors. It consists of a high frequency generator (frequency; 13.56 MHz, out put power; 500 watts), a control unit, a cooling unit for the applicators, an I/F unit (communicate the thermometer to RF generator and plotter printer), a thermometer (thermocouple thermometer or fiber fluorothermometer) and a plotter printer. Heating profile of HEH-500 C was presented with thermographic picture on TX-150 muscle equivalent phantom. Effects of bone and fat layer on heating profile of phantom were also examined. Points to be solved on thermometry, electromagnetic field environment and clinical use were also discussed.     

Analysis of 127 stem cell donations of the regional Bone Marrow Donor Bank Europdonor Nijmegen,The Netherlands

In December 2000, the Bone Marrow Donor Bank Europdonor Nijmegen in the Netherlands celebrated its tenth anniversary. We describe the organisation and activities in the first 10 years of this regional bone marrow donor bank. A concise inquiry was sent to all transplant centres who had received a graft from our donors. Response rate was 88% and data were available from 127 recipients. Three donors donated twice to different patients. Median age of the 124 donors (42 females and 82 males) was 37 years and 30 years for the 127 recipients (48 females and 79 males). Time interval between first request of a blood sample and collection of bone marrow varied from 13 to 695 days (median, 113 days). All but two donors received general anaesthesia for 25-120 min (median; 60 min). Hospital stay has been reduced to 24 h. Most donors experienced pain from the collection sites for 3-5 days. However, 9 donors (7%) suffered from pain for 2-3 weeks. All but two donors (98%) were willing to donate a second time for the same patient and 119 (96%) donors wished to remain in the register. The number of nucleated cells (NC) in the collected marrow varied from 0.2 to 8.3 ×10 8 /kg body weight of the recipient (median, 3.5 ×10 8 /kg ) with 6.4-470.0 ×10 4 CFU-GM/kg body weight of the recipient (median, 18.0 ×10 4 /kg body weight). The 3-year projected probability of survival of the 127 recipients transplanted with marrow from donors provided by Bone Marrow Donor Bank Europdonor Nijmegen was 27 ±9% ( ±95% CI).     

Computer modeling of the effect of perfusion on heating patterns in radiofrequency tumor ablation.

PURPOSE: To use an established computer simulation model of radiofrequency (RF) ablation to further characterize the effect of varied perfusion on RF heating for commonly used RF durations and electrode types, and different tumor sizes. METHODS: Computer simulation of RF heating using 2-D and 3-D finite element analysis (Etherm) was performed. Simulated RF application was systematically modeled on clinically relevant application parameters for a range of inner tumor perfusion (0-5 kg/m3-s) and outer normal surrounding tissue perfusion (0-5 kg/m3-s) for internally cooled 3-cm single and 2.5-cm cluster electrodes over a range of tumor diameters (2-5 cm), and RF application times (5-60 min; n = 4618 simulations). Tissue heating patterns and the time required to heat the entire tumor +/- a 5-mm margin to > 50 degrees C were assessed. Three-dimensional surface response contours were generated, and linear and higher order curve-fitting was performed. RESULTS: For both electrodes, increasing overall tissue perfusion exponentially decreased the overall distance of the 50 degrees C isotherm (R2 = 0.94). Simultaneously, increasing overall perfusion exponentially decreased the time required to achieve thermal equilibrium (R2 = 0.94). Furthermore, the relative effect of inner and outer perfusion varied with increasing tumor size. For smaller tumors (2 cm diameter, 3-cm single; 2-3 cm diameter, cluster), the ability and time to achieve tumor ablation was largely determined by the outer tissue perfusion value. However, for larger tumors (4-5 cm diameter single; 5 cm diameter cluster), inner tumor perfusion had the predominant effect. CONCLUSION: Computer modeling demonstrates that perfusion reduces both RF coagulation and the time to achieve thermal equilibrium. These results further show the importance of considering not only tumor perfusion, but also size (in addition to background tissue perfusion) when attempting to predict the effect of perfusion on RF heating and ablation times.     

Nanoparticle-mediated radiofrequency capacitive hyperthermia: A phantom study with magnetic resonance thermometry

Abstract

In hyperthermia, focusing heat generation on tumour tissues and precisely monitoring the temperature around the tumour region is important. To focus heat generation in radiofrequency (RF) capacitive heating, magnetic nanoparticles suspended in sodium carboxymethyl cellulose (CMC) solution were used, based on the hypothesis that the nanoparticle suspension would elevate electrical conductivity and RF current density at the nanoparticle-populated region. A tissue-mimicking phantom with compartments with and without nanoparticles was made for RF capacitive heating experiments. An FDTD model of the phantom was developed to simulate temperature increases at the phantom. To monitor temperature inside the phantom, MR thermometry was performed intermittently during RF heating inside a 3Tesla MRI magnet bore. FDTD simulation on the phantom model was performed in two steps: electromagnetic simulation to compute specific absorption rate and thermal simulation to compute temperature changes. Experimental temperature maps were similar to simulated temperature maps, demonstrating that nanoparticle-populated regions drew more heat than background regions. Nanoparticle-mediated RF heating could mitigate concerns about normal tissue death during RF capacitive hyperthermia.     

Thermosensitive liposomes: Extravasation and release of contents in tumor microvascular networks

: The purpose of this study was to determine whether hyperthermic exposure would accelerate drug release from thermosensitive sterically stabilized liposomes and enhance their extravasation in tumor tissues.

: In vivo fluorescence video microscopy was used to measure the extravasation of liposomes, as well as release of their contents, in a rat skin flap window chamber containing a vascularized mammary adenocarcinoma under defined thermal conditions (34°, 42°, and 45°C). Images of tissue areas containing multiple blood vessels were recorded via a SIT camera immediately before, and for upto 2 h after i.v. injection of two liposome populations with identical lipid composition: one liposome preparation was surface labeled with Rhodamine-PE (Rh-PE) and the other contained either Doxorubicin (Dox) or calcein at self-quenching concentrations. The light intensity of the entire tissue area was measured at 34°C (the physiological temperature of the skin) for 1 h, and at 42° or 45°C for a second hour. These measurements were then used to calculate the fluorescent light intensity arising from each tracer (liposome surface label and the released contents) inside the vessel and in the interstitial region.

: The calculated intensity of Rh-PE for the thermosensitive liposomes in the interstitial space (which represents the amout of extravasated liposomes) was low during the first hour, while temperature was maintained at 34°C and increased to 47 times its level before heating, when the tumor was heated at 42° or 45° C for 1 h. The calculated intensity of the liposome contents (Dox) in the interstitial space was negligible at 34°C, and increased by 38- and 76-fold, when the tumor was heated at 42° and 45° C for 1 h, respectively. Similar values were obtained when calcein was encapsulated in liposomes instead of Dox. A similar increase in liposome extravasation was seen with nonthermosensitive liposomes, but negligible release of Dox occurred when the window chamber was heated to 45°C for 1 h. Extravasation of liposomes continued after heating was stopped, but content release stopped after removal of heat. Release of Dox from extravasated liposomes was also seen if heating was applied 24 h after liposome administration, but no further enhancement of liposome extravasation occurred in this case.

: Our data suggest that hyperthermia can be used to selectively enhance both the delivery and the rate of release of drugs from thermosensitive liposomes to targeted tissues.     

Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins

Purpose: To determine the role of hepatic radiofrequency ablation (RFA) heating parameters and their activation of heat shock proteins (HSPs) in modulating distant tumor growth.

Methods and materials: First, to study the effects of RFA dose on distant tumor growth, rats with subcutaneous R3230 adenocarcinoma (10?±?1?mm) were assigned to 3 different hepatic RF doses (60?°C?×?10?min, 70?°C?×?5?min or 90?°C?×?2?min) that induced identical sized ablation or sham (n?=?6/arm). Post-RFA tumor growth rates, cellular proliferation (Ki-67) and microvascular density (MVD) were compared at 7d. Next, the effect of low and high power doses on local HSP70 expression and cellular infiltration (α-SMA +?myofibroblasts and CD68?+?macrophages), cytokine (IL-6) and growth factor (HGF and VEGF) expression was assessed. Finally, 60?°C?×?10?min and 90?°C?×?2?min RFA were combined with anti-HSP micellar quercetin (MicQ, 2?mg/ml). A total of 150 animals were used.

Results: Lower RF heating (70?°C?×?5?min and 60?°C?×?10?min) resulted in larger distant tumors at 7d (19.2?±?0.8?mm for both) while higher RF heating (90?°C?×?2) led to less distant tumor growth (16.7?±?1.5?mm, p?p?p?p?p?p?p?Conclusion: Hepatic RF heating parameters alter periablational HSP70, which can influence and stimulate distant tumor growth. Modulation of RF heating parameters alone or in combination with adjuvant HSP inhibition can reduce unwanted, off-target systemic tumorigenic effects.