Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver

PURPOSE: To assess whether porosity and compressibility of calibrated spherical polyvinyl alcohol (PVA) microspheres affect doxorubicin plasma and tumor concentrations after transcatheter arterial chemoembolization (TACE) in a VX2 rabbit model. MATERIALS AND METHODS: Fifteen rabbits were divided into three groups of five rabbits each. Three different types of calibrated spherical PVA microspheres with variable levels of porosity and compressibility were blindly evaluated. TACE was performed by injecting a mixture of doxorubicin (5 mg) and iodized oil (0.5 mL) followed by injection of the embolic material (0.3-0.5 mL). Plasma concentrations of doxorubicin and doxorubicinol were analyzed 20, 40, 60, and 120 minutes and 2 days after TACE, and liver tissue and tumor doxorubicin concentrations were measured 2 days after TACE. RESULTS: All calibrated spherical PVA microspheres showed similar patterns of plasma doxorubicin and doxorubicinol release and tumor concentration of doxorubicin. There were no significant differences of drug levels in either plasma or tumor in each group (P > .05). CONCLUSIONS: After TACE in a rabbit model of liver cancer, testing of three different types of spherical PVA microspheres with varying degrees of porosity and compressibility showed no significant differences in the plasma doxorubicin release pattern and tumor doxorubicin uptake.     

Radio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model

PURPOSE: To determine whether intratumoral accumulation of liposomal doxorubicin or free unencapsulated doxorubicin is increased when combined with radio-frequency (RF) ablation. MATERIALS AND METHODS: Two 1.2-1.5-cm R3230 mammary adenocarcinomas were grown within the mammary fat pads of 19 female Fischer rats. One tumor of each pair was treated with RF ablation (tip temperature, 70 degrees C +/- 2 [SD]; 120 mA +/- 75) for 5 minutes, whereas the other tumor was a control. Intravenous liposomal doxorubicin (1 mg in 500 micro L, n = 6) or intravenous free unencapsulated doxorubicin (n = 7) was administered immediately following RF ablation. Doxorubicin was extracted in acid alcohol from tumors 24 hours following RF ablation, and fluorescent spectrophotometry was used to quantify extracted doxorubicin. Comparisons of intratumoral doxorubicin accumulation in tumors treated with RF ablation and in untreated tumors were analyzed with parametric (paired Student t test) and nonparametric (Wilcoxon rank sum test) statistics. Findings at autoradiography with densitometry (six additional tumors) demonstrated the spatial distribution of the intratumoral accumulation of liposomal doxorubicin. RESULTS: When RF ablation preceded administration of liposomal doxorubicin, mean intratumoral doxorubicin concentration was 5.6 micro g/g +/- 2.1 (range, 1.9-7.7 micro g/g), whereas 1.0 micro g/g +/- 0.4 (range, 0.5-1.5 micro g/g) was present in control tumors not treated with RF ablation (P <.05). Thus, there was a mean 7.1-fold +/- 4.9 increase in intratumoral doxorubicin accumulation following RF ablation (range, 2.1-14.5-fold) compared with the amount without RF pretreatment (P <.05). Increased intratumoral accumulation was not seen in animals receiving free doxorubicin with (mean, 0.4 micro g/g +/- 0.1) or without (mean, 0.8 micro g/g +/- 0.4) RF pretreatment (P =.07). Autoradiographic findings demonstrated accumulation of liposomal doxorubicin in a peripheral rim of tumor adjacent to the zone of coagulation. CONCLUSION: RF ablation augments the delivery of systemic antineoplastic agents such as liposomal doxorubicin.     

The effect of prior heat treatment on the thermal enhancement of radiation damage in the mouse ear.

The effects of prior heat treatment on the skin reaction produced by a subsequent treatment with combined heat and X-rays were investigated in the mouse ear. Ears were heated by immersion in hot water. The priming heat treatment was always 43.5 degrees C for 40 minutes. Its effect was transient, beginning between 24 and 48 hours after the priming treatment and reaching a maximum at 48 to 96 hours when there was a reduction in the skin response to combined heat and X rays, i.e. it caused a reduction in the thermal enhancement ratio (TER). The effect was lost by 192 hours. At 96 hours after the priming treatment the TER for 30 minutes at 42.5 degrees C or at 43.5 degrees C was reduced by a value equivalent to decreasing the temperature by about 0.4 degrees C. This was equivalent to increasing the heating at 43.5 degrees C required to produce a given enhancement of radiation damage by a factor of 1.4 relative to that required without prior heating. The effect was smaller than induced resistance to damage caused by severe heat treatment alone (i.e. necrosis) and it occurred later. These differences support the concept that two separate mechanisms underlie direct heat necrosis and thermal enhancement of radiation damage.     

Percutaneous tumor ablation: reduced tumor growth with combined radio-frequency ablation and liposomal doxorubicin in a rat breast tumor model

PURPOSE: To determine whether combined intravenous liposomal doxorubicin and radio-frequency (RF) ablation decreases tumor growth and increases endpoint survival over those with RF or liposomal doxorubicin alone in an animal tumor model. MATERIALS AND METHODS: Subcutaneous R3230 mammary adenocarcinoma (1.1-1.4 cm) was implanted in female Fischer rats. Initially, 35 tumors were randomized into four experimental groups: (a) conventional monopolar RF (70 degrees C for 5 minutes) alone, (b) liposomal doxorubicin (1 mg) alone, (c) RF ablation followed by liposomal doxorubicin, and (d) no treatment. Ten additional tumors were randomized into two groups that received a 90 degrees C RF dose either with or without liposomal doxorubicin. Tumor growth rates and the defined survival endpoint, the time at which the tumor reached 3.0 cm in diameter, were recorded. The effect of treatments on endpoint survival and tumor doubling time were analyzed by means of the Kaplan-Meier method and analysis of variance statistics. RESULTS: Differences in endpoint survival and tumor doubling time in the six groups were highly significant (P <.001). Endpoint survivals were 9.1 days +/- 2.5 for the control group, 16 days +/- 3.7 for tumors treated with 70 degrees C RF alone, 16.5 days +/- 3.2 for tumors treated with liposomal doxorubicin alone, and 26.6 +/- 5.3 days with combined treatment. For 90 degrees C RF ablation, endpoint survivals were 16.6 days +/- 1.2 and 31.5 days +/- 3.0 without and with liposomal doxorubicin (P <.01). Mean endpoint survival and tumor doubling times for the three RF levels (0, 70 degrees C, and 90 degrees C) were all significantly different (P =.01). Additionally, animals that received combined liposomal doxorubicin and 90 degrees C RF ablation survived longer than did animals that received combined liposomal doxorubicin and 70 degrees C RF ablation (P <.01). CONCLUSION: Combined RF ablation and liposomal doxorubicin retards tumor growth and may increase animal survival compared with that with either therapy alone or no therapy.     

Combination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals

PURPOSE: To determine whether use of radiofrequency (RF) ablation combined with intravenously (IV) administered liposomal doxorubicin, as compared with use of RF ablation or doxorubicin alone, facilitates increased tissue coagulation and interstitial drug accumulation in animal models. MATERIALS AND METHODS: The institutional animal care and use committee approved this study. In experiment 1, multiple canine sarcomas were implanted in seven mildly immunosuppressed dogs and grown to a mean diameter of 4.8 cm. Tumors were assigned to three treatment groups: internally cooled RF ablation (12 minutes, 2000-mA pulsed technique) followed by IV liposomal doxorubicin (10 mg per animal) (n = 6), RF ablation alone (n = 6), and liposomal doxorubicin alone (n = 4). In experiment 2, the livers and kidneys of 10 rabbits and the thigh muscles of 10 rats were randomly assigned to one of two treatment groups: conventional RF ablation (90 degrees C +/- 2, 5 minutes) followed by IV liposomal doxorubicin (5 mg per rabbit, 1 mg per rat) or RF ablation alone (n = 5, each). Coagulation diameter and interstitial doxorubicin concentration (tissues were homogenized in acid alcohol, with doxorubicin extracted for 24 hours at 5 degrees C and quantified with fluorimetry) were measured 48 hours after treatment and compared. Multivariate analysis of variance and subsequent pairwise t tests (alpha = .05, two-tailed test) were performed. RESULTS: Data are means +/- standard errors of the mean. A larger diameter of tumor destruction was observed in canine sarcomas treated with RF ablation-liposomal doxorubicin (3.7 cm +/- 0.6) compared with that in tumors treated with RF ablation (2.3 cm +/- 0.1) or liposomal doxorubicin (0.0 cm +/- 0.0) alone (P < .01). A new finding was a completely necrotic red zone (1.6 cm +/- 0.7) surrounding the central RF ablation-induced white coagulation zone. Greater but nonuniform drug uptake was observed particularly in this red zone (77.0 ng/g +/- 18.2) compared with uptake in the central zone (15.1 ng/g +/- 3.2), peripheral area of untreated tumor (38.9 ng/g +/- 8.0), and tumors treated with liposomal doxorubicin alone (43.9 ng/g +/- 6.7 for all regions) (P < .01 for all individual comparisons). In experiment 2, use of combined therapy led to increased coagulation in all tissues (liver: 17.6 mm +/- 3.1, P = .03; kidney: 11.0 mm +/- 3.1, P = .03; muscle: 13.1 mm +/- 1.3, P < .01) compared with use of RF ablation alone (liver, 13.4 mm +/- 1.5; kidney, 7.9 mm +/- 0.7; muscle, 8.6 mm +/- 0.5). Combined therapy, as compared with liposomal doxorubicin therapy alone, was also associated with increased doxorubicin accumulation in liver, kidney, and muscle (1.56 microg/g +/- 0.34, 4.36 microg/g +/- 1.78, and 3.63 microg/g +/- 1.43, respectively, vs 1.00 microg/g +/- 0.18, 1.23 microg/g +/- 0.32, and 0.87 microg/g +/- 0.53, respectively) (P < or = .01 for all individual comparisons). CONCLUSION: Use of RF ablation combined with liposomal doxorubicin facilitates increased tissue coagulation and interstitial doxorubicin accumulation in multiple tissues and tumor types and may be useful for treatment of large tumors and achieving an ablative margin within the untreated tissue surrounding RF ablation-treated tumors.     

Percutaneous tumor ablation: increased necrosis with combined radio-frequency ablation and intravenous liposomal doxorubicin in a rat breast tumor model

PURPOSE: To determine whether a combination of intravenous liposomal doxorubicin and radio-frequency (RF) ablation increases tumor destruction compared with RF alone in an animal tumor model. MATERIALS AND METHODS: R3230 mammary adenocarcinoma 1.4-1.8-cm- diameter nodules were implanted subcutaneously in 132 female Fischer rats. Initially, tumors were treated with (a) conventional, monopolar RF (mean, 250 mA +/- 25 [SD] at 70 degrees C +/- 1 for 5 minutes) ablation alone, (b) RF ablation followed by intravenous administration of 1 mg of liposomal doxorubicin, (c) RF ablation followed by intravenous administration of 1 mg of empty liposomes, (d) RF ablation and direct intratumoral administration of liposomal doxorubicin, or (e) no treatment. Subsequently, the dose (0.06-2.00 mg) of liposomal doxorubicin, the timing of administration (3 days before to 3 days after RF ablation), and the time of pathologic examination (0-72 hours after treatment) were varied. RESULTS: Mean coagulation diameter for treated tumors follows: 6.7 mm +/- 0.6, RF ablation alone; 11.1 mm +/- 1.5, RF ablation and intravenous administration of empty liposomes (P <.05, compared with RF ablation alone); and 8.4 mm +/- 1.1, RF ablation with intratumoral administration of liposomal doxorubicin (P <.05, compared with RF ablation alone). Maximal increased mean coagulation diameter (13.1 mm +/- 1.5) was observed with a combination of liposomal doxorubicin and RF ablation (P <.001, for all comparisons). The increased coagulation for combination therapy developed over 48 hours after therapy. Coagulation diameter did not vary with the doxorubicin concentration range and was not dependent on the timing of administration of liposomal doxorubicin from 3 days before to 24 hours after RF ablation. CONCLUSION: Intravenous administration of liposomal doxorubicin can improve RF ablation, since it increases coagulation diameter in solid tumors compared with RF ablation alone or a combination of RF ablation with administration of empty liposomes.     

Induced thermal resistance in the mouse ear.

The mouse ear (pinna) was used to investigate the effect of two hyperthermic treatments. Heating was by immersion in hot water at 43.5 degrees C. A single treatment of about 50 minutes was required to cause necrosis in 50% of the ears heated. When heat treatment was given in two equal fractions the total heating time had to be increased if the interval between fractions was greater than four hours. By 24 hours a total treatment of about 100 minutes was required, indicating almost complete recovery from the first heating. Priming treatments at 43.5 degrees C induced thermal resistance to a second heat treatment at 43.5 degrees C. Maximum resistance was observed one day after a 20 minute priming and two days after a 40 minute priming, when the heating time had to be increased to 120 minutes, an increase by a factor of 2.4. Shorter priming treatments induced less resistance, the minimum heating time to produce an effect being two minutes. In all cases the effect decreased during the next four to five days. These results indicate that the reduced response of tissues to fractionated hyperthermia is due both to the repair of sublethal heat damage and induction of thermal resistance.     

Work in progress: the effect of heat on bleomycin cytotoxicity in vitro and on the accumulation of 57Co-bleomycin in heat-treated rat tumors

The cytotoxic effects of the sequence and timing in combined hyperthermia and bleomycin treatment were tested in vitro using V79 Chinese hamster cells. The order of treatment was important; heat treatment followed by the administration of bleomycin yielded greater cytotoxicity than when the opposite order was used. To determine whether heat-treated tumors have an altered uptake of bleomycin, rat rhabdomyosarcoma (BA 1112) tumors were heated locally with RF current (43 degrees C, 90 min.), injected with 57Co-bleomycin, and imaged on a radioisotope camera. Results of tumor-to-background (T/B) ratio analysis indicate that (a) local hyperthermia (43 degrees C) does not appear to alter tumor uptake patterns of 57Co-bleomycin; and (b) intravenous and intraperitoneal injections produce similar T/B uptake ratios, typically between 2 and 3 at 120 minutes postinjection. In the BA 1112/WAG/Rij tumor system, local hyperthermia treatment does not seem to interfere with the subsequent accumulation of bleomycin in the tumor.     

Toe temperatures during arctic training

The surface toe temperature of 10 subjects was monitored in the field in Arctic Norway (minimum air temperature -27 degrees C). The lowest skin temperature recorded was 1.9 degrees C. The mean estimated time for the toe temperature to cool from 25 degrees C to 5 degrees C was 109 minutes (SD, 10.2) at an ambient temperature of -21 degrees C. One subject experienced a toe temperature below 5 degrees C for 2.9 hours during a 27-hour period. Surprisingly none of the subjects demonstrated clinical signs of cold injury, but this does not mean that this exposure was without risk. Cold sensitization could have occurred.     

Superparamagnetic iron oxide-enhanced magnetic resonance imaging of experimental liver tumors after mitomycin C administration.

The influence of mitomycin C chemotherapy on superparamagnetic iron oxide (SPIO) uptake by the liver was studied in rats (n = 70). This commonly used antineoplastic drug induces a decrease in the phagocytic function of the macrophage-phagocytic system (MPS). The plasma clearance of SPIO measured by relaxometry followed a biexponential model. The fast component half-life increased from 2.9 minutes in controls to 4.5 minutes in mitomycin C-treated animals. The slow component half-life increased from 11.3 to 36.7 minutes. Nevertheless, the magnetic resonance imaging (MRI) diagnostic efficacy 2 hours after infusion of the superparamagnetic agent AMI 25 (n = 10) was as satisfactory in the treated group as in the untreated one. These MRI results were consistent with the relaxometric T2* liver measurements, which were identical in both groups.     

Testing the effectiveness of techniques for reducing heat strain in Royal Navy nuclear, biological and chemical cleansing stations' teams

Nine personnel simulating the work of an NBC cleansing station (CS) in conditions expected in Middle Eastern waters had a limited work duration due to incapacitating heat strain. When the subjects were allowed five minutes rest periods after every 10 minutes of work, the endurance of seven of the subjects was limited to between 75-105 minutes due to heat strain and heat illness. By the point of withdrawal mean (SD) rectal temperature (Tre) had risen by 1.8 degrees C (0.4 degree C). The other two subjects were withdrawn earlier because they reached cardiac safety limits. When the hands were immersed (HI) in 10 degrees C water during the five minute rest periods heat strain was significantly lower (P < 0.01) and work endurance times were increased. One subject was withdrawn early on reaching cardiac safety limits, two on reaching Tre limits (39 degrees C) at 105 minutes, and six subjects completed the 180 minute exposure with a final Tre of 38.4 degrees C (0.3 degree C). Using 'iced' (0 degree C) rather than 10 degrees C water for HI further reduced heat strain (P < 0.01) and increased endurance times. Three subjects were withdrawn early on reaching cardiac safety limits, the remaining six completing the 180 minute exposure, with a final Tre of 38.3 degrees C (0.5 degree C). Using an ice-vest (IV) in conjunction with HI further reduced heat strain (P < 0.01) and increased endurance times. Two subjects were withdrawn early on reaching cardiac safety limits, the remaining seven completing the 180 minute exposure, with a final Tre of 38.2 degrees C (0.8 degree C) when 10 degrees C HI water was used, and Tre 38.0 degrees C (0.4 degree C) when 0 degree C HI water was used. There were no reports of finger numbness or loss of dexterity due to HI, and all personnel were able to remove their own individual Protective Equipment (IPE) without difficulty. It is expected that using HI will not reduce the ability to decontaminate or undress others. The HI technique and IV equipment should be introduced into the Fleet. 'Iced' water should be used in preference to 10 degrees C, although any water colder than 25 degrees C will provide some benefit. The IVs increased torso girth and personnel should try them on (with frozen ice packs inserted) prior to their use and ensure that their protective clothing still fits, or obtain a larger size.     

Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells.

Specific tumors express high amounts of receptors for somatostatin (SST), providing the basis for imaging and treatment using radiolabeled SST analogs. However, little is known about the potential influence of cytotoxic drugs on SST receptor (SSTR) expression in malignant cells. METHODS: To study the interaction between cytotoxic drugs and SSTR expression, the pancreatic cancer-derived tumor cell lines BxPC-3, Panc-1, Capan-1, and ASPC-1 were exposed to a range of cytotoxic drugs in vitro: Gemcitabine, 5-fluorouracil, cisplatin (cis-diaminedichloroplatinum [II]), camptothecin, mitomycin C, and doxorubicin were checked for changes in binding characteristics of the SSTR ligand (111)In-1,4,7,10-tetraazacyclododecane- N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN). Chemosensitivity was quantitated by measurements of reduction in cell numbers, changes in cell cycle distribution, and appearance of apoptotic subG1 (subG1/0 cell DNA content) cells. RESULTS: Cells were treated with gemcitabine (1.0 or 2.0 microg/mL), 5-fluorouracil (65-520 microg/mL), camptothecin (1.5 or 3 microg/mL), mitomycin C (0.1 or 0.2 microg/mL), and doxorubicin (1.0 or 2.0 microg/mL). Each of the chemotherapeutic agents induced a loss of high-affinity receptors. In addition, gemcitabine caused a reduction of low-affinity receptors in BxPC-3, Panc-1, and ASPC-1 cells. Mitomycin C, camptothecin, and 5-fluorouracil also induced an overexpression of low-affinity receptors. In cells pretreated with cisplatin (2-10 microg/mL), binding of DOTA-LAN was increased. Excluding gemcitabine, the increase in low-affinity binding sites exhibits a weak correlation with apoptosis (r(2) = 0.62). For gemcitabine, these effects were reversed after 4 d of recovery of the cell lines, eventually revealing overexpression of low- and high-affinity sites for BxPC-3 and Panc-1 cells and low-affinity sites for ASPC-1 cells. CONCLUSION: Our results clearly show that the pancreatic tumor lines reduce the expression of high-affinity DOTA-LAN binding sites during application of chemotherapeutic drugs, which is accompanied by variable overexpression of low-affinity binding sites. In the case of gemcitabine, SSTRs are overexpressed during recovery from drug exposure within 4 d. These findings may have implications on the interpretation of scintigraphic results obtained by receptor ligands.     

Thermal balance effects on vigilance during 2-hour exposures to -20 degrees C

INTRODUCTION: Human mental performance is markedly affected by environmental temperature, body temperature, body heat content, and comfort, but the effects of these different factors are not entirely clear. A liquid conditioning garment (LCG) can be used to manipulate these factors independently. We hypothesized that cold exposure (coldEX) has negative effects on vigilance which can be alleviated by increasing body heat content throughout or prior to coldEX. METHODS: Subjects (n = 10) were tested for vigilance during a 130-min coldEX to -20 degrees C while warmly clothed; a period of moderate exercise occurred at minutes 64-74. An LCG was used to provide heating either before coldEX (prior heating, PH) or throughout coldEX (heating, H); the control condition involved no heating (NH). RESULTS: There were significant differences among conditions for rectal temperature (PH: 37.3 +/- 0.26 degrees C, H: 37.0 +/- 0.24 degrees C, NH: 37.05 +/- 0.26 degrees C) and mean skin temperature (PH: 33.85 +/- 1.21 degrees C, H: 35.11 +/- 1.35 degrees C, NH: 32.84 +/- 0.65 degrees C). Reaction time decreased significantly after the 45th minute of coldEX in H and NH. At the same time, signal detection criteria in all conditions demonstrated considerable alterations, indicating bias in favor of 'target-present' responses, which were associated with lower mean skin temperature and thermal comfort vote. PH was more effective than H and NH in preserving reaction time and response consistency. Relative to men, women demonstrated increased heat loss and more deteriorated vigilance and signal detection. CONCLUSION: Vigilance deteriorates in cold conditions within 45 min of exposure. Increasing body heat content prior to coldEX is efficacious in preserving vigilance performance during exposures lasting up to 2 h.     

Combined radiofrequency ablation and adjuvant liposomal chemotherapy: effect of chemotherapeutic agent, nanoparticle size, and circulation time

PURPOSE: To evaluate the effects of liposomal chemotherapeutic agent, nanoparticle size, and liposome circulation time on tissue coagulation and intratumoral drug uptake when radiofrequency (RF) ablation is combined with adjuvant intravenous liposomal chemotherapy in an animal breast tumor model. MATERIALS AND METHODS: Ninety-one R3230 mammary adenocarcinoma nodules were implanted in 48 Fischer rats. First, standardized RF ablation was combined with intravenous liposomal doxorubicin, cisplatin, or 5-fluorouracil (35 tumors each). Second, three different-sized doxorubicin-containing nanoparticle preparations were combined with standardized RF ablation. Last, two doxorubicin-containing liposome preparations with different blood elimination half-lives were combined with RF ablation. Coagulation diameter and interstitial doxorubicin concentration were measured 48 hours after treatment and compared with use of statistical analysis. RESULTS: All combinations of RF with liposomal chemotherapy caused significantly greater tumor necrosis than RF alone (P<.05). Significantly increased necrosis was observed with intravenous liposomal RF/doxorubicin and RF/cisplatin compared with intravenous liposomal RF/5-fluorouracil (P<.01). Greater coagulation was observed with RF combined with 100-nm nanoparticles compared with 20-nm or 250-nm nanoparticles (P=.01 and P=.04, respectively). Additionally, greater intratumoral doxorubicin uptake was observed in the group treated with 20-nm nanoparticles compared with those treated with other sizes of nanoparticles (P<.05). RF plus liposomal doxorubicin produced greater coagulation and intratumoral doxorubicin uptake than RF plus 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid (P<.05). CONCLUSION: When combined with RF ablation, modification of adjuvant intravenous liposomal chemotherapy, including nanoparticle size, circulation time, and chemotherapeutic agent, can influence intratumoral drug accumulation and tissue coagulation.     

Effect of daily versus intermittent exposure on heat acclimation

In order to compare the effectiveness of a daily to an intermittent acclimation protocol, 14 competitive rowers (mean +/- SD VO2peak = 48 +/- 7 ml x kg x min(-1)) were randomly assigned to either a consecutive (10 consecutive days) or intermittent acclimation group (10 sessions over 3 weeks). For every heat exposure, subjects in each group exercised for 30 min at 70% VO2peak in an environmental chamber set at 38 degrees C and 70% relative humidity. Acclimation state was monitored by measuring heart rate (HR), rectal and skin temperature (Tre and Tsk), ratings of perceived exertion (RPE) and whole body sweat rate (SR) during each heat exposure. Final exercise Tre decreased significantly by 0.6 +/- 0.7 degrees C with intermittent heat exposure but the decrease was significantly larger (p < 0.05) with consecutive day heat exposure (1.0 +/- 0.1 degrees C). Final exercise HR also decreased significantly by 13 +/- 12 bpm (p < 0.05) in the consecutive group, and non-significantly by 5 +/- 13 bpm in the intermittent group. RPE decreased with daily (5 +/- 1, p < 0.05) but did not significantly decrease with intermittent heat exposure (1 +/- 3). Similarly, Tsk significantly decreased with consecutive (0.4 +/- 0.2 degrees C, p < 0.05) but not intermittent exposure (0.2 +/- 0.3 degrees C) and SR did not change in either group. Minimal adaptation occurs with intermittent heat exposure and it appears that daily heat exposure is the most effective acclimation strategy.     

Transcatheter Treatment of Hepatocellular Carcinoma with Doxorubicin-loaded DC Bead (DEBDOX): Technical Recommendations

Tranarterial chemoembolization (TACE) has been established by a meta-analysis of randomized controlled trials as the standard of care for nonsurgical patients with large or multinodular noninvasive hepatocellular carcinoma (HCC) isolated to the liver and with preserved liver function. Although conventional TACE with administration of an anticancer-in-oil emulsion followed by embolic agents has been the most popular technique, the introduction of embolic drug-eluting beads has provided an alternative to lipiodol-based regimens. Experimental studies have shown that TACE with drug-eluting beads has a safe pharmacokinetic profile and results in effective tumor killing in animal models. Early clinical experiences have confirmed that drug-eluting beads provide a combined ischemic and cytotoxic effect locally with low systemic toxic exposure. Recently, the clinical value of a TACE protocol performed by using the embolic microsphere DC Bead loaded with doxorubicin (DEBDOX; drug-eluting bead doxorubicin) has been shown by randomized controlled trials. An important limitation of conventional TACE has been the inconsistency in the technique and the treatment schedules. This limitation has hampered the acceptance of TACE as a standard oncology treatment. Doxorubicin-loaded DC Bead provides levels of consistency and repeatability not available with conventional TACE and offers the opportunity to implement a standardized approach to HCC treatment. With this in mind, a panel of physicians took part in a consensus meeting held during the European Conference on Interventional Oncology in Florence, Italy, to develop a set of technical recommendations for the use of DEBDOX in HCC treatment. The conclusions of the expert panel are summarized.     

Lung radiofrequency ablation with and without bronchial occlusion: experimental study in porcine lungs

PURPOSE: This study was undertaken to compare the thermal lesion volumes in normal pig lungs when radiofrequency (RF) ablation is performed with and without airway occlusion. MATERIALS AND METHODS: RF ablation was performed in six pigs. A straight 17-gauge internally cooled-tip electrode with a 2-cm exposed tip was inserted into the center of the lower lobe of the lung under biplane fluoroscopic guidance. In each animal, RF ablation was performed for 12 minutes with balloon occlusion of the main bronchus in one lung and without balloon occlusion in the contralateral lung. The tissue temperature around the electrode tip was measured immediately after RF application. The volumes of the thermal lesions were compared by histologic examination of the groups of lungs ablated with and without airway occlusion. RESULTS: Tissue temperature was significantly higher in the bronchial occlusion group than in the group with normal ventilation (51 degrees C +/- 7 vs. 44 degrees C +/- 2; P < .05). RF ablation with bronchial occlusion resulted in the creation of a significantly greater thermal lesion volume compared with RF ablation with normal ventilation (6,535 mm(3) +/- 1,114 vs 3,368 mm(3) +/- 676; P < .03). CONCLUSION: Prevention of ventilation in the normal swine lung via bronchial balloon occlusion during RF ablation increases the thermal ablation lesion volume, suggesting that active ventilation is a significant cause of in vivo heat loss.     

Cytokine levels in patients with previous heatstroke under heat stress

We attempted to determine whether persons susceptible to heatstroke produced higher serum concentrations of interleukin-6, tumor necrosis factor-alpha, and interleukin-10 when subjected to heat stress. Nine patients with previous heatstroke and 21 matched controls were subjected to a heat-stress test (at 32 degrees C, 67% humidity, 900 W/m2 solar radiation, and wind speed of 2.5 m/s) for 60 minutes and rested at 24 degrees C for another 60 minutes in full battle gear. During the heat-stress test, blood was drawn at intervals of 0, 30, 60, and 120 minutes, and serum lipopolysaccharide, interleukin-6, tumor necrosis factor-alpha, and interleukin-10 concentrations were measured. Patients with previous heatstroke had a higher mean core temperature (0.6 degree C; p < 0.05) and sweated less (0.3 liters; p < 0.05). During the heat-stress test, the lipopolysaccharide levels were not increased and there was no difference in the serum cytokine concentrations between patients with previous heatstroke and controls. However, patients with previous heatstroke had higher absolute serum cytokine concentrations and poorer thermoregulatory response to heat stress in terms of core temperature and sweat loss.     

Temperature changes caused by MR imaging of the brain with a head coil

Tissue heating caused by exposure to RF radiation is a primary safety concern in MR imaging. Therefore, to determine temperature changes caused by high field strength MR imaging of the brain with a head coil, we measured body and skin temperatures in 35 patients immediately before and after clinical MR imaging. MR imaging was performed with a 1.5 T MR system using a 28-cm, open-bore RF transmit/receive head coil specifically designed for examinations of the brain. The average body temperature was 36.6 +/- 0.2 degrees C before MR imaging and 36.6 +/- 0.2 degrees C immediately afterward (mean +/- SD, p = not significant). The average forehead skin temperature increased from 32.6 +/- 0.6 to 32.8 +/- 0.5 degrees C (p less than .01), and the average outer canthus skin temperature increased from 32.1 +/- 0.6 to 32.7 +/- 0.6 degrees C (p less than .01) after MR imaging. The highest skin temperature recorded was 34.2 degrees C, and the largest temperature change was +2.1 degrees There were no statistically significant changes in the average skin temperatures of the upper arm and hand. We conclude that patients undergoing MR imaging of the brain with a head coil at the RF radiation exposure we studied experience no significant changes in average body temperature and statistically significant increases in local (i.e., areas within the head coil) skin temperatures. The observed elevations in skin temperatures were physiologically inconsequential.     

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current Results

Transarterial chemoembolization (TACE) involves the emulsification of a chemotherapeutic agent in a viscous drug carrier, delivered intra-arterially to liver tumor for maximum effect. TACE reduces arterial inflow, diminishes washout of the chemotherapeutic agent, and decreases systemic exposure. Despite evidence of some clinical success with TACE, a new type of microspheres with drug-eluting capabilities may offer a precisely controlled and sustainable release of the chemotherapeutic agent into the tumor bed. In animal trials tumor necrosis (approaching 100%) was greatest at 7 days, with significantly lower plasma concentrations of doxorubicin than in control animals treated with doxorubicin intra-arterially. Clinically, drug-eluting microspheres loaded with doxorubicin, either at 75 mg/m² or at a fixed dose of 150 mg, were used recently and no severe disorders of the hepatic function were observed postprocedure, while a substantial reduction of the fetoprotein levels occurred. An interim analysis of the first 15 patients from the Hong Kong group at 3 months showed an objective response rate of 61.54% and 53.84% according to EASL criteria and RECIST criteria, respectively, and a survival rate of 93.3%. In this paper we present how to use microspheres loaded with doxorubicin and review their clinical value and preliminary performance for treatment of unresectable liver cancer.